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Mappings

ICD-11 Foundation

icd11f:835503193 Ageing associated decline in intrinsic capacity

The ICD-11 Foundation entity is the source of this entry's identity: the entry was created to model the concept behind MMS linearisation code MG2A, and the Foundation label is reproduced verbatim as the entry name. The entity resolves under General symptoms within Symptoms, signs or clinical findings, not elsewhere classified, and has no children, so the mapping is one-to-one.

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Definitions

4

WHO definition of intrinsic capacity

Intrinsic capacity is the composite of all the physical and mental capacities an individual can draw on. With the environment and the interaction between the two, it determines functional ability, which is what the WHO healthy-ageing model treats as the object of care rather than the presence or absence of disease.

OTHER Defines the construct whose decline this entry models; it is not a diagnostic threshold and does not by itself identify an affected individual.

Show evidence (2 references)

PMID:26520231 SUPPORT Other

"The report is built around a redefinition of healthy ageing that centres on the notion of functional ability: the combination of the intrinsic capacity of the individual, relevant environmental characteristics, and the interactions between the individual and these characteristics."

States the WHO model in which intrinsic capacity is one of the two determinants of functional ability. Evidence source is OTHER because this is a policy framework paper rather than a study.

PMID:31275941 SUPPORT Other

"the World Health Organization introduced the concept of intrinsic capacity (IC), defined as the composite of all physical and mental capacities that an individual can draw upon during his/her life."

Gives the definitional wording of the construct itself, separate from the functional-ability model it sits inside.

Five-domain operational model of intrinsic capacity

Intrinsic capacity is operationalised as five domains - locomotion, vitality, cognition, psychological, and sensory - which is what makes the construct measurable. Factor-analytic work in a population cohort recovers a general intrinsic-capacity factor plus these five subfactors, so the domain structure is an empirical finding and not only a conceptual convenience.

OTHER Applies to the whole entry; the `has_subtypes` records reproduce these five domains and the phenotypes are grouped against them.

Show evidence (3 references)

PMID:29408961 SUPPORT Other

"five domains (i.e., locomotion, vitality, cognition, psychological, sensory) are identified as pivotal for capturing the individual's intrinsic capacity"

The consensus paper that fixed the five-domain structure used throughout this entry. Evidence source is OTHER because it is an expert review.

PMID:31678933 SUPPORT Human Clinical

"One general factor (intrinsic capacity) and five subfactors emerged: locomotor, cognitive; psychological; sensory; and 'vitality'."

Recovers the five-domain structure empirically by factor analysis in 2560 participants of the English Longitudinal Study of Ageing, so the domains are not merely stipulated.

PMID:35569785 SUPPORT Other

"There is overall consensus on the definition of IC as well as on its different dimensions, that is: locomotion, vitality, sensory, cognition and psychological."

Confirms across 33 studies that the five dimensions are agreed even where the measurement instruments are not.

WHO working definition of vitality capacity

Vitality capacity is the physiological substrate of intrinsic capacity: a state arising from the interaction of energy and metabolism, neuromuscular function, and immune and stress-response function. It is the domain closest to the biology of ageing, which is why it is treated in this entry as gating the other four rather than sitting beside them.

OTHER Defines the vitality subtype; the claim that vitality gates the other domains is a mechanistic reading of this definition and is recorded as such in the pathophysiology, not as an established finding.

Show evidence (1 reference)

PMID:36356628 SUPPORT Other

"vitality capacity is a physiological state (due to normal or accelerated biological ageing processes) resulting from the interaction between multiple physiological systems, reflected in (the level of) energy and metabolism, neuromuscular function, and immune and stress response functions of the body."

The WHO expert-group working definition, quoted verbatim, which is what makes vitality the domain where hallmark ageing biology enters the construct.

WHO ICOPE Step 1 screening for decline in intrinsic capacity

The ICOPE Step 1 instrument is a short, equipment-free screen applied in primary care to adults aged 60 and over, testing six practical sub-domains - locomotion (chair rises), cognition (orientation and three-word recall), vitality (recent weight and appetite loss), vision, hearing, and depressive symptoms. A positive screen triggers Step 2 in-depth assessment rather than a diagnosis; the whole point of the instrument is triage into a care pathway.

PHENOTYPE_ALGORITHM Community-dwelling and primary-care populations aged 60 years and older. Not a diagnostic replacement for organ-specific assessment of any single domain.

Show evidence (1 reference)

PMID:36098317 SUPPORT Human Clinical

"Individuals aged ≥60 years were screened (step 1) by health-care providers or through self-assessments using digital tools (the ICOPE MONITOR app and the ICOPEBOT conversational robot)."

Describes how the Step 1 screen is actually applied at scale, in the 10 903-person Occitania implementation that this definition is drawn from.

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Inheritance

1

Polygenic inheritance HP:0010982

Intrinsic capacity is a complex trait with many small-effect common variants, not a Mendelian condition. SNP-based heritability is about 25% in UK Biobank and about 20% in the Canadian Longitudinal Study on Aging - substantial, but leaving most of the variance to environment, life course, and measurement. There is no carrier state, no penetrance, and no consanguinity effect to record.

Polygenic inheritance

Show evidence (1 reference)

PMID:41066301 SUPPORT Human Clinical

"Overall, this study provides comprehensive evidence on the genetic architecture of IC, identifying novel genetic variants and biological pathways"

Establishes that the trait has a genetic architecture worth recording at all, which was open before this study - the paper notes no prior GWAS existed.

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Subtypes

5

Locomotor capacity decline

Loss of the capacity to move: reduced muscle strength, slowed gait, and impaired balance and chair-rise performance. This is the domain most strongly tied to a named disease process, sarcopenia, and the domain that most consistently predicts dependence in basic activities of daily living.

Show evidence (1 reference)

PMID:29408961 SUPPORT Other

"five domains (i.e., locomotion, vitality, cognition, psychological, sensory) are identified as pivotal for capturing the individual's intrinsic capacity"

Establishes locomotion as one of the five constituent domains.

Vitality capacity decline

Loss of the underlying physiological reserve expressed as energy and metabolism, neuromuscular function, and immune and stress-response function. Clinically it surfaces as unintentional weight loss, appetite loss, and fatigue. Vitality is the domain in which the biology of ageing is most directly measured, and it is treated in the WHO framework as underpinning rather than paralleling the others.

Show evidence (1 reference)

PMID:36356628 SUPPORT Other

"Vitality capacity is considered the underlying physiological determinant of intrinsic capacity."

States the special status of vitality among the five domains, which is why this subtype is described as underpinning the others.

Cognitive capacity decline

Loss of memory, orientation, and executive function short of dementia. Screened by orientation questions and three-word recall; impairment in this domain interacts strongly with genetic susceptibility in predicting incident dementia.

Show evidence (1 reference)

PMID:38843484 SUPPORT Human Clinical

"Compared with participants with an IC score of 0, individuals with an IC score of 4+ had a markedly elevated risk of dementia (hazard ratio [HR] 2.17, 95% CI 1.92-2.45)."

Establishes the clinical consequence that distinguishes this domain, in 366 406 UK Biobank participants.

Psychological capacity decline

Loss of mood, motivation, and sociability, screened in ICOPE by depressive-symptom questions. It is the domain most readily confounded with primary psychiatric disease, and the one most strongly associated with pain.

Show evidence (1 reference)

PMID:41360071 SUPPORT Human Clinical

"Pain at all intensities, mild (0·512, 0·163, p=0·0017), moderate (1·111, 0·191, p<0·0001), or intense (1·532, 0·263, p<0·0001), was significantly associated with lower scores in the psychological domain."

Shows the psychological domain responding to a graded exposure across the whole intensity range, which is not true of the other domains in the same cohort.

Sensory capacity decline

Age-related loss of hearing and vision. Structurally the two are separate ageing processes in separate organs, and measurement work has found they do not load onto a single sensory factor, so the domain is a clinical grouping rather than a single mechanism.

Show evidence (1 reference)

PMID:37960903 SUPPORT Human Clinical

"Vision and hearing items did not form a single sensory domain, so six domains were considered."

Directly supports treating hearing and vision as separate measurement axes inside one clinical domain.

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Discussions and Knowledge Gaps

3

Do the hallmarks of ageing cause the decline in measured intrinsic capacity, or do the two merely track a common clock?

KNOWLEDGE GAP OPEN gap_ic_hallmark_causality

Attached to

pathophysiology#Accumulation of Hallmark Ageing Damage pathophysiology#Loss of Physiological Reserve Across Organ Systems

This entry's upstream chain is assembled from geroscience literature that was not written about intrinsic capacity, and the human evidence joining the two is associative. The strongest link available is that plasma markers of inflammation and mitochondrial stress separate multi-impaired from high-stable capacity trajectories in 1271 people - which is consistent with causation and equally consistent with both being downstream of the same ageing process. No human study has shown that reducing a hallmark burden raises measured intrinsic capacity. The gap matters practically, because it is exactly the assumption that geroscience intervention programmes make when they adopt intrinsic capacity as an early endpoint in place of decades-long disease outcomes.

Show evidence (2 references)

PMID:37620614 SUPPORT INDIRECT Human Clinical

"Intrinsic capacity (IC), the composite of physical and mental capacities, declines with age at different rates and patterns between individuals."

Frames the between-person variation that the hallmark-causality question would have to explain, from the study that supplies the best current link.

PMID:34883201 SUPPORT Other

"to date, there has been very limited analysis to guide scientists or physicians on how to practically apply the intrinsic capacity (IC) and reserve concepts so that they can inform the development of effective interventions"

The review that proposes joining geroscience to the WHO framework states the gap in its own terms.

Is the ICOPE Step 1 screening tool a valid measure of intrinsic capacity, or a useful triage instrument whose composite score should not be used as a measure at all?

CONTROVERSY OPEN controversy_icope_screening_tool_structure

Attached to

definitions#WHO ICOPE Step 1 screening for decline in intrinsic capacity

Two well-conducted validation studies reach compatible numbers and incompatible conclusions. In INSPIRE-T the tool identified domain impairments with high specificity and acceptable sensitivity, and the authors recommend it as a low-cost screen. In the Toledo Study of Healthy Ageing the cognitive items did not associate with age, education, or dependence as the measurement model requires, vision and hearing did not form one sensory factor, and the composite added nothing over the individual domains for predicting dependence or hospitalisation. The disagreement is not about the data but about what the instrument is for: a triage screen may be fit for purpose while failing as a measurement model, and the literature routinely uses the composite as though it were the latter.

Show evidence (2 references)

PMID:37960903 SUPPORT Human Clinical

"The IST included as a composite in a model with the individual domains showed no statistically significant associations with any of the outcomes"

The finding that the composite adds nothing over its components, which is the substance of the disagreement.

PMID:38676323 REFUTE Human Clinical

"The ICOPE screening tool can be a useful instrument enabling the identification of older people with impairments in IC domains, but studies with different populations are needed."

The opposing position, stated with its own caveat about generalisability.

Should a MONDO class be requested for ageing associated decline in intrinsic capacity, so this entry can carry a disease_term?

CURATION TODO OPEN gap_ic_no_mondo_class

Attached to

disease#Ageing Associated Decline in Intrinsic Capacity

MONDO carries no class for intrinsic capacity or its decline, so this entry is anchored only on the ICD-11 Foundation entity. That is workable but it leaves the entry outside every MONDO-keyed query, grouping, and coverage report in this repository, and it means the concept cannot be related to neighbouring MONDO classes such as sarcopenia or frailty by ontology. Against requesting one: MG2A is classified by WHO under symptoms and clinical findings rather than as a disease, and this project does not mint terms, so the request would have to be made to MONDO with an argument about whether a functional-reserve construct belongs in a disease ontology at all. The decision is recorded here rather than taken.

Show evidence (1 reference)

PMID:26520231 SUPPORT INDIRECT Other

"The report is built around a redefinition of healthy ageing that centres on the notion of functional ability"

The framing that makes the ontological question live: the construct is defined against function rather than against pathology, which is why it has no natural home in a disease ontology.

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Pathophysiology

13

Accumulation of Hallmark Ageing Damage

The upstream lesion is not a single defect but the parallel accumulation of the twelve hallmarks of ageing - genomic instability, telomere attrition, epigenetic drift, loss of proteostasis, disabled macroautophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. This node stands for that accumulating damage load; the individual hallmarks are modelled in their own modules rather than restated here.

DNA damage response GO:0006974 ↑ INCREASED

Downstream

Mitochondrial Bioenergetic Decline

Senescent Cell Accumulation in Ageing Tissue

Decline in Tissue Regenerative Reserve

Show evidence (2 references)

PMID:36599349 SUPPORT Other

"We propose the following twelve hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular..."

Enumerates the damage set this node stands for. Evidence source is OTHER because this is a synthesis review.

PMID:23746838 SUPPORT Other

"Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death."

States the loss-of-integrity framing that connects this molecular node to the organism-level reserve loss downstream.

Mitochondrial Bioenergetic Decline

Age-associated mitochondrial damage lowers oxidative phosphorylation capacity while raising reactive oxygen species output. This is the cellular step closest to the vitality domain, which the WHO working definition frames in terms of energy and metabolism, and it is one of the two hallmark axes for which human plasma markers separate intrinsic-capacity trajectories.

oxidative phosphorylation GO:0006119 ↓ DECREASED reactive oxygen species metabolic process GO:0072593 ↑ INCREASED

Downstream

Chronic Low-Grade Sterile Inflammation

Loss of Physiological Reserve Across Organ Systems

Show evidence (3 references)

PMID:37620614 SUPPORT INDIRECT Human Clinical

"Our findings found that plasma biomarkers reflecting inflammation and mitochondrial impairment distinguished older people with multi-impaired IC trajectories from those with high-stable IC."

Links mitochondrial impairment to measured intrinsic-capacity trajectories in humans. Marked INDIRECT because the measurement is a circulating surrogate (GDF-15) rather than mitochondrial function itself.

PMID:41113460 SUPPORT Other

"Mitochondrial dysfunction plays a central role, characterized by impaired biogenesis, excessive reactive oxygen species (ROS) production, compromised autophagy/mitophagy, and accumulation of mitochondrial DNA (mtDNA) mutations."

Specifies the mitochondrial defects this node stands for, in the tissue where they reach a measured capacity domain.

PMID:38396729 SUPPORT Other

"Mitochondrial dysfunction has been indicated as a key contributor to skeletal myocyte decline and loss of physical performance with aging."

Independent review naming loss of physical performance - the measured content of the locomotor domain - as the downstream consequence of this node.

Senescent Cell Accumulation in Ageing Tissue

Cells that have entered senescence are cleared less efficiently with age and accumulate in tissue, where their secretory phenotype sustains local and systemic inflammation. This is the principal cellular source feeding the inflammaging node.

fibroblast CL:0000057

cellular senescence GO:0090398 ↑ INCREASED

Downstream

Chronic Low-Grade Sterile Inflammation

Show evidence (1 reference)

PMID:36599349 SUPPORT Other

"Aging is driven by hallmarks fulfilling the following three premises: (1) their age-associated manifestation, (2) the acceleration of aging by experimentally accentuating them, and (3) the opportunity to decelerate, stop, or reverse aging by therapeutic interventions on them."

Supplies the criterion under which cellular senescence counts as a driver of ageing rather than a correlate, which is what licenses this node as causal.

Chronic Low-Grade Sterile Inflammation

Persistent, low-grade systemic inflammation without overt infection - inflammaging. In this entry it is the hallmark axis with the most direct human evidence against measured intrinsic capacity: circulating IL-6 and TNF receptor-1 both raise the risk of belonging to the worst multi-domain capacity trajectory.

leukocyte CL:0000738

inflammatory response GO:0006954 ↑ INCREASED cytokine production GO:0001816 ↑ INCREASED

Downstream

Loss of Physiological Reserve Across Organ Systems

Show evidence (2 references)

PMID:37620614 SUPPORT Human Clinical

"Higher IL-6 and GDF-15 also increased the risk of being in the "low locomotion" group."

Ties the inflammatory axis specifically to a domain-level capacity trajectory rather than to a global score alone.

PMID:38145874 SUPPORT Other

"Chronic inflammation, a mechanism of aging, is associated with decreased intrinsic capacity, which may mirror the broader relationship between aging and functional ability."

The one review written specifically about this node's link to intrinsic capacity, rather than about inflammaging in general.

Decline in Tissue Regenerative Reserve

Loss of tissue-specific stem cell number and function erodes the capacity to repair after everyday injury. This is the arm of the cascade that converts accumulated damage into a falling ceiling on recovery, and it is the reason capacity loss compounds after acute insults such as hospitalisation.

stem cell CL:0000034

stem cell population maintenance GO:0019827 ↓ DECREASED tissue regeneration GO:0042246 ↓ DECREASED

Downstream

Loss of Physiological Reserve Across Organ Systems

Show evidence (1 reference)

PMID:23746838 SUPPORT Other

"These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication."

Establishes stem cell exhaustion as one of the canonical hallmarks this node instantiates.

Loss of Physiological Reserve Across Organ Systems

The convergence point of the entry. Reserve is the margin by which an organ system's capacity exceeds the demand placed on it; when repeated repair after everyday injury leaves progressive tissue degeneration, that margin narrows across systems simultaneously. This is where the entry's own content begins: everything upstream is generic ageing biology, and everything downstream is measured as intrinsic capacity.

Animal models

Naturally ageing mouse frailty index Mouse partially recapitulates Captures whole-organism functional reserve loss with age, at a prevalence comparable to humans of matched survival age.

Downstream

Locomotor Capacity Decline

Vitality Capacity Decline

Cognitive Capacity Decline

Psychological Capacity Decline

Sensory Capacity Decline

Show evidence (1 reference)

PMID:34883201 SUPPORT Other

"While robustness is associated with homeostasis achieved by an optimal structure/function relationship in all organs, successive repair processes occurring after daily injuries and infections result in accumulation of scar healing leading to progressive tissue degeneration, allostasis and frailty."

States the whole-organism reserve-erosion model this node encodes, and is the review that explicitly joins the geroscience hallmarks to the WHO intrinsic capacity framework.

Vitality Capacity Decline

Loss of the energy, metabolic, neuromuscular, and immune-stress-response capacity that the WHO working definition identifies as the physiological determinant of intrinsic capacity. Clinically it appears as the anorexia of ageing, unintentional weight loss, and fatigue. It is placed upstream of the locomotor domain here because both the WHO working definition and a subsequent framework analysis treat it as the highest-order, energy-dependent domain on which the others rest. That ordering is argued from physiology rather than demonstrated by intervention.

Whole organism (energy metabolism, neuromuscular and immune systems)

Downstream

Locomotor Capacity Decline

Composite Intrinsic Capacity Decline

Show evidence (4 references)

PMID:36356628 SUPPORT Other

"Vitality capacity is considered the underlying physiological determinant of intrinsic capacity."

Supports both the content of the node and its upstream placement.

PMID:40060276 SUPPORT Other

"The vitality domain or energy metabolism-related capacity, is the highest order dimension and the basis of other intrinsic capacity domains."

Directly supports placing this node upstream of the other four domains, which is the entry's one non-obvious ordering decision.

PMID:40060276 SUPPORT Other

"Vitality vulnerability manifests as a pre-frailty status in function-centered healthy aging."

Places loss of this domain at the pre-frailty stage, which is where the intervention evidence in this entry is concentrated.

+ 1 more reference

Locomotor Capacity Decline

Loss of muscle strength, gait speed, and balance, whose principal tissue substrate is sarcopenia - a muscle disease in its own right, accruing across the lifespan and defined by low muscle strength with confirmatory low muscle quantity. This is the domain that most consistently predicts dependence in basic activities of daily living.

skeletal muscle fiber CL:0008002

skeletal muscle atrophy GO:0014732 ↑ INCREASED

Skeletal muscle UBERON:0001134

Downstream

Composite Intrinsic Capacity Decline

Show evidence (1 reference)

PMID:30312372 SUPPORT Other

"sarcopenia is a muscle disease (muscle failure) rooted in adverse muscle changes that accrue across a lifetime; sarcopenia is common among adults of older age but can also occur earlier in life"

Establishes the tissue-level process underlying this domain and its lifelong accrual, which is why locomotor decline is detectable well before old age.

Cognitive Capacity Decline

Loss of memory, orientation, and executive function short of dementia. The domain is continuous with, but not the same as, incident dementia: capacity deficits raise dementia risk about twofold on their own and multiplicatively in combination with high polygenic risk.

neuron CL:0000540

cognition GO:0050890 ↓ DECREASED

Brain UBERON:0000955

Downstream

Composite Intrinsic Capacity Decline

Show evidence (1 reference)

PMID:38843484 SUPPORT Human Clinical

"In the joint analysis, for participants with a high polygenic risk score (PRS) and an IC score of 4 or more, the HR of all-cause dementia was 8.11 (95% CI 6.28-10.47) compared with individuals with a low PRS and an IC score of 0."

Quantifies the joint effect of capacity deficit and genetic susceptibility, which is the strongest evidence that this domain is not merely prodromal dementia relabelled.

Psychological Capacity Decline

Loss of mood, motivation, and sociability. In the INSPIRE-T cohort it is the domain that responds across the whole range of pain intensity, including mild pain, whereas the other domains respond only from moderate intensity upward - making it the most sensitive domain to a treatable exposure.

Downstream

Composite Intrinsic Capacity Decline

Show evidence (1 reference)

PMID:41360071 SUPPORT Human Clinical

"Pain was associated with reduced intrinsic capacity, with no evidence of a moderating role of iAge in this association."

Supports the node and, in its negative half, records that the inflammatory-age clock did not moderate the association - relevant because the entry's upstream chain runs through inflammation.

Sensory Capacity Decline

Age-related hearing and vision loss. Measurement work finds the two do not form a single factor, so this node bundles two anatomically separate ageing processes that happen to be screened together. Its edge to the cognitive domain reflects the widely reported sensory-cognitive coupling and is marked INDIRECT because the one randomised test of that link was null overall.

Inner ear UBERON:0001846 Eye UBERON:0000970

Downstream

Cognitive Capacity Decline

Composite Intrinsic Capacity Decline

Show evidence (1 reference)

PMID:37960903 SUPPORT Human Clinical

"Vision and hearing items did not form a single sensory domain, so six domains were considered."

Supports modelling this node as a bundle rather than a single mechanism.

Composite Intrinsic Capacity Decline

The measured construct itself: a general capacity factor over the five domains. Modelling it as a node rather than as a mere sum matters because the general factor carries predictive information the individual domains do not, and because it is the level at which interventions and the ICD-11 code are defined.

Downstream

Loss of Functional Ability and Care Dependence

Show evidence (1 reference)

PMID:31678933 SUPPORT Human Clinical

"The summary score of intrinsic capacity and specific subfactors showed good construct validity."

Supports treating the composite as a coherent measured entity rather than an arithmetic convenience.

Loss of Functional Ability and Care Dependence

The terminal state of the chain: inability to carry out the activities that matter, and eventual dependence on others. In the WHO model this is functional ability, which is intrinsic capacity as modified by environment - so the environment can widen or narrow the gap between the two, and this node is the only one in the entry whose value is not a property of the individual alone.

Show evidence (2 references)

PMID:31678933 SUPPORT Human Clinical

"The WHO construct of intrinsic capacity appears to provide valuable predictive information on an individual's subsequent functioning, even after accounting for the number of multimorbidities."

Supports the edge from measured capacity to subsequent functioning, adjusted for the obvious confounder.

PMID:34571043 SUPPORT Human Clinical

"Our results contribute to preliminary evidence linking greater IC levels and lower risk of late-life adverse outcomes."

Extends the same relationship into the nursing-home setting, where the construct had barely been tested.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

9

Digestive 1

Malnutrition VERY_RARE HP:0004395

Show evidence (1 reference)

PMID:35395736 SUPPORT Human Clinical

"The percentage of impairment in locomotion (117, 39.8%), cognition (75, 25.5%), psychological well-being (34, 11.6%), vision (75, 24.7%), hearing capacity (82, 27.9%), and vitality (8, 2.7%)."

Vitality-domain impairment at 2.7% in this community sample is the source of the VERY_RARE band recorded here.

Ear 1

Hearing impairment OCCASIONAL HP:0000365

Course: PROGRESSIVE

Show evidence (2 references)

PMID:35395736 SUPPORT Human Clinical

"The percentage of impairment in locomotion (117, 39.8%), cognition (75, 25.5%), psychological well-being (34, 11.6%), vision (75, 24.7%), hearing capacity (82, 27.9%), and vitality (8, 2.7%)."

Hearing impairment at 27.9% places this phenotype in the OCCASIONAL band.

PMID:37478886 SUPPORT Human Clinical

"Hearing loss is associated with increased cognitive decline and incident dementia in older adults."

States the observational association with the cognitive domain that motivates screening for this phenotype.

Eye 1

Visual impairment OCCASIONAL HP:0000505

Course: PROGRESSIVE

Show evidence (2 references)

PMID:35395736 SUPPORT Human Clinical

"The percentage of impairment in locomotion (117, 39.8%), cognition (75, 25.5%), psychological well-being (34, 11.6%), vision (75, 24.7%), hearing capacity (82, 27.9%), and vitality (8, 2.7%)."

Vision impairment at 24.7% places this phenotype in the OCCASIONAL band.

PMID:38676323 SUPPORT Human Clinical

"High specificity (>70%) was observed for all the IC domains, except for vision (2.7%)."

Quantifies the specificity failure in this domain that the description warns about.

Musculoskeletal 1

Muscle weakness FREQUENT HP:0001324

Course: PROGRESSIVE

Show evidence (3 references)

PMID:35395736 SUPPORT Human Clinical

"The percentage of impairment in locomotion (117, 39.8%), cognition (75, 25.5%), psychological well-being (34, 11.6%), vision (75, 24.7%), hearing capacity (82, 27.9%), and vitality (8, 2.7%)."

Gives the domain-wise impairment frequencies used across this phenotype section; locomotion at 39.8% places this phenotype in the FREQUENT band.

PMID:37960903 SUPPORT Human Clinical

"The least preserved indicators were ability to recall three words (18%) and to perform chair stands (54%)."

Identifies chair-rise failure as one of the two least preserved screening indicators in the Toledo cohort, which is the operational form of this phenotype.

PMID:30312372 SUPPORT Other

"focuses on low muscle strength as a key characteristic of sarcopenia"

Anchors the phenotype to the consensus definition of the muscle disease that underlies it.

Nervous System 4

Impaired gait and balance Gait disturbance HP:0001288

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:38676323 SUPPORT Human Clinical

"Responses at screening were compared to results of the subsequent in-depth assessment (ie, Mini-Mental State Examination, Mini Nutritional Assessment, Short Physical Performance Battery, Patient Health Questionnaire-9, and clinical investigation of vision problems)"

Establishes the Short Physical Performance Battery - a timed gait, balance and chair-rise composite - as the reference measure for the locomotion domain.

Memory impairment OCCASIONAL HP:0002354

Show evidence (2 references)

PMID:37960903 SUPPORT Human Clinical

"The least preserved indicators were ability to recall three words (18%) and to perform chair stands (54%)."

Only 18% of participants preserved three-word recall, making this the most commonly impaired screening indicator.

PMID:35395736 SUPPORT Human Clinical

"The percentage of impairment in locomotion (117, 39.8%), cognition (75, 25.5%), psychological well-being (34, 11.6%), vision (75, 24.7%), hearing capacity (82, 27.9%), and vitality (8, 2.7%)."

Cognitive-domain impairment at 25.5% on full assessment places this phenotype in the OCCASIONAL band.

Cognitive impairment OCCASIONAL HP:0100543

Show evidence (1 reference)

PMID:38843484 SUPPORT Human Clinical

"Compared with participants with an IC score of 0, individuals with an IC score of 4+ had a markedly elevated risk of dementia (hazard ratio [HR] 2.17, 95% CI 1.92-2.45)."

Shows the phenotype is prognostically distinct from dementia rather than an early label for it, since it predicts incident dementia in people who did not have it at baseline.

Depressive symptoms OCCASIONAL Depression HP:0000716

Show evidence (1 reference)

PMID:35395736 SUPPORT Human Clinical

"The percentage of impairment in locomotion (117, 39.8%), cognition (75, 25.5%), psychological well-being (34, 11.6%), vision (75, 24.7%), hearing capacity (82, 27.9%), and vitality (8, 2.7%)."

Psychological-domain impairment at 11.6% places this phenotype in the OCCASIONAL band.

Growth 1

Unintentional weight loss and appetite loss HP:0001824

Show evidence (2 references)

PMID:26195100 SUPPORT Other

"The anorexia of aging is common, leading to adverse health consequences."

Supports the phenotype and its consequences. Evidence source is OTHER because this is a narrative clinical review.

PMID:26195100 SUPPORT Other

"There are currently no approved pharmacologic treatment strategies to prevent or treat the anorexia of aging."

Records the therapeutic vacuum for this phenotype, which is why the treatments section carries no pharmacological entry for the vitality domain.

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Genetic Associations

2

Polygenic background of intrinsic capacity (Common variation of small individual effect, explaining roughly a fifth to a quarter of variance in measured intrinsic capacity.)

relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:41066301 SUPPORT Human Clinical

"The h2snp for IC was estimated at 25.2% in UKB and 19.5% in CLSA. Our GWAS identified 38 independent SNPs for IC across 10 genomic loci and 4289 candidate SNPs, mapped to 197 genes."

The first GWAS of intrinsic capacity, giving both the heritability estimate and the locus count in two independent cohorts (UK Biobank n=44 631, CLSA n=13 085).

PMID:41066301 SUPPORT Human Clinical

"Post-GWAS analysis revealed the role of these genes in cellular processes such as cell proliferation, immune function, metabolism, and neurodegeneration, with high expression in muscle, heart, brain, adipose, and nerve tissues."

Worth recording because the tissue enrichment recovers the same organs this entry's domain nodes are anchored in, independently of how those nodes were chosen.

APOE (Does not cause capacity decline, but multiplies the dementia risk that a given level of capacity deficit carries.)

Gene: APOE hgnc:613 relationship_type: MODIFIER

Show evidence (1 reference)

PMID:38843484 SUPPORT Human Clinical

"In the joint analysis, for participants with a high polygenic risk score (PRS) and an IC score of 4 or more, the HR of all-cause dementia was 8.11 (95% CI 6.28-10.47) compared with individuals with a low PRS and an IC score of 0."

Quantifies the joint effect. The hazard is far above the product of either factor alone, which is what makes this a modifier rather than an additive risk.

💊

Medical Actions

8

Multicomponent Physical Activity with Nutritional Counselling

Category: Therapeutic Action: multicomponent physical activity and nutrition programme Ontology label: Lifestyle Therapy NCIT:C15900

Structured moderate-intensity physical activity, delivered twice weekly at a centre and up to four times weekly at home with activity-monitor tailoring, plus personalised nutritional counselling. In SPRINTT this reduced mobility disability over an average 26 months in older adults with physical frailty and sarcopenia - the largest randomised demonstration that the locomotor domain is modifiable.

Mechanism Target:

INHIBITS Locomotor Capacity Decline — Slows the loss of muscle strength and physical performance that constitutes the locomotor domain, and preserves appendicular lean mass.

Show evidence (3 references)

PMID:35545258 SUPPORT Human Clinical

"Among participants with SPPB scores of 3-7, mobility disability occurred in 283/605 (46.8%) assigned to the multicomponent intervention and 316/600 (52.7%) controls (hazard ratio 0.78, 95% confidence interval 0.67 to 0.92; P=0.005)."

The primary randomised result in 1205 participants, giving the effect size for this treatment on the locomotor domain's principal outcome.

PMID:35545258 SUPPORT Human Clinical

"The between group difference in SPPB score was 0.8 points (95% confidence interval 0.5 to 1.1 points; P<0.001) and 1.0 point (95% confidence interval 0.5 to 1.6 points; P<0.001) in favour of the multicomponent intervention at 24 and 36 months, respectively."

Gives the effect on the continuous physical-performance measure used at ICOPE Step 2, which is the measure this entry's locomotor domain is scored on.

PMID:36341237 SUPPORT INDIRECT Human Clinical

"The differential risk profiles associated with prefrailty may be attributable to underlying intrinsic capacity (IC)."

A caution rather than a confirmation: in this non-randomised study baseline capacity, not intervention exposure, predicted who reverted to robustness. It is recorded here because it bears on who this treatment is expected to help.

In-Hospital Multicomponent Exercise Training

Category: Therapeutic Action: in-hospital multicomponent exercise training Ontology label: Physical Therapy NCIT:C15302

A supervised multicomponent exercise programme delivered during acute admission in Acute Care for Elders units. It is the clearest demonstration that the composite construct itself responds to intervention, and it does so over days rather than years, in patients of mean age 87.

Mechanism Target:

INHIBITS Composite Intrinsic Capacity Decline — Raises the composite capacity score at discharge, with gains in every domain, counteracting the step decline that hospitalisation otherwise produces.

Show evidence (1 reference)

PMID:40188489 SUPPORT Human Clinical

"The exercise intervention significantly improved IC compared to the control group [7.74 points, 95% confidence interval (CI) 6.45-9.03, P < .001], with benefits observed in all IC domains."

Randomised evidence that the composite score, not merely a single domain, is modifiable.

Combined Exercise and Cognitive Stimulation Therapy

Category: Therapeutic Action: combined exercise and cognitive stimulation programme Ontology label: Lifestyle Therapy NCIT:C15900

Six months of exercise with or without three months of added cognitive stimulation therapy, in pre-frail older adults attending primary care. Included because it is one of the few studies whose outcome is the intrinsic-capacity composite itself rather than a single-domain proxy. It is a pre-post intervention study, not a randomised trial, so the effect estimate is weaker than SPRINTT's.

Mechanism Target:

INHIBITS Composite Intrinsic Capacity Decline — Improves the composite score and the locomotor domain within three months in pre-frail participants.

Show evidence (1 reference)

PMID:38616369 SUPPORT INDIRECT Human Clinical

"At 3 months, both Ex and Ex +CST showed improvement in IC composite scores"

Supports the effect on the composite. Marked INDIRECT because the design is pre-post with a self-selected control group rather than randomised.

Group-Based Multidomain Intervention with Brain-Structure Outcomes

Category: Therapeutic Action: group-based multidomain lifestyle intervention Ontology label: Lifestyle Therapy NCIT:C15900

The ENHANCE randomised trial: twelve months of twice-weekly group sessions combining physical exercise, cognitive training and nutrition education, against quarterly telephone education. It is the one trial here with a structural imaging endpoint, so it speaks to whether multidomain intervention reaches the substrate of the cognitive domain rather than only its test scores. The trial is small - 88 completers, 76 with longitudinal MRI - and the groups differed at baseline in age and BMI.

Mechanism Target:

INHIBITS Cognitive Capacity Decline — Slows loss of grey matter volume, the structural correlate of the cognitive domain.

Show evidence (2 references)

PMID:40464147 SUPPORT Human Clinical

"The ENHANCE trial delivered twice-weekly group-based multidomain sessions (physical exercise, cognitive training and nutrition education) in urban and rural communities for 12 months, while the control group received quarterly telephone education."

Describes the intervention and its comparator, which is what this treatment record encodes.

PMID:40464147 SUPPORT INDIRECT Human Clinical

"The intervention group (n = 44; 75.0% female) was significantly older than the control group (n = 44; 70.5% female) (75.0 ± 6.6 vs. 72.3 ± 5.0 years, p = 0.035) and had lower BMI (23.4 vs. 25.2 kg/m2, p = 0.016) at baseline."

Records the baseline imbalance, which limits how much weight the structural result can carry. Marked INDIRECT because it bears on the claim by qualifying it.

Multidomain Lifestyle Intervention for Cognitive Decline

Category: Therapeutic Action: multidomain lifestyle intervention Ontology label: Lifestyle Therapy NCIT:C15900

Combined dietary guidance, exercise, cognitive training, and vascular risk monitoring over two years in at-risk older adults, as tested in FINGER. The effect on cognition is real but small, and the trial is included here as the benchmark for what multidomain intervention achieves in the cognitive domain rather than as a strong recommendation.

Mechanism Target:

INHIBITS Cognitive Capacity Decline — Slows the rate of cognitive change measured by a comprehensive neuropsychological battery.

Show evidence (2 references)

PMID:25771249 SUPPORT Human Clinical

"Between-group difference in the change of NTB total score per year was 0·022 (95% CI 0·002-0·042, p=0·030)."

The primary randomised result in 1260 participants; the confidence interval almost touching zero is why the description calls the effect small.

PMID:25771249 SUPPORT Human Clinical

"Adverse events occurred in 46 (7%) participants in the intervention group compared with six (1%) participants in the control group; the most common adverse event was musculoskeletal pain (32 [5%] individuals for intervention vs no individuals for control)."

Records the harm side of the multidomain intervention, which is not zero and is concentrated in the exercise component.

ICOPE Integrated Person-Centred Care Pathway

Category: Therapeutic Action: integrated person-centred care for older people Ontology label: Supportive Care NCIT:C15747

The WHO ICOPE care pathway itself, delivered as a service intervention: Step 1 screening, Step 2 in-depth assessment, a personalised care plan, referral, and monitoring, coordinated by integrated care managers. A randomised trial in Beijing primary care found it feasible and associated with small improvements in the vitality, mobility, and psychological domains at six months.

Mechanism Target:

INHIBITS Composite Intrinsic Capacity Decline — Acts on the composite by routing each detected domain impairment to a domain-specific intervention, rather than by any single mechanism of its own.

Show evidence (1 reference)

PMID:38251736 SUPPORT Human Clinical

"All outcomes showed improvements after a 6-month intervention, while statistically significant least-squares mean differences (control-intervention) in vitality (Mini-Nutritional Assessment Short Form to measure vitality, -0.21, 95% CI, -0.40-0.02), mobility (Short Physical Performance Battery..."

The randomised effect of the pathway itself on three of the five domains, in 938 propensity-matched participants.

Hearing Intervention with Hearing Aid Provision

Category: Therapeutic Action: hearing device fitting and audiological rehabilitation Ontology label: Rehabilitation NCIT:C15315

Audiological needs assessment, fitting of hearing devices, and counselling. It addresses the sensory domain directly. It does not, on the best available randomised evidence, slow cognitive decline in the general population of older adults with hearing loss - the ACHIEVE primary result was null - so the observational sensory-to-cognitive link is not a basis for prescribing it as a cognitive intervention.

Mechanism Target:

RESTORES Sensory Capacity Decline — Restores audibility, which is the measured content of the hearing half of the sensory domain.

MODULATES Cognitive Capacity Decline — Proposed but not demonstrated. The randomised test of this edge was null overall, with a benefit confined to a prespecified higher-risk subgroup, so the edge is recorded as unresolved rather than as a therapeutic effect.

Show evidence (2 references)

PMID:37478886 REFUTE Human Clinical

"In the primary analysis combining the ARIC and de novo cohorts, 3-year cognitive change (in SD units) was not significantly different between the hearing intervention and health education control groups"

Refutes the claim that hearing intervention slows cognitive decline in this population; it does not bear on the intervention's effect within the sensory domain, which was not the trial's outcome.

PMID:37478886 SUPPORT INDIRECT Human Clinical

"However, a prespecified sensitivity analysis showed a significant difference in the effect of the hearing intervention on 3-year cognitive change between the ARIC and de novo cohorts (pinteraction=0·010)."

Supports the narrower claim that the effect may exist in a higher-risk subgroup. Marked INDIRECT because it is a subgroup interaction, not the trial's answer.

Systematic ICOPE Step 1 Screening in Primary Care

Category: Screening Action: screening for decline in intrinsic capacity Ontology label: Disease Screening NCIT:C15419

Population screening of adults aged 60 and over with the ICOPE Step 1 instrument, by health-care providers or self-assessment through digital tools. Listed as a non-therapeutic action: it changes nothing by itself, but it is the entry point to everything else in this section, and the feasibility of doing it at scale was the open question that the Occitania implementation answered.

Show evidence (2 references)

PMID:36098317 SUPPORT Human Clinical

"The high number of participants included in our study, as well as the high rates of follow-up, provides evidence to suggest that the large-scale implementation of ICOPE in clinical practice is feasible."

Establishes feasibility at a scale of 10 903 people with 70.4% six-month follow-up, which is the claim this action rests on.

PMID:36098317 SUPPORT Human Clinical

"Most recommendations in step 3 (care plan) were related to locomotion, vitality, and cognition."

Records which domains screening actually routes people into care for, which is the practical output of the screen.

🌍

Environmental Factors

3

Ambient and household air pollution

The evidence is against frailty, not against intrinsic capacity. Those are related but distinct constructs - this entry's own definitions section says so - and no meta-analysis of air pollution against measured intrinsic capacity yet exists. The mechanism edge is therefore marked PREDISPOSES with INDIRECT evidence rather than asserted as a capacity effect, and it attaches at the reserve node rather than at any single domain, because the frailty outcome does not resolve to one.

Exposure to fine particulate matter, household solid-fuel combustion, and secondhand smoke. A meta-analysis of 18 studies finds each raises the risk of frailty in middle-aged and older adults, with the largest pooled effect for secondhand smoke - although that estimate's confidence interval crosses one, so the ordering of the three exposures is not established.

Show evidence (1 reference)

PMID:40391839 SUPPORT INDIRECT Human Clinical

"Meta-analyses indicated a 19% increased risk of frailty due to air pollution (fine particulate matter ≤2.5 microns) [n = 9 studies; pooled odds ratio (OR) 1.19; 95% confidence interval (CI) 1.10-1.27], a 28% increase with exposure to household solid fuels (n = 4 studies; OR 1.28; 95% CI..."

Gives the pooled effect sizes for all three exposures. Marked INDIRECT because the outcome is frailty rather than measured intrinsic capacity.

Mechanism Target:

PREDISPOSES Loss of Physiological Reserve Across Organ Systems — Sustained particulate exposure is proposed to erode reserve through systemic inflammation and oxidative stress, the same axes this entry's upstream nodes already carry.

Show evidence (1 reference)

PMID:40391839 SUPPORT INDIRECT Human Clinical

"Environmental exposures, including air pollution, the use of unclean household fuels and exposure to secondhand smoke, significantly increase the risk of frailty."

Supports the edge through one inference step: the measured outcome is frailty, and this entry models frailty as downstream of reserve loss rather than as the same thing.

Chronic pain

No ECTO or XCO term is bound. Exposure ontologies model pain poorly - it is an experience rather than an environmental agent - and binding a stress or nociceptive-stimulus term would misstate what was measured, which was self-reported pain presence and intensity.

Self-reported pain over the preceding days, graded by intensity. Across a lifespan cohort spanning ages 20 to 102, pain of any intensity was associated with lower psychological capacity, and intense pain with lower scores in every domain except sensory.

Show evidence (2 references)

PMID:41360071 SUPPORT Human Clinical

"Both moderate pain (β 0·264, SE 0·076, p=0·0006) and intense pain (0·479, 0·105, p<0·0001) were negatively associated with intrinsic capacity values."

Establishes the entry-level association between pain and the composite capacity score in 971 INSPIRE-T participants.

PMID:41360071 SUPPORT INDIRECT Human Clinical

"Further research is needed to determine whether effective pain management could help prevent declines in intrinsic capacity."

The authors' own statement that the exposure is not yet demonstrated to be causally modifiable, which is why this entry is recorded as an exacerbating exposure rather than a treatment target.

Mechanism Target:

EXACERBATES Psychological Capacity Decline — Pain lowers psychological-domain scores across the whole intensity range, including mild pain, which is not true of any other domain.

Show evidence (1 reference)

PMID:41360071 SUPPORT Human Clinical

"Pain at all intensities, mild (0·512, 0·163, p=0·0017), moderate (1·111, 0·191, p<0·0001), or intense (1·532, 0·263, p<0·0001), was significantly associated with lower scores in the psychological domain."

Supports the edge specifically, including the dose-response across intensity bands.

Acute hospitalisation

No ECTO term is bound. Hospitalisation is a healthcare episode rather than an environmental exposure in the ECTO sense, and no suitable term was found.

Admission for acute illness, which in older adults is followed by functional and cognitive decline independent of the admitting diagnosis. It is included as an environmental exposure because it is a discrete, dated, often avoidable event that steps intrinsic capacity down, unlike the continuous background of ageing.

Show evidence (1 reference)

PMID:40188489 SUPPORT Human Clinical

"IC score at discharge was inversely associated with mortality risk during follow-up (OR = 0.98 per each increase in IC score at discharge, 95% CI = 0.96, 0.99, P = .010)"

Establishes that capacity measured at the end of this exposure carries prognostic weight, in 570 patients of mean age 87.3 years.

Mechanism Target:

EXACERBATES Composite Intrinsic Capacity Decline — The functional and cognitive decline that follows acute admission is a decrement in the composite construct rather than in any one domain, which is why the edge attaches at the composite node.

Show evidence (1 reference)

PMID:40188489 SUPPORT Human Clinical

"Hospitalisation often results in adverse effects in older adults, particularly an increased risk of functional and cognitive decline."

Supports the exposure acting on the composite construct.

🔬

Biochemical Markers

3

Plasma interleukin-6 (Elevated in the worst multi-domain intrinsic-capacity trajectory)

Context: Community-dwelling older adults followed for four years in the MAPT trial cohort.

Show evidence (1 reference)

PMID:37620614 SUPPORT Human Clinical

"Higher IL-6 and GDF-15 also increased the risk of being in the "low locomotion" group."

Associates circulating IL-6 with a specific impaired-capacity trajectory in 1271 participants.

Plasma growth differentiation factor-15 (GDF-15) (Elevated in the worst multi-domain intrinsic-capacity trajectory)

Context: Community-dwelling older adults followed for four years in the MAPT trial cohort.

Show evidence (1 reference)

PMID:37620614 SUPPORT Human Clinical

"GDF-15 outperformed other biomarkers by showing the strongest associations with IC trajectory groups."

Ranks GDF-15 above the inflammatory markers for association with capacity trajectories.

C-reactive protein and tumor necrosis factor-alpha (Reported both elevated and unchanged across studies of intrinsic capacity)

Context: Reviewed across the intrinsic-capacity literature rather than measured in one cohort.

Show evidence (2 references)

PMID:38145874 SUPPORT Other

"Interleukin-6, C-reactive protein, and tumor necrosis factor-alpha may potentially indicate changes in intrinsic capacity, but their results with intrinsic capacity or each intrinsic capacity domain are inconsistent."

Names the candidate markers and states the inconsistency in one sentence.

PMID:38145874 REFUTE Other

"To date, there is still no inflammatory markers with high specificity and sensitivity to monitor intrinsic capacity decline."

Refutes any reading of the two markers above as clinically usable monitoring tests, which is a claim this section could otherwise be taken to make.

🔬

Diagnosis

1

WHO ICOPE two-step assessment

Assessment runs in two steps. Step 1 is the short screen modelled in `definitions` and `treatments`; Step 2 is the in-depth assessment applied to whoever screens positive, using the reference instruments for each domain - Mini-Mental State Examination for cognition, Mini Nutritional Assessment for vitality, Short Physical Performance Battery for locomotion, PHQ-9 for the psychological domain, and clinical assessment for vision. Step 2 is what "impairment" means in this entry's phenotype frequencies; Step 1 alone over-calls, as this entry's prevalence records show.

Show evidence (2 references)

PMID:36809987 SUPPORT Human Clinical

"IC assessment proposed by the WHO ICOPE guidelines is composed by two steps: First, Screening for decreased IC by the ICOPE Screening tool; second, by the reference standard methods."

States the two-step structure that this diagnosis record encodes.

PMID:38676323 SUPPORT Human Clinical

"Responses at screening were compared to results of the subsequent in-depth assessment (ie, Mini-Mental State Examination, Mini Nutritional Assessment, Short Physical Performance Battery, Patient Health Questionnaire-9, and clinical investigation of vision problems)"

Names the Step 2 reference instruments, one per domain.

📈

Progression

4

Heterogeneous multi-domain trajectories rather than one uniform slope

The clinically useful fact about progression here is that there is no single course. Group-based multi-trajectory modelling over four years separates distinct patterns - decline in all domains, isolated locomotor decline, isolated psychological decline, and two largely preserved patterns - which is why a single composite score can hide the thing that matters for care planning.

Show evidence (4 references)

PMID:37620614 SUPPORT Human Clinical

"Five IC multi-trajectory groups were determined: low in all domains (8.4%), low locomotion (24.6%), low psychological domain (16.7%), robust (i.e., high in all domains except vitality; 28.3%), and robust with high vitality (22.0%)."

Names and quantifies the distinct trajectory groups in 1271 MAPT participants followed for four years.

PMID:38029399 SUPPORT Human Clinical

"We identified four subtypes of IC decline: robust with mild decline (n=902), hearing loss with cognitive decline (n=197), physio-cognitive decline (PCD) with depression (n=373), and severe IC decline (n=310)."

Independent replication of the multi-trajectory finding in 1782 Taiwanese participants, and it recovers different groupings from the MAPT analysis - which is why this section reports that trajectories are heterogeneous rather than naming a canonical set.

PMID:38029399 SUPPORT Human Clinical

"Individuals in the severe IC decline group faced a substantially increased risk of all outcomes of interest."

Shows the trajectories carry different outcome risks, so the grouping is prognostically meaningful rather than descriptive.

+ 1 more reference

Progression to loss of activities of daily living and care dependence

Intrinsic capacity predicts subsequent dependence, and does so more strongly than multimorbidity does - which is the empirical claim that justifies treating capacity rather than disease count as the target of care in this population.

Show evidence (2 references)

PMID:31678933 SUPPORT Human Clinical

"More of the indirect effect of personal characteristics on incident loss of ADLs and IADLs was mediated by intrinsic capacity than multimorbidity."

Establishes both the progression to dependence and its precedence over multimorbidity as a mediator.

PMID:38945130 SUPPORT Human Clinical

"Intrinsic capacity is inversely associated with functional decline and mortality risk in older adults."

The pooled conclusion of 37 longitudinal studies and 206 693 participants, which is the broadest evidence that capacity loss progresses to dependence and death.

Prediction of dementia and death, above what frailty measures capture

The reason to measure capacity rather than count deficits is that it predicts the hard outcomes at least as well and adds information beyond frailty instruments built on the same underlying tests. Two independent cohorts show this over a decade or more.

Show evidence (3 references)

PMID:41086232 SUPPORT Human Clinical

"IC was associated with lower hazard (risk) of dementia (HR = 0.567, p < 0.001) over 10-year and lower hazard of mortality (HR = 0.649, p < 0.001) over 12-year, controlling for age, sex, and education."

Gives the long-horizon effect sizes for both outcomes in an Australian cohort that also replicates the five-factor structure this entry's subtypes encode.

PMID:41086232 SUPPORT Human Clinical

"Finally, IC explained additional variance beyond the Frailty Phenotype when predicting both incident dementia and mortality risk."

The specific claim that capacity is not redundant with frailty, which is the justification for curating this entry separately from frailty.

PMID:37517058 SUPPORT Human Clinical

"Participants with deteriorated IC had a significantly higher risk of frailty, disability and dementia than people with high IC."

Establishes the same ordering - capacity loss precedes frailty, disability and dementia - in a low- and middle-income-country cohort rather than a high-income one.

Secular improvement across birth cohorts

Recorded because it cuts against the natural reading of the rest of this section. The trajectory of an individual is downward, but successive birth cohorts enter old age with more capacity and lose it more slowly, so population-level burden is not simply a function of chronological ageing.

Show evidence (1 reference)

PMID:39702725 SUPPORT Human Clinical

"we found that more recent cohorts entered older ages with higher levels of capacity, while subsequent age-related declines were somewhat compressed compared to earlier cohorts."

Establishes the cohort effect in two independent national ageing cohorts (ELSA and CHARLS).

📊

Prevalence

2

Community-dwelling adults aged 60 years and older, pooled across 15 studies

Point Prevalence 67800.0 per 100,000 (57000.0–78500.0) >1 in 1,000

Random-effects pooled prevalence of any intrinsic-capacity decline, 33 070 participants. Converted from 67.8% (95% CI 57.0-78.5%). The figure is high because "decline" here means any impaired domain on screening, not a severity threshold, and screening cutoffs differ between the pooled studies; it should not be read as a prevalence of a discrete disease state.

Show evidence (1 reference)

PMID:39088112 SUPPORT Human Clinical

"The pooled prevalence of IC decline in community settings was 67.8% (95% CI: 57.0-78.5%; P < 0.001)."

The pooled community estimate this record reports.

Primary-care users aged 60 years and older, Occitania region, France (ICOPE Step 1 screening)

Point Prevalence 94300.0 per 100,000 >1 in 1,000

Positive Step 1 screen in a real-world implementation of 10 903 people. Even higher than the pooled community figure, which is informative about the instrument rather than the population: a screen designed for sensitivity in a self-selected primary-care sample calls almost everyone positive, and only 9.3% went on to Step 2.

Show evidence (1 reference)

PMID:36098317 SUPPORT Human Clinical

"10 285 (94·3%) participants had a positive intrinsic capacity result during screening at baseline."

The screening-positive proportion this record reports.

⚖️

Clinical Burden

High

The burden is high not because any one domain is severe but because the composite predicts the outcomes that matter most: pooled across 37 longitudinal studies and 206 693 participants, lower intrinsic capacity is inversely associated with both functional decline and mortality, and the relationship is graded across the whole range rather than confined to a severely impaired tail. The condition is also close to universal in the population it is defined for, with more than two-thirds of community-dwelling older adults screening positive, so even a modest per-person effect aggregates into a large population burden. Against that, it is the one geriatric burden with a demonstrated intervention response, which is why it is a target rather than merely a prognostic marker.

Show evidence (6 references)

PMID:38945130 SUPPORT Human Clinical

"Intrinsic capacity is inversely associated with functional decline and mortality risk in older adults."

The pooled association with both functional decline and mortality that underlies the HIGH assessment.

PMID:38945130 SUPPORT Human Clinical

"We included 37 studies (206 693 participants; average age range 65·3-85·9 years) in the systematic review"

Establishes the scale of the pooled evidence quoted in the rationale.

PMID:35963450 SUPPORT Human Clinical

"IC is associated with mortality in a dose-response fashion."

Supports the graded rather than threshold character of the burden, in a 10-year cohort of 2032 people aged 70 and over.

+ 3 more references

🔬

Clinical Trials

5

NCT02582138 NOT_APPLICABLE COMPLETED

SPRINTT - a multicomponent physical activity, nutritional counselling and ICT-supported intervention versus healthy-ageing education, in 1519 community-dwelling people aged 70 and over with physical frailty and sarcopenia, across 16 sites in 11 European countries.

Target Phenotypes: Reduced muscle strength on chair-rise testing HP:0001324 Slowed gait and impaired balance HP:0001288

Show evidence (1 reference)

clinicaltrials:NCT02582138 SUPPORT Human Clinical

"The SPRINTT study will evaluate the efficacy of a multicomponent intervention programme (physical activity, nutritional counselling/dietary intervention, and information and communications technology intervention) compared with a healthy aging lifestyle education programme on mobility..."

The registration record for the trial behind this entry's principal locomotor treatment.

NCT03243422 NOT_APPLICABLE COMPLETED

ACHIEVE - hearing intervention versus health education in 977 adults aged 70-84 with untreated hearing loss, nested within the ARIC cohort infrastructure, with three-year global cognition as the primary endpoint.

Target Phenotypes: Age-related hearing impairment HP:0000365 Cognitive impairment short of dementia HP:0100543

Show evidence (1 reference)

clinicaltrials:NCT03243422 SUPPORT Human Clinical

"We plan to enroll 850 70-84 year-old cognitively normal older adults with hearing loss, who will be randomized 1:1 to the hearing intervention (hearing needs assessment, fitting of hearing devices, education/counseling) or successful aging health education intervention (individual sessions with..."

The registration record for the only randomised test of the sensory-to-cognitive edge in this entry.

NCT01041989 NOT_APPLICABLE COMPLETED

FINGER - a two-year multidomain intervention of nutritional guidance, exercise, cognitive training, social activity and vascular risk management in 1260 people aged 60-77 at elevated dementia risk.

Target Phenotypes: Cognitive impairment short of dementia HP:0100543

Show evidence (1 reference)

clinicaltrials:NCT01041989 SUPPORT Human Clinical

"The 2-year multi-domain life-style intervention includes nutritional guidance, exercise, cognitive training, increased social activity, and intensive monitoring and management of metabolic and vascular risk factors."

The registration record describing the multidomain package this entry cites for the cognitive domain.

NCT00672685 PHASE_III COMPLETED

MAPT - omega-3 supplementation, a multidomain intervention, or both, in community-dwelling older adults. Its cohort is the source of this entry's biomarker-to-trajectory evidence, so the trial appears here both as an intervention study and as the platform behind the biochemical section.

Target Phenotypes: Cognitive impairment short of dementia HP:0100543

Show evidence (1 reference)

clinicaltrials:NCT00672685 SUPPORT Human Clinical

"The main objective of this study is to assess the efficacy of isolated supplementation with omega-3 fatty acid, an isolated multi-domain intervention"

The registration record for the trial whose cohort supplies this entry's plasma biomarker evidence.

NCT04224038 NOT_APPLICABLE RECRUITING

INSPIRE-T - a ten-year observational bio-resource platform recruiting from age 30 upward with no upper age limit, across the full range of functional capacity, built specifically to identify markers of ageing and of intrinsic-capacity evolution. It is the source of this entry's pain and ICOPE-tool-validation evidence.

Show evidence (1 reference)

clinicaltrials:NCT04224038 SUPPORT Human Clinical

"the main objective of Inspire Bio-resource Research Platform for Healthy Aging is to build a comprehensive research platform gathering biological, clinical (including imaging) and digital resources that will be explored to identify robust (set of) markers of aging, age-related diseases and IC evolution."

The registration record establishing that this platform's stated purpose is exactly the biomarker-to-capacity question this entry leaves open.

🐁

Animal Models

1

Naturally ageing mouse frailty index

A deficit-accumulation index scored in naturally aged mice, built to match the human clinical criteria of weakness, slow walking speed, low activity and poor endurance. It is the closest available preclinical instrument for whole-organism functional reserve, and it is what geroscience intervention studies score when they claim an effect on function rather than on lifespan.

Species

Mouse

Genotype

C57BL/6 wild type, naturally aged

Publication

PMID:24336799

Pathograph links

Loss of Physiological Reserve Across Organ Systems partially recapitulates fidelity: moderate Captures whole-organism functional reserve loss with age, at a prevalence comparable to humans of matched survival age.

Limitations: Measures frailty by deficit accumulation rather than capacity, and covers only the physical domains. The psychological and sensory domains of intrinsic capacity have no counterpart in this index, and the cognitive domain is not scored at all - so three of the entry's five domains are outside what this model can address.

Readouts

Frailty Index score from grip strength, walking speed, activity and endurance

Direction: INCREASED

Interpretation: A higher index means more accumulated deficits, that is, less reserve.

Show evidence (1 reference)

PMID:24336799 SUPPORT Model Organism

"The selected criteria included grip strength, walking speed, physical activity, and endurance."

Names the four measurements that make up this readout.

Show evidence (1 reference)

PMID:24336799 SUPPORT Model Organism

"This prevalence of 9% frailty is consistent with the prevalence of frailty in humans at the same survival age."

The comparability argument that makes this model informative for the human reserve node rather than merely analogous.

This is a frailty instrument, not an intrinsic-capacity instrument. No validated rodent measure of intrinsic capacity as WHO defines it exists, which is why the link below is PARTIALLY_RECAPITULATES and attaches at the reserve node rather than at the composite construct.

Show evidence (2 references)

PMID:28463656 SUPPORT Model Organism

"The recent development of an FI in naturally ageing mice provides an opportunity to conduct frailty research in a validated preclinical model."

Establishes the index as a validated preclinical tool rather than a single-lab construct.

PMID:28463656 SUPPORT INDIRECT Model Organism

"however, there are some factors that should be considered in implementing this tool"

Flags the inter-rater and environmental sensitivity of the index, which is why fidelity is recorded as MODERATE rather than HIGH.

{ }

Source YAML

click to show

name: Ageing Associated Decline in Intrinsic Capacity
creation_date: '2026-08-31T00:00:00Z'
category: Complex
categories:
- Geriatric Syndrome
- Ageing-Related Functional Decline
parents:
- general symptoms, signs or clinical findings
- ageing-related functional decline
synonyms:
- ageing-associated decline in intrinsic capacity
- age-related decline in intrinsic capacity
- intrinsic capacity decline
- loss of intrinsic capacity
- IC decline
description: >-
  Ageing associated decline in intrinsic capacity (ICD-11 MG2A) is the age-related
  erosion of intrinsic capacity - the composite of all the physical and mental
  capacities an individual can draw on at any point in time. Intrinsic capacity is
  one of the two determinants (with the environment) of functional ability in the
  WHO healthy-ageing model, and is operationalised across five domains: locomotion,
  vitality, cognition, psychological capacity, and sensory capacity. Decline is
  graded rather than binary, is usually insidious and multi-domain, and typically
  precedes and predicts frailty, care dependence, and death. Mechanistically the
  entry treats the condition as the clinical convergence point of the molecular and
  cellular hallmarks of ageing: accumulating damage drives mitochondrial bioenergetic
  decline, senescent-cell accumulation, inflammaging, and loss of regenerative
  reserve, which together erode physiological reserve across organ systems and
  surface as domain-specific capacity loss. Unlike a single-organ disease, the entity
  is defined at the level of the whole organism, and its principal management is
  multidomain and person-centred rather than pharmacological. This entry deliberately
  models the construct as WHO and ICD-11 define it, and does not treat it as a
  synonym for frailty, sarcopenia, or disability, each of which is modelled
  separately.
notes: >-
  Modelling decisions for this entry, recorded because several are unusual.
  (1) There is no `disease_term`: MONDO carries no class for intrinsic capacity or
  its decline (searched 2026-08-31 via OLS against MONDO), so the entry is anchored
  on the ICD-11 Foundation entity icd11f:835503193 in `mappings.icd11f_mappings`
  instead. That entity is the Foundation counterpart of MMS linearisation code MG2A,
  sits under General symptoms, and has no children. Twenty-six other entries in
  `kb/disorders/` likewise carry no MONDO anchor, so this is an accepted state, not
  a defect; if MONDO later mints a class it should be added as the `disease_term`.
  (2) The five ICOPE domains are modelled as `has_subtypes` rather than as bare
  phenotype categories. They are not aetiological subtypes in the Mendelian sense;
  they are the axes along which the construct is measured and along which impairment
  is genuinely dissociable - a person can have isolated locomotor decline with intact
  cognition, and cohort studies report domain-specific trajectories. Using
  `has_subtypes` gives the phenotypes, prevalence, and progression records a foreign
  key to hang domain-specific claims on, which a free-text category would not.
  (3) The pathophysiology chain conforms to the hallmarks-of-ageing modules in
  `kb/modules/` rather than restating them. The upstream biology is not specific to
  this entity - what is specific is the convergence onto measured capacity domains,
  so the entry's own content starts at "Loss of Physiological Reserve Across Organ
  Systems" and works forward.
  (4) The causal direction from hallmark biology to measured intrinsic capacity is
  supported in humans by association, not by intervention: the strongest human link
  is that plasma markers of inflammation and mitochondrial impairment separate
  multi-impaired from high-stable IC trajectories. This is recorded as an open
  knowledge gap rather than asserted, and the relevant edges are marked
  `causal_link_type: INDIRECT`.
  (5) References fetched but not cited. This entry's `references_cache/` additions are
  larger than its citation list because the deep-research run resolved its own
  citations into the same cache, so the cache reflects what the report cited, not what
  a curator selected. Of the remainder, the following were read and deliberately set
  aside: PMID:37543528 (a second prevalence meta-analysis reporting 76.1%, superseded
  here by the larger and more recent PMID:39088112, whose estimate is anchored to a
  stated cutoff); PMID:34179933, PMID:35830956 and PMID:36901237 (measurement and
  screening reviews whose substance is already carried by PMID:35569785 in the
  five-domain definition); PMID:36832984 and PMID:41227125 (scoping reviews of outcome
  prediction, superseded by the PMID:38945130 meta-analysis); PMID:36612480 (ICOPE
  adoption worldwide - implementation policy rather than mechanism or outcome);
  PMID:36750172 (I-Lan 10-year mortality, consistent with and weaker than the cohorts
  already cited); PMID:35775483 and PMID:40666427 (general hallmarks-of-ageing reviews,
  where the entry cites the primary Lopez-Otin statements instead); PMID:38719530
  (deprescribing, a real intervention for older adults but with no measured
  intrinsic-capacity outcome); and PMID:28359749 (the MAPT primary cognitive result,
  where the entry instead cites MAPT's registration record and the biomarker
  sub-study that is actually about capacity).
  (6) Programmatic context, for readers arriving from geroscience rather than
  geriatrics: WHO's Integrated Care for Older People (ICOPE) programme is the
  operational framework that turned intrinsic capacity from a construct into a
  screening and care pathway, and is what most of the clinical literature cited here
  measures. Separately, the US ARPA-H programme PROSPR (Proactive Solutions for
  Prolonging Resilience) funds work that uses intrinsic capacity as an early,
  actionable endpoint for healthspan interventions, on the argument that
  conventional trials of ageing interventions are too slow because the diseases they
  target take decades to appear. PROSPR is a funding programme rather than a
  published finding, so it is named here and not curated as evidence.
mappings:
  icd11f_mappings:
  - term:
      id: icd11f:835503193
      label: Ageing associated decline in intrinsic capacity
    mapping_predicate: skos:exactMatch
    mapping_source: manual curation
    mapping_justification: >-
      The ICD-11 Foundation entity is the source of this entry's identity: the entry
      was created to model the concept behind MMS linearisation code MG2A, and the
      Foundation label is reproduced verbatim as the entry name. The entity resolves
      under General symptoms within Symptoms, signs or clinical findings, not
      elsewhere classified, and has no children, so the mapping is one-to-one.
definitions:
- name: WHO definition of intrinsic capacity
  definition_type: OTHER
  derivation_basis: ESTABLISHED_CRITERIA
  description: >-
    Intrinsic capacity is the composite of all the physical and mental capacities an
    individual can draw on. With the environment and the interaction between the two,
    it determines functional ability, which is what the WHO healthy-ageing model
    treats as the object of care rather than the presence or absence of disease.
  scope: >-
    Defines the construct whose decline this entry models; it is not a diagnostic
    threshold and does not by itself identify an affected individual.
  evidence:
  - reference: PMID:26520231
    reference_title: 'The World report on ageing and health: a policy framework for healthy ageing.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The report is built around a redefinition of healthy ageing that centres on the notion of functional ability: the combination of the intrinsic capacity of the individual, relevant environmental characteristics, and the interactions between the individual and these characteristics.
    explanation: >-
      States the WHO model in which intrinsic capacity is one of the two determinants
      of functional ability. Evidence source is OTHER because this is a policy
      framework paper rather than a study.
  - reference: PMID:31275941
    reference_title: 'Frailty and Intrinsic Capacity: Two Distinct but Related Constructs.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the World Health Organization introduced the concept of intrinsic capacity (IC), defined as the composite of all physical and mental capacities that an individual can draw upon during his/her life.
    explanation: >-
      Gives the definitional wording of the construct itself, separate from the
      functional-ability model it sits inside.
- name: Five-domain operational model of intrinsic capacity
  definition_type: OTHER
  derivation_basis: ESTABLISHED_CRITERIA
  description: >-
    Intrinsic capacity is operationalised as five domains - locomotion, vitality,
    cognition, psychological, and sensory - which is what makes the construct
    measurable. Factor-analytic work in a population cohort recovers a general
    intrinsic-capacity factor plus these five subfactors, so the domain structure is
    an empirical finding and not only a conceptual convenience.
  scope: >-
    Applies to the whole entry; the `has_subtypes` records reproduce these five
    domains and the phenotypes are grouped against them.
  evidence:
  - reference: PMID:29408961
    reference_title: Evidence for the Domains Supporting the Construct of Intrinsic Capacity.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      five domains (i.e., locomotion, vitality, cognition, psychological, sensory) are identified as pivotal for capturing the individual's intrinsic capacity
    explanation: >-
      The consensus paper that fixed the five-domain structure used throughout this
      entry. Evidence source is OTHER because it is an expert review.
  - reference: PMID:31678933
    reference_title: The structure and predictive value of intrinsic capacity in a longitudinal study of ageing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One general factor (intrinsic capacity) and five subfactors emerged: locomotor, cognitive; psychological; sensory; and 'vitality'.
    explanation: >-
      Recovers the five-domain structure empirically by factor analysis in 2560
      participants of the English Longitudinal Study of Ageing, so the domains are
      not merely stipulated.
  - reference: PMID:35569785
    reference_title: 'Defining and assessing intrinsic capacity in older people: A systematic review and a proposed scoring system.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      There is overall consensus on the definition of IC as well as on its different dimensions, that is: locomotion, vitality, sensory, cognition and psychological.
    explanation: >-
      Confirms across 33 studies that the five dimensions are agreed even where the
      measurement instruments are not.
- name: WHO working definition of vitality capacity
  definition_type: OTHER
  derivation_basis: ESTABLISHED_CRITERIA
  description: >-
    Vitality capacity is the physiological substrate of intrinsic capacity: a state
    arising from the interaction of energy and metabolism, neuromuscular function,
    and immune and stress-response function. It is the domain closest to the biology
    of ageing, which is why it is treated in this entry as gating the other four
    rather than sitting beside them.
  scope: >-
    Defines the vitality subtype; the claim that vitality gates the other domains is
    a mechanistic reading of this definition and is recorded as such in the
    pathophysiology, not as an established finding.
  evidence:
  - reference: PMID:36356628
    reference_title: WHO working definition of vitality capacity for healthy longevity monitoring.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      vitality capacity is a physiological state (due to normal or accelerated biological ageing processes) resulting from the interaction between multiple physiological systems, reflected in (the level of) energy and metabolism, neuromuscular function, and immune and stress response functions of the body.
    explanation: >-
      The WHO expert-group working definition, quoted verbatim, which is what makes
      vitality the domain where hallmark ageing biology enters the construct.
- name: WHO ICOPE Step 1 screening for decline in intrinsic capacity
  definition_type: PHENOTYPE_ALGORITHM
  derivation_basis: ESTABLISHED_CRITERIA
  description: >-
    The ICOPE Step 1 instrument is a short, equipment-free screen applied in primary
    care to adults aged 60 and over, testing six practical sub-domains - locomotion
    (chair rises), cognition (orientation and three-word recall), vitality (recent
    weight and appetite loss), vision, hearing, and depressive symptoms. A positive
    screen triggers Step 2 in-depth assessment rather than a diagnosis; the whole
    point of the instrument is triage into a care pathway.
  scope: >-
    Community-dwelling and primary-care populations aged 60 years and older. Not a
    diagnostic replacement for organ-specific assessment of any single domain.
  validation_status:
    status: VALIDATED_AGAINST_GOLD_STANDARD
    rationale: >-
      Validated against the Step 2 in-depth assessments (MMSE, Mini Nutritional
      Assessment, Short Physical Performance Battery, PHQ-9, clinical vision
      assessment) as the reference standard, and against incident dependence and
      hospitalisation in cohort follow-up. The result is genuinely mixed rather than
      clean: specificity exceeds 70% for every domain except vision, but sensitivity
      falls to 42% for some domains, and a separate structural analysis found the
      cognitive items behaving poorly and the composite adding nothing over the
      individual domains. The instrument is therefore recorded as validated and
      imperfect, not as a settled case definition.
    evidence:
    - reference: PMID:38676323
      reference_title: 'Predictive Capacity of the Integrated Care for Older People Screening Tool for Intrinsic Capacity Impairments: Results From the INSPIRE-T Cohort.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The ICOPE screening items provided very high sensitivity for identifying abnormality in vision (97.2%) and varied from 42.0% to 69.6% for the other domains.
      explanation: >-
        Quantifies the instrument's operating characteristics against the in-depth
        assessment used as reference standard in 603 INSPIRE-T participants.
    - reference: PMID:37960903
      reference_title: 'The icope Intrinsic Capacity Screening Tool: Measurement Structure and Predictive Validity of Dependence and Hospitalization.'
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The cognitive domain of the IST, and probably other of its items, may need a reformulation.
      explanation: >-
        Refutes the stronger reading that the instrument is validated as a whole: in
        the Toledo Study of Healthy Ageing the cognitive items did not behave as the
        model requires and the global composite added nothing over the individual
        domains.
  evidence:
  - reference: PMID:36098317
    reference_title: 'Implementation of the WHO integrated care for older people (ICOPE) programme in clinical practice: a prospective study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals aged ≥60 years were screened (step 1) by health-care providers or through self-assessments using digital tools (the ICOPE MONITOR app and the ICOPEBOT conversational robot).
    explanation: >-
      Describes how the Step 1 screen is actually applied at scale, in the 10 903-person
      Occitania implementation that this definition is drawn from.
has_subtypes:
- name: Locomotor
  display_name: Locomotor capacity decline
  description: >-
    Loss of the capacity to move: reduced muscle strength, slowed gait, and impaired
    balance and chair-rise performance. This is the domain most strongly tied to a
    named disease process, sarcopenia, and the domain that most consistently predicts
    dependence in basic activities of daily living.
  evidence:
  - reference: PMID:29408961
    reference_title: Evidence for the Domains Supporting the Construct of Intrinsic Capacity.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      five domains (i.e., locomotion, vitality, cognition, psychological, sensory) are identified as pivotal for capturing the individual's intrinsic capacity
    explanation: Establishes locomotion as one of the five constituent domains.
- name: Vitality
  display_name: Vitality capacity decline
  description: >-
    Loss of the underlying physiological reserve expressed as energy and metabolism,
    neuromuscular function, and immune and stress-response function. Clinically it
    surfaces as unintentional weight loss, appetite loss, and fatigue. Vitality is
    the domain in which the biology of ageing is most directly measured, and it is
    treated in the WHO framework as underpinning rather than paralleling the others.
  evidence:
  - reference: PMID:36356628
    reference_title: WHO working definition of vitality capacity for healthy longevity monitoring.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Vitality capacity is considered the underlying physiological determinant of intrinsic capacity.
    explanation: >-
      States the special status of vitality among the five domains, which is why this
      subtype is described as underpinning the others.
- name: Cognitive
  display_name: Cognitive capacity decline
  description: >-
    Loss of memory, orientation, and executive function short of dementia. Screened
    by orientation questions and three-word recall; impairment in this domain
    interacts strongly with genetic susceptibility in predicting incident dementia.
  evidence:
  - reference: PMID:38843484
    reference_title: 'Intrinsic Capacity, Polygenic Risk Score, APOE Genotype, and Risk of Dementia: A Prospective Cohort Study Based on the UK Biobank.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compared with participants with an IC score of 0, individuals with an IC score of 4+ had a markedly elevated risk of dementia (hazard ratio [HR] 2.17, 95% CI 1.92-2.45).
    explanation: >-
      Establishes the clinical consequence that distinguishes this domain, in 366 406
      UK Biobank participants.
- name: Psychological
  display_name: Psychological capacity decline
  description: >-
    Loss of mood, motivation, and sociability, screened in ICOPE by depressive-symptom
    questions. It is the domain most readily confounded with primary psychiatric
    disease, and the one most strongly associated with pain.
  evidence:
  - reference: PMID:41360071
    reference_title: 'The association of pain with intrinsic capacity and the moderating role of inflammation in France: a cross-sectional analysis of the INSPIRE-T project.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pain at all intensities, mild (0·512, 0·163, p=0·0017), moderate (1·111, 0·191, p<0·0001), or intense (1·532, 0·263, p<0·0001), was significantly associated with lower scores in the psychological domain.
    explanation: >-
      Shows the psychological domain responding to a graded exposure across the whole
      intensity range, which is not true of the other domains in the same cohort.
- name: Sensory
  display_name: Sensory capacity decline
  description: >-
    Age-related loss of hearing and vision. Structurally the two are separate ageing
    processes in separate organs, and measurement work has found they do not load onto
    a single sensory factor, so the domain is a clinical grouping rather than a single
    mechanism.
  evidence:
  - reference: PMID:37960903
    reference_title: 'The icope Intrinsic Capacity Screening Tool: Measurement Structure and Predictive Validity of Dependence and Hospitalization.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Vision and hearing items did not form a single sensory domain, so six domains were considered.
    explanation: >-
      Directly supports treating hearing and vision as separate measurement axes
      inside one clinical domain.
prevalence:
- population: Community-dwelling adults aged 60 years and older, pooled across 15 studies
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 67800.0
  rate_low: 57000.0
  rate_high: 78500.0
  notes: >-
    Random-effects pooled prevalence of any intrinsic-capacity decline, 33 070
    participants. Converted from 67.8% (95% CI 57.0-78.5%). The figure is high
    because "decline" here means any impaired domain on screening, not a severity
    threshold, and screening cutoffs differ between the pooled studies; it should not
    be read as a prevalence of a discrete disease state.
  evidence:
  - reference: PMID:39088112
    reference_title: 'Prevalence of intrinsic capacity decline among community-dwelling older adults: a systematic review and meta-analysis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pooled prevalence of IC decline in community settings was 67.8% (95% CI: 57.0-78.5%; P < 0.001).
    explanation: The pooled community estimate this record reports.
- population: Primary-care users aged 60 years and older, Occitania region, France (ICOPE Step 1 screening)
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 94300.0
  notes: >-
    Positive Step 1 screen in a real-world implementation of 10 903 people. Even
    higher than the pooled community figure, which is informative about the
    instrument rather than the population: a screen designed for sensitivity in a
    self-selected primary-care sample calls almost everyone positive, and only 9.3%
    went on to Step 2.
  evidence:
  - reference: PMID:36098317
    reference_title: 'Implementation of the WHO integrated care for older people (ICOPE) programme in clinical practice: a prospective study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      10 285 (94·3%) participants had a positive intrinsic capacity result during screening at baseline.
    explanation: The screening-positive proportion this record reports.
progression:
- phase: Heterogeneous multi-domain trajectories rather than one uniform slope
  notes: >-
    The clinically useful fact about progression here is that there is no single
    course. Group-based multi-trajectory modelling over four years separates
    distinct patterns - decline in all domains, isolated locomotor decline, isolated
    psychological decline, and two largely preserved patterns - which is why a single
    composite score can hide the thing that matters for care planning.
  evidence:
  - reference: PMID:37620614
    reference_title: Association between aging-related biomarkers and longitudinal trajectories of intrinsic capacity in older adults.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five IC multi-trajectory groups were determined: low in all domains (8.4%), low locomotion (24.6%), low psychological domain (16.7%), robust (i.e., high in all domains except vitality; 28.3%), and robust with high vitality (22.0%).
    explanation: >-
      Names and quantifies the distinct trajectory groups in 1271 MAPT participants
      followed for four years.
  - reference: PMID:38029399
    reference_title: 'Multi-Trajectories of Intrinsic Capacity Decline and Their Impact on Age-Related Outcomes: A 20-Year National Longitudinal Cohort Study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified four subtypes of IC decline: robust with mild decline (n=902), hearing loss with cognitive decline (n=197), physio-cognitive decline (PCD) with depression (n=373), and severe IC decline (n=310).
    explanation: >-
      Independent replication of the multi-trajectory finding in 1782 Taiwanese
      participants, and it recovers different groupings from the MAPT analysis - which
      is why this section reports that trajectories are heterogeneous rather than
      naming a canonical set.
  - reference: PMID:38029399
    reference_title: 'Multi-Trajectories of Intrinsic Capacity Decline and Their Impact on Age-Related Outcomes: A 20-Year National Longitudinal Cohort Study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals in the severe IC decline group faced a substantially increased risk of all outcomes of interest.
    explanation: >-
      Shows the trajectories carry different outcome risks, so the grouping is
      prognostically meaningful rather than descriptive.
  - reference: PMID:37517058
    reference_title: 'Exploring the natural history of intrinsic capacity impairments: longitudinal patterns in the 10/66 study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 61% of the participants worsened over time, 35% were stable, and 3% improved to a healthier status.
    explanation: >-
      Quantifies the direction of movement between capacity states in 14 923
      participants across eight middle-income countries, including the small but
      non-zero fraction who improve.
- phase: Progression to loss of activities of daily living and care dependence
  notes: >-
    Intrinsic capacity predicts subsequent dependence, and does so more strongly than
    multimorbidity does - which is the empirical claim that justifies treating
    capacity rather than disease count as the target of care in this population.
  evidence:
  - reference: PMID:31678933
    reference_title: The structure and predictive value of intrinsic capacity in a longitudinal study of ageing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More of the indirect effect of personal characteristics on incident loss of ADLs and IADLs was mediated by intrinsic capacity than multimorbidity.
    explanation: >-
      Establishes both the progression to dependence and its precedence over
      multimorbidity as a mediator.
  - reference: PMID:38945130
    reference_title: 'Association of intrinsic capacity with functional decline and mortality in older adults: a systematic review and meta-analysis of longitudinal studies.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intrinsic capacity is inversely associated with functional decline and mortality risk in older adults.
    explanation: >-
      The pooled conclusion of 37 longitudinal studies and 206 693 participants, which
      is the broadest evidence that capacity loss progresses to dependence and death.
- phase: Prediction of dementia and death, above what frailty measures capture
  notes: >-
    The reason to measure capacity rather than count deficits is that it predicts the
    hard outcomes at least as well and adds information beyond frailty instruments
    built on the same underlying tests. Two independent cohorts show this over a
    decade or more.
  evidence:
  - reference: PMID:41086232
    reference_title: Intrinsic Capacity Predictors of Dementia and Mortality in the Sydney Memory and Ageing Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IC was associated with lower hazard (risk) of dementia (HR = 0.567, p < 0.001) over 10-year and lower hazard of mortality (HR = 0.649, p < 0.001) over 12-year, controlling for age, sex, and education.
    explanation: >-
      Gives the long-horizon effect sizes for both outcomes in an Australian cohort
      that also replicates the five-factor structure this entry's subtypes encode.
  - reference: PMID:41086232
    reference_title: Intrinsic Capacity Predictors of Dementia and Mortality in the Sydney Memory and Ageing Study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Finally, IC explained additional variance beyond the Frailty Phenotype when predicting both incident dementia and mortality risk.
    explanation: >-
      The specific claim that capacity is not redundant with frailty, which is the
      justification for curating this entry separately from frailty.
  - reference: PMID:37517058
    reference_title: 'Exploring the natural history of intrinsic capacity impairments: longitudinal patterns in the 10/66 study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Participants with deteriorated IC had a significantly higher risk of frailty, disability and dementia than people with high IC.
    explanation: >-
      Establishes the same ordering - capacity loss precedes frailty, disability and
      dementia - in a low- and middle-income-country cohort rather than a
      high-income one.
- phase: Secular improvement across birth cohorts
  notes: >-
    Recorded because it cuts against the natural reading of the rest of this section.
    The trajectory of an individual is downward, but successive birth cohorts enter
    old age with more capacity and lose it more slowly, so population-level burden is
    not simply a function of chronological ageing.
  evidence:
  - reference: PMID:39702725
    reference_title: Cohort trends in intrinsic capacity in England and China.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we found that more recent cohorts entered older ages with higher levels of capacity, while subsequent age-related declines were somewhat compressed compared to earlier cohorts.
    explanation: >-
      Establishes the cohort effect in two independent national ageing cohorts
      (ELSA and CHARLS).
clinical_burden:
  burden_level: HIGH
  rationale: >-
    The burden is high not because any one domain is severe but because the composite
    predicts the outcomes that matter most: pooled across 37 longitudinal studies and
    206 693 participants, lower intrinsic capacity is inversely associated with both
    functional decline and mortality, and the relationship is graded across the whole
    range rather than confined to a severely impaired tail. The condition is also close to universal in the
    population it is defined for, with more than two-thirds of community-dwelling
    older adults screening positive, so even a modest per-person effect aggregates
    into a large population burden. Against that, it is the one geriatric burden with
    a demonstrated intervention response, which is why it is a target rather than
    merely a prognostic marker.
  evidence:
  - reference: PMID:38945130
    reference_title: 'Association of intrinsic capacity with functional decline and mortality in older adults: a systematic review and meta-analysis of longitudinal studies.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intrinsic capacity is inversely associated with functional decline and mortality risk in older adults.
    explanation: >-
      The pooled association with both functional decline and mortality that underlies
      the HIGH assessment.
  - reference: PMID:38945130
    reference_title: 'Association of intrinsic capacity with functional decline and mortality in older adults: a systematic review and meta-analysis of longitudinal studies.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We included 37 studies (206 693 participants; average age range 65·3-85·9 years) in the systematic review
    explanation: >-
      Establishes the scale of the pooled evidence quoted in the rationale.
  - reference: PMID:35963450
    reference_title: 'Intrinsic capacity and 10-year mortality: Findings from a cohort of older people.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IC is associated with mortality in a dose-response fashion.
    explanation: >-
      Supports the graded rather than threshold character of the burden, in a 10-year
      cohort of 2032 people aged 70 and over.
  - reference: PMID:37434422
    reference_title: 'Association of intrinsic capacity with incidence and mortality of cardiovascular disease: Prospective study in UK Biobank.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IC deficit score is a powerful predictor of functional trajectories and vulnerabilities of the individual in relation to CVD incidence and premature death.
    explanation: >-
      Extends the burden beyond function and all-cause death to incident
      cardiovascular disease in 443 130 participants.
  - reference: PMID:40927083
    reference_title: Impact of Intrinsic Capacity on 5-year Mortality of Older Patients With Cardiovascular Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 86 patients (16.5%) experienced all-cause mortality over the 5-year follow-up period.
    explanation: >-
      Shows the burden is not confined to community populations: it is measurable in
      an already-sick hospital cardiology cohort over five years.
  - reference: PMID:37886051
    reference_title: 'Associations of intrinsic capacity, fall risk and frailty in old inpatients.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Declined IC composite scores were associated with increased risks of falls [odds ratio (OR) = 0.64, 95% confidence interval (CI): 0.57-0.72] and frailty (OR = 0.45, 95%CI: 0.37-0.54) among older hospitalized patients after adjusting for the related potential confounders.
    explanation: >-
      Adds falls to the burden picture in 703 inpatients aged 75 and over, which is
      the proximate harm most likely to trigger the next admission.
pathophysiology:
- name: Accumulation of Hallmark Ageing Damage
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: cellular_senescence#Senescence-Inducing Stress
  description: >-
    The upstream lesion is not a single defect but the parallel accumulation of the
    twelve hallmarks of ageing - genomic instability, telomere attrition, epigenetic
    drift, loss of proteostasis, disabled macroautophagy, deregulated nutrient
    sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion,
    altered intercellular communication, chronic inflammation, and dysbiosis. This
    node stands for that accumulating damage load; the individual hallmarks are
    modelled in their own modules rather than restated here.
  biological_processes:
  - preferred_term: DNA damage response
    term:
      id: GO:0006974
      label: DNA damage response
    modifier: INCREASED
  evidence:
  - reference: PMID:36599349
    reference_title: 'Hallmarks of aging: An expanding universe.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      We propose the following twelve hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis.
    explanation: >-
      Enumerates the damage set this node stands for. Evidence source is OTHER
      because this is a synthesis review.
  - reference: PMID:23746838
    reference_title: The hallmarks of aging.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death.
    explanation: >-
      States the loss-of-integrity framing that connects this molecular node to the
      organism-level reserve loss downstream.
  downstream:
  - target: Mitochondrial Bioenergetic Decline
    causal_link_type: DIRECT
  - target: Senescent Cell Accumulation in Ageing Tissue
    causal_link_type: DIRECT
  - target: Decline in Tissue Regenerative Reserve
    causal_link_type: DIRECT
- name: Mitochondrial Bioenergetic Decline
  biological_scale: CELLULAR
  role: effector
  conforms_to: mitochondrial_dysfunction#Bioenergetic Decline and Oxidative Stress
  description: >-
    Age-associated mitochondrial damage lowers oxidative phosphorylation capacity
    while raising reactive oxygen species output. This is the cellular step closest
    to the vitality domain, which the WHO working definition frames in terms of
    energy and metabolism, and it is one of the two hallmark axes for which human
    plasma markers separate intrinsic-capacity trajectories.
  biological_processes:
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: DECREASED
  - preferred_term: reactive oxygen species metabolic process
    term:
      id: GO:0072593
      label: reactive oxygen species metabolic process
    modifier: INCREASED
  evidence:
  - reference: PMID:37620614
    reference_title: Association between aging-related biomarkers and longitudinal trajectories of intrinsic capacity in older adults.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings found that plasma biomarkers reflecting inflammation and mitochondrial impairment distinguished older people with multi-impaired IC trajectories from those with high-stable IC.
    explanation: >-
      Links mitochondrial impairment to measured intrinsic-capacity trajectories in
      humans. Marked INDIRECT because the measurement is a circulating surrogate
      (GDF-15) rather than mitochondrial function itself.
  - reference: PMID:41113460
    reference_title: 'Mitochondrial dysfunction in age-related sarcopenia: mechanistic insights, diagnostic advances, and therapeutic prospects.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mitochondrial dysfunction plays a central role, characterized by impaired biogenesis, excessive reactive oxygen species (ROS) production, compromised autophagy/mitophagy, and accumulation of mitochondrial DNA (mtDNA) mutations.
    explanation: >-
      Specifies the mitochondrial defects this node stands for, in the tissue where
      they reach a measured capacity domain.
  - reference: PMID:38396729
    reference_title: Mitochondrial Quantity and Quality in Age-Related Sarcopenia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mitochondrial dysfunction has been indicated as a key contributor to skeletal myocyte decline and loss of physical performance with aging.
    explanation: >-
      Independent review naming loss of physical performance - the measured content of
      the locomotor domain - as the downstream consequence of this node.
  downstream:
  - target: Chronic Low-Grade Sterile Inflammation
    causal_link_type: DIRECT
  - target: Loss of Physiological Reserve Across Organ Systems
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Senescent Cell Accumulation in Ageing Tissue
  biological_scale: CELLULAR
  role: effector
  conforms_to: cellular_senescence#Senescent Cell Accumulation
  description: >-
    Cells that have entered senescence are cleared less efficiently with age and
    accumulate in tissue, where their secretory phenotype sustains local and systemic
    inflammation. This is the principal cellular source feeding the inflammaging node.
  biological_processes:
  - preferred_term: cellular senescence
    term:
      id: GO:0090398
      label: cellular senescence
    modifier: INCREASED
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:36599349
    reference_title: 'Hallmarks of aging: An expanding universe.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Aging is driven by hallmarks fulfilling the following three premises: (1) their age-associated manifestation, (2) the acceleration of aging by experimentally accentuating them, and (3) the opportunity to decelerate, stop, or reverse aging by therapeutic interventions on them.
    explanation: >-
      Supplies the criterion under which cellular senescence counts as a driver of
      ageing rather than a correlate, which is what licenses this node as causal.
  downstream:
  - target: Chronic Low-Grade Sterile Inflammation
    causal_link_type: DIRECT
- name: Chronic Low-Grade Sterile Inflammation
  biological_scale: ORGANISM
  role: amplifier
  conforms_to: inflammaging#Chronic Low-Grade Sterile Inflammation
  description: >-
    Persistent, low-grade systemic inflammation without overt infection - inflammaging.
    In this entry it is the hallmark axis with the most direct human evidence against
    measured intrinsic capacity: circulating IL-6 and TNF receptor-1 both raise the
    risk of belonging to the worst multi-domain capacity trajectory.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  - preferred_term: cytokine production
    term:
      id: GO:0001816
      label: cytokine production
    modifier: INCREASED
  cell_types:
  - preferred_term: leukocyte
    term:
      id: CL:0000738
      label: leukocyte
  evidence:
  - reference: PMID:37620614
    reference_title: Association between aging-related biomarkers and longitudinal trajectories of intrinsic capacity in older adults.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Higher IL-6 and GDF-15 also increased the risk of being in the "low locomotion" group.
    explanation: >-
      Ties the inflammatory axis specifically to a domain-level capacity trajectory
      rather than to a global score alone.
  - reference: PMID:38145874
    reference_title: 'From biological aging to functional decline: Insights into chronic inflammation and intrinsic capacity.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Chronic inflammation, a mechanism of aging, is associated with decreased intrinsic capacity, which may mirror the broader relationship between aging and functional ability.
    explanation: >-
      The one review written specifically about this node's link to intrinsic
      capacity, rather than about inflammaging in general.
  downstream:
  - target: Loss of Physiological Reserve Across Organ Systems
    causal_link_type: DIRECT
- name: Decline in Tissue Regenerative Reserve
  biological_scale: TISSUE
  role: effector
  conforms_to: stem_cell_exhaustion#Decline in Stem Cell Self-Renewal and Function
  description: >-
    Loss of tissue-specific stem cell number and function erodes the capacity to
    repair after everyday injury. This is the arm of the cascade that converts
    accumulated damage into a falling ceiling on recovery, and it is the reason
    capacity loss compounds after acute insults such as hospitalisation.
  biological_processes:
  - preferred_term: stem cell population maintenance
    term:
      id: GO:0019827
      label: stem cell population maintenance
    modifier: DECREASED
  - preferred_term: tissue regeneration
    term:
      id: GO:0042246
      label: tissue regeneration
    modifier: DECREASED
  cell_types:
  - preferred_term: stem cell
    term:
      id: CL:0000034
      label: stem cell
  evidence:
  - reference: PMID:23746838
    reference_title: The hallmarks of aging.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication.
    explanation: >-
      Establishes stem cell exhaustion as one of the canonical hallmarks this node
      instantiates.
  downstream:
  - target: Loss of Physiological Reserve Across Organ Systems
    causal_link_type: DIRECT
- name: Loss of Physiological Reserve Across Organ Systems
  biological_scale: ORGANISM
  role: central_effector
  description: >-
    The convergence point of the entry. Reserve is the margin by which an organ
    system's capacity exceeds the demand placed on it; when repeated repair after
    everyday injury leaves progressive tissue degeneration, that margin narrows
    across systems simultaneously. This is where the entry's own content begins:
    everything upstream is generic ageing biology, and everything downstream is
    measured as intrinsic capacity.
  evidence:
  - reference: PMID:34883201
    reference_title: A gerophysiology perspective on healthy ageing.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      While robustness is associated with homeostasis achieved by an optimal structure/function relationship in all organs, successive repair processes occurring after daily injuries and infections result in accumulation of scar healing leading to progressive tissue degeneration, allostasis and frailty.
    explanation: >-
      States the whole-organism reserve-erosion model this node encodes, and is the
      review that explicitly joins the geroscience hallmarks to the WHO intrinsic
      capacity framework.
  downstream:
  - target: Locomotor Capacity Decline
    causal_link_type: DIRECT
  - target: Vitality Capacity Decline
    causal_link_type: DIRECT
  - target: Cognitive Capacity Decline
    causal_link_type: DIRECT
  - target: Psychological Capacity Decline
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Sensory Capacity Decline
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Vitality Capacity Decline
  biological_scale: ORGANISM
  role: effector
  subtypes:
  - Vitality
  description: >-
    Loss of the energy, metabolic, neuromuscular, and immune-stress-response capacity
    that the WHO working definition identifies as the physiological determinant of
    intrinsic capacity. Clinically it appears as the anorexia of ageing, unintentional
    weight loss, and fatigue. It is placed upstream of the locomotor domain here
    because both the WHO working definition and a subsequent framework analysis treat
    it as the highest-order, energy-dependent domain on which the others rest. That
    ordering is argued from physiology rather than demonstrated by intervention.
  locations:
  - preferred_term: Whole organism (energy metabolism, neuromuscular and immune systems)
  evidence:
  - reference: PMID:36356628
    reference_title: WHO working definition of vitality capacity for healthy longevity monitoring.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Vitality capacity is considered the underlying physiological determinant of intrinsic capacity.
    explanation: Supports both the content of the node and its upstream placement.
  - reference: PMID:40060276
    reference_title: The Biological Rationale for Integrating Intrinsic Capacity Into Frailty Models.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The vitality domain or energy metabolism-related capacity, is the highest order dimension and the basis of other intrinsic capacity domains.
    explanation: >-
      Directly supports placing this node upstream of the other four domains, which is
      the entry's one non-obvious ordering decision.
  - reference: PMID:40060276
    reference_title: The Biological Rationale for Integrating Intrinsic Capacity Into Frailty Models.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Vitality vulnerability manifests as a pre-frailty status in function-centered healthy aging.
    explanation: >-
      Places loss of this domain at the pre-frailty stage, which is where the
      intervention evidence in this entry is concentrated.
  - reference: PMID:26195100
    reference_title: Anorexia of Aging.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The anorexia of aging is common, leading to adverse health consequences.
    explanation: >-
      Supports the principal clinical expression of this node, which is what ICOPE
      Step 1 screens for in the vitality items.
  downstream:
  - target: Locomotor Capacity Decline
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Composite Intrinsic Capacity Decline
    causal_link_type: DIRECT
- name: Locomotor Capacity Decline
  biological_scale: ORGANISM
  role: effector
  subtypes:
  - Locomotor
  description: >-
    Loss of muscle strength, gait speed, and balance, whose principal tissue substrate
    is sarcopenia - a muscle disease in its own right, accruing across the lifespan
    and defined by low muscle strength with confirmatory low muscle quantity. This is
    the domain that most consistently predicts dependence in basic activities of
    daily living.
  biological_processes:
  - preferred_term: skeletal muscle atrophy
    term:
      id: GO:0014732
      label: skeletal muscle atrophy
    modifier: INCREASED
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  locations:
  - preferred_term: Skeletal muscle
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  evidence:
  - reference: PMID:30312372
    reference_title: 'Sarcopenia: revised European consensus on definition and diagnosis.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      sarcopenia is a muscle disease (muscle failure) rooted in adverse muscle changes that accrue across a lifetime; sarcopenia is common among adults of older age but can also occur earlier in life
    explanation: >-
      Establishes the tissue-level process underlying this domain and its lifelong
      accrual, which is why locomotor decline is detectable well before old age.
  downstream:
  - target: Composite Intrinsic Capacity Decline
    causal_link_type: DIRECT
- name: Cognitive Capacity Decline
  biological_scale: ORGANISM
  role: effector
  subtypes:
  - Cognitive
  description: >-
    Loss of memory, orientation, and executive function short of dementia. The domain
    is continuous with, but not the same as, incident dementia: capacity deficits
    raise dementia risk about twofold on their own and multiplicatively in
    combination with high polygenic risk.
  biological_processes:
  - preferred_term: cognition
    term:
      id: GO:0050890
      label: cognition
    modifier: DECREASED
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: Brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:38843484
    reference_title: 'Intrinsic Capacity, Polygenic Risk Score, APOE Genotype, and Risk of Dementia: A Prospective Cohort Study Based on the UK Biobank.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the joint analysis, for participants with a high polygenic risk score (PRS) and an IC score of 4 or more, the HR of all-cause dementia was 8.11 (95% CI 6.28-10.47) compared with individuals with a low PRS and an IC score of 0.
    explanation: >-
      Quantifies the joint effect of capacity deficit and genetic susceptibility,
      which is the strongest evidence that this domain is not merely prodromal
      dementia relabelled.
  downstream:
  - target: Composite Intrinsic Capacity Decline
    causal_link_type: DIRECT
- name: Psychological Capacity Decline
  biological_scale: ORGANISM
  role: effector
  subtypes:
  - Psychological
  description: >-
    Loss of mood, motivation, and sociability. In the INSPIRE-T cohort it is the
    domain that responds across the whole range of pain intensity, including mild
    pain, whereas the other domains respond only from moderate intensity upward -
    making it the most sensitive domain to a treatable exposure.
  evidence:
  - reference: PMID:41360071
    reference_title: 'The association of pain with intrinsic capacity and the moderating role of inflammation in France: a cross-sectional analysis of the INSPIRE-T project.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pain was associated with reduced intrinsic capacity, with no evidence of a moderating role of iAge in this association.
    explanation: >-
      Supports the node and, in its negative half, records that the inflammatory-age
      clock did not moderate the association - relevant because the entry's upstream
      chain runs through inflammation.
  downstream:
  - target: Composite Intrinsic Capacity Decline
    causal_link_type: DIRECT
- name: Sensory Capacity Decline
  biological_scale: ORGANISM
  role: effector
  subtypes:
  - Sensory
  description: >-
    Age-related hearing and vision loss. Measurement work finds the two do not form a
    single factor, so this node bundles two anatomically separate ageing processes
    that happen to be screened together. Its edge to the cognitive domain reflects the
    widely reported sensory-cognitive coupling and is marked INDIRECT because the one
    randomised test of that link was null overall.
  locations:
  - preferred_term: Inner ear
    term:
      id: UBERON:0001846
      label: internal ear
  - preferred_term: Eye
    term:
      id: UBERON:0000970
      label: eye
  evidence:
  - reference: PMID:37960903
    reference_title: 'The icope Intrinsic Capacity Screening Tool: Measurement Structure and Predictive Validity of Dependence and Hospitalization.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Vision and hearing items did not form a single sensory domain, so six domains were considered.
    explanation: >-
      Supports modelling this node as a bundle rather than a single mechanism.
  downstream:
  - target: Cognitive Capacity Decline
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Composite Intrinsic Capacity Decline
    causal_link_type: DIRECT
- name: Composite Intrinsic Capacity Decline
  biological_scale: ORGANISM
  role: consequence
  description: >-
    The measured construct itself: a general capacity factor over the five domains.
    Modelling it as a node rather than as a mere sum matters because the general
    factor carries predictive information the individual domains do not, and because
    it is the level at which interventions and the ICD-11 code are defined.
  evidence:
  - reference: PMID:31678933
    reference_title: The structure and predictive value of intrinsic capacity in a longitudinal study of ageing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The summary score of intrinsic capacity and specific subfactors showed good construct validity.
    explanation: >-
      Supports treating the composite as a coherent measured entity rather than an
      arithmetic convenience.
  downstream:
  - target: Loss of Functional Ability and Care Dependence
    causal_link_type: DIRECT
- name: Loss of Functional Ability and Care Dependence
  biological_scale: ORGANISM
  role: consequence
  description: >-
    The terminal state of the chain: inability to carry out the activities that
    matter, and eventual dependence on others. In the WHO model this is functional
    ability, which is intrinsic capacity as modified by environment - so the
    environment can widen or narrow the gap between the two, and this node is the only
    one in the entry whose value is not a property of the individual alone.
  evidence:
  - reference: PMID:31678933
    reference_title: The structure and predictive value of intrinsic capacity in a longitudinal study of ageing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The WHO construct of intrinsic capacity appears to provide valuable predictive information on an individual's subsequent functioning, even after accounting for the number of multimorbidities.
    explanation: >-
      Supports the edge from measured capacity to subsequent functioning, adjusted
      for the obvious confounder.
  - reference: PMID:34571043
    reference_title: 'Associations Between Intrinsic Capacity and Adverse Events Among Nursing Home Residents: The INCUR Study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results contribute to preliminary evidence linking greater IC levels and lower risk of late-life adverse outcomes.
    explanation: >-
      Extends the same relationship into the nursing-home setting, where the
      construct had barely been tested.
phenotypes:
- category: Locomotor
  name: Muscle weakness
  subtype: Locomotor
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Reduced muscle strength on chair-rise testing
    term:
      id: HP:0001324
      label: Muscle weakness
    clinical_course: PROGRESSIVE
  description: >-
    Reduced strength, screened in ICOPE by the ability to rise from a chair five
    times without using the arms. Low muscle strength is the defining feature of
    sarcopenia in the EWGSOP2 consensus, which makes this the phenotype where the
    locomotor domain touches a named disease.
  evidence:
  - reference: PMID:35395736
    reference_title: 'Intrinsic capacity of older people in the community using WHO Integrated Care for Older People (ICOPE) framework: a cross-sectional study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The percentage of impairment in locomotion (117, 39.8%), cognition (75, 25.5%), psychological well-being (34, 11.6%), vision (75, 24.7%), hearing capacity (82, 27.9%), and vitality (8, 2.7%).
    explanation: >-
      Gives the domain-wise impairment frequencies used across this phenotype section;
      locomotion at 39.8% places this phenotype in the FREQUENT band.
  - reference: PMID:37960903
    reference_title: 'The icope Intrinsic Capacity Screening Tool: Measurement Structure and Predictive Validity of Dependence and Hospitalization.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The least preserved indicators were ability to recall three words (18%) and to perform chair stands (54%).
    explanation: >-
      Identifies chair-rise failure as one of the two least preserved screening
      indicators in the Toledo cohort, which is the operational form of this phenotype.
  - reference: PMID:30312372
    reference_title: 'Sarcopenia: revised European consensus on definition and diagnosis.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      focuses on low muscle strength as a key characteristic of sarcopenia
    explanation: >-
      Anchors the phenotype to the consensus definition of the muscle disease that
      underlies it.
- category: Locomotor
  name: Impaired gait and balance
  subtype: Locomotor
  phenotype_term:
    preferred_term: Slowed gait and impaired balance
    term:
      id: HP:0001288
      label: Gait disturbance
    clinical_course: PROGRESSIVE
  description: >-
    Slowed walking speed and impaired balance, assessed in the ICOPE pathway by gait
    speed and by the Short Physical Performance Battery at Step 2. Frequency is not
    recorded separately from the locomotor domain as a whole.
  evidence:
  - reference: PMID:38676323
    reference_title: 'Predictive Capacity of the Integrated Care for Older People Screening Tool for Intrinsic Capacity Impairments: Results From the INSPIRE-T Cohort.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Responses at screening were compared to results of the subsequent in-depth assessment (ie, Mini-Mental State Examination, Mini Nutritional Assessment, Short Physical Performance Battery, Patient Health Questionnaire-9, and clinical investigation of vision problems)
    explanation: >-
      Establishes the Short Physical Performance Battery - a timed gait, balance and
      chair-rise composite - as the reference measure for the locomotion domain.
- category: Cognitive
  name: Memory impairment
  subtype: Cognitive
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Failure of three-word recall
    term:
      id: HP:0002354
      label: Memory impairment
  description: >-
    Short-term recall failure, screened by three-word recall. In the Toledo cohort
    this was the single least preserved of all ICOPE screening indicators.
  evidence:
  - reference: PMID:37960903
    reference_title: 'The icope Intrinsic Capacity Screening Tool: Measurement Structure and Predictive Validity of Dependence and Hospitalization.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The least preserved indicators were ability to recall three words (18%) and to perform chair stands (54%).
    explanation: >-
      Only 18% of participants preserved three-word recall, making this the most
      commonly impaired screening indicator.
  - reference: PMID:35395736
    reference_title: 'Intrinsic capacity of older people in the community using WHO Integrated Care for Older People (ICOPE) framework: a cross-sectional study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The percentage of impairment in locomotion (117, 39.8%), cognition (75, 25.5%), psychological well-being (34, 11.6%), vision (75, 24.7%), hearing capacity (82, 27.9%), and vitality (8, 2.7%).
    explanation: >-
      Cognitive-domain impairment at 25.5% on full assessment places this phenotype in
      the OCCASIONAL band.
- category: Cognitive
  name: Cognitive impairment
  subtype: Cognitive
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Cognitive impairment short of dementia
    term:
      id: HP:0100543
      label: Cognitive impairment
  description: >-
    Impairment of orientation and executive function below the threshold for
    dementia. Distinguished from dementia deliberately: the ICOPE pathway screens
    this domain in order to intervene before a dementia diagnosis is reachable.
  evidence:
  - reference: PMID:38843484
    reference_title: 'Intrinsic Capacity, Polygenic Risk Score, APOE Genotype, and Risk of Dementia: A Prospective Cohort Study Based on the UK Biobank.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compared with participants with an IC score of 0, individuals with an IC score of 4+ had a markedly elevated risk of dementia (hazard ratio [HR] 2.17, 95% CI 1.92-2.45).
    explanation: >-
      Shows the phenotype is prognostically distinct from dementia rather than an
      early label for it, since it predicts incident dementia in people who did not
      have it at baseline.
- category: Vitality
  name: Malnutrition
  subtype: Vitality
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Malnutrition on Mini Nutritional Assessment
    term:
      id: HP:0004395
      label: Malnutrition
  description: >-
    Impaired nutritional status on the Mini Nutritional Assessment used at ICOPE Step
    2. The very low measured frequency is worth flagging: it comes from a
    community-centre sample in Hong Kong, and vitality is the domain whose measured
    prevalence varies most between instruments, so this frequency should not be
    generalised.
  evidence:
  - reference: PMID:35395736
    reference_title: 'Intrinsic capacity of older people in the community using WHO Integrated Care for Older People (ICOPE) framework: a cross-sectional study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The percentage of impairment in locomotion (117, 39.8%), cognition (75, 25.5%), psychological well-being (34, 11.6%), vision (75, 24.7%), hearing capacity (82, 27.9%), and vitality (8, 2.7%).
    explanation: >-
      Vitality-domain impairment at 2.7% in this community sample is the source of the
      VERY_RARE band recorded here.
- category: Vitality
  name: Unintentional weight loss and appetite loss
  subtype: Vitality
  phenotype_term:
    preferred_term: Unintentional weight loss
    term:
      id: HP:0001824
      label: Weight loss
  description: >-
    Recent unintentional weight loss and loss of appetite - the anorexia of ageing -
    which are the two questions the ICOPE Step 1 screen uses for the vitality domain.
    No approved pharmacological treatment exists.
  evidence:
  - reference: PMID:26195100
    reference_title: Anorexia of Aging.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The anorexia of aging is common, leading to adverse health consequences.
    explanation: >-
      Supports the phenotype and its consequences. Evidence source is OTHER because
      this is a narrative clinical review.
  - reference: PMID:26195100
    reference_title: Anorexia of Aging.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      There are currently no approved pharmacologic treatment strategies to prevent or treat the anorexia of aging.
    explanation: >-
      Records the therapeutic vacuum for this phenotype, which is why the treatments
      section carries no pharmacological entry for the vitality domain.
- category: Psychological
  name: Depressive symptoms
  subtype: Psychological
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Depressive symptoms on geriatric depression screening
    term:
      id: HP:0000716
      label: Depression
  description: >-
    Low mood and loss of interest, screened by geriatric depression items at Step 1
    and by the PHQ-9 at Step 2. The phenotype is the ICOPE psychological domain, not
    a diagnosis of major depressive disorder, which remains a differential.
  evidence:
  - reference: PMID:35395736
    reference_title: 'Intrinsic capacity of older people in the community using WHO Integrated Care for Older People (ICOPE) framework: a cross-sectional study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The percentage of impairment in locomotion (117, 39.8%), cognition (75, 25.5%), psychological well-being (34, 11.6%), vision (75, 24.7%), hearing capacity (82, 27.9%), and vitality (8, 2.7%).
    explanation: >-
      Psychological-domain impairment at 11.6% places this phenotype in the
      OCCASIONAL band.
- category: Sensory
  name: Hearing impairment
  subtype: Sensory
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Age-related hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
    clinical_course: PROGRESSIVE
  description: >-
    Age-related hearing loss, screened by a whisper test or self-report. It is
    associated with faster cognitive decline observationally, but correcting it did
    not slow cognitive decline in the one randomised test - see the treatments
    section.
  evidence:
  - reference: PMID:35395736
    reference_title: 'Intrinsic capacity of older people in the community using WHO Integrated Care for Older People (ICOPE) framework: a cross-sectional study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The percentage of impairment in locomotion (117, 39.8%), cognition (75, 25.5%), psychological well-being (34, 11.6%), vision (75, 24.7%), hearing capacity (82, 27.9%), and vitality (8, 2.7%).
    explanation: >-
      Hearing impairment at 27.9% places this phenotype in the OCCASIONAL band.
  - reference: PMID:37478886
    reference_title: 'Hearing intervention versus health education control to reduce cognitive decline in older adults with hearing loss in the USA (ACHIEVE): a multicentre, randomised controlled trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hearing loss is associated with increased cognitive decline and incident dementia in older adults.
    explanation: >-
      States the observational association with the cognitive domain that motivates
      screening for this phenotype.
- category: Sensory
  name: Visual impairment
  subtype: Sensory
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Age-related visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
    clinical_course: PROGRESSIVE
  description: >-
    Reduced vision, screened by self-reported difficulty and near-vision testing. It
    is the domain where the ICOPE screen is most sensitive and least specific, so a
    positive vision screen carries less information than a positive screen in any
    other domain.
  evidence:
  - reference: PMID:35395736
    reference_title: 'Intrinsic capacity of older people in the community using WHO Integrated Care for Older People (ICOPE) framework: a cross-sectional study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The percentage of impairment in locomotion (117, 39.8%), cognition (75, 25.5%), psychological well-being (34, 11.6%), vision (75, 24.7%), hearing capacity (82, 27.9%), and vitality (8, 2.7%).
    explanation: >-
      Vision impairment at 24.7% places this phenotype in the OCCASIONAL band.
  - reference: PMID:38676323
    reference_title: 'Predictive Capacity of the Integrated Care for Older People Screening Tool for Intrinsic Capacity Impairments: Results From the INSPIRE-T Cohort.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      High specificity (>70%) was observed for all the IC domains, except for vision (2.7%).
    explanation: >-
      Quantifies the specificity failure in this domain that the description warns
      about.
biochemical:
- name: Plasma interleukin-6
  presence: Elevated in the worst multi-domain intrinsic-capacity trajectory
  context: Community-dwelling older adults followed for four years in the MAPT trial cohort.
  subtype: Vitality
  notes: >-
    Recorded as a correlate of trajectory group, not as a diagnostic threshold. No
    reference interval is given because none has been established for this use.
  evidence:
  - reference: PMID:37620614
    reference_title: Association between aging-related biomarkers and longitudinal trajectories of intrinsic capacity in older adults.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Higher IL-6 and GDF-15 also increased the risk of being in the "low locomotion" group.
    explanation: >-
      Associates circulating IL-6 with a specific impaired-capacity trajectory in 1271
      participants.
- name: Plasma growth differentiation factor-15 (GDF-15)
  presence: Elevated in the worst multi-domain intrinsic-capacity trajectory
  context: Community-dwelling older adults followed for four years in the MAPT trial cohort.
  subtype: Vitality
  notes: >-
    The strongest of the tested markers against capacity trajectories, and the one
    usually read as reflecting mitochondrial stress rather than inflammation - which
    is why it is the biochemical anchor for the mitochondrial arm of this entry's
    pathophysiology.
  evidence:
  - reference: PMID:37620614
    reference_title: Association between aging-related biomarkers and longitudinal trajectories of intrinsic capacity in older adults.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      GDF-15 outperformed other biomarkers by showing the strongest associations with IC trajectory groups.
    explanation: >-
      Ranks GDF-15 above the inflammatory markers for association with capacity
      trajectories.
- name: C-reactive protein and tumor necrosis factor-alpha
  presence: Reported both elevated and unchanged across studies of intrinsic capacity
  context: Reviewed across the intrinsic-capacity literature rather than measured in one cohort.
  notes: >-
    Included to record a negative: no inflammatory marker currently has the specificity
    and sensitivity to track capacity decline, and results for CRP and TNF-alpha are
    inconsistent between studies and between domains. This is the honest state of
    biomarker development for this entity, and it is why the two markers above are
    recorded as trajectory correlates rather than as a monitoring panel.
  evidence:
  - reference: PMID:38145874
    reference_title: 'From biological aging to functional decline: Insights into chronic inflammation and intrinsic capacity.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Interleukin-6, C-reactive protein, and tumor necrosis factor-alpha may potentially indicate changes in intrinsic capacity, but their results with intrinsic capacity or each intrinsic capacity domain are inconsistent.
    explanation: >-
      Names the candidate markers and states the inconsistency in one sentence.
  - reference: PMID:38145874
    reference_title: 'From biological aging to functional decline: Insights into chronic inflammation and intrinsic capacity.'
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      To date, there is still no inflammatory markers with high specificity and sensitivity to monitor intrinsic capacity decline.
    explanation: >-
      Refutes any reading of the two markers above as clinically usable monitoring
      tests, which is a claim this section could otherwise be taken to make.
genetic:
- name: Polygenic background of intrinsic capacity
  relationship_type: SUSCEPTIBILITY
  association: >-
    Common variation of small individual effect, explaining roughly a fifth to a
    quarter of variance in measured intrinsic capacity.
  notes: >-
    No gene_term is bound because the claim is about the aggregate architecture rather
    than any one locus: the GWAS maps 4289 candidate SNPs to 197 genes and the abstract
    names none of them individually, so naming a lead gene here would be a curatorial
    invention rather than a curatorial reading. Per-gene entries should be added when a
    replicated locus is characterised.
  evidence:
  - reference: PMID:41066301
    reference_title: A genome-wide association study identified 10 novel genomic loci associated with intrinsic capacity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The h2snp for IC was estimated at 25.2% in UKB and 19.5% in CLSA. Our GWAS identified 38 independent SNPs for IC across 10 genomic loci and 4289 candidate SNPs, mapped to 197 genes.
    explanation: >-
      The first GWAS of intrinsic capacity, giving both the heritability estimate and
      the locus count in two independent cohorts (UK Biobank n=44 631, CLSA n=13 085).
  - reference: PMID:41066301
    reference_title: A genome-wide association study identified 10 novel genomic loci associated with intrinsic capacity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Post-GWAS analysis revealed the role of these genes in cellular processes such as cell proliferation, immune function, metabolism, and neurodegeneration, with high expression in muscle, heart, brain, adipose, and nerve tissues.
    explanation: >-
      Worth recording because the tissue enrichment recovers the same organs this
      entry's domain nodes are anchored in, independently of how those nodes were
      chosen.
- name: APOE
  gene_term:
    preferred_term: APOE
    term:
      id: hgnc:613
      label: APOE
  relationship_type: MODIFIER
  association: >-
    Does not cause capacity decline, but multiplies the dementia risk that a given
    level of capacity deficit carries.
  evidence:
  - reference: PMID:38843484
    reference_title: 'Intrinsic Capacity, Polygenic Risk Score, APOE Genotype, and Risk of Dementia: A Prospective Cohort Study Based on the UK Biobank.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the joint analysis, for participants with a high polygenic risk score (PRS) and an IC score of 4 or more, the HR of all-cause dementia was 8.11 (95% CI 6.28-10.47) compared with individuals with a low PRS and an IC score of 0.
    explanation: >-
      Quantifies the joint effect. The hazard is far above the product of either factor
      alone, which is what makes this a modifier rather than an additive risk.
inheritance:
- name: Polygenic inheritance
  inheritance_term:
    preferred_term: Polygenic inheritance
    term:
      id: HP:0010982
      label: Polygenic inheritance
  description: >-
    Intrinsic capacity is a complex trait with many small-effect common variants, not a
    Mendelian condition. SNP-based heritability is about 25% in UK Biobank and about
    20% in the Canadian Longitudinal Study on Aging - substantial, but leaving most of
    the variance to environment, life course, and measurement. There is no carrier
    state, no penetrance, and no consanguinity effect to record.
  evidence:
  - reference: PMID:41066301
    reference_title: A genome-wide association study identified 10 novel genomic loci associated with intrinsic capacity.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, this study provides comprehensive evidence on the genetic architecture of IC, identifying novel genetic variants and biological pathways
    explanation: >-
      Establishes that the trait has a genetic architecture worth recording at all,
      which was open before this study - the paper notes no prior GWAS existed.
environmental:
- name: Ambient and household air pollution
  description: >-
    Exposure to fine particulate matter, household solid-fuel combustion, and
    secondhand smoke. A meta-analysis of 18 studies finds each raises the risk of
    frailty in middle-aged and older adults, with the largest pooled effect for
    secondhand smoke - although that estimate's confidence interval crosses one, so the
    ordering of the three exposures is not established.
  effect: Raises the risk of frailty, the clinical state that capacity loss progresses into
  exposure_term:
    preferred_term: exposure to air pollution
    term:
      id: ECTO:8000036
      label: exposure to air pollution
  notes: >-
    The evidence is against frailty, not against intrinsic capacity. Those are related
    but distinct constructs - this entry's own definitions section says so - and no
    meta-analysis of air pollution against measured intrinsic capacity yet exists. The
    mechanism edge is therefore marked PREDISPOSES with INDIRECT evidence rather than
    asserted as a capacity effect, and it attaches at the reserve node rather than at
    any single domain, because the frailty outcome does not resolve to one.
  influences_mechanisms:
  - target: Loss of Physiological Reserve Across Organ Systems
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Sustained particulate exposure is proposed to erode reserve through systemic
      inflammation and oxidative stress, the same axes this entry's upstream nodes
      already carry.
    evidence:
    - reference: PMID:40391839
      reference_title: A systematic review and meta-analysis of air pollution and increased risk of frailty.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Environmental exposures, including air pollution, the use of unclean household fuels and exposure to secondhand smoke, significantly increase the risk of frailty.
      explanation: >-
        Supports the edge through one inference step: the measured outcome is frailty,
        and this entry models frailty as downstream of reserve loss rather than as the
        same thing.
  evidence:
  - reference: PMID:40391839
    reference_title: A systematic review and meta-analysis of air pollution and increased risk of frailty.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Meta-analyses indicated a 19% increased risk of frailty due to air pollution (fine particulate matter ≤2.5 microns) [n = 9 studies; pooled odds ratio (OR) 1.19; 95% confidence interval (CI) 1.10-1.27], a 28% increase with exposure to household solid fuels (n = 4 studies; OR 1.28; 95% CI 1.16-1.40) and a 59% increase due to exposure to secondhand smoke (n = 3 studies; OR 1.59; 95% CI 0.46-2.72).
    explanation: >-
      Gives the pooled effect sizes for all three exposures. Marked INDIRECT because
      the outcome is frailty rather than measured intrinsic capacity.
- name: Chronic pain
  description: >-
    Self-reported pain over the preceding days, graded by intensity. Across a
    lifespan cohort spanning ages 20 to 102, pain of any intensity was associated
    with lower psychological capacity, and intense pain with lower scores in every
    domain except sensory.
  effect: Lowers measured intrinsic capacity, most consistently in the psychological domain
  notes: >-
    No ECTO or XCO term is bound. Exposure ontologies model pain poorly - it is an
    experience rather than an environmental agent - and binding a stress or
    nociceptive-stimulus term would misstate what was measured, which was
    self-reported pain presence and intensity.
  influences_mechanisms:
  - target: Psychological Capacity Decline
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >-
      Pain lowers psychological-domain scores across the whole intensity range,
      including mild pain, which is not true of any other domain.
    evidence:
    - reference: PMID:41360071
      reference_title: 'The association of pain with intrinsic capacity and the moderating role of inflammation in France: a cross-sectional analysis of the INSPIRE-T project.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Pain at all intensities, mild (0·512, 0·163, p=0·0017), moderate (1·111, 0·191, p<0·0001), or intense (1·532, 0·263, p<0·0001), was significantly associated with lower scores in the psychological domain.
      explanation: >-
        Supports the edge specifically, including the dose-response across intensity
        bands.
  evidence:
  - reference: PMID:41360071
    reference_title: 'The association of pain with intrinsic capacity and the moderating role of inflammation in France: a cross-sectional analysis of the INSPIRE-T project.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both moderate pain (β 0·264, SE 0·076, p=0·0006) and intense pain (0·479, 0·105, p<0·0001) were negatively associated with intrinsic capacity values.
    explanation: >-
      Establishes the entry-level association between pain and the composite capacity
      score in 971 INSPIRE-T participants.
  - reference: PMID:41360071
    reference_title: 'The association of pain with intrinsic capacity and the moderating role of inflammation in France: a cross-sectional analysis of the INSPIRE-T project.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further research is needed to determine whether effective pain management could help prevent declines in intrinsic capacity.
    explanation: >-
      The authors' own statement that the exposure is not yet demonstrated to be
      causally modifiable, which is why this entry is recorded as an exacerbating
      exposure rather than a treatment target.
- name: Acute hospitalisation
  description: >-
    Admission for acute illness, which in older adults is followed by functional and
    cognitive decline independent of the admitting diagnosis. It is included as an
    environmental exposure because it is a discrete, dated, often avoidable event that
    steps intrinsic capacity down, unlike the continuous background of ageing.
  effect: Precipitates a step decline in measured intrinsic capacity
  notes: >-
    No ECTO term is bound. Hospitalisation is a healthcare episode rather than an
    environmental exposure in the ECTO sense, and no suitable term was found.
  influences_mechanisms:
  - target: Composite Intrinsic Capacity Decline
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >-
      The functional and cognitive decline that follows acute admission is a decrement
      in the composite construct rather than in any one domain, which is why the edge
      attaches at the composite node.
    evidence:
    - reference: PMID:40188489
      reference_title: 'Exercise effects on intrinsic capacity in acutely hospitalised older adults: a pooled analysis of two randomised controlled trials.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hospitalisation often results in adverse effects in older adults, particularly an increased risk of functional and cognitive decline.
      explanation: Supports the exposure acting on the composite construct.
  evidence:
  - reference: PMID:40188489
    reference_title: 'Exercise effects on intrinsic capacity in acutely hospitalised older adults: a pooled analysis of two randomised controlled trials.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IC score at discharge was inversely associated with mortality risk during follow-up (OR = 0.98 per each increase in IC score at discharge, 95% CI = 0.96, 0.99, P = .010)
    explanation: >-
      Establishes that capacity measured at the end of this exposure carries prognostic
      weight, in 570 patients of mean age 87.3 years.
treatments:
- name: Multicomponent Physical Activity with Nutritional Counselling
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  description: >-
    Structured moderate-intensity physical activity, delivered twice weekly at a
    centre and up to four times weekly at home with activity-monitor tailoring, plus
    personalised nutritional counselling. In SPRINTT this reduced mobility disability
    over an average 26 months in older adults with physical frailty and sarcopenia -
    the largest randomised demonstration that the locomotor domain is modifiable.
  treatment_term:
    preferred_term: multicomponent physical activity and nutrition programme
    term:
      id: NCIT:C15900
      label: Lifestyle Therapy
  target_mechanisms:
  - target: Locomotor Capacity Decline
    treatment_effect: INHIBITS
    description: >-
      Slows the loss of muscle strength and physical performance that constitutes the
      locomotor domain, and preserves appendicular lean mass.
  evidence:
  - reference: PMID:35545258
    reference_title: 'Multicomponent intervention to prevent mobility disability in frail older adults: randomised controlled trial (SPRINTT project).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among participants with SPPB scores of 3-7, mobility disability occurred in 283/605 (46.8%) assigned to the multicomponent intervention and 316/600 (52.7%) controls (hazard ratio 0.78, 95% confidence interval 0.67 to 0.92; P=0.005).
    explanation: >-
      The primary randomised result in 1205 participants, giving the effect size for
      this treatment on the locomotor domain's principal outcome.
  - reference: PMID:35545258
    reference_title: 'Multicomponent intervention to prevent mobility disability in frail older adults: randomised controlled trial (SPRINTT project).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The between group difference in SPPB score was 0.8 points (95% confidence interval 0.5 to 1.1 points; P<0.001) and 1.0 point (95% confidence interval 0.5 to 1.6 points; P<0.001) in favour of the multicomponent intervention at 24 and 36 months, respectively.
    explanation: >-
      Gives the effect on the continuous physical-performance measure used at ICOPE
      Step 2, which is the measure this entry's locomotor domain is scored on.
  - reference: PMID:36341237
    reference_title: 'Intrinsic capacity rather than intervention exposure influences reversal to robustness among prefrail community-dwelling older adults: A non-randomized controlled study of a multidomain exercise and nutrition intervention.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The differential risk profiles associated with prefrailty may be attributable to underlying intrinsic capacity (IC).
    explanation: >-
      A caution rather than a confirmation: in this non-randomised study baseline
      capacity, not intervention exposure, predicted who reverted to robustness. It is
      recorded here because it bears on who this treatment is expected to help.
- name: In-Hospital Multicomponent Exercise Training
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  description: >-
    A supervised multicomponent exercise programme delivered during acute admission in
    Acute Care for Elders units. It is the clearest demonstration that the composite
    construct itself responds to intervention, and it does so over days rather than
    years, in patients of mean age 87.
  treatment_term:
    preferred_term: in-hospital multicomponent exercise training
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_mechanisms:
  - target: Composite Intrinsic Capacity Decline
    treatment_effect: INHIBITS
    description: >-
      Raises the composite capacity score at discharge, with gains in every domain,
      counteracting the step decline that hospitalisation otherwise produces.
  evidence:
  - reference: PMID:40188489
    reference_title: 'Exercise effects on intrinsic capacity in acutely hospitalised older adults: a pooled analysis of two randomised controlled trials.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The exercise intervention significantly improved IC compared to the control group [7.74 points, 95% confidence interval (CI) 6.45-9.03, P < .001], with benefits observed in all IC domains.
    explanation: >-
      Randomised evidence that the composite score, not merely a single domain, is
      modifiable.
- name: Combined Exercise and Cognitive Stimulation Therapy
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  description: >-
    Six months of exercise with or without three months of added cognitive stimulation
    therapy, in pre-frail older adults attending primary care. Included because it is
    one of the few studies whose outcome is the intrinsic-capacity composite itself
    rather than a single-domain proxy. It is a pre-post intervention study, not a
    randomised trial, so the effect estimate is weaker than SPRINTT's.
  treatment_term:
    preferred_term: combined exercise and cognitive stimulation programme
    term:
      id: NCIT:C15900
      label: Lifestyle Therapy
  target_mechanisms:
  - target: Composite Intrinsic Capacity Decline
    treatment_effect: INHIBITS
    description: >-
      Improves the composite score and the locomotor domain within three months in
      pre-frail participants.
  evidence:
  - reference: PMID:38616369
    reference_title: 'The Impact of Exercise and Cognitive Stimulation Therapy on Intrinsic Capacity Composite Score in Pre-Frail Older Adults: A Pre-Post Intervention Study.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 3 months, both Ex and Ex +CST showed improvement in IC composite scores
    explanation: >-
      Supports the effect on the composite. Marked INDIRECT because the design is
      pre-post with a self-selected control group rather than randomised.
- name: Group-Based Multidomain Intervention with Brain-Structure Outcomes
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  description: >-
    The ENHANCE randomised trial: twelve months of twice-weekly group sessions
    combining physical exercise, cognitive training and nutrition education, against
    quarterly telephone education. It is the one trial here with a structural imaging
    endpoint, so it speaks to whether multidomain intervention reaches the substrate
    of the cognitive domain rather than only its test scores. The trial is small - 88
    completers, 76 with longitudinal MRI - and the groups differed at baseline in age
    and BMI.
  treatment_term:
    preferred_term: group-based multidomain lifestyle intervention
    term:
      id: NCIT:C15900
      label: Lifestyle Therapy
  target_mechanisms:
  - target: Cognitive Capacity Decline
    treatment_effect: INHIBITS
    description: >-
      Slows loss of grey matter volume, the structural correlate of the cognitive
      domain.
  evidence:
  - reference: PMID:40464147
    reference_title: 'Enhancing Neurocognitive Health via Activity, Nutrition and Cognitive Exercise (ENHANCE): A Randomized Controlled Trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ENHANCE trial delivered twice-weekly group-based multidomain sessions (physical exercise, cognitive training and nutrition education) in urban and rural communities for 12 months, while the control group received quarterly telephone education.
    explanation: >-
      Describes the intervention and its comparator, which is what this treatment
      record encodes.
  - reference: PMID:40464147
    reference_title: 'Enhancing Neurocognitive Health via Activity, Nutrition and Cognitive Exercise (ENHANCE): A Randomized Controlled Trial.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The intervention group (n = 44; 75.0% female) was significantly older than the control group (n = 44; 70.5% female) (75.0 ± 6.6 vs. 72.3 ± 5.0 years, p = 0.035) and had lower BMI (23.4 vs. 25.2 kg/m2, p = 0.016) at baseline.
    explanation: >-
      Records the baseline imbalance, which limits how much weight the structural
      result can carry. Marked INDIRECT because it bears on the claim by qualifying it.
- name: Multidomain Lifestyle Intervention for Cognitive Decline
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  description: >-
    Combined dietary guidance, exercise, cognitive training, and vascular risk
    monitoring over two years in at-risk older adults, as tested in FINGER. The effect
    on cognition is real but small, and the trial is included here as the benchmark
    for what multidomain intervention achieves in the cognitive domain rather than as
    a strong recommendation.
  treatment_term:
    preferred_term: multidomain lifestyle intervention
    term:
      id: NCIT:C15900
      label: Lifestyle Therapy
  target_mechanisms:
  - target: Cognitive Capacity Decline
    treatment_effect: INHIBITS
    description: >-
      Slows the rate of cognitive change measured by a comprehensive neuropsychological
      battery.
  evidence:
  - reference: PMID:25771249
    reference_title: 'A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Between-group difference in the change of NTB total score per year was 0·022 (95% CI 0·002-0·042, p=0·030).
    explanation: >-
      The primary randomised result in 1260 participants; the confidence interval
      almost touching zero is why the description calls the effect small.
  - reference: PMID:25771249
    reference_title: 'A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adverse events occurred in 46 (7%) participants in the intervention group compared with six (1%) participants in the control group; the most common adverse event was musculoskeletal pain (32 [5%] individuals for intervention vs no individuals for control).
    explanation: >-
      Records the harm side of the multidomain intervention, which is not zero and is
      concentrated in the exercise component.
- name: ICOPE Integrated Person-Centred Care Pathway
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  description: >-
    The WHO ICOPE care pathway itself, delivered as a service intervention: Step 1
    screening, Step 2 in-depth assessment, a personalised care plan, referral, and
    monitoring, coordinated by integrated care managers. A randomised trial in Beijing
    primary care found it feasible and associated with small improvements in the
    vitality, mobility, and psychological domains at six months.
  treatment_term:
    preferred_term: integrated person-centred care for older people
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Composite Intrinsic Capacity Decline
    treatment_effect: INHIBITS
    description: >-
      Acts on the composite by routing each detected domain impairment to a
      domain-specific intervention, rather than by any single mechanism of its own.
  evidence:
  - reference: PMID:38251736
    reference_title: 'Implementation and impact of the World Health Organization integrated care for older people (ICOPE) program in China: a randomised controlled trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All outcomes showed improvements after a 6-month intervention, while statistically significant least-squares mean differences (control-intervention) in vitality (Mini-Nutritional Assessment Short Form to measure vitality, -0.21, 95% CI, -0.40-0.02), mobility (Short Physical Performance Battery to measure mobility, -0.29, 95% CI, -0.44-0.14) and psychological health (Geriatric Depression Scale five items to measure psychological health, 0.09, 95% CI, 0.03-0.14) were observed (P < 0.05).
    explanation: >-
      The randomised effect of the pathway itself on three of the five domains, in 938
      propensity-matched participants.
- name: Hearing Intervention with Hearing Aid Provision
  action_category: THERAPEUTIC
  therapeutic_modality: DEVICE
  description: >-
    Audiological needs assessment, fitting of hearing devices, and counselling. It
    addresses the sensory domain directly. It does not, on the best available
    randomised evidence, slow cognitive decline in the general population of older
    adults with hearing loss - the ACHIEVE primary result was null - so the
    observational sensory-to-cognitive link is not a basis for prescribing it as a
    cognitive intervention.
  treatment_term:
    preferred_term: hearing device fitting and audiological rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: hearing aid
        term:
          id: NCIT:C183182
          label: Hearing Aid
  target_mechanisms:
  - target: Sensory Capacity Decline
    treatment_effect: RESTORES
    description: >-
      Restores audibility, which is the measured content of the hearing half of the
      sensory domain.
  - target: Cognitive Capacity Decline
    treatment_effect: MODULATES
    description: >-
      Proposed but not demonstrated. The randomised test of this edge was null overall,
      with a benefit confined to a prespecified higher-risk subgroup, so the edge is
      recorded as unresolved rather than as a therapeutic effect.
  evidence:
  - reference: PMID:37478886
    reference_title: 'Hearing intervention versus health education control to reduce cognitive decline in older adults with hearing loss in the USA (ACHIEVE): a multicentre, randomised controlled trial.'
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the primary analysis combining the ARIC and de novo cohorts, 3-year cognitive change (in SD units) was not significantly different between the hearing intervention and health education control groups
    explanation: >-
      Refutes the claim that hearing intervention slows cognitive decline in this
      population; it does not bear on the intervention's effect within the sensory
      domain, which was not the trial's outcome.
  - reference: PMID:37478886
    reference_title: 'Hearing intervention versus health education control to reduce cognitive decline in older adults with hearing loss in the USA (ACHIEVE): a multicentre, randomised controlled trial.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, a prespecified sensitivity analysis showed a significant difference in the effect of the hearing intervention on 3-year cognitive change between the ARIC and de novo cohorts (pinteraction=0·010).
    explanation: >-
      Supports the narrower claim that the effect may exist in a higher-risk subgroup.
      Marked INDIRECT because it is a subgroup interaction, not the trial's answer.
- name: Systematic ICOPE Step 1 Screening in Primary Care
  action_category: SCREENING
  description: >-
    Population screening of adults aged 60 and over with the ICOPE Step 1 instrument,
    by health-care providers or self-assessment through digital tools. Listed as a
    non-therapeutic action: it changes nothing by itself, but it is the entry point to
    everything else in this section, and the feasibility of doing it at scale was the
    open question that the Occitania implementation answered.
  treatment_term:
    preferred_term: screening for decline in intrinsic capacity
    term:
      id: NCIT:C15419
      label: Disease Screening
  evidence:
  - reference: PMID:36098317
    reference_title: 'Implementation of the WHO integrated care for older people (ICOPE) programme in clinical practice: a prospective study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The high number of participants included in our study, as well as the high rates of follow-up, provides evidence to suggest that the large-scale implementation of ICOPE in clinical practice is feasible.
    explanation: >-
      Establishes feasibility at a scale of 10 903 people with 70.4% six-month
      follow-up, which is the claim this action rests on.
  - reference: PMID:36098317
    reference_title: 'Implementation of the WHO integrated care for older people (ICOPE) programme in clinical practice: a prospective study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most recommendations in step 3 (care plan) were related to locomotion, vitality, and cognition.
    explanation: >-
      Records which domains screening actually routes people into care for, which is
      the practical output of the screen.
diagnosis:
- name: WHO ICOPE two-step assessment
  description: >-
    Assessment runs in two steps. Step 1 is the short screen modelled in `definitions`
    and `treatments`; Step 2 is the in-depth assessment applied to whoever screens
    positive, using the reference instruments for each domain - Mini-Mental State
    Examination for cognition, Mini Nutritional Assessment for vitality, Short Physical
    Performance Battery for locomotion, PHQ-9 for the psychological domain, and
    clinical assessment for vision. Step 2 is what "impairment" means in this entry's
    phenotype frequencies; Step 1 alone over-calls, as this entry's prevalence records
    show.
  evidence:
  - reference: PMID:36809987
    reference_title: 'Identification of decreased intrinsic capacity: Performance of diagnostic measures of the ICOPE Screening tool in community dwelling older people in the VIMCI study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      IC assessment proposed by the WHO ICOPE guidelines is composed by two steps: First, Screening for decreased IC by the ICOPE Screening tool; second, by the reference standard methods.
    explanation: >-
      States the two-step structure that this diagnosis record encodes.
  - reference: PMID:38676323
    reference_title: 'Predictive Capacity of the Integrated Care for Older People Screening Tool for Intrinsic Capacity Impairments: Results From the INSPIRE-T Cohort.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Responses at screening were compared to results of the subsequent in-depth assessment (ie, Mini-Mental State Examination, Mini Nutritional Assessment, Short Physical Performance Battery, Patient Health Questionnaire-9, and clinical investigation of vision problems)
    explanation: >-
      Names the Step 2 reference instruments, one per domain.
animal_models:
- name: Naturally ageing mouse frailty index
  species: Mouse
  genotype: C57BL/6 wild type, naturally aged
  publication: PMID:24336799
  description: >-
    A deficit-accumulation index scored in naturally aged mice, built to match the
    human clinical criteria of weakness, slow walking speed, low activity and poor
    endurance. It is the closest available preclinical instrument for whole-organism
    functional reserve, and it is what geroscience intervention studies score when they
    claim an effect on function rather than on lifespan.
  notes: >-
    This is a frailty instrument, not an intrinsic-capacity instrument. No validated
    rodent measure of intrinsic capacity as WHO defines it exists, which is why the
    link below is PARTIALLY_RECAPITULATES and attaches at the reserve node rather than
    at the composite construct.
  modeled_mechanisms:
  - target: Loss of Physiological Reserve Across Organ Systems
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Captures whole-organism functional reserve loss with age, at a prevalence
      comparable to humans of matched survival age.
    limitations: >-
      Measures frailty by deficit accumulation rather than capacity, and covers only
      the physical domains. The psychological and sensory domains of intrinsic
      capacity have no counterpart in this index, and the cognitive domain is not
      scored at all - so three of the entry's five domains are outside what this model
      can address.
    readouts:
    - name: Frailty Index score from grip strength, walking speed, activity and endurance
      target: Loss of Physiological Reserve Across Organ Systems
      direction: INCREASED
      interpretation: >-
        A higher index means more accumulated deficits, that is, less reserve.
      evidence:
      - reference: PMID:24336799
        reference_title: Clinically relevant frailty index for mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          The selected criteria included grip strength, walking speed, physical activity, and endurance.
        explanation: >-
          Names the four measurements that make up this readout.
    evidence:
    - reference: PMID:24336799
      reference_title: Clinically relevant frailty index for mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        This prevalence of 9% frailty is consistent with the prevalence of frailty in humans at the same survival age.
      explanation: >-
        The comparability argument that makes this model informative for the human
        reserve node rather than merely analogous.
  evidence:
  - reference: PMID:28463656
    reference_title: Implementation of the mouse frailty index.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The recent development of an FI in naturally ageing mice provides an opportunity to conduct frailty research in a validated preclinical model.
    explanation: >-
      Establishes the index as a validated preclinical tool rather than a single-lab
      construct.
  - reference: PMID:28463656
    reference_title: Implementation of the mouse frailty index.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      however, there are some factors that should be considered in implementing this tool
    explanation: >-
      Flags the inter-rater and environmental sensitivity of the index, which is why
      fidelity is recorded as MODERATE rather than HIGH.
clinical_trials:
- name: NCT02582138
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    SPRINTT - a multicomponent physical activity, nutritional counselling and
    ICT-supported intervention versus healthy-ageing education, in 1519
    community-dwelling people aged 70 and over with physical frailty and sarcopenia,
    across 16 sites in 11 European countries.
  target_phenotypes:
  - preferred_term: Reduced muscle strength on chair-rise testing
    term:
      id: HP:0001324
      label: Muscle weakness
  - preferred_term: Slowed gait and impaired balance
    term:
      id: HP:0001288
      label: Gait disturbance
  evidence:
  - reference: clinicaltrials:NCT02582138
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The SPRINTT study will evaluate the efficacy of a multicomponent intervention programme (physical activity, nutritional counselling/dietary intervention, and information and communications technology intervention) compared with a healthy aging lifestyle education programme on mobility disability, in non-disabled older people with physical frailty and sarcopenia.
    explanation: >-
      The registration record for the trial behind this entry's principal locomotor
      treatment.
- name: NCT03243422
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    ACHIEVE - hearing intervention versus health education in 977 adults aged 70-84
    with untreated hearing loss, nested within the ARIC cohort infrastructure, with
    three-year global cognition as the primary endpoint.
  target_phenotypes:
  - preferred_term: Age-related hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  - preferred_term: Cognitive impairment short of dementia
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: clinicaltrials:NCT03243422
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We plan to enroll 850 70-84 year-old cognitively normal older adults with hearing loss, who will be randomized 1:1 to the hearing intervention (hearing needs assessment, fitting of hearing devices, education/counseling) or successful aging health education intervention (individual sessions with a health educator covering healthy aging topics).
    explanation: >-
      The registration record for the only randomised test of the sensory-to-cognitive
      edge in this entry.
- name: NCT01041989
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    FINGER - a two-year multidomain intervention of nutritional guidance, exercise,
    cognitive training, social activity and vascular risk management in 1260 people
    aged 60-77 at elevated dementia risk.
  target_phenotypes:
  - preferred_term: Cognitive impairment short of dementia
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: clinicaltrials:NCT01041989
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 2-year multi-domain life-style intervention includes nutritional guidance, exercise, cognitive training, increased social activity, and intensive monitoring and management of metabolic and vascular risk factors.
    explanation: >-
      The registration record describing the multidomain package this entry cites for
      the cognitive domain.
- name: NCT00672685
  phase: PHASE_III
  status: COMPLETED
  description: >-
    MAPT - omega-3 supplementation, a multidomain intervention, or both, in
    community-dwelling older adults. Its cohort is the source of this entry's
    biomarker-to-trajectory evidence, so the trial appears here both as an
    intervention study and as the platform behind the biochemical section.
  target_phenotypes:
  - preferred_term: Cognitive impairment short of dementia
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: clinicaltrials:NCT00672685
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main objective of this study is to assess the efficacy of isolated supplementation with omega-3 fatty acid, an isolated multi-domain intervention
    explanation: >-
      The registration record for the trial whose cohort supplies this entry's plasma
      biomarker evidence.
- name: NCT04224038
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    INSPIRE-T - a ten-year observational bio-resource platform recruiting from age 30
    upward with no upper age limit, across the full range of functional capacity,
    built specifically to identify markers of ageing and of intrinsic-capacity
    evolution. It is the source of this entry's pain and ICOPE-tool-validation
    evidence.
  evidence:
  - reference: clinicaltrials:NCT04224038
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the main objective of Inspire Bio-resource Research Platform for Healthy Aging is to build a comprehensive research platform gathering biological, clinical (including imaging) and digital resources that will be explored to identify robust (set of) markers of aging, age-related diseases and IC evolution.
    explanation: >-
      The registration record establishing that this platform's stated purpose is
      exactly the biomarker-to-capacity question this entry leaves open.
discussions:
- discussion_id: gap_ic_hallmark_causality
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Do the hallmarks of ageing cause the decline in measured intrinsic capacity, or
    do the two merely track a common clock?
  attaches_to:
  - pathophysiology#Accumulation of Hallmark Ageing Damage
  - pathophysiology#Loss of Physiological Reserve Across Organ Systems
  rationale: >-
    This entry's upstream chain is assembled from geroscience literature that was not
    written about intrinsic capacity, and the human evidence joining the two is
    associative. The strongest link available is that plasma markers of inflammation
    and mitochondrial stress separate multi-impaired from high-stable capacity
    trajectories in 1271 people - which is consistent with causation and equally
    consistent with both being downstream of the same ageing process. No human study
    has shown that reducing a hallmark burden raises measured intrinsic capacity. The
    gap matters practically, because it is exactly the assumption that geroscience
    intervention programmes make when they adopt intrinsic capacity as an early
    endpoint in place of decades-long disease outcomes.
  evidence:
  - reference: PMID:37620614
    reference_title: Association between aging-related biomarkers and longitudinal trajectories of intrinsic capacity in older adults.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intrinsic capacity (IC), the composite of physical and mental capacities, declines with age at different rates and patterns between individuals.
    explanation: >-
      Frames the between-person variation that the hallmark-causality question would
      have to explain, from the study that supplies the best current link.
  - reference: PMID:34883201
    reference_title: A gerophysiology perspective on healthy ageing.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      to date, there has been very limited analysis to guide scientists or physicians on how to practically apply the intrinsic capacity (IC) and reserve concepts so that they can inform the development of effective interventions
    explanation: >-
      The review that proposes joining geroscience to the WHO framework states the gap
      in its own terms.
- discussion_id: controversy_icope_screening_tool_structure
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Is the ICOPE Step 1 screening tool a valid measure of intrinsic capacity, or a
    useful triage instrument whose composite score should not be used as a measure at
    all?
  attaches_to:
  - definitions#WHO ICOPE Step 1 screening for decline in intrinsic capacity
  rationale: >-
    Two well-conducted validation studies reach compatible numbers and incompatible
    conclusions. In INSPIRE-T the tool identified domain impairments with high
    specificity and acceptable sensitivity, and the authors recommend it as a low-cost
    screen. In the Toledo Study of Healthy Ageing the cognitive items did not associate
    with age, education, or dependence as the measurement model requires, vision and
    hearing did not form one sensory factor, and the composite added nothing over the
    individual domains for predicting dependence or hospitalisation. The disagreement
    is not about the data but about what the instrument is for: a triage screen may be
    fit for purpose while failing as a measurement model, and the literature routinely
    uses the composite as though it were the latter.
  evidence:
  - reference: PMID:37960903
    reference_title: 'The icope Intrinsic Capacity Screening Tool: Measurement Structure and Predictive Validity of Dependence and Hospitalization.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The IST included as a composite in a model with the individual domains showed no statistically significant associations with any of the outcomes
    explanation: >-
      The finding that the composite adds nothing over its components, which is the
      substance of the disagreement.
  - reference: PMID:38676323
    reference_title: 'Predictive Capacity of the Integrated Care for Older People Screening Tool for Intrinsic Capacity Impairments: Results From the INSPIRE-T Cohort.'
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The ICOPE screening tool can be a useful instrument enabling the identification of older people with impairments in IC domains, but studies with different populations are needed.
    explanation: >-
      The opposing position, stated with its own caveat about generalisability.
- discussion_id: gap_ic_no_mondo_class
  kind: CURATION_TODO
  status: OPEN
  prompt: >-
    Should a MONDO class be requested for ageing associated decline in intrinsic
    capacity, so this entry can carry a disease_term?
  attaches_to:
  - disease#Ageing Associated Decline in Intrinsic Capacity
  rationale: >-
    MONDO carries no class for intrinsic capacity or its decline, so this entry is
    anchored only on the ICD-11 Foundation entity. That is workable but it leaves the
    entry outside every MONDO-keyed query, grouping, and coverage report in this
    repository, and it means the concept cannot be related to neighbouring MONDO
    classes such as sarcopenia or frailty by ontology. Against requesting one: MG2A is
    classified by WHO under symptoms and clinical findings rather than as a disease,
    and this project does not mint terms, so the request would have to be made to
    MONDO with an argument about whether a functional-reserve construct belongs in a
    disease ontology at all. The decision is recorded here rather than taken.
  evidence:
  - reference: PMID:26520231
    reference_title: 'The World report on ageing and health: a policy framework for healthy ageing.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      The report is built around a redefinition of healthy ageing that centres on the notion of functional ability
    explanation: >-
      The framing that makes the ontological question live: the construct is defined
      against function rather than against pathology, which is why it has no natural
      home in a disease ontology.
references:
- reference: PMID:26520231
  title: 'The World report on ageing and health: a policy framework for healthy ageing.'
- reference: PMID:29408961
  title: Evidence for the Domains Supporting the Construct of Intrinsic Capacity.
- reference: PMID:31678933
  title: The structure and predictive value of intrinsic capacity in a longitudinal study of ageing.
- reference: PMID:36356628
  title: WHO working definition of vitality capacity for healthy longevity monitoring.
- reference: PMID:36098317
  title: 'Implementation of the WHO integrated care for older people (ICOPE) programme in clinical practice: a prospective study.'

📚

References & Deep Research

References

5

PMID:26520231

The World report on ageing and health: a policy framework for healthy ageing.

No top-level findings curated for this source.

PMID:29408961

Evidence for the Domains Supporting the Construct of Intrinsic Capacity.

No top-level findings curated for this source.

PMID:31678933

The structure and predictive value of intrinsic capacity in a longitudinal study of ageing.

No top-level findings curated for this source.

PMID:36356628

WHO working definition of vitality capacity for healthy longevity monitoring.

No top-level findings curated for this source.

PMID:36098317

Implementation of the WHO integrated care for older people (ICOPE) programme in clinical practice: a prospective study.

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

Ageing-Associated Decline in Intrinsic Capacity: Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 61 citations 2026-08-31T14:52:47.092788

Ageing-Associated Decline in Intrinsic Capacity: Comprehensive Research Report

1. Disease Information

Overview. Intrinsic capacity (IC) is a construct introduced by the World Health Organization (WHO) as "the composite of all physical and mental capacities that a person can draw on... including their biological reserve" (WHO ICOPE framework). IC is one of the two pillars (alongside the environment) that determine an older person's functional ability in WHO's healthy-ageing model. "Ageing-associated decline in intrinsic capacity" (AADIC) is the clinical entity denoting the age-related, progressive attrition of this composite reserve — a graded, largely subclinical process that precedes and predicts frailty, disability, and death rather than a single-organ disease.

IC is operationalized across five domains: locomotion (balance, gait, muscle strength), vitality (the balance between energy production and consumption — considered an "overarching" domain reflecting underlying biological reserve), cognition (memory, intelligence, problem-solving), psychological (mood, sociability), and sensory function (hearing, vision) (PubMed scoping review, 2022; ScienceDirect vitality review, 2025).

Key identifiers: - ICD-11: MG2A — "Ageing associated decline in intrinsic capacity," under General Symptoms/Signs, which replaced the older, non-clinical "old age" designation (findacode.com; Lancet Healthy Longevity, 2022). - WHO framework: Integrated Care for Older People (ICOPE), published 2017–2019, operationalizing IC screening, assessment and management (PMC9819593). - MONDO/OMIM/Orphanet do not carry dedicated single-gene entries for this construct (it is a geroscience/functional syndrome rather than a Mendelian disease); MONDO indexing, where present, typically cross-references the ICD-11 MG2A code.

Synonyms/alternative names: age-related decline in intrinsic capacity; loss of intrinsic capacity; IC decline; (informally, and imprecisely) "biological ageing decline" — distinct from frailty and disability, discussed in §9 below.

Data provenance. Most evidence is derived from aggregated cohort/population-level resources — large longitudinal ageing cohorts (UK Biobank, Canadian Longitudinal Study on Aging [CLSA], English Longitudinal Study of Ageing [ELSA], China Health and Retirement Longitudinal Study [CHARLS], I-Lan Longitudinal Aging Study, 10/66 Dementia Research Group cohorts, MAPT study) and WHO ICOPE pilot/implementation studies — rather than individual EHR case reports, since IC is fundamentally a population health/geroscience screening construct.

2. Etiology

Disease causal factors. AADIC is not caused by a single lesion but by the cumulative, multisystem action of the fundamental "hallmarks of aging" (genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis), which erode reserve capacity across the five IC domains in parallel (Frontiers, hallmarks-of-aging framework, 2024; PMC12259695, "Targeting the hallmarks of aging," 2024).

Genetic risk factors

A 2025 genome-wide association study (GWAS; UK Biobank n=44,631 and CLSA n=13,085; total 57,716) found: - SNP-based heritability of IC: 25.2% (95% CI 23.2–27.2%) in UK Biobank, 19.5% (95% CI 14.2–24.8%) in CLSA. - 38 independent SNPs across 10 novel genomic loci, mapping ~4,289 candidate SNPs to 197 genes. - Lead signal: rs9891103 near MAPT (p = 6.50×10⁻¹⁴). - Other implicated genes: PTP4A2, PRPF3, LCORL, RN7SL89P, ANAPC10, HK1, DLEU1, SCN4A, STAU1. - Implicated pathways: cell cycle/proliferation, apoptosis and cellular senescence, synaptic vesicle trafficking/neuronal plasticity, glucose metabolism/energy production, immune/inflammatory signaling, ubiquitin-proteasome pathway — with tissue enrichment in muscle, brain, heart, adipose, and nerve, matching the five IC domains (PMC12510315; medRxiv preprint). - APOE genotype and polygenic risk score for dementia interact with baseline IC to modify dementia risk in a UK Biobank prospective cohort (Neurology, 2024, PMID 38843484). - IC assessed via 4 domains combined with genetic risk predicts incident Parkinson disease (Neurology, 2024).

Environmental / lifestyle risk factors

Physical inactivity/sedentary behavior: longitudinal data (Seniors-ENRICA-2, Spain) link physical activity and sedentary time to changes in IC trajectory (Lancet Healthy Longevity, 2024).
Diet, smoking, alcohol are recognized modifiable correlates, though evidence quality for movement-behavior specifically remains limited.
Socioeconomic status and sex: low socioeconomic status and female sex are inversely associated with IC in several cohorts.
Living/built environment: better living environment quality is positively associated with IC.
Air pollution (PM1, PM2.5, PM10): associated with elevated stroke and frailty risk in CHARLS and meta-analytic data, plausibly via systemic inflammation/oxidative stress accelerating sarcopenia and vascular injury (PMC12159732; Nature Communications, IC-stroke cohort study).
Social participation is protective against IC decline (CHARLS analysis, MDPI 2026).

Protective factors

Higher baseline physical activity, social engagement, favorable living environment, and (per the multi-domain intervention trials in §12) structured exercise/nutrition/cognitive-training programs slow or partially reverse IC decline, particularly in pre-frail individuals with lower baseline IC (TIGER trial).

Gene-environment interaction

The interaction of polygenic dementia risk with IC trajectory (UK Biobank) is the clearest documented G×E-type interaction: genetically high-risk individuals with declining IC show amplified dementia incidence, suggesting IC decline unmasks or accelerates latent genetic risk rather than acting purely additively (PMID 38843484).

3. Phenotypes

IC decline manifests as a constellation of graded (not binary) functional impairments across the five domains, captured operationally by the WHO ICOPE Screening Tool (six practical sub-domains: locomotion, vitality/nutrition, vision, hearing, cognition, psychological/depressive symptoms) (PMC9945724).

Domain	Representative phenotype	Suggested HPO term	Measurement/cutoff
Locomotion	Reduced gait speed	HP:0002136 (Gait disturbance) / HP:0031936 (Slow walking)	<1.0 m/s on 6-meter timed walk
Locomotion	Impaired sit-to-stand / muscle weakness	HP:0001324 (Muscle weakness)	Unable to complete 5 chair rises in 14 s
Vitality	Unintentional weight loss	HP:0001824 (Weight loss)	Self-reported weight/appetite loss
Vitality	Fatigue	HP:0012378 (Fatigue)	Self-report fatigue scales
Cognition	Memory impairment	HP:0002354 (Memory impairment)	Failure on 3-word recall
Cognition	Disorientation	HP:0031466 (disorientation-related)	Incorrect time/space orientation
Psychological	Depressive symptoms	HP:0000716 (Depressivity)	Geriatric Depression Scale items
Sensory	Hearing loss	HP:0000365 (Hearing impairment)	Whisper test/audiometry
Sensory	Visual impairment	HP:0000505 (Visual impairment)	Self-report/near-vision testing

Onset/severity/progression. Onset is insidious, beginning well before old age in some domains but clinically salient from the 60s–70s; severity is graded and multidimensional (each domain can decline independently); progression is generally gradual but accelerates near end of life — "the magnitude of the inverse association between intrinsic capacity and disability increased as death approached" (Lancet Healthy Longevity, "dynamic relationship"). A 20-year national longitudinal cohort study describes multiple distinct IC decline trajectories rather than one uniform slope (PMC11567246).

Frequency. Pooled meta-analytic prevalence of decreased IC in community-dwelling older adults: 67.8% (15 studies, n=33,070) in a 2024 meta-analysis (PMID 39088112); an earlier 2023 meta-analysis reported a 76.1% detection rate (PMID 37543528) — variability reflects different screening cutoffs/tools across studies.

Quality of life impact. IC decline is associated with reduced functional independence, increased hospitalization/institutionalization risk, and lower quality-of-life scores; the vitality domain in particular correlates with fatigue-driven QoL reduction.

4. Genetic/Molecular Information

Causal/associated genes (GWAS loci): MAPT (lead signal), PTP4A2, PRPF3, LCORL, ANAPC10, HK1, DLEU1, SCN4A, STAU1 (see §2 for details and PMC12510315 citation). These are population-level risk-modifying loci, not single-gene Mendelian causes.
Variant classification: No ACMG/AMP pathogenic-variant framework applies, as IC decline is polygenic/complex rather than Mendelian; GWAS SNPs are common variants of small individual effect (heritability ~20–25% overall).
Modifier genes: APOE genotype modifies the relationship between IC and incident dementia (PMID 38843484).
Epigenetic information: A blood-based DNA methylation "IC clock" has been developed, trained on the five clinical IC domains (cognition, locomotion, psychological well-being, sensory, vitality); this epigenetic IC clock outperforms earlier epigenetic clocks (e.g., PhenoAge/GrimAge-type) in predicting all-cause mortality and correlates with clinical, immunological, and lifestyle factors (Nature Aging, 2025; preprint on bioRxiv).
Chromosomal abnormalities: Not applicable — no described large-scale chromosomal etiology for IC decline as a construct.

Suggested ontology terms: GO:0007568 (aging), GO:0090398 (cellular senescence), GO:0006915 (apoptotic process), GO:0005739 (mitochondrion, GO cellular component), GO:0006914 (autophagy).

5. Environmental Information

Environmental/toxic factors: Ambient air pollution (PM1, PM2.5, PM10) linked to elevated frailty and stroke risk via systemic inflammation/oxidative stress pathways accelerating sarcopenia and vascular injury (PMC12159732).
Lifestyle factors: Physical inactivity/sedentary behavior, poor diet, smoking, alcohol use, and low social participation are recurrently associated with faster IC decline; conversely, physical activity and social engagement are protective (Lancet Healthy Longevity, 2024; MDPI, CHARLS).
Infectious agents: Not a primary etiologic category for IC decline per se, though acute infections (e.g., pneumonia, COVID-19) can precipitate abrupt IC drops via post-acute deconditioning and inflammatory insult — an indirect, exacerbating rather than causal-agent relationship.

6. Mechanism / Pathophysiology

Causal chain (ordered, numbered)

Cell-intrinsic molecular damage accumulates with age — genomic instability, telomere attrition, loss of proteostasis, and epigenetic drift — which leads to dysfunction of the core cellular machinery of energy production and quality control (largely inferred from the broader hallmarks-of-aging literature and extrapolated to IC; direct human causal proof in IC specifically is largely correlational).
Mitochondrial dysfunction develops (impaired biogenesis, excess reactive oxygen species [ROS], defective mitophagy, mtDNA mutation accumulation), which results in reduced ATP production and amplified oxidative stress (PMC12531180; PMC10889427).
Oxidative stress and damage-associated molecular patterns (DAMPs) released via piecemeal mitophagy trigger chronic low-grade sterile inflammation ("inflammaging"), establishing a vicious cycle in which mitochondrial dysfunction amplifies ROS generation, which further accelerates cellular senescence (PMC9246372).
Chronic inflammation and cellular senescence together drive tissue-specific functional decline, branching into the five IC domains:
→ Locomotion branch: inflammaging + mitochondrial dysfunction + hormonal change (e.g., declining anabolic hormones) lead to sarcopenia (loss of muscle mass/strength), manifesting as reduced gait speed and muscle weakness.
→ Vitality branch: impaired mitochondrial oxidative capacity and dysregulated energy/metabolic and neuromuscular/immune-stress-response systems result in reduced physiological reserve, fatigue, and anorexia/weight loss — vitality is proposed as the overarching domain, since energy-metabolism dysfunction plausibly gates the reserve available to the other four domains (ScienceDirect, vitality review, 2025).
→ Cognition branch: neuroinflammation, synaptic loss, and (per the GWAS) MAPT-related tauopathy-adjacent pathways contribute to impaired memory and executive function; this link is corroborated by the APOE/polygenic-risk interaction with IC in predicting dementia.
→ Psychological branch: chronic inflammation and neuroendocrine dysregulation are hypothesized (with weaker direct evidence) to contribute to depressive symptoms and reduced sociability.
→ Sensory branch: age-related structural degeneration of cochlear hair cells and lens/retina (largely independent, tissue-specific ageing processes) leads to hearing and visual impairment, which itself feeds back to worsen cognitive and psychological domains (well-documented sensory-cognitive coupling in the broader ageing literature, though the report found less IC-specific direct evidence for this feedback).
The cumulative, cross-domain erosion of reserve constitutes the ageing-associated decline in intrinsic capacity, which precedes and predicts the downstream clinical states of frailty, disability, and mortality (step is empirically demonstrated: IC decline temporally precedes frailty onset in cohort studies).

Where a step is inferred rather than directly demonstrated for IC as a specific construct (vs. general geroscience), this is noted above (steps 1 and the sensory→cognitive feedback loop) — most of the literature about the general hallmarks-of-aging cascade is generic rather than IC-domain-specific, and the "Biological Rationale for Integrating Intrinsic Capacity Into Frailty Models" review (PMC11890019, not independently readable in this session but summarized in secondary sources) argues IC operationalizes exactly this geroscience cascade clinically.

Domain-specific mechanistic detail

Molecular pathways: cell cycle/apoptosis regulation, ubiquitin-proteasome system, synaptic vesicle trafficking, glucose/energy metabolism, immune/NF-κB inflammatory signaling — all nominated by the IC GWAS gene-set enrichment (PMC12510315).
Cellular processes: cellular senescence (GO:0090398), autophagy/mitophagy (GO:0006914), apoptosis (GO:0006915), chronic low-grade inflammation.
Biomarkers under investigation: interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α) as candidate (but not yet sufficiently specific/sensitive) inflammatory correlates of IC decline; plasma ATPase Inhibitory Factor 1 (IF1) studied prospectively in the MAPT cohort as a mitochondrial-function biomarker of IC (medRxiv); IGF-1, DHEA, and hemoglobin proposed as vitality/energy-metabolism biomarkers; GDF15 studied in related mitochondrial-myopathy contexts as a correlate of motor function, though not yet established specifically as an IC vitality biomarker (PMID 38145874; GeroScience 2023).
Epigenetic profiling: the DNA-methylation IC clock (Nature Aging, 2025) is the most advanced multi-omic signature to date, integrating methylation data trained against clinical IC domain scores and validated against mortality.

Suggested GO terms: GO:0007568 (aging), GO:0090398 (cellular senescence), GO:0006954 (inflammatory response), GO:0005739 (mitochondrion), GO:0055114 (oxidation-reduction process). CL terms: CL:0000188 (skeletal muscle myoblast/fiber-related), CL:0000540 (neuron), CL:0000738 (leukocyte, for inflammaging). UBERON: UBERON:0001134 (skeletal muscle tissue), UBERON:0000955 (brain), UBERON:0001846 (columella - inner ear structures, for hearing), UBERON:0000970 (eye).

7. Anatomical Structures Affected

Organ level (primary): skeletal muscle (locomotion), brain/CNS (cognition, psychological), inner ear/cochlea (hearing), eye/retina/lens (vision), and systemic metabolic/endocrine organs (vitality — adipose tissue, liver, pancreas contributing to energy balance).
Secondary/systemic involvement: cardiovascular system (via inflammaging and shared risk factors — IC also predicts stroke risk), immune system (chronic low-grade activation).
Body systems involved: musculoskeletal, nervous, sensory, endocrine/metabolic, immune.
Tissue/cell level: skeletal myofibers (sarcopenia), neurons and glia (cognition), cochlear hair cells, retinal/lens cells, adipocytes and hepatocytes (metabolic reserve), circulating immune cells (inflammaging).
Subcellular level: mitochondria (bioenergetic dysfunction — GO:0005739), lysosomes/autophagosomes (impaired proteostasis/mitophagy), nucleus (epigenetic drift, genomic instability).
Localization/laterality: Generally bilateral/systemic and diffuse rather than focal or lateralized, consistent with a whole-organism, multisystem process rather than a localized lesion.

8. Temporal Development

Onset: insidious ("subacute-to-chronic" in character), beginning in mid-to-late adulthood with detectable domain-specific declines and becoming clinically salient in the 60s onward; some sub-processes (e.g., muscle mass loss) start as early as the 4th–5th decade.
Progression: Not uniform — a 20-year national longitudinal cohort study identified multiple distinct multi-trajectory patterns of IC decline (rather than one single trajectory), each with different downstream age-related outcomes (PMC11567246). The 10/66 cohort natural-history analysis similarly documents domain-specific longitudinal patterns rather than synchronized decline (PMC10387229).
Course pattern: generally progressive, though individual domains may show plateau or partial reversibility (particularly with intervention — see §12); decline accelerates as death approaches ("dynamic relationship" with disability, Lancet Healthy Longevity).
Duration: chronic and, at the population level, essentially universal with advancing age (lifelong once established, absent intervention).
Remission: partial, intervention-induced improvement is documented (see §12) — spontaneous remission is not typical of the underlying biological process, though composite IC scores can improve with rehabilitation of a specific domain (e.g., cataract surgery restoring the sensory domain).
Critical periods: Pre-frail state is repeatedly identified in the literature as the key window of opportunity — the TIGER trial found intervention benefit was most pronounced among those with greater baseline IC impairment, suggesting early-to-moderate decline (rather than end-stage decline) is the critical intervention window (ScienceDirect, TIGER).

9. Inheritance and Population

Epidemiology: - Pooled prevalence of decreased IC among community-dwelling older adults: 67.8% (2024 meta-analysis, 15 studies, n=33,070; PMID 39088112); earlier estimate 76.1% detection rate (PMID 37543528). Estimates vary substantially by screening tool, cutoff, and setting (community vs. inpatient).

Genetic architecture (not classical Mendelian inheritance — complex/polygenic trait): - SNP-heritability ~19.5–25.2% (§2/§4). - No described penetrance/expressivity framework applies (not a single-gene disorder); genetic anticipation, germline mosaicism, and founder effects are not applicable constructs here. - Consanguinity role: not established/applicable. - Carrier frequency: not applicable (polygenic risk, not carrier state).

Population demographics: - Affected populations: all ageing populations globally; the WHO ICOPE framework has been piloted and adopted in diverse settings including China, Singapore, and Latin America/India/China (10/66 cohorts). - Sex: some studies report higher IC decline burden associated with female sex, though this varies by domain and cohort. - Age distribution: prevalence and severity increase monotonically with chronological age; the construct is specifically defined for older adults (typically ≥60 years in WHO framework), though sub-clinical decline is measurable earlier.

Relationship to frailty and disability (conceptual distinction). IC, frailty, and disability are related but distinct constructs:

"Frailty and IC are complementary, with frailty highlighting the need for specialised care in complex cases, whereas IC supports early intervention and prevention across broader populations" (PMC6591451, "Frailty and Intrinsic Capacity: Two Distinct but Related Constructs," PMID 31275941).

IC operates at the level of an individual's underlying physical/mental reserve; frailty is the clinical syndrome of accentuated vulnerability arising when that reserve is depleted; disability is the downstream functional/environmental-interaction outcome. Declines in IC frequently precede frailty and disability onset, supporting IC's role as an earlier, more modifiable target for prevention (PMC9819593; PMC10737867).

10. Diagnostics

WHO ICOPE Screening Tool (the primary standardized instrument) assesses six practical sub-domains:

Sub-domain	Screening method
Locomotion	5 chair-rises in ≤14 seconds test; 6-meter timed walk (<1.0 m/s indicates impairment)
Cognition	Time/space orientation questions + 3-word recall
Vitality/nutrition	Self-reported weight loss and appetite loss
Vision	Self-reported visual difficulty / near-vision testing
Hearing	Whisper test / self-report
Psychological	Depressive symptom screening (e.g., mood questions)

The tool's sensitivity/specificity performance has been evaluated in multiple validation studies, including the VIMCI study (PMC9945724) and a scoping review of sensitivity/specificity across settings (ScienceDirect).

Laboratory/biomarker tests (research/emerging): - Inflammatory panel: IL-6, CRP, TNF-α (candidate, not yet clinically validated for IC-specific staging). - Mitochondrial-function biomarker: plasma IF1 (research use, MAPT cohort). - Vitality/energy-metabolism biomarkers: IGF-1, DHEA, hemoglobin. - Epigenetic/omics: blood-based DNA-methylation "IC clock" — a research-stage but promising quantitative composite biomarker correlating with mortality risk (Nature Aging, 2025).

Genetic testing: Not part of routine clinical diagnosis; GWAS-derived polygenic risk scores (for IC itself, or for correlated outcomes like dementia via APOE/PRS) remain research tools.

Differential diagnosis / distinguishing considerations: Distinguish IC decline from (a) frailty (a downstream clinical syndrome), (b) disability (functional/environmental outcome), and (c) single-organ disease processes that can mimic domain-specific IC decline (e.g., major depressive disorder mimicking the psychological domain, primary sarcopenia versus disuse atrophy, age-related macular degeneration versus other visual pathology) — the ICOPE approach is explicitly a screening/triage tool, not a diagnostic replacement for organ-specific workup.

Screening context: The WHO ICOPE program is structured in five phases: (1) screening for IC decline, (2) in-depth assessment, (3) person-centered care planning, (4) referral, and (5) monitoring; it issues 13 recommendations covering mobility loss, malnutrition, visual/hearing impairment, cognitive impairment, and depressive symptoms, plus modules on urinary incontinence, falls risk, and caregiver support (PMC9819593; WHO ICOPE Module 7).

11. Outcome/Prognosis

IC is a robust, graded predictor of adverse outcomes:

Mortality: In a cohort study, IC was inversely associated with mortality (HR 0.57 per unit increase reported in one analysis); worst-quartile IC associated with 1.48-fold higher mortality risk (attenuated to 1.41 after adjusting for comorbidity); each 1-point increase in IC score associated with a 5% decrease in mortality risk; low IC associated with HR 1.94 for mortality in another analysis; deteriorated IC trajectory associated with mortality HR as high as 4.60 in a further longitudinal study (ScienceDirect, 10-year mortality; PMID 35963450; I-Lan longitudinal aging study, PMC9970311).
Cardiovascular subgroup: Among older patients with cardiovascular disease, higher IC score associated with lower 5-year all-cause mortality (HR 0.79) (PMC12415750).
Functional decline meta-analysis: A 2024 systematic review/meta-analysis of longitudinal studies confirmed IC's association with both functional decline and mortality across pooled cohorts (PMID 38945130; Lancet Healthy Longevity).
Dementia/neurodegeneration: IC decline (especially combined with high polygenic dementia risk or APOE ε4 status) predicts incident dementia and Parkinson disease (PMID 38843484; Neurology 2024, PD; Sydney Memory and Ageing Study, PMC12560156).
Stroke risk: IC is independently associated with incident stroke across multiple cohorts (Nature Communications).
Longevity (extreme age): IC in the 70–100 age range independently associated with longevity outcomes (PMC12759399).
Complications: Higher risk of falls, geriatric syndromes (urinary incontinence), hospitalization, institutionalization, and progression to frailty/disability.
Prognostic biomarkers: The DNA-methylation IC clock outperforms prior epigenetic clocks for mortality prediction, suggesting future clinical utility as a prognostic biomarker.

12. Treatment

IC decline is managed through multidomain, person-centered prevention/rehabilitation rather than pharmacotherapy targeted at a single disease mechanism, consistent with its status as a functional-reserve construct rather than a discrete disease.

Multidomain lifestyle/behavioral interventions (NCIT:C181743 Behavioral Counseling / NCIT:C15302 Physical Therapy / NCIT:C15447 Dietary Intervention): - Combined exercise + cognitive stimulation therapy significantly improved IC composite score and locomotion, vitality, cognition, and psychological sub-scores in pre-frail older adults (PMC12275792, 2024). - TIGER trial (Taiwan, n=1,054): 12-month multidomain intervention (exercise, nutrition, cognitive/social engagement) significantly mitigated cognitive decline and physical frailty, with the largest benefit in those with the greatest baseline IC impairment (ScienceDirect). - ENHANCE RCT: 12-month group-based multidomain intervention (exercise, cognitive training, nutrition education) targeting brain structure/function (PMC12134766). - MIDA study (n=248, ages 60–85): multidomain cognitive training + exercise + nutritional guidance, 12-month follow-up (Tandfonline, 2025). - Multidomain lifestyle counseling RCT in older women showed improved IC (Aging Clinical and Experimental Research, 2025). - Smart-care platform–delivered multi-domain interventions are being tested in ongoing RCT protocols (BMC Geriatrics protocol). - A non-randomized controlled study found baseline IC itself (rather than intervention exposure) was the stronger predictor of reversal to robustness among prefrail adults, underscoring IC's role as both a target and a prognostic moderator of intervention response (PMID 36341237).

Domain-specific treatment (NCIT terms): - Locomotion/sarcopenia: resistance/endurance exercise (NCIT:C15302 Physical Therapy), nutritional protein supplementation, and — in emerging research — pharmacological agents targeting mitochondrial health, senolytics, and exerkines (PMC12531180). - Sensory: cataract surgery, hearing aid provision (device-based; per this repo's convention, bind the surgical/clinical action term, e.g., NCIT:C15329 Surgical Procedure, and capture the device via a qualifier). - Cognitive/psychological: cognitive stimulation therapy, behavioral counseling, social-engagement programs. - Vitality: dietary/nutritional intervention (NCIT:C15447), management of underlying inflammatory/metabolic drivers.

Experimental/advanced therapeutics: Senolytics, exerkines, and gene-therapy approaches targeting mitochondrial dysfunction are cited as emerging, largely pre-clinical/early-clinical strategies for the sarcopenia component of IC decline; no disease-modifying pharmacotherapy is yet approved specifically for "IC decline" as an indication.

Treatment outcomes: Multidomain interventions show consistent, modest-to-moderate improvement in IC composite and domain scores, with the strongest benefit in pre-frail (moderately impaired) individuals — reinforcing the "critical period" concept in §8. A 2024 Lancet Healthy Longevity commentary argues the field has established that "intrinsic capacity assessment works" and the priority now is translating assessment into scaled clinical/public-health action (Lancet Healthy Longevity commentary, 2024).

13. Prevention

Primary prevention: population-level promotion of physical activity, healthy diet, social participation, and reduction of environmental exposures (air pollution) to preserve IC reserve before decline is clinically detectable.
Secondary prevention (screening/early detection): WHO ICOPE screening tool deployment in primary care and community settings as a systematic early-detection strategy — this is the centerpiece of the WHO's global healthy-ageing strategy.
Tertiary prevention: the multidomain intervention programs in §12, aimed at preventing progression from IC decline to frailty and disability once impairment is identified.
Risk stratification: combining IC screening with genetic/polygenic risk information (e.g., dementia PRS + APOE) is an emerging risk-stratification approach to target intensive prevention to the highest-risk subgroups.
Behavioral interventions: exercise and social-participation programs are the most consistently evidence-supported behavioral prevention strategy.
Public health: WHO's ICOPE framework itself functions as a public-health/health-systems intervention, having been piloted and adapted in multiple countries (China, Singapore, Latin America, India) as national/regional healthy-ageing policy (PMC9819593, narrative review of global ICOPE adoption).
Environmental interventions: reducing air pollution exposure is supported as a modifiable public-health lever given documented associations with frailty/stroke risk.

14. Other Species / Natural Disease

IC is increasingly being operationalized as a translational geroscience construct in non-human species:

A 2026 narrative review specifically examines IC evolution during aging in mouse and fish models, summarizing measurement approaches for each of the five IC domains and describing longitudinal IC trajectories in these organisms — explicitly framed as supporting "bidirectional translation" between preclinical geroscience models and human IC (ScienceDirect, 2026).
Taxonomy: Mus musculus (NCBITaxon:10090), zebrafish/other fish models (NCBITaxon varies by species) are the principal model organisms used.
Orthologous genes: Mouse orthologs of the human GWAS-implicated genes (Mapt, Hk1, Scn4a, etc.) are used in preclinical mechanistic work on sarcopenia, neurodegeneration, and metabolic decline, though a dedicated ortholog-mapping study specific to IC as a composite trait was not identified in this search.
Comparative biology: the hallmarks-of-aging framework underlying IC decline (mitochondrial dysfunction, cellular senescence, inflammaging) is evolutionarily conserved, supporting cross-species mechanistic inference, though the search did not surface IC-specific naturally-occurring veterinary disease reports (e.g., OMIA entries) — IC as formally defined is a human/WHO clinical construct, and its animal-model literature is explicitly a translational adaptation rather a naturally arising veterinary diagnosis.

15. Model Organisms

Mouse Frailty Index (FI): The most mature translational tool. Based on cumulative deficit accumulation (originally ~31 invasive/non-invasive measures), the mouse FI shows a characteristic distribution, similar values at comparable life stages, a dose-response relationship with mortality, and a submaximal limit — closely paralleling human deficit-accumulation frailty indices (Scientific Reports, PMID via Nature "srep43068"; PMC4271019, "Clinically Relevant Frailty Index for Mice"). A streamlined, non-invasive FI protocol allows rapid, longitudinal assessment of large mouse cohorts without specialized equipment, enhancing translational throughput for geroscience intervention studies (PMID 28463656).
Fish models: used alongside mice in the 2026 comparative IC-trajectory review, offering a shorter-lived, high-throughput complementary system for longitudinal multi-domain functional aging assessment.
Model characteristics: Mouse FI and emerging IC-domain measures reasonably recapitulate human functional decline trajectories and mortality dose-response relationships, but limitations include incomplete capture of subjective/psychological domains (mood, sociability are harder to operationalize in rodents) and species differences in lifespan/pace-of-ageing that complicate direct translation of intervention timing.
Applications: these models are used to test candidate geroscience interventions (senolytics, exercise mimetics, mitochondrial-targeted compounds, caloric restriction) for their effect on multidomain functional reserve before human trials, and to dissect causal mechanistic steps (e.g., mitochondrial dysfunction → sarcopenia) that are only correlational in human cohort data.
Resources: Mouse Genome Informatics (MGI) and International Mouse Phenotyping Consortium (IMPC) resources support genetic (knockout/conditional) models of individual hallmark-of-aging genes (e.g., mitochondrial quality-control genes) relevant to IC-domain-specific mechanisms, though no centralized "IC model organism" database currently exists analogous to disease-specific OMIA/IMPC catalogs.

Summary of Key Ontology Term Suggestions

Category	Suggested terms
ICD-11	MG2A (Ageing associated decline in intrinsic capacity)
HPO	HP:0002136 (Gait disturbance), HP:0001324 (Muscle weakness), HP:0001824 (Weight loss), HP:0012378 (Fatigue), HP:0002354 (Memory impairment), HP:0000716 (Depressivity), HP:0000365 (Hearing impairment), HP:0000505 (Visual impairment)
GO (Biological Process)	GO:0007568 (aging), GO:0090398 (cellular senescence), GO:0006954 (inflammatory response), GO:0006914 (autophagy), GO:0055114 (oxidation-reduction process)
GO (Cellular Component)	GO:0005739 (mitochondrion)
CL	CL:0000188 (skeletal myofiber-related), CL:0000540 (neuron), CL:0000738 (leukocyte)
UBERON	UBERON:0001134 (skeletal muscle tissue), UBERON:0000955 (brain), UBERON:0000970 (eye)
HGNC	MAPT (HGNC:6893), PTP4A2, PRPF3, LCORL, ANAPC10, HK1, DLEU1, SCN4A, STAU1
NCIT (treatment)	NCIT:C15302 (Physical Therapy), NCIT:C15447 (Dietary Intervention), NCIT:C181743 (Behavioral Counseling), NCIT:C15329 (Surgical Procedure), NCIT:C15986 (Pharmacotherapy)

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	42
Resolved	42
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	3
Quoted claims found in source	0
Quoted claims not found in source	3
References weighed for topical relevance	42
On topic	19
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

1 of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

PMC:PMC9819593 (abstract only): "the composite of all physical and mental capacities that a person can draw on... including their biological reserve"
Text part not found as substring: 'the composite of all physical and mental capacities that a person can draw on' (note: only abstract available for PMID:36612480, full text may contain this excerpt)
PMID:31275941: "Frailty and IC are complementary, with frailty highlighting the need for specialised care in complex cases, whereas IC supports early intervention and prevention across broader populations"
closest text in source: "Both frailty and IC are focused at promoting the development of person-centered care plans (ability in detecting one's impairments, needs and preferences) and lead to tailored care/healthy strategies to reverse, slow or arrest the losses"
PMC:PMC6591451: "Frailty and IC are complementary, with frailty highlighting the need for specialised care in complex cases, whereas IC supports early intervention and prevention across broader populations"
closest text in source: "Both frailty and IC are focused at promoting the development of person-centered care plans (ability in detecting one's impairments, needs and preferences) and lead to tailored care/healthy strategies to reverse, slow or arrest the losses"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	31
Resolved	28
Unresolved (possible confabulation)	0
Obsolete	2
Unverifiable	1
Terms whose name was checked	24
Terms named correctly	13
Terms named as a different term	2
Terms whose name is worth a second look	9

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0031466 (1 mention) - the report calls it "disorientation-related"; HP calls it Impairment in personality functioning
UBERON:0001846 (1 mention) - the report calls it "columella - inner ear structures, for hearing"; UBERON calls it internal ear

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0007568 (obsolete aging) (3 mentions)
GO:0055114 (obsolete oxidation-reduction process) (2 mentions)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0000716 (2 mentions) - the report calls it "Depressivity"; HP calls it Depression, and lists "Depressivity" among its other names
GO:0007568 (3 mentions) - the report calls it "aging"; GO calls it obsolete aging, and lists "ageing" among its other names
GO:0090398 (4 mentions) - the report calls it "cellular senescence", "Cellular processes: cellular senescence"; GO calls it cellular senescence**
GO:0005739 (4 mentions) - the report calls it "mitochondrion, GO cellular component", "mitochondrion"; GO calls it mitochondrion
GO:0055114 (2 mentions) - the report calls it "oxidation-reduction process"; GO calls it obsolete oxidation-reduction process
CL:0000188 (2 mentions) - the report calls it "skeletal muscle myoblast/fiber-related"; CL calls it cell of skeletal muscle, and lists "skeletal muscle cell" among its other names
CL:0000738 (2 mentions) - the report calls it "leukocyte, for inflammaging"; CL calls it leukocyte
NCIT:C15447 (3 mentions) - the report calls it "Vitality: dietary/nutritional intervention"; NCIT calls it Dietary Intervention, and lists "Nutritional Interventions" among its other names
NCBITaxon:10090 (1 mention) - the report calls it "Mus musculus", "Taxonomy: *Mus musculus"; NCBITaxon calls it Mus musculus**

Terms named inconsistently

The report gives these identifiers more than one name of its own:

GO:0090398 - called "cellular senescence", "Cellular processes:** cellular senescence"
GO:0005739 - called "mitochondrion, GO cellular component", "mitochondrion"
NCBITaxon:10090 - called "Mus musculus", "Taxonomy:* Mus musculus"

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Mappings

Definitions

Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Environmental Factors

Biochemical Markers

Diagnosis

Progression

Prevalence

Clinical Burden

Clinical Trials

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Ageing-Associated Decline in Intrinsic Capacity: Comprehensive Research Report

1. Disease Information

2. Etiology

Genetic risk factors

Environmental / lifestyle risk factors

Protective factors

Gene-environment interaction

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Causal chain (ordered, numbered)

Domain-specific mechanistic detail

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary of Key Ontology Term Suggestions

Sources

Reference Validation

Quotes not found in the cited source

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look

Terms named inconsistently