Ageing Associated Decline in Intrinsic Capacity

Complex Pathograph 21 Show in embeddings browser general symptoms, signs or clinical findings ageing-related functional decline

Ageing associated decline in intrinsic capacity (ICD-11 MG2A) describes loss of physical and mental capacities across locomotion, vitality, cognition, psychological capacity and sensory capacity. Hearing and vision are assessed separately in the WHO ICOPE care pathway. The pattern and extent of loss vary between people and over time; a positive basic assessment requires further evaluation of the affected domains, underlying diseases, medications and environment. Lower capacity is associated with later disability, care dependence and mortality, but is distinct from frailty, sarcopenia and disability. Biological ageing mechanisms are candidate contributors; human biomarker and genetic associations do not establish a single causal pathway for the composite. Management combines a personalized care plan, domain-specific interventions and support for the person and carers.

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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

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 REVIEW SYNTHESIS 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 REVIEW SYNTHESIS 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

The conceptual model comprises locomotion, vitality, cognition, psychological and sensory capacity. A general factor and five subfactors were recovered in one ELSA analysis, but operational measures and composite construction differ across studies. ICOPE assesses hearing and vision separately in practice.

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 REVIEW SYNTHESIS Other

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

The expert review identified the proposed five domains used in this conceptual framework.

PMID:31678933 SUPPORT PRIMARY RESULT 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 REVIEW SYNTHESIS 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

The WHO expert group proposed a working definition of vitality capacity as a physiological state arising from interactions among energy/metabolism, neuromuscular function and immune/stress responses. It is a conceptual framework for measurement development; its proposed position beneath other domains is not an established causal ordering in patients.

OTHER Working definition of the vitality domain; not a diagnostic cutoff or demonstrated intervention-mediated pathway.

Show evidence (1 reference)

PMID:36356628 SUPPORT REVIEW SYNTHESIS 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 expert group proposed this working definition and candidate attributes; the statement does not establish a causal pathway from ageing hallmarks to clinical IC.

WHO ICOPE Step 1 screening for decline in intrinsic capacity

The original ICOPE Step 1 instrument uses brief questions and tests for cognition, mobility, nutrition, vision, hearing and depressive symptoms. A positive result prompts domain-specific assessment. The second-edition handbook expands Step 1 into basic assessment and community-level interventions, also considering urinary incontinence, social support and carers. Vision/hearing testing can require equipment; the instrument is not an equipment-free case definition.

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 (2 references)

PMID:36098317 SUPPORT PRIMARY RESULT 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.

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"The term "basic assessment" is used, rather than screening, to reflect the move from a sole focus on potential losses in intrinsic capacity, to also identify social support needs, carers’ needs for support and presence of urinary incontinence"

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 1.4 explains the expanded first step.

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Inheritance

Polygenic inheritance HP:0010982

A complex quantitative trait with cohort-specific common-variant heritability estimates, rather than a Mendelian pattern. SNP heritability is not the proportion of individual decline caused by genes, and the unexplained variance cannot be assigned solely to environment.

Polygenic inheritance

Show evidence (1 reference)

PMID:41066301 SUPPORT PRIMARY RESULT Human Clinical

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

The GWAS supports a common-variant contribution to variation in measured IC, with low individual predictive performance; it does not establish Mendelian inheritance or clinical genetic testing.

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Subtypes

Locomotor capacity decline

Capacity for movement, assessed through strength, walking, balance and chair-rise performance. Muscle, joint, neurological and other conditions can contribute; locomotor decline is broader than sarcopenia.

Show evidence (1 reference)

PMID:29408961 SUPPORT REVIEW SYNTHESIS 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

A proposed physiological dimension encompassing energy and metabolism, neuromuscular function, and immune and stress responses. Practical assessments often use nutrition, strength or fatigue, with substantial variation between studies.

Show evidence (1 reference)

PMID:40060276 SUPPORT REVIEW SYNTHESIS Other

"However, vitality may not be the earliest impairment among IC domains, and other dimension vulnerabilities may present earlier than vitality due to internal environmental (genetic) and external environmental factors."

The proposed vitality hierarchy has explicit exceptions and is not an obligatory causal ordering.

Cognitive capacity decline

Memory, orientation and other cognitive functions. Basic assessment identifies possible impairment and prompts investigation of reversible causes and dementia where appropriate; the domain is not restricted to impairment below a dementia threshold.

Show evidence (1 reference)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"For a person with dementia, a more specific, targeted or tailored approach is appropriate."

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). The cognition pathway also addresses people with dementia; screening is not confined to a pre-dementia state.

Psychological capacity decline

Psychological well-being, commonly assessed through depressed mood and loss of interest. Positive symptom questions require further assessment and do not by themselves diagnose major depression.

Show evidence (1 reference)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"Interventions to manage depressive symptoms should always be provided as part of a comprehensive personalized care plan responding to underlying factors, along with interventions that address other domains of intrinsic capacity."

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Depressive symptoms constitute the practical psychological assessment and care domain.

Sensory capacity decline

Hearing and vision capacities. These are assessed separately and need not change together; their grouping into one conceptual domain does not imply a shared lesion.

Show evidence (1 reference)

PMID:37960903 SUPPORT PRIMARY RESULT 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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Mechanistic Hypotheses

Candidate contributions from ageing biology

geroscience_contributors EMERGING

Evidence balance 2 support

General ageing biology supports possible contributions from muscle mitochondrial dysfunction and senescence-associated secretion. The clinical evidence curated here does not establish that these mechanisms explain the composite, that they occur in every affected person, or that modifying them improves IC.

Pathograph links

Mitochondrial Bioenergetic Decline -> Locomotor Capacity Decline INDIRECT KNOWN INTERMEDIATES Candidate contribution through impaired muscle energetics and contractile performance; neither all locomotor impairment nor all intrinsic-capacity decline is attributed to this process. Intermediates: Reduced energy provision for sustained skeletal-muscle contraction

Senescent Cell Accumulation in Ageing Tissue -> Senescence-Associated Proinflammatory Secretion DIRECT Senescent cells can acquire a proinflammatory secretory phenotype; its disease-specific contribution remains a hypothesis.

Senescence-Associated Proinflammatory Secretion -> Chronic Low-Grade Inflammation INDIRECT UNKNOWN INTERMEDIATES Persistent proinflammatory secretion is one candidate contributor to systemic inflammation; clinical IC mediation has not been established.

Show evidence (2 references)

PMID:38396729 SUPPORT INDIRECT REVIEW SYNTHESIS Other

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

The review synthesizes human associations and experimental muscle biology. It supports a candidate contribution to physical performance, not a demonstrated cause of the five-domain IC composite.

PMID:23746838 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"senescent cells manifest dramatic alterations in their secretome, which is particularly enriched in pro-inflammatory cytokines and matrix metalloproteinases"

This synthesis describes the senescence-associated secretory phenotype in general ageing biology; it does not show that this is the principal inflammatory source in people with low IC.

Discussions and Knowledge Gaps

Which ageing mechanisms causally contribute to changes in measured intrinsic capacity?

KNOWLEDGE GAP OPEN gap_ic_hallmark_causality

Attached to

pathophysiology#Mitochondrial Bioenergetic Decline pathophysiology#Chronic Low-Grade Inflammation

The curated human biomarker, genetic and methylation studies provide associations. General ageing reviews supply plausible mechanisms, but neither evidence type establishes mediation of the clinical composite. Studies combining validated repeated IC measures, tissue-specific functional measurements and interventions are needed to test the candidate links. The absence of such evidence in this curated set is not a claim that no relevant human study exists.

Show evidence (2 references)

PMID:38145874 SUPPORT REVIEW SYNTHESIS 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 review describes association rather than an intervention establishing causation, and reports inconsistent biomarker findings.

PMID:40467932 SUPPORT PRIMARY RESULT Human Clinical

"Also, despite identifying a strong association between IC and the immune system, it is unclear whether causal relationships underlie this association"

The primary methylation study states the causal uncertainty.

Does treating pain improve intrinsic capacity?

KNOWLEDGE GAP OPEN gap_pain_management_and_capacity

Attached to

pathophysiology#Psychological Capacity Decline pathophysiology#Locomotor Capacity Decline

A cross-sectional INSPIRE-T study of 971 adults aged 20–102 associated pain during the previous eight days with lower IC. It did not establish chronic pain, direction of causation, inflammatory-clock moderation or an effect of pain treatment. This clinical association is not classified as a proven external environmental cause of ageing-associated IC decline.

Show evidence (2 references)

PMID:41360071 SUPPORT PRIMARY RESULT 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 PRIMARY RESULT Human Clinical

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

The authors call for future investigation of pain management; the cross-sectional association does not establish that treating pain improves IC.

Which IC instruments are suitable for triage, repeated measurement and prediction in each population?

CONTROVERSY OPEN controversy_icope_screening_tool_structure

Attached to

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

The original ICOPE screen, its local adaptations, factor-derived research scores and the expanded second-edition basic assessment serve different purposes. INSPIRE-T reported vision sensitivity 97.2% but specificity 2.7%, with sensitivity 42.0–69.6% for the other evaluated domains. The adapted Toledo composite added no statistically significant prognostic information over its domains in that sample. Hong Kong validation data also contain denominator and diagnostic-table inconsistencies. These findings require population- and instrument-specific interpretation, not a universal endorsement or rejection of all IC measurement.

Show evidence (2 references)

PMID:38676323 SUPPORT PRIMARY RESULT Human Clinical

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

The low vision specificity is necessary context for its high sensitivity.

PMID:37960903 SUPPORT PRIMARY RESULT 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 adapted Toledo instrument had no added composite association in the specified outcome models.

Should a MONDO term be requested for this ICD-11-anchored clinical construct?

CURATION TODO OPEN gap_ic_no_mondo_class

Attached to

disease#Ageing Associated Decline in Intrinsic Capacity

This entry retains its ICD-11 Foundation mapping without substituting a MONDO term for frailty or sarcopenia. Any future MONDO request should address the distinction between a functional-capacity construct and an aetiological disease and should be checked against the then-current ontology. The unresolved mapping is not evidence that related concepts are equivalent.

Show evidence (1 reference)

PMID:31275941 SUPPORT REVIEW SYNTHESIS Other

"IC should not be seen as the mere opposite of frailty."

The conceptual review cautions against equating these related constructs.

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Pathophysiology

Mitochondrial Bioenergetic Decline

Reduced skeletal-muscle mitochondrial oxidative capacity can limit energy provision for contraction. Human muscle studies and experimental models support its relevance to physical performance, but the magnitude and direction of its contribution to measured intrinsic capacity remain unresolved. Circulating GDF-15 is a stress correlate rather than a direct mitochondrial-function measurement.

Candidate contributions from ageing biology

oxidative phosphorylation GO:0006119 ↓ DECREASED

Downstream

Locomotor Capacity Decline Candidate contribution through impaired muscle energetics and contractile performance; neither all locomotor impairment nor all intrinsic-capacity decline is attributed to this process.

Show evidence (1 reference)

PMID:38396729 SUPPORT INDIRECT REVIEW SYNTHESIS Other

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

The review synthesizes human associations and experimental muscle biology. It supports a candidate contribution to physical performance, not a demonstrated cause of the five-domain IC composite.

Senescent Cell Accumulation in Ageing Tissue

Senescent cells can accumulate with age in some tissues. Increased generation and reduced clearance are possible contributors, with variation between tissues and models. This is a candidate ageing mechanism; the cited sources do not directly measure senescent-cell burden against the clinical IC composite.

Candidate contributions from ageing biology

cellular senescence GO:0090398 ↑ INCREASED

Downstream

Senescence-Associated Proinflammatory Secretion Senescent cells can acquire a proinflammatory secretory phenotype; its disease-specific contribution remains a hypothesis.

Show evidence (1 reference)

PMID:23746838 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Conceivably, the accumulation of senescent cells with aging can reflect an increase in the rate of generation of senescent cells and/or a decrease in their rate of clearance, for example, as a consequence of an attenuated immune response."

The review proposes alternative routes to accumulation and reports tissue heterogeneity. It does not establish impaired clearance as the sole mechanism in human IC decline.

Senescence-Associated Proinflammatory Secretion

The senescence-associated secretory phenotype includes proinflammatory cytokines and matrix-remodelling factors. Persistent secretion is a proposed contributor to age-associated inflammation, without evidence here that it dominates other inflammatory sources or mediates observed IC trajectories.

Candidate contributions from ageing biology

cytokine production GO:0001816 ↑ INCREASED

Downstream

Chronic Low-Grade Inflammation Persistent proinflammatory secretion is one candidate contributor to systemic inflammation; clinical IC mediation has not been established.

Show evidence (1 reference)

PMID:23746838 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"senescent cells manifest dramatic alterations in their secretome, which is particularly enriched in pro-inflammatory cytokines and matrix metalloproteinases"

This synthesis describes the senescence-associated secretory phenotype in general ageing biology; it does not show that this is the principal inflammatory source in people with low IC.

Chronic Low-Grade Inflammation

Age-associated low-grade inflammation is a candidate contributor to functional decline. In the MAPT cohort, higher IL-6 and TNF receptor-1 were associated with adverse IC trajectory groups. Circulating markers neither identify a unique cellular source nor establish sterile inflammation, causal mediation or a treatment target for every person with IC decline.

inflammatory response GO:0006954 ↑ INCREASED

Show evidence (2 references)

PMID:38145874 SUPPORT REVIEW SYNTHESIS 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 review describes association rather than an intervention establishing causation, and reports inconsistent biomarker findings.

PMID:37620614 SUPPORT PRIMARY RESULT Human Clinical

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

This is an observational association with trajectory membership, not an experimentally induced change in locomotion.

Vitality Capacity Decline

Reduced physiological capacity across energy and metabolism, neuromuscular function, and immune and stress responses, as proposed by the WHO expert working group. Studies operationalize vitality differently using nutritional assessment, strength, fatigue or other measures. Its proposed position beneath the other IC domains is a conceptual hypothesis, not a demonstrated universal causal hierarchy.

Show evidence (1 reference)

PMID:36356628 SUPPORT REVIEW SYNTHESIS Other

The expert consensus supplies a working definition and candidate attributes; operational measurement still requires validation.

Locomotor Capacity Decline

Reduced movement capacity can involve strength, gait, balance and chair-rise performance. Muscle disease is one contributor among musculoskeletal, neurological and other conditions. Locomotor impairment is not equivalent to sarcopenia, and a performance score does not by itself establish muscle atrophy.

Animal models

Four-performance-criterion frailty model in aged mice Mouse partially recapitulates Captures selected physical performance limitations that overlap with locomotor capacity.

Show evidence (1 reference)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"The SPPB comprises a balance test, a walking speed test and a chair rise test with scores added together to determine a person’s physical performance, including locomotor capacity."

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 6.3 describes the measured domain without assigning a single tissue pathology.

Cognitive Capacity Decline

Reduced memory, orientation and other cognitive functions may reflect reversible conditions, medication effects, vascular or neurodegenerative disease. The domain includes people with dementia and is not defined by a pre-dementia ceiling. Associations between overall IC deficit scores and incident dementia do not isolate the causal effect of the cognitive domain.

cognition GO:0050890 ↓ DECREASED

Brain UBERON:0000955

Show evidence (2 references)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"Common reversible conditions and risk factors that can cause cognitive decline include delirium, medication(s) and cerebrovascular diseases."

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 5.5 directs investigation of contributing conditions.

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"For a person with dementia, a more specific, targeted or tailored approach is appropriate."

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). The cognition care pathway includes dementia.

Psychological Capacity Decline

Reduced psychological well-being is assessed through depressed mood and loss of interest, with further evaluation of severity, stressors, underlying conditions and social context. Associations with recent pain do not demonstrate that pain causes subsequent decline or that treating pain restores this domain.

Show evidence (1 reference)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 10.4 describes psychological care in the multidomain context.

Hearing Capacity Decline

Reduced auditory function affects access to speech and other sounds. Age-associated impairment, ear disease and reversible causes require assessment. Amplification and rehabilitation may improve communication while underlying hearing loss persists; cognitive prevention is not assumed from improvement in audibility.

Show evidence (1 reference)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"It is important to explain to people that hearing aids do not cure or treat hearing loss."

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 9.4.3 separates communication support from reversal of the lesion.

Visual Capacity Decline

Reduced near or distance vision can result from refractive error and eye disease. Its mechanism and reversibility depend on the cause. Vision and hearing remain separate clinical processes even when included within one conceptual sensory domain.

Show evidence (1 reference)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"Management of refractive errors includes regular eye examinations and comprehensive vision and eye care."

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 8.4.2 identifies one cause-specific management route.

Composite Intrinsic Capacity Decline

A reduction in a composite measure of physical and mental capacity across the assessed domains. Instruments differ in item choice, scoring and domain coverage; factor structure and prediction are properties of each operational measure. Combining domain scores is a measurement relation, not evidence that one biological state causes another. Functional ability also depends on the surrounding environment.

Show evidence (2 references)

PMID:26520231 SUPPORT REVIEW SYNTHESIS Other

"the combination of the intrinsic capacity of the individual, relevant environmental characteristics, and the interactions between the individual and these characteristics."

The WHO policy framework distinguishes capacity from functional ability and its environmental determinants.

PMID:37960903 SUPPORT PRIMARY RESULT 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"

In the adapted Toledo instrument, the composite added no statistically significant prognostic information for these outcomes; this result does not invalidate all IC instruments.

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Pathograph

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Phenotypes

Digestive 2

Malnutrition HP:0004395

Show evidence (1 reference)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"In cases of malnutrition, health workers need to give immediate personalized dietary advice (nutritional counselling) and assess and manage contributing factors."

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 7.4.2 distinguishes established malnutrition from the risk category.

Poor appetite HP:0004396

Show evidence (1 reference)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"Have you experienced loss of appetite?"

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Table 3.1, visually verified on printed page 19; a positive response prompts further assessment.

Ear 1

Hearing impairment HP:0000365

Show evidence (2 references)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"It is important to explain to people that hearing aids do not cure or treat hearing loss."

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 9.4.3 distinguishes amplification from reversal of the underlying impairment.

PMID:37478886 SUPPORT PRIMARY RESULT Human Clinical

"The hearing intervention demonstrated evidence of target engagement based on self-reported hours of hearing aid use and reduction in self-perceived communication impairment after HI"

The ACHIEVE result supports communication benefit; its cognitive endpoint is assessed separately.

Eye 1

Visual impairment HP:0000505

Show evidence (1 reference)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"Management of refractive errors includes regular eye examinations and comprehensive vision and eye care."

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 8.4.2 describes a treatable cause of visual impairment.

Musculoskeletal 1

Muscle weakness HP:0001324

Show evidence (1 reference)

PMID:30312372 SUPPORT REVIEW SYNTHESIS Other

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

The sarcopenia consensus identifies low strength as a clinical finding. This is one possible contributor to locomotor decline, not a diagnosis shared by everyone with low IC.

Nervous System 4

Gait disturbance HP:0001288

Show evidence (1 reference)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"The SPPB comprises a balance test, a walking speed test and a chair rise test with scores added together to determine a person’s physical performance, including locomotor capacity."

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 6.3 identifies distinct components of locomotor assessment.

Memory impairment HP:0002354

Show evidence (1 reference)

PMID:37960903 SUPPORT PRIMARY RESULT Human Clinical

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

The adapted Toledo assessment reported preserved recall in 18% of its selected cohort. This is not a general frequency of memory impairment; the recall item had near-zero factor loading and was removed from the revised measurement model.

Cognitive impairment HP:0100543

Show evidence (1 reference)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"Common reversible conditions and risk factors that can cause cognitive decline include delirium, medication(s) and cerebrovascular diseases."

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 5.5 requires investigation of contributing conditions. The handbook also provides care for people with dementia.

Depressive symptoms Depression HP:0000716

Show evidence (1 reference)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"Feeling down, depressed or hopeless?"

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Table 3.1 asks about depressive symptoms during the previous two weeks; diagnostic assessment is separate.

Growth 1

Unintentional weight loss HP:0001824

Show evidence (1 reference)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"Have you unintentionally lost more than 3 kg over the last 3 months?"

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Table 3.1, visually checked on printed page 19: this is a screening question, not a diagnostic criterion for every person with IC decline.

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Genetic Associations

Polygenic background of intrinsic capacity (Common genetic variation is associated with variation in measured intrinsic capacity. Cohort-specific SNP-based heritability estimates were 25.2% in UK Biobank and 19.5% in CLSA.)

relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:41066301 SUPPORT PRIMARY RESULT 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."

Reports SNP-based heritability and mapped loci in UK Biobank (44,631 participants) and CLSA (13,085 participants). These are associations with measured capacity, not causal determinants of longitudinal decline.

PMID:41066301 SUPPORT PRIMARY RESULT 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."

The paper summarizes exploratory gene mapping, expression and enrichment analyses. None of the nominal pathway enrichments survived correction for multiple testing, so the wording is not treated as pathway validation.

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Medical Actions

Multicomponent Physical Activity with Nutritional Counselling

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

Platform: Behavioral / lifestyle

SPRINTT tested moderate-intensity physical activity with technological support and nutritional counselling in 1519 community-dwelling adults aged 70 or older with physical frailty and sarcopenia. In the prespecified SPPB 3–7 group (1205 participants), first mobility disability/death was reduced (HR 0.78, 95% CI 0.67–0.92); persistent mobility disability was not significantly reduced. The exploratory SPPB 8–9 group did not show benefit on the primary outcome. Strength and lean-mass benefits were sex-specific, and falls were more frequent in the lower-function intervention group. Exercise should be individualized and supervised where needed; component-specific effects cannot be separated.

Mechanism Target:

INHIBITS Locomotor Capacity Decline — Improved physical performance and reduced first mobility disability in the prespecified lower-function subgroup; no claim of universal recovery of strength or muscle mass.

Show evidence (3 references)

PMID:35545258 SUPPORT PRIMARY RESULT 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 PRIMARY RESULT 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."

Reports a physical-performance outcome in the selected trial population; SPPB is one locally applicable locomotor assessment.

PMID:35545258 SUPPORT PRIMARY RESULT Human Clinical

"Falls were recorded in 80/605 (13.2%) participants in the multicomponent intervention group and 49/600 (8.2%) in the lifestyle education group (1.62, 1.16 to 2.27)."

Safety result in the prespecified SPPB 3–7 group; improvement in mobility does not imply fewer falls.

In-Hospital Multicomponent Exercise Training

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

Platform: Behavioral / lifestyle

A pooled analysis of two randomized trials enrolled 570 acutely hospitalized adults aged 75 or older (mean 87.3 years). In-hospital multicomponent exercise improved a five-domain IC score by 7.74 points versus standard care. Higher discharge IC was associated with lower subsequent mortality, but this association is not proof that exercise reduced mortality. Emergency visits and readmissions were not associated with discharge IC in this analysis.

Mechanism Target:

INHIBITS Composite Intrinsic Capacity Decline — Improved the measured five-domain IC score during acute hospitalization; does not establish the causal effect of hospitalization or a survival benefit.

Show evidence (1 reference)

PMID:40188489 SUPPORT PRIMARY RESULT 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

Platform: Behavioral / lifestyle

A Singapore pre/post study compared exercise, exercise plus cognitive stimulation, and a control group from another clinic. Allocation was not randomized, participants and assessors were unblinded, and analyses included 187 participants completing baseline and three-month assessments. A four-domain IC composite improved in the intervention groups; cognition improved at three months in the combined group. Baseline differences, clinic selection and varying vitality definitions limit causal interpretation; hearing and vision were not measured.

Show evidence (3 references)

PMID:38616369 SUPPORT PRIMARY RESULT Human Clinical

"Participants and outcome assessors were not blinded and there was no concealment."

Methodological limit of this nonrandomized evaluation.

PMID:38616369 SUPPORT PRIMARY RESULT Human Clinical

"There was no randomisation within the intervention groups and enrolment was based on which of the two research staff who recruited them."

Recruiter-dependent allocation prevents treating the comparison as a randomized estimate.

PMID:38616369 SUPPORT PRIMARY RESULT Human Clinical

"At 3 months, both Ex and Ex +CST showed improvement in IC composite scores, locomotion, and psychological domain scores but improvement in cognition domain only in Ex + CST group."

Reported short-term changes in the four-domain composite; no definitive isolated cognitive-stimulation effect is inferred.

Group-Based Multidomain Intervention with Brain-Structure Outcomes

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

Platform: Behavioral / lifestyle

ENHANCE randomized 102 Taiwanese community-dwelling adults to twice-weekly exercise, cognitive training and nutrition education or quarterly telephone education. Analyses were explicitly per-protocol: 88 completed functional follow-up and a smaller MRI subset was analyzed. Adjusted imaging analyses found less left inferior temporal grey-matter volume loss, with different regional results between urban and rural subgroups. Age/BMI imbalance, attrition, inconsistent MRI denominators in the report and the small sample limit interpretation. MRI volume changes do not establish a cellular mechanism or dementia prevention.

Show evidence (2 references)

PMID:40464147 SUPPORT PRIMARY RESULT Human Clinical

"All analyses followed a per‐protocol approach rather than intention‐to‐treat, as the study's focus on neuroanatomical changes required complete longitudinal data for meaningful interpretation."

The main methods explicitly limit the analysis to complete longitudinal data.

PMID:40464147 SUPPORT PRIMARY RESULT Human Clinical

"The results showed that the intervention group had less volume reduction or a volume increment in regions over the left inferior temporal lobe (left inferior temporal gyrus) than the control group over 12 months."

Adjusted imaging finding; does not identify a biological mediator or show prevention of dementia.

Multidomain Lifestyle Intervention for Cognitive Decline

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

Platform: Behavioral / lifestyle

FINGER randomized 1,260 adults aged 60–77 at increased dementia risk to two years of diet, exercise, cognitive training and vascular-risk monitoring or general advice. Modified intention-to-treat analysis showed a small benefit in neuropsychological test performance (between-group annual change 0.022 z-score units, 95% CI 0.002–0.042). This was not a demonstrated reduction in incident dementia. Adverse events were more common in the intervention group, principally musculoskeletal pain.

Mechanism Target:

INHIBITS Cognitive Capacity Decline — Small improvement in the trajectory of neuropsychological test performance in the studied at-risk population; no dementia-incidence effect is established by this report.

Show evidence (2 references)

PMID:25771249 SUPPORT PRIMARY RESULT 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 modified intention-to-treat analysis included 1,190 of 1,260 randomized participants and found a small annual difference in neuropsychological test performance.

PMID:25771249 SUPPORT PRIMARY RESULT 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)."

Adverse events were more frequent in the intervention arm and were principally musculoskeletal pain; the combined intervention does not isolate component-specific causation.

ICOPE Integrated Person-Centred Care Pathway

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

Platform: Other

The second-edition WHO ICOPE pathway comprises basic assessment and community-level interventions, in-depth assessment, a personalized care plan, and implementation with monitoring. Care addresses the person’s goals, affected domains, underlying diseases, medications, social and physical environment, and support needs of carers. A Beijing implementation trial reported small six-month domain differences after propensity-score matching; it supports feasibility in that setting rather than a uniform effect of every pathway component.

Show evidence (2 references)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"The ICOPE care pathway consists of four rather than five steps:"

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 1.4 describes the revised pathway.

PMID:38251736 SUPPORT PRIMARY RESULT Human Clinical

"After 1 to 1 propensity score matching, participants in intervention and control groups (totally 938) had comparable baseline characteristics"

Published results used a propensity-matched subset after initial randomization; the report supports context-specific feasibility and preliminary domain effects.

Hearing Intervention with Hearing Aid Provision

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

Platform: Device

Audiological assessment, hearing-aid fitting, communication strategies and follow-up can improve audibility and communication. In ACHIEVE (977 adults aged 70–84), hearing intervention did not reduce three-year global cognitive decline overall. A prespecified recruitment-source analysis found less decline in the higher-risk ARIC subgroup, but not in healthier newly recruited volunteers; incident cognitive impairment was not significantly reduced. Hearing aids compensate for impairment and do not reverse its underlying cause.

Mechanism Target:

MODULATES Hearing Capacity Decline — Amplification and rehabilitation improve communication despite persistent underlying hearing impairment.

Show evidence (1 reference)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"It helps to amplify sounds to allow a person with hearing loss to better hear speech and other sounds."

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 9.4.3 explains the functional action of a hearing aid.

Show evidence (3 references)

PMID:37478886 SUPPORT PRIMARY RESULT Human Clinical

"The hearing intervention did not reduce 3-year cognitive decline in the primary analysis of the total cohort."

Primary randomized cognitive endpoint was null.

PMID:37478886 SUPPORT PRIMARY RESULT Human Clinical

"In the ARIC cohort, HI was associated with a 48% reduction in 3-year cognitive change compared to SA control"

Prespecified recruitment-source subgroup result; it does not establish universal cognitive or dementia prevention.

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"It is important to explain to people that hearing aids do not cure or treat hearing loss."

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Hearing aid amplification supports function without repairing the cause.

ICOPE Basic Assessment and Referral

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

Brief questions and tests identify possible losses in cognition, mobility, nutrition, vision, hearing and psychological capacity. The second-edition first step also considers urinary incontinence, social support and carers, and can provide immediate community-level advice and support. Positive results prompt further assessment; testing alone does not demonstrate prevention of disability.

Show evidence (3 references)

PMID:36098317 SUPPORT PRIMARY RESULT 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."

Of 7,367 participants eligible for six-month follow-up, 5,185 (70.4%) repeated Step 1. This supports implementation feasibility without establishing clinical benefit.

PMID:36098317 SUPPORT PRIMARY RESULT 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.

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"A potential impairment of intrinsic capacity needs to be confirmed by applying the tools/tests, that are locally available and validated."

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 3.2.1 requires confirmation of potential impairment.

Individualized Nutritional Care

Category: Therapeutic Action: Individualized Nutritional Care Ontology label: Supportive Care NCIT:C15747

Platform: Other

Assess nutritional status, food access, oral/swallowing problems, diseases and medications; provide personalized dietary advice and weight follow-up. Oral supplemental nutrition is considered when ordinary food intake is insufficient, with specialist assessment for established malnutrition.

Mechanism Target:

MODULATES Malnutrition — Assess nutritional status, food access, oral/swallowing problems, diseases and medications; provide personalized dietary advice and weight follow-up. Oral supplemental nutrition is considered when ordinary food intake is insufficient, with specialist assessment for established malnutrition.

Show evidence (1 reference)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"OSN should be prescribed only when a person cannot consume sufficient calorie- and nutrient-dense regular food or when OSN is a temporary strategy in addition to regular food to increase caloric intake."

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 7.4.2 bounds the indication for oral supplemental nutrition.

Show evidence (1 reference)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 7.4.2 bounds the indication for oral supplemental nutrition.

Vision Correction and Rehabilitation

Category: Therapeutic Action: Vision Correction and Rehabilitation Ontology label: Supportive Care NCIT:C15747

Platform: Other

Assess the cause of visual impairment and provide appropriate refractive correction or referral for eye disease. Low-vision rehabilitation and assistive products support daily activities where correction cannot restore adequate vision.

Mechanism Target:

MODULATES Visual impairment — Assess the cause of visual impairment and provide appropriate refractive correction or referral for eye disease. Low-vision rehabilitation and assistive products support daily activities where correction cannot restore adequate vision.

Show evidence (1 reference)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"Corrective measures such as spectacles, contact lenses and refractive surgery can effectively manage refractive errors."

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 8.4.2 supports correction for refractive causes; section 8.4.3 separately addresses irreversible impairment.

Show evidence (1 reference)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"Corrective measures such as spectacles, contact lenses and refractive surgery can effectively manage refractive errors."

Stepped Psychological Care

Category: Therapeutic Action: Stepped Psychological Care Ontology label: Supportive Care NCIT:C15747

Platform: Other

Assess depressive symptoms, severity and underlying stressors; offer stress management, psychoeducation and, when needed, structured psychological interventions. Moderate-to-severe depression requires a specific mental-health assessment and treatment plan, including assessment of self-harm risk.

Mechanism Target:

MODULATES Depressive symptoms — Assess depressive symptoms, severity and underlying stressors; offer stress management, psychoeducation and, when needed, structured psychological interventions. Moderate-to-severe depression requires a specific mental-health assessment and treatment plan, including assessment of self-harm risk.

Show evidence (1 reference)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"It is recommended to apply a stepped care approach , starting with a self-help low-intensity intervention (stress management) and monitoring symptoms and provision of further interventions, in case of no improvement or worsening."

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 10.4 recommends stepped care, with separate management of established moderate-to-severe depression.

Show evidence (1 reference)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 10.4 recommends stepped care, with separate management of established moderate-to-severe depression.

Cognitive Assessment and Rehabilitation

Category: Therapeutic Action: Cognitive Assessment and Rehabilitation Ontology label: Supportive Care NCIT:C15747

Platform: Other

Investigate delirium, medication effects, vascular and other causes of cognitive loss. Consider cognitive stimulation, training and rehabilitation within an individualized plan; people with dementia may need a specific pathway. Cognitive decline alone is not an indication for anti-dementia medication.

Mechanism Target:

MODULATES Cognitive Capacity Decline — Investigate delirium, medication effects, vascular and other causes of cognitive loss. Consider cognitive stimulation, training and rehabilitation within an individualized plan; people with dementia may need a specific pathway. Cognitive decline alone is not an indication for anti-dementia medication.

Show evidence (1 reference)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"Cognitive stimulation therapy, cognitive training, CBT, and referral to rehabilitation services"

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 5.4 lists interventions to consider alongside management of underlying conditions.

Show evidence (2 references)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"Cognitive stimulation therapy, cognitive training, CBT, and referral to rehabilitation services"

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 5.4 lists interventions to consider alongside management of underlying conditions.

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"Prescription of anti-dementia medicines for cognitive decline without diagnosis of dementia is not recommended."

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 5.4 explicitly separates domain impairment from a dementia diagnosis.

Integrated Multidomain Care in Multimorbid Older Adults

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

Platform: Behavioral / lifestyle

An ancillary TIGER randomized-trial analysis in 398 community-dwelling adults aged 65 or older with at least three chronic conditions found greater improvement in measured IC during a 12-month integrated multidomain program than usual care, mainly in locomotion and cognition. Biomarker changes were associated with IC changes but do not establish mediation or efficacy of an isolated component.

Mechanism Target:

MODULATES Composite Intrinsic Capacity Decline — Improved the measured composite in this selected multimorbid population.

Show evidence (1 reference)

PMID:37949432 SUPPORT PRIMARY RESULT Human Clinical

"The intervention arm had greater improvement in IC than the usual care arm (overall difference 1.5; 95% CI 0.5-2.5; P = .005)"

Ancillary analysis of 398 randomized participants; the result is tied to the study-specific IC instrument.

🔬

Biochemical Markers

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 PRIMARY RESULT 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 PRIMARY RESULT 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 REVIEW SYNTHESIS 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 REVIEW SYNTHESIS 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.

DNA methylation estimate of intrinsic capacity (Research score associated with measured IC and later mortality)

Context: Elastic-net model using 91 CpG sites in 933 INSPIRE-T participants; external mortality associations evaluated in 1,680 Framingham Heart Study participants.

Show evidence (3 references)

PMID:40467932 SUPPORT PRIMARY RESULT Human Clinical

"We built the predictive model using elastic net regression and tenfold cross-validation"

Describes derivation of the research predictor, not prospective clinical utility.

PMID:40467932 SUPPORT PRIMARY RESULT Human Clinical

"Therefore, we excluded samples with an IC below 0.55, which accounted for 2.9% of the total data."

A material limitation for the people with the most severely reduced capacity.

PMID:40467932 SUPPORT PRIMARY RESULT Human Clinical

"Also, despite identifying a strong association between IC and the immune system, it is unclear whether causal relationships underlie this association"

The authors explicitly distinguish association from a causal immune mechanism.

🔬

Diagnosis

WHO ICOPE Basic and In-Depth Assessment

Use brief domain questions/tests as the first assessment, followed by locally validated confirmatory measures for affected domains. In-depth assessment also reviews diseases, medication, the person’s goals, and social and physical environments. Examples include cognitive testing, nutritional assessment, SPPB and vision/hearing assessment; instruments and cutoffs require local adaptation. No single composite cutoff defines all affected people.

Show evidence (2 references)

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"There are three key elements to an in-depth assessment; investigating and confirming impairment of intrinsic capacity; evaluating underlying diseases and risk factors; and assessing the person’s social and physical environment."

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 3.2 specifies the content of assessment.

url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content SUPPORT REVIEW SYNTHESIS Other

"A potential impairment of intrinsic capacity needs to be confirmed by applying the tools/tests, that are locally available and validated."

WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 3.2.1 separates potential loss on basic assessment from confirmation.

📈

Progression

Heterogeneous measured trajectories

In 1,271 MAPT participants, four assessed domains followed five model-derived patterns over four years. A separate Taiwan analysis identified four different groups from repeated adapted domain measures in 1,782 selected survivors through the trajectory period, followed for later outcomes. These are cohort-specific statistical groups, not a universal sequence or causal disease subtypes. The Taiwanese sensory, appetite and several other measures were self-reported; appetite loss alone is not a general diagnosis of malnutrition.

Show evidence (2 references)

PMID:37620614 SUPPORT PRIMARY RESULT 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%)."

Reports the fitted MAPT groups; low levels within a trajectory are not necessarily newly incident decline.

PMID:38029399 SUPPORT PRIMARY RESULT 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)."

The Taiwan study used 1996–2007 trajectories and subsequent four- and eight-year outcome follow-up. Its grouping differs from MAPT and does not establish a common molecular cause.

Transitions between capacity states

The 10/66 analysis used two-wave latent transition models in 14,923 adults aged 65 years and older from selected catchments in seven countries. Some model-estimated improvement occurred, but movement to high IC was not observed over the studied interval. This does not prove biological irreversibility. The abstract and main Discussion conflict about whether 61% worsened or remained stable, so the disputed overall proportions are not used here.

Show evidence (2 references)

PMID:37517058 SUPPORT PRIMARY RESULT Human Clinical

"The latent statuses consider the quantity and quality of the domains affected."

The status labels describe patterns of impairment rather than prior within-person rates of decline.

PMID:37517058 SUPPORT PRIMARY RESULT Human Clinical

"There was no reversion to the high IC status."

A finding of this fitted model over one follow-up interval; it does not show that an individual cannot improve or that treatment cannot help.

Association with later functional limitation and mortality

Lower baseline IC predicts later functional difficulty in several cohorts, but an association does not establish the effect of changing the score. In ELSA, participants with baseline ADL/IADL difficulty were excluded; both IC and multimorbidity predicted incident ADL loss, while only IC independently predicted IADL loss. In 10/66, baseline latent status, rather than within-person change itself, predicted outcomes; the highest-impairment group had adjusted mortality HR 1.89 (95% CI 1.63–2.19) relative to high IC, compared with unadjusted HR 4.60. Neither analysis establishes universal superiority over frailty measures or inevitable care dependence.

Show evidence (3 references)

PMID:31678933 SUPPORT PRIMARY RESULT Human Clinical

"Both intrinsic capacity score and multimorbidity independently predicted incident loss of ADLs, however only intrinsic capacity independently predicted incident loss of IADLs."

The ELSA analysis used baseline capacity and later self-reported functional difficulty; this is prognostic information beyond the included disease count.

PMID:37517058 SUPPORT PRIMARY RESULT Human Clinical

"Mortality was nearly five times higher amongst those with high deterioration with cognitive impairment latent status than those with high IC latent status (HR = 4.60, 95%CI 4.16; 5.09), and about twofold when adjusted for age, sex, education and comorbidities (aHR = 1.89, 95%CI 1.63; 2.19)."

The fully qualified main-text result distinguishes adjusted from unadjusted association.

PMID:38945130 SUPPORT REVIEW SYNTHESIS Human Clinical

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

The systematic review included 37 longitudinal studies, with 31 contributing to meta-analyses. Instruments, populations and effect estimates varied.

Birth-cohort differences in capacity

Analyses of 14,710 ELSA and 11,411 CHARLS participants aged 60 years and older found higher entry levels and less steep average IC declines in more recent birth cohorts. These population averages do not imply a uniformly downward individual trajectory, identify a treatment effect, or generalize to other countries and future cohorts. CHARLS had shorter follow-up and its domain measurement invariance was incomplete; sex-specific scores were not directly comparable.

Show evidence (1 reference)

PMID:39702725 SUPPORT PRIMARY RESULT 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."

Repeated-measure cohort models support secular differences. Proposed education, nutrition and healthcare explanations were not experimentally established.

📊

Prevalence

Community-dwelling adults aged 60 years and older in 15 studies, predominantly from Asia

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

Random-effects pooled prevalence of impairment in at least one IC domain among 33,070 participants: 67.8% (95% CI 57.0–78.5%). Between-study heterogeneity was extreme (I² 99.86%); estimates ranged from 17.1% to 98.2%. Fourteen studies were from Asia, including eleven from China, and one was from Spain. Instruments and thresholds differed. This is not a worldwide disease prevalence, a longitudinal incidence of decline, or evidence that decline is inevitable.

Show evidence (1 reference)

PMID:39088112 SUPPORT REVIEW SYNTHESIS 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

Baseline Step 1 positivity in 10,903 primary-care participants aged 60 years and older in Occitania. Of 10,285 positive participants, only 958 underwent Step 2 assessment and 865 of those had confirmed impairment. Selective follow-up prevents estimation of the overall false-positive proportion; the 94.3% figure does not establish overdiagnosis or general-population prevalence.

Show evidence (1 reference)

PMID:36098317 SUPPORT PRIMARY RESULT 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

Impairments across physical and mental capacity can affect independence, communication, mobility and well-being. A systematic review of 37 longitudinal studies comprising 206,693 participants found associations with subsequent functional decline and mortality. Burden varies with affected domains, severity, coexisting disease and environmental support. The evidence does not make this condition universal in older adults or establish that every improvement in an IC score prevents death or disability.

Show evidence (1 reference)

PMID:38945130 SUPPORT REVIEW SYNTHESIS Human Clinical

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

Supports substantial prognostic burden while remaining observational.

🔬

Clinical Trials

NCT02582138 NOT_APPLICABLE UNKNOWN

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: Muscle weakness HP:0001324 Gait disturbance HP:0001288

Show evidence (1 reference)

clinicaltrials:NCT02582138 SUPPORT PRIMARY RESULT 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 randomized 977 adults aged 70–84 with untreated hearing loss to hearing intervention or health education. Recruitment included 238 ARIC participants and 739 newly recruited volunteers; the primary outcome was three-year global cognitive change.

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

Show evidence (1 reference)

clinicaltrials:NCT03243422 SUPPORT PRIMARY RESULT 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 registry identifies the hearing-intervention study. The overall null cognitive result and prespecified subgroup finding are described with publication evidence in treatments.

NCT01041989 NOT_APPLICABLE UNKNOWN

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 HP:0100543

Show evidence (1 reference)

clinicaltrials:NCT01041989 SUPPORT PRIMARY RESULT 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 NOT_APPLICABLE 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 HP:0100543

Show evidence (1 reference)

clinicaltrials:NCT00672685 SUPPORT PRIMARY RESULT 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 is an observational longitudinal bio-resource platform, not a randomized treatment trial. The registry describes recruitment from age 30 upward; published cohort analyses include adults from age 20. It supports investigation of IC trajectories and biomarkers.

Show evidence (1 reference)

clinicaltrials:NCT04224038 SUPPORT PRIMARY RESULT 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.

NCT03528005 NOT_APPLICABLE COMPLETED

TIGER randomized 398 community-dwelling older adults with multimorbidity to integrated multidomain care or usual care. The ancillary IC analysis reports study-specific composite and domain outcomes over 12 months.

Show evidence (1 reference)

clinicaltrials:NCT03528005 SUPPORT PRIMARY RESULT Other

"This project aims to examine the effectiveness of the community-based integrated care service model , based on a multi-domain intervention program, among community-dwelling older adults"

Registry summary identifies the registered intervention; it does not by itself establish efficacy.

NCT05828043 NOT_APPLICABLE COMPLETED

ENHANCE randomized 102 community-dwelling older adults in urban and rural Taiwan. Its published functional and MRI outcomes use smaller per-protocol samples, not all randomized participants.

Show evidence (1 reference)

clinicaltrials:NCT05828043 SUPPORT PRIMARY RESULT Other

"The primary goal is to develop a multidomain intervention program focused on preserving global or regional brain volume and functions while simultaneously improving physical mobility and cognitive functions in older individuals with mobility frailty"

Registry summary identifies the registered intervention; it does not by itself establish efficacy.

🐁

Animal Models

Four-performance-criterion frailty model in aged mice

The Liu study assessed weakness, walking performance, activity and endurance in 27- to 28-month-old mice. Each criterion used a cutoff 1.5 standard deviations below the cohort mean; three low criteria defined frailty and two mild frailty. This is a performance-based frailty classification, not a 31-deficit index.

Species

Mouse

Genotype

Naturally aged C57BL/6 mice

Publication

PMID:24336799

Pathograph links

Locomotor Capacity Decline partially recapitulates fidelity: moderate Captures selected physical performance limitations that overlap with locomotor capacity.

Limitations: Frailty classification rather than an IC-specific mechanism or five-domain instrument.

Readouts

Inverted-cling, rotarod, wheel-running and derived endurance performance

Direction: DECREASED

Interpretation: Low performance on multiple cohort-relative criteria identifies physical frailty in this model.

Show evidence (1 reference)

PMID:24336799 SUPPORT PRIMARY RESULT Model Organism

"The criteria in mice were evaluated by the inverted-cling grip test, rotarod test, voluntary wheel running, and derived endurance scores."

These are four performance criteria in 27- to 28-month-old C57BL/6 mice, not the separate 31-item deficit-accumulation instrument.

Show evidence (1 reference)

PMID:24336799 SUPPORT PRIMARY RESULT Model Organism

"The criteria in mice were evaluated by the inverted-cling grip test, rotarod test, voluntary wheel running, and derived endurance scores."

These are four performance criteria in 27- to 28-month-old C57BL/6 mice, not the separate 31-item deficit-accumulation instrument.

The small initial cohort and cohort-relative cutoffs limit transportability. The source does not validate a five-domain human IC equivalent or measure cognitive, psychological and sensory capacity.

Show evidence (1 reference)

PMID:24336799 SUPPORT PRIMARY RESULT Model Organism

"The criteria in mice were evaluated by the inverted-cling grip test, rotarod test, voluntary wheel running, and derived endurance scores."

These are four performance criteria in 27- to 28-month-old C57BL/6 mice, not the separate 31-item deficit-accumulation instrument.

Clinical deficit-accumulation frailty index in mice

The reviewed Whitehead clinical mouse frailty index scores 31 observations across integumentary, musculoskeletal, auditory, ocular and other systems, together with body weight and temperature. It measures accumulated deficits and should not be conflated with the Liu performance criteria.

Species

Mouse

Publication

PMID:28463656

Observer characteristics, testing conditions and strain-specific deficits can influence scoring. Sensory observations are included, but comprehensive cognition and the human psychological IC domain are not established by this tool. The source evaluates frailty, not validation of the WHO IC composite.

Show evidence (1 reference)

PMID:28463656 SUPPORT INDIRECT REVIEW SYNTHESIS Model Organism

"It assesses 31 different deficits across a range of domains including the in tegument, musculoskeletal system, vestibulocochlear/auditory systems, ocular and nasa l systems, digestive system, urogenital system, respiratory system, signs of discomfort, as well as the body weight, and body surface..."

The review describes the Whitehead clinical frailty index, including auditory and ocular observations. This instrument is distinct from the four-performance-criterion model.

{ }

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) describes loss of physical and mental capacities across locomotion, vitality, cognition, psychological capacity and sensory capacity. Hearing and vision are assessed separately in the WHO ICOPE care pathway. The pattern and extent of loss vary between people and over time; a positive basic assessment requires further evaluation of the affected domains, underlying diseases, medications and environment. Lower capacity is associated with later disability, care dependence and mortality, but is distinct from frailty, sarcopenia and disability. Biological ageing mechanisms are candidate contributors; human biomarker and genetic associations do not establish a single causal pathway for the composite. Management combines a personalized care plan, domain-specific interventions and support for the person and carers.
notes: >-
  The entry retains its ICD-11 Foundation anchor; no MONDO disease term is
  substituted from the related constructs of frailty or sarcopenia. The five
  has_subtypes records are measurement domains, not mutually exclusive
  aetiological diseases. They provide subtype references for domain-specific
  records. ICOPE separates hearing and vision into six practical assessment
  domains. Screening items, confirmatory domain assessments and particular
  clinical phenotypes are kept distinct; screen-positive domain percentages are
  not phenotype frequencies. General ageing mechanisms are qualified separately
  from direct measurements of intrinsic capacity. Environmental exposure edges
  for acute hospitalization and ambient or household air pollution were
  intentionally removed rather than retargeted in this review: the
  hospitalization source now supports only the in-hospital exercise treatment,
  and the air-pollution source measured frailty rather than intrinsic capacity.
  The second-edition WHO handbook uses four care steps and calls its expanded
  first step basic assessment. Its PDF carries a 2024 copyright/suggested
  citation, although the publication website displays a later date.
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.
    quote_role: REVIEW_SYNTHESIS
  - 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.
    quote_role: REVIEW_SYNTHESIS
- name: Five-domain operational model of intrinsic capacity
  definition_type: OTHER
  derivation_basis: ESTABLISHED_CRITERIA
  description: The conceptual model comprises locomotion, vitality, cognition, psychological and sensory capacity. A general factor and five subfactors were recovered in one ELSA analysis, but operational measures and composite construction differ across studies. ICOPE assesses hearing and vision separately in practice.
  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 expert review identified the proposed five domains used in this conceptual framework.
    quote_role: REVIEW_SYNTHESIS
  - 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.
    quote_role: PRIMARY_RESULT
  - 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.
    quote_role: REVIEW_SYNTHESIS
- name: WHO working definition of vitality capacity
  definition_type: OTHER
  derivation_basis: ESTABLISHED_CRITERIA
  description: The WHO expert group proposed a working definition of vitality capacity as a physiological state arising from interactions among energy/metabolism, neuromuscular function and immune/stress responses. It is a conceptual framework for measurement development; its proposed position beneath other domains is not an established causal ordering in patients.
  scope: Working definition of the vitality domain; not a diagnostic cutoff or demonstrated intervention-mediated pathway.
  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 expert group proposed this working definition and candidate attributes; the statement does not establish a causal pathway from ageing hallmarks to clinical IC.
    quote_role: REVIEW_SYNTHESIS
- name: WHO ICOPE Step 1 screening for decline in intrinsic capacity
  definition_type: PHENOTYPE_ALGORITHM
  derivation_basis: ESTABLISHED_CRITERIA
  description: The original ICOPE Step 1 instrument uses brief questions and tests for cognition, mobility, nutrition, vision, hearing and depressive symptoms. A positive result prompts domain-specific assessment. The second-edition handbook expands Step 1 into basic assessment and community-level interventions, also considering urinary incontinence, social support and carers. Vision/hearing testing can require equipment; the instrument is not an equipment-free case definition.
  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: Published studies evaluated versions of the original screen against operational domain reference assessments. INSPIRE-T reported variable sensitivity across domains. The Toledo study evaluated an adapted instrument and found no added prognostic information from its composite over individual domains in that cohort. These results do not validate every adaptation or establish a universal diagnostic threshold, and do not constitute validation of the expanded second-edition pathway.
    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.
      quote_role: PRIMARY_RESULT
    - 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.  # codespell:ignore-line
      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.'
      quote_role: PRIMARY_RESULT
    - 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
      quote_role: PRIMARY_RESULT
      snippet: High specificity (>70%) was observed for all the IC domains, except for vision (2.7%).
      explanation: Very low vision specificity qualifies the high sensitivity quoted above.
  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.
    quote_role: PRIMARY_RESULT
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: The term "basic assessment" is used, rather than screening, to reflect the move from a sole focus on potential losses in intrinsic capacity, to also identify social support needs, carers’ needs for support and presence of urinary incontinence
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 1.4 explains the expanded first step.'
has_subtypes:
- name: Locomotor
  display_name: Locomotor capacity decline
  description: Capacity for movement, assessed through strength, walking, balance and chair-rise performance. Muscle, joint, neurological and other conditions can contribute; locomotor decline is broader than sarcopenia.
  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.
    quote_role: REVIEW_SYNTHESIS
- name: Vitality
  display_name: Vitality capacity decline
  description: A proposed physiological dimension encompassing energy and metabolism, neuromuscular function, and immune and stress responses. Practical assessments often use nutrition, strength or fatigue, with substantial variation between studies.
  evidence:
  - reference: PMID:40060276
    reference_title: The Biological Rationale for Integrating Intrinsic Capacity Into Frailty Models.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: However, vitality may not be the earliest impairment among IC domains, and other dimension vulnerabilities may present earlier than vitality due to internal environmental (genetic) and external environmental factors.
    explanation: The proposed vitality hierarchy has explicit exceptions and is not an obligatory causal ordering.
- name: Cognitive
  display_name: Cognitive capacity decline
  description: Memory, orientation and other cognitive functions. Basic assessment identifies possible impairment and prompts investigation of reversible causes and dementia where appropriate; the domain is not restricted to impairment below a dementia threshold.
  evidence:
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: For a person with dementia, a more specific, targeted or tailored approach is appropriate.
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). The cognition pathway also addresses people with dementia; screening is not confined to a pre-dementia state.'
- name: Psychological
  display_name: Psychological capacity decline
  description: Psychological well-being, commonly assessed through depressed mood and loss of interest. Positive symptom questions require further assessment and do not by themselves diagnose major depression.
  evidence:
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Interventions to manage depressive symptoms should always be provided as part of a comprehensive personalized care plan responding to underlying factors, along with interventions that address other domains of intrinsic capacity.
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Depressive symptoms constitute the practical psychological assessment and care domain.'
- name: Sensory
  display_name: Sensory capacity decline
  description: Hearing and vision capacities. These are assessed separately and need not change together; their grouping into one conceptual domain does not imply a shared lesion.
  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.
    quote_role: PRIMARY_RESULT
prevalence:
- population: Community-dwelling adults aged 60 years and older in 15 studies, predominantly from Asia
  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 impairment in at least one IC domain among 33,070 participants: 67.8% (95% CI 57.0–78.5%). Between-study heterogeneity was extreme (I² 99.86%); estimates ranged from 17.1% to 98.2%. Fourteen studies were from Asia, including eleven from China, and one was from Spain. Instruments and thresholds differed. This is not a worldwide disease prevalence, a longitudinal incidence of decline, or evidence that decline is inevitable.'
  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.
    quote_role: REVIEW_SYNTHESIS
- 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: Baseline Step 1 positivity in 10,903 primary-care participants aged 60 years and older in Occitania. Of 10,285 positive participants, only 958 underwent Step 2 assessment and 865 of those had confirmed impairment. Selective follow-up prevents estimation of the overall false-positive proportion; the 94.3% figure does not establish overdiagnosis or general-population prevalence.
  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.
    quote_role: PRIMARY_RESULT
progression:
- phase: Heterogeneous measured trajectories
  notes: In 1,271 MAPT participants, four assessed domains followed five model-derived patterns over four years. A separate Taiwan analysis identified four different groups from repeated adapted domain measures in 1,782 selected survivors through the trajectory period, followed for later outcomes. These are cohort-specific statistical groups, not a universal sequence or causal disease subtypes. The Taiwanese sensory, appetite and several other measures were self-reported; appetite loss alone is not a general diagnosis of malnutrition.
  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
    quote_role: PRIMARY_RESULT
    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: Reports the fitted MAPT groups; low levels within a trajectory are not necessarily newly incident decline.
  - 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
    quote_role: PRIMARY_RESULT
    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: The Taiwan study used 1996–2007 trajectories and subsequent four- and eight-year outcome follow-up. Its grouping differs from MAPT and does not establish a common molecular cause.
- phase: Transitions between capacity states
  notes: The 10/66 analysis used two-wave latent transition models in 14,923 adults aged 65 years and older from selected catchments in seven countries. Some model-estimated improvement occurred, but movement to high IC was not observed over the studied interval. This does not prove biological irreversibility. The abstract and main Discussion conflict about whether 61% worsened or remained stable, so the disputed overall proportions are not used here.
  evidence:
  - 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
    quote_role: PRIMARY_RESULT
    snippet: The latent statuses consider the quantity and quality of the domains affected.
    explanation: The status labels describe patterns of impairment rather than prior within-person rates of decline.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: There was no reversion to the high IC status.
    explanation: A finding of this fitted model over one follow-up interval; it does not show that an individual cannot improve or that treatment cannot help.
- phase: Association with later functional limitation and mortality
  notes: Lower baseline IC predicts later functional difficulty in several cohorts, but an association does not establish the effect of changing the score. In ELSA, participants with baseline ADL/IADL difficulty were excluded; both IC and multimorbidity predicted incident ADL loss, while only IC independently predicted IADL loss. In 10/66, baseline latent status, rather than within-person change itself, predicted outcomes; the highest-impairment group had adjusted mortality HR 1.89 (95% CI 1.63–2.19) relative to high IC, compared with unadjusted HR 4.60. Neither analysis establishes universal superiority over frailty measures or inevitable care dependence.
  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
    quote_role: PRIMARY_RESULT
    snippet: Both intrinsic capacity score and multimorbidity independently predicted incident loss of ADLs, however only intrinsic capacity independently predicted incident loss of IADLs.
    explanation: The ELSA analysis used baseline capacity and later self-reported functional difficulty; this is prognostic information beyond the included disease count.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: Mortality was nearly five times higher amongst those with high deterioration with cognitive impairment latent status than those with high IC latent status (HR = 4.60, 95%CI 4.16; 5.09), and about twofold when adjusted for age, sex, education and comorbidities (aHR = 1.89, 95%CI 1.63; 2.19).
    explanation: The fully qualified main-text result distinguishes adjusted from unadjusted association.
  - 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
    quote_role: REVIEW_SYNTHESIS
    snippet: Intrinsic capacity is inversely associated with functional decline and mortality risk in older adults.
    explanation: The systematic review included 37 longitudinal studies, with 31 contributing to meta-analyses. Instruments, populations and effect estimates varied.
- phase: Birth-cohort differences in capacity
  notes: Analyses of 14,710 ELSA and 11,411 CHARLS participants aged 60 years and older found higher entry levels and less steep average IC declines in more recent birth cohorts. These population averages do not imply a uniformly downward individual trajectory, identify a treatment effect, or generalize to other countries and future cohorts. CHARLS had shorter follow-up and its domain measurement invariance was incomplete; sex-specific scores were not directly comparable.
  evidence:
  - reference: PMID:39702725
    reference_title: Cohort trends in intrinsic capacity in England and China.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    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: Repeated-measure cohort models support secular differences. Proposed education, nutrition and healthcare explanations were not experimentally established.
clinical_burden:
  burden_level: HIGH
  rationale: Impairments across physical and mental capacity can affect independence, communication, mobility and well-being. A systematic review of 37 longitudinal studies comprising 206,693 participants found associations with subsequent functional decline and mortality. Burden varies with affected domains, severity, coexisting disease and environmental support. The evidence does not make this condition universal in older adults or establish that every improvement in an IC score prevents death or disability.
  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
    quote_role: REVIEW_SYNTHESIS
    snippet: Intrinsic capacity is inversely associated with functional decline and mortality risk in older adults.
    explanation: Supports substantial prognostic burden while remaining observational.
pathophysiology:
- name: Mitochondrial Bioenergetic Decline
  biological_scale: CELLULAR
  description: Reduced skeletal-muscle mitochondrial oxidative capacity can limit energy provision for contraction. Human muscle studies and experimental models support its relevance to physical performance, but the magnitude and direction of its contribution to measured intrinsic capacity remain unresolved. Circulating GDF-15 is a stress correlate rather than a direct mitochondrial-function measurement.
  evidence:
  - reference: PMID:38396729
    reference_title: Mitochondrial Quantity and Quality in Age-Related Sarcopenia.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Mitochondrial dysfunction has been indicated as a key contributor to skeletal myocyte decline and loss of physical performance with aging.
    explanation: The review synthesizes human associations and experimental muscle biology. It supports a candidate contribution to physical performance, not a demonstrated cause of the five-domain IC composite.
    directness: INDIRECT
  biological_processes:
  - preferred_term: oxidative phosphorylation
    term:
      id: GO:0006119
      label: oxidative phosphorylation
    modifier: DECREASED
  downstream:
  - target: Locomotor Capacity Decline
    description: Candidate contribution through impaired muscle energetics and contractile performance; neither all locomotor impairment nor all intrinsic-capacity decline is attributed to this process.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38396729
      reference_title: Mitochondrial Quantity and Quality in Age-Related Sarcopenia.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: Mitochondrial dysfunction has been indicated as a key contributor to skeletal myocyte decline and loss of physical performance with aging.
      explanation: The review synthesizes human associations and experimental muscle biology. It supports a candidate contribution to physical performance, not a demonstrated cause of the five-domain IC composite.
      directness: INDIRECT
    hypothesis_groups:
    - geroscience_contributors
    intermediate_mechanisms:
    - Reduced energy provision for sustained skeletal-muscle contraction
- name: Senescent Cell Accumulation in Ageing Tissue
  biological_scale: CELLULAR
  description: Senescent cells can accumulate with age in some tissues. Increased generation and reduced clearance are possible contributors, with variation between tissues and models. This is a candidate ageing mechanism; the cited sources do not directly measure senescent-cell burden against the clinical IC composite.
  evidence:
  - reference: PMID:23746838
    reference_title: The hallmarks of aging.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Conceivably, the accumulation of senescent cells with aging can reflect an increase in the rate of generation of senescent cells and/or a decrease in their rate of clearance, for example, as a consequence of an attenuated immune response.
    explanation: The review proposes alternative routes to accumulation and reports tissue heterogeneity. It does not establish impaired clearance as the sole mechanism in human IC decline.
    directness: INDIRECT
  conforms_to: cellular_senescence#Senescent Cell Accumulation
  biological_processes:
  - preferred_term: cellular senescence
    term:
      id: GO:0090398
      label: cellular senescence
    modifier: INCREASED
  downstream:
  - target: Senescence-Associated Proinflammatory Secretion
    description: Senescent cells can acquire a proinflammatory secretory phenotype; its disease-specific contribution remains a hypothesis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23746838
      reference_title: The hallmarks of aging.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: senescent cells manifest dramatic alterations in their secretome, which is particularly enriched in pro-inflammatory cytokines and matrix metalloproteinases
      explanation: This synthesis describes the senescence-associated secretory phenotype in general ageing biology; it does not show that this is the principal inflammatory source in people with low IC.
      directness: INDIRECT
    hypothesis_groups:
    - geroscience_contributors
- name: Senescence-Associated Proinflammatory Secretion
  biological_scale: CELLULAR
  description: The senescence-associated secretory phenotype includes proinflammatory cytokines and matrix-remodelling factors. Persistent secretion is a proposed contributor to age-associated inflammation, without evidence here that it dominates other inflammatory sources or mediates observed IC trajectories.
  evidence:
  - reference: PMID:23746838
    reference_title: The hallmarks of aging.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: senescent cells manifest dramatic alterations in their secretome, which is particularly enriched in pro-inflammatory cytokines and matrix metalloproteinases
    explanation: This synthesis describes the senescence-associated secretory phenotype in general ageing biology; it does not show that this is the principal inflammatory source in people with low IC.
    directness: INDIRECT
  biological_processes:
  - preferred_term: cytokine production
    term:
      id: GO:0001816
      label: cytokine production
    modifier: INCREASED
  downstream:
  - target: Chronic Low-Grade Inflammation
    description: Persistent proinflammatory secretion is one candidate contributor to systemic inflammation; clinical IC mediation has not been established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23746838
      reference_title: The hallmarks of aging.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: senescent cells manifest dramatic alterations in their secretome, which is particularly enriched in pro-inflammatory cytokines and matrix metalloproteinases
      explanation: This synthesis describes the senescence-associated secretory phenotype in general ageing biology; it does not show that this is the principal inflammatory source in people with low IC.
      directness: INDIRECT
    hypothesis_groups:
    - geroscience_contributors
- name: Chronic Low-Grade Inflammation
  biological_scale: ORGANISM
  description: Age-associated low-grade inflammation is a candidate contributor to functional decline. In the MAPT cohort, higher IL-6 and TNF receptor-1 were associated with adverse IC trajectory groups. Circulating markers neither identify a unique cellular source nor establish sterile inflammation, causal mediation or a treatment target for every person with IC decline.
  evidence:
  - reference: PMID:38145874
    reference_title: 'From biological aging to functional decline: Insights into chronic inflammation and intrinsic capacity.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    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 review describes association rather than an intervention establishing causation, and reports inconsistent biomarker findings.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: Higher IL-6 and GDF-15 also increased the risk of being in the "low locomotion" group.
    explanation: This is an observational association with trajectory membership, not an experimentally induced change in locomotion.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
- name: Vitality Capacity Decline
  biological_scale: ORGANISM
  description: Reduced physiological capacity across energy and metabolism, neuromuscular function, and immune and stress responses, as proposed by the WHO expert working group. Studies operationalize vitality differently using nutritional assessment, strength, fatigue or other measures. Its proposed position beneath the other IC domains is a conceptual hypothesis, not a demonstrated universal causal hierarchy.
  evidence:
  - reference: PMID:36356628
    reference_title: WHO working definition of vitality capacity for healthy longevity monitoring.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    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 expert consensus supplies a working definition and candidate attributes; operational measurement still requires validation.
  subtypes:
  - Vitality
- name: Locomotor Capacity Decline
  biological_scale: ORGANISM
  description: Reduced movement capacity can involve strength, gait, balance and chair-rise performance. Muscle disease is one contributor among musculoskeletal, neurological and other conditions. Locomotor impairment is not equivalent to sarcopenia, and a performance score does not by itself establish muscle atrophy.
  evidence:
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: The SPPB comprises a balance test, a walking speed test and a chair rise test with scores added together to determine a person’s physical performance, including locomotor capacity.
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 6.3 describes the measured domain without assigning a single tissue pathology.'
  subtypes:
  - Locomotor
- name: Cognitive Capacity Decline
  biological_scale: ORGANISM
  description: Reduced memory, orientation and other cognitive functions may reflect reversible conditions, medication effects, vascular or neurodegenerative disease. The domain includes people with dementia and is not defined by a pre-dementia ceiling. Associations between overall IC deficit scores and incident dementia do not isolate the causal effect of the cognitive domain.
  evidence:
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Common reversible conditions and risk factors that can cause cognitive decline include delirium, medication(s) and cerebrovascular diseases.
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 5.5 directs investigation of contributing conditions.'
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: For a person with dementia, a more specific, targeted or tailored approach is appropriate.
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). The cognition care pathway includes dementia.'
  subtypes:
  - Cognitive
  biological_processes:
  - preferred_term: cognition
    term:
      id: GO:0050890
      label: cognition
    modifier: DECREASED
  locations:
  - preferred_term: Brain
    term:
      id: UBERON:0000955
      label: brain
- name: Psychological Capacity Decline
  biological_scale: ORGANISM
  description: Reduced psychological well-being is assessed through depressed mood and loss of interest, with further evaluation of severity, stressors, underlying conditions and social context. Associations with recent pain do not demonstrate that pain causes subsequent decline or that treating pain restores this domain.
  evidence:
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Interventions to manage depressive symptoms should always be provided as part of a comprehensive personalized care plan responding to underlying factors, along with interventions that address other domains of intrinsic capacity.
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 10.4 describes psychological care in the multidomain context.'
  subtypes:
  - Psychological
- name: Hearing Capacity Decline
  biological_scale: ORGANISM
  description: Reduced auditory function affects access to speech and other sounds. Age-associated impairment, ear disease and reversible causes require assessment. Amplification and rehabilitation may improve communication while underlying hearing loss persists; cognitive prevention is not assumed from improvement in audibility.
  evidence:
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: It is important to explain to people that hearing aids do not cure or treat hearing loss.
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 9.4.3 separates communication support from reversal of the lesion.'
  subtypes:
  - Sensory
- name: Visual Capacity Decline
  biological_scale: ORGANISM
  description: Reduced near or distance vision can result from refractive error and eye disease. Its mechanism and reversibility depend on the cause. Vision and hearing remain separate clinical processes even when included within one conceptual sensory domain.
  evidence:
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Management of refractive errors includes regular eye examinations and comprehensive vision and eye care.
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 8.4.2 identifies one cause-specific management route.'
  subtypes:
  - Sensory
- name: Composite Intrinsic Capacity Decline
  biological_scale: ORGANISM
  description: A reduction in a composite measure of physical and mental capacity across the assessed domains. Instruments differ in item choice, scoring and domain coverage; factor structure and prediction are properties of each operational measure. Combining domain scores is a measurement relation, not evidence that one biological state causes another. Functional ability also depends on the surrounding environment.
  evidence:
  - reference: PMID:26520231
    reference_title: 'The World report on ageing and health: a policy framework for healthy ageing.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: the combination of the intrinsic capacity of the individual, relevant environmental characteristics, and the interactions between the individual and these characteristics.
    explanation: The WHO policy framework distinguishes capacity from functional ability and its environmental determinants.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: The IST included as a composite in a model with the individual domains showed no statistically significant associations with any of the outcomes  # codespell:ignore-line
    explanation: In the adapted Toledo instrument, the composite added no statistically significant prognostic information for these outcomes; this result does not invalidate all IC instruments.
phenotypes:
- category: Locomotor
  name: Muscle weakness
  subtype: Locomotor
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  description: Reduced muscle strength can contribute to locomotor impairment. Chair-rise performance is a functional assessment influenced by several systems; a low locomotor-domain score alone does not establish muscle weakness or sarcopenia.
  evidence:
  - 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: The sarcopenia consensus identifies low strength as a clinical finding. This is one possible contributor to locomotor decline, not a diagnosis shared by everyone with low IC.
    quote_role: REVIEW_SYNTHESIS
- category: Locomotor
  name: Gait disturbance
  subtype: Locomotor
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  description: Impaired walking performance is one manifestation of locomotor decline. Walking speed is evaluated alongside balance and chair-rise ability in the Short Physical Performance Battery; the composite score is not specific to gait.
  evidence:
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: The SPPB comprises a balance test, a walking speed test and a chair rise test with scores added together to determine a person’s physical performance, including locomotor capacity.
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 6.3 identifies distinct components of locomotor assessment.'
- category: Cognitive
  name: Memory impairment
  subtype: Cognitive
  phenotype_term:
    preferred_term: Memory impairment
    term:
      id: HP:0002354
      label: Memory impairment
  description: Difficulty recalling information can be detected by brief memory questions and recall testing. Failure on a brief test requires interpretation in context and further cognitive assessment; no general phenotype frequency is inferred from a cohort screening result.
  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: The adapted Toledo assessment reported preserved recall in 18% of its selected cohort. This is not a general frequency of memory impairment; the recall item had near-zero factor loading and was removed from the revised measurement model.
    quote_role: PRIMARY_RESULT
- category: Cognitive
  name: Cognitive impairment
  subtype: Cognitive
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  description: Impaired cognition may involve memory, orientation and other functions. Evaluation considers delirium, medication effects, vascular disease and dementia; the IC construct does not require the absence of dementia.
  evidence:
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Common reversible conditions and risk factors that can cause cognitive decline include delirium, medication(s) and cerebrovascular diseases.
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 5.5 requires investigation of contributing conditions. The handbook also provides care for people with dementia.'
- category: Vitality
  name: Malnutrition
  subtype: Vitality
  phenotype_term:
    preferred_term: Malnutrition
    term:
      id: HP:0004395
      label: Malnutrition
  description: Malnutrition can accompany low vitality. It requires nutritional assessment and is distinct from an initial positive weight-loss or appetite screen and from being at risk of malnutrition.
  evidence:
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: In cases of malnutrition, health workers need to give immediate personalized dietary advice (nutritional counselling) and assess and manage contributing factors.
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 7.4.2 distinguishes established malnutrition from the risk category.'
- category: Vitality
  name: Unintentional weight loss
  subtype: Vitality
  phenotype_term:
    preferred_term: Unintentional weight loss
    term:
      id: HP:0001824
      label: Weight loss
  description: Recent unintentional weight loss is assessed separately from appetite loss in ICOPE basic assessment. It prompts nutritional evaluation and investigation of underlying causes.
  evidence:
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Have you unintentionally lost more than 3 kg over the last 3 months?
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Table 3.1, visually checked on printed page 19: this is a screening question, not a diagnostic criterion for every person with IC decline.'
- category: Psychological
  name: Depressive symptoms
  subtype: Psychological
  phenotype_term:
    preferred_term: Depressive symptoms
    term:
      id: HP:0000716
      label: Depression
  description: Depressed mood is assessed alongside loss of interest in the psychological domain. A positive symptom assessment prompts evaluation of severity, stressors and other causes; it does not by itself establish major depressive disorder.
  evidence:
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Feeling down, depressed or hopeless?
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Table 3.1 asks about depressive symptoms during the previous two weeks; diagnostic assessment is separate.'
- category: Sensory
  name: Hearing impairment
  subtype: Sensory
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  description: Reduced hearing can impair communication. Assessment includes history and hearing tests, with investigation of reversible causes and referral when needed. A hearing aid can improve audibility and communication without reversing the underlying lesion.
  evidence:
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: It is important to explain to people that hearing aids do not cure or treat hearing loss.
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 9.4.3 distinguishes amplification from reversal of the underlying impairment.'
  - 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
    quote_role: PRIMARY_RESULT
    snippet: The hearing intervention demonstrated evidence of target engagement based on self-reported hours of hearing aid use and reduction in self-perceived communication impairment after HI
    explanation: The ACHIEVE result supports communication benefit; its cognitive endpoint is assessed separately.
- category: Sensory
  name: Visual impairment
  subtype: Sensory
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  description: Reduced visual function may reflect refractive error or eye disease. Basic assessment includes near and distance vision with usual correction, followed by eye assessment where indicated; the cause and potential reversibility vary.
  evidence:
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Management of refractive errors includes regular eye examinations and comprehensive vision and eye care.
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 8.4.2 describes a treatable cause of visual impairment.'
- category: Vitality
  name: Poor appetite
  subtype: Vitality
  phenotype_term:
    preferred_term: Poor appetite
    term:
      id: HP:0004396
      label: Poor appetite
  description: Loss of appetite is a separate ICOPE nutrition screening item. It can coexist with weight loss but does not imply established malnutrition.
  evidence:
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Have you experienced loss of appetite?
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Table 3.1, visually verified on printed page 19; a positive response prompts further assessment.'
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.
  notes: Associated with trajectory-group membership in a selected MAPT cohort; not an IC-specific diagnostic threshold or evidence that lowering IL-6 improves capacity.
  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.
    quote_role: PRIMARY_RESULT
- 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.
  notes: GDF-15 showed the strongest association among the measured markers in this cohort. A circulating stress marker is not a direct assay of mitochondrial oxidative phosphorylation, and the association does not establish causal mediation.
  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.
    quote_role: PRIMARY_RESULT
- 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: The review reports inconsistent associations across studies and domains and no inflammatory marker with sufficient specificity and sensitivity for this purpose.
  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.
    quote_role: REVIEW_SYNTHESIS
  - 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.
    quote_role: REVIEW_SYNTHESIS
- name: DNA methylation estimate of intrinsic capacity
  presence: Research score associated with measured IC and later mortality
  context: Elastic-net model using 91 CpG sites in 933 INSPIRE-T participants; external mortality associations evaluated in 1,680 Framingham Heart Study participants.
  notes: Tenfold cross-validation correlated 0.61 with measured IC, but participants with IC below 0.55 were excluded, limiting application to severe impairment. The external cohort tested mortality associations rather than calibration against the same measured IC score. The score is not a validated diagnostic threshold, rate of decline, intervention-response surrogate, or evidence that changing methylation restores capacity. Immune-cell estimates and pathway enrichment remain associative.
  evidence:
  - reference: PMID:40467932
    reference_title: A blood-based epigenetic clock for intrinsic capacity predicts mortality and is associated with clinical, immunological and lifestyle factors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: We built the predictive model using elastic net regression and tenfold cross-validation
    explanation: Describes derivation of the research predictor, not prospective clinical utility.
  - reference: PMID:40467932
    reference_title: A blood-based epigenetic clock for intrinsic capacity predicts mortality and is associated with clinical, immunological and lifestyle factors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Therefore, we excluded samples with an IC below 0.55, which accounted for 2.9% of the total data.
    explanation: A material limitation for the people with the most severely reduced capacity.
  - reference: PMID:40467932
    reference_title: A blood-based epigenetic clock for intrinsic capacity predicts mortality and is associated with clinical, immunological and lifestyle factors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Also, despite identifying a strong association between IC and the immune system, it is unclear whether causal relationships underlie this association
    explanation: The authors explicitly distinguish association from a causal immune mechanism.
genetic:
- name: Polygenic background of intrinsic capacity
  relationship_type: SUSCEPTIBILITY
  association: Common genetic variation is associated with variation in measured intrinsic capacity. Cohort-specific SNP-based heritability estimates were 25.2% in UK Biobank and 19.5% in CLSA.
  notes: The GWAS analyzed 57,716 participants, including middle-aged adults, from predominantly European-ancestry cohorts. It studied separately derived cross-sectional IC composites, not the rate of longitudinal decline. Loci were near PTP4A2, PRPF3, LCORL, RN7SL89P, ANAPC10, HK1, DLEU1, MAPT, SCN4A and STAU1; positional/eQTL/chromatin gene mapping does not identify proven causal genes. None of 88 nominal pathway enrichments survived multiple-testing correction. The polygenic score explained 0.3% of IC variation. APOE and FOXO3 are not lead findings of this study, and no gene-specific clinical testing indication is established.
  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: Reports SNP-based heritability and mapped loci in UK Biobank (44,631 participants) and CLSA (13,085 participants). These are associations with measured capacity, not causal determinants of longitudinal decline.
    quote_role: PRIMARY_RESULT
  - 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: The paper summarizes exploratory gene mapping, expression and enrichment analyses. None of the nominal pathway enrichments survived correction for multiple testing, so the wording is not treated as pathway validation.
    quote_role: PRIMARY_RESULT
inheritance:
- name: Polygenic inheritance
  inheritance_term:
    preferred_term: Polygenic inheritance
    term:
      id: HP:0010982
      label: Polygenic inheritance
  description: A complex quantitative trait with cohort-specific common-variant heritability estimates, rather than a Mendelian pattern. SNP heritability is not the proportion of individual decline caused by genes, and the unexplained variance cannot be assigned solely to environment.
  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: The GWAS supports a common-variant contribution to variation in measured IC, with low individual predictive performance; it does not establish Mendelian inheritance or clinical genetic testing.
    quote_role: PRIMARY_RESULT
treatments:
- name: Multicomponent Physical Activity with Nutritional Counselling
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  description: SPRINTT tested moderate-intensity physical activity with technological support and nutritional counselling in 1519 community-dwelling adults aged 70 or older with physical frailty and sarcopenia. In the prespecified SPPB 3–7 group (1205 participants), first mobility disability/death was reduced (HR 0.78, 95% CI 0.67–0.92); persistent mobility disability was not significantly reduced. The exploratory SPPB 8–9 group did not show benefit on the primary outcome. Strength and lean-mass benefits were sex-specific, and falls were more frequent in the lower-function intervention group. Exercise should be individualized and supervised where needed; component-specific effects cannot be separated.
  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: Improved physical performance and reduced first mobility disability in the prespecified lower-function subgroup; no claim of universal recovery of strength or muscle 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.
    quote_role: PRIMARY_RESULT
  - 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: Reports a physical-performance outcome in the selected trial population; SPPB is one locally applicable locomotor assessment.
    quote_role: PRIMARY_RESULT
  - 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
    quote_role: PRIMARY_RESULT
    snippet: Falls were recorded in 80/605 (13.2%) participants in the multicomponent intervention group and 49/600 (8.2%) in the lifestyle education group (1.62, 1.16 to 2.27).
    explanation: Safety result in the prespecified SPPB 3–7 group; improvement in mobility does not imply fewer falls.
- name: In-Hospital Multicomponent Exercise Training
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  description: A pooled analysis of two randomized trials enrolled 570 acutely hospitalized adults aged 75 or older (mean 87.3 years). In-hospital multicomponent exercise improved a five-domain IC score by 7.74 points versus standard care. Higher discharge IC was associated with lower subsequent mortality, but this association is not proof that exercise reduced mortality. Emergency visits and readmissions were not associated with discharge IC in this analysis.
  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: Improved the measured five-domain IC score during acute hospitalization; does not establish the causal effect of hospitalization or a survival benefit.
  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.
    quote_role: PRIMARY_RESULT
- name: Combined Exercise and Cognitive Stimulation Therapy
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  description: A Singapore pre/post study compared exercise, exercise plus cognitive stimulation, and a control group from another clinic. Allocation was not randomized, participants and assessors were unblinded, and analyses included 187 participants completing baseline and three-month assessments. A four-domain IC composite improved in the intervention groups; cognition improved at three months in the combined group. Baseline differences, clinic selection and varying vitality definitions limit causal interpretation; hearing and vision were not measured.
  treatment_term:
    preferred_term: combined exercise and cognitive stimulation programme
    term:
      id: NCIT:C15900
      label: Lifestyle Therapy
  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
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Participants and outcome assessors were not blinded and there was no concealment.
    explanation: Methodological limit of this nonrandomized evaluation.
  - 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
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: There was no randomisation within the intervention groups and enrolment was based on which of the two research staff who recruited them.
    explanation: Recruiter-dependent allocation prevents treating the comparison as a randomized estimate.
  - 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
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: At 3 months, both Ex and Ex +CST showed improvement in IC composite scores, locomotion, and psychological domain scores but improvement in cognition domain only in Ex + CST group.
    explanation: Reported short-term changes in the four-domain composite; no definitive isolated cognitive-stimulation effect is inferred.
- name: Group-Based Multidomain Intervention with Brain-Structure Outcomes
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  description: 'ENHANCE randomized 102 Taiwanese community-dwelling adults to twice-weekly exercise, cognitive training and nutrition education or quarterly telephone education. Analyses were explicitly per-protocol: 88 completed functional follow-up and a smaller MRI subset was analyzed. Adjusted imaging analyses found less left inferior temporal grey-matter volume loss, with different regional results between urban and rural subgroups. Age/BMI imbalance, attrition, inconsistent MRI denominators in the report and the small sample limit interpretation. MRI volume changes do not establish a cellular mechanism or dementia prevention.'
  treatment_term:
    preferred_term: group-based multidomain lifestyle intervention
    term:
      id: NCIT:C15900
      label: Lifestyle Therapy
  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
    quote_role: PRIMARY_RESULT
    snippet: All analyses followed a per‐protocol approach rather than intention‐to‐treat, as the study's focus on neuroanatomical changes required complete longitudinal data for meaningful interpretation.
    explanation: The main methods explicitly limit the analysis to complete longitudinal data.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: The results showed that the intervention group had less volume reduction or a volume increment in regions over the left inferior temporal lobe (left inferior temporal gyrus) than the control group over 12 months.
    explanation: Adjusted imaging finding; does not identify a biological mediator or show prevention of dementia.
- name: Multidomain Lifestyle Intervention for Cognitive Decline
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  description: FINGER randomized 1,260 adults aged 60–77 at increased dementia risk to two years of diet, exercise, cognitive training and vascular-risk monitoring or general advice. Modified intention-to-treat analysis showed a small benefit in neuropsychological test performance (between-group annual change 0.022 z-score units, 95% CI 0.002–0.042). This was not a demonstrated reduction in incident dementia. Adverse events were more common in the intervention group, principally musculoskeletal pain.
  treatment_term:
    preferred_term: multidomain lifestyle intervention
    term:
      id: NCIT:C15900
      label: Lifestyle Therapy
  target_mechanisms:
  - target: Cognitive Capacity Decline
    treatment_effect: INHIBITS
    description: Small improvement in the trajectory of neuropsychological test performance in the studied at-risk population; no dementia-incidence effect is established by this report.
  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 modified intention-to-treat analysis included 1,190 of 1,260 randomized participants and found a small annual difference in neuropsychological test performance.
    quote_role: PRIMARY_RESULT
  - 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: Adverse events were more frequent in the intervention arm and were principally musculoskeletal pain; the combined intervention does not isolate component-specific causation.
    quote_role: PRIMARY_RESULT
- name: ICOPE Integrated Person-Centred Care Pathway
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  description: The second-edition WHO ICOPE pathway comprises basic assessment and community-level interventions, in-depth assessment, a personalized care plan, and implementation with monitoring. Care addresses the person’s goals, affected domains, underlying diseases, medications, social and physical environment, and support needs of carers. A Beijing implementation trial reported small six-month domain differences after propensity-score matching; it supports feasibility in that setting rather than a uniform effect of every pathway component.
  treatment_term:
    preferred_term: integrated person-centred care for older people
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: 'The ICOPE care pathway consists of four rather than five steps:'
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 1.4 describes the revised pathway.'
  - 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
    quote_role: PRIMARY_RESULT
    snippet: After 1 to 1 propensity score matching, participants in intervention and control groups (totally 938) had comparable baseline characteristics
    explanation: Published results used a propensity-matched subset after initial randomization; the report supports context-specific feasibility and preliminary domain effects.
- name: Hearing Intervention with Hearing Aid Provision
  action_category: THERAPEUTIC
  therapeutic_modality: DEVICE
  description: Audiological assessment, hearing-aid fitting, communication strategies and follow-up can improve audibility and communication. In ACHIEVE (977 adults aged 70–84), hearing intervention did not reduce three-year global cognitive decline overall. A prespecified recruitment-source analysis found less decline in the higher-risk ARIC subgroup, but not in healthier newly recruited volunteers; incident cognitive impairment was not significantly reduced. Hearing aids compensate for impairment and do not reverse its underlying cause.
  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: Hearing Capacity Decline
    treatment_effect: MODULATES
    description: Amplification and rehabilitation improve communication despite persistent underlying hearing impairment.
    evidence:
    - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
      reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: It helps to amplify sounds to allow a person with hearing loss to better hear speech and other sounds.
      explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 9.4.3 explains the functional action of a hearing aid.'
  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: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The hearing intervention did not reduce 3-year cognitive decline in the primary analysis of the total cohort.
    explanation: Primary randomized cognitive endpoint was null.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: In the ARIC cohort, HI was associated with a 48% reduction in 3-year cognitive change compared to SA control
    explanation: Prespecified recruitment-source subgroup result; it does not establish universal cognitive or dementia prevention.
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: It is important to explain to people that hearing aids do not cure or treat hearing loss.
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Hearing aid amplification supports function without repairing the cause.'
- name: ICOPE Basic Assessment and Referral
  action_category: SCREENING
  description: Brief questions and tests identify possible losses in cognition, mobility, nutrition, vision, hearing and psychological capacity. The second-edition first step also considers urinary incontinence, social support and carers, and can provide immediate community-level advice and support. Positive results prompt further assessment; testing alone does not demonstrate prevention of disability.
  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: Of 7,367 participants eligible for six-month follow-up, 5,185 (70.4%) repeated Step 1. This supports implementation feasibility without establishing clinical benefit.
    quote_role: PRIMARY_RESULT
  - 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.
    quote_role: PRIMARY_RESULT
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: A potential impairment of intrinsic capacity needs to be confirmed by applying the tools/tests, that are locally available and validated.
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 3.2.1 requires confirmation of potential impairment.'
- name: Individualized Nutritional Care
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  description: Assess nutritional status, food access, oral/swallowing problems, diseases and medications; provide personalized dietary advice and weight follow-up. Oral supplemental nutrition is considered when ordinary food intake is insufficient, with specialist assessment for established malnutrition.
  treatment_term:
    preferred_term: Individualized Nutritional Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: OSN should be prescribed only when a person cannot consume sufficient calorie- and nutrient-dense regular food or when OSN is a temporary strategy in addition to regular food to increase caloric intake.
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 7.4.2 bounds the indication for oral supplemental nutrition.'
  target_mechanisms:
  - target: Malnutrition
    treatment_effect: MODULATES
    description: Assess nutritional status, food access, oral/swallowing problems, diseases and medications; provide personalized dietary advice and weight follow-up. Oral supplemental nutrition is considered when ordinary food intake is insufficient, with specialist assessment for established malnutrition.
    evidence:
    - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
      reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: OSN should be prescribed only when a person cannot consume sufficient calorie- and nutrient-dense regular food or when OSN is a temporary strategy in addition to regular food to increase caloric intake.
      explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 7.4.2 bounds the indication for oral supplemental nutrition.'
- name: Vision Correction and Rehabilitation
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  description: Assess the cause of visual impairment and provide appropriate refractive correction or referral for eye disease. Low-vision rehabilitation and assistive products support daily activities where correction cannot restore adequate vision.
  treatment_term:
    preferred_term: Vision Correction and Rehabilitation
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Corrective measures such as spectacles, contact lenses and refractive surgery can effectively manage refractive errors.
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 8.4.2 supports correction for refractive causes; section 8.4.3 separately addresses irreversible impairment.'
  target_mechanisms:
  - target: Visual impairment
    treatment_effect: MODULATES
    description: Assess the cause of visual impairment and provide appropriate refractive correction or referral for eye disease. Low-vision rehabilitation and assistive products support daily activities where correction cannot restore adequate vision.
    evidence:
    - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
      reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: Corrective measures such as spectacles, contact lenses and refractive surgery can effectively manage refractive errors.
      explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 8.4.2 supports correction for refractive causes; section 8.4.3 separately addresses irreversible impairment.'
- name: Stepped Psychological Care
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  description: Assess depressive symptoms, severity and underlying stressors; offer stress management, psychoeducation and, when needed, structured psychological interventions. Moderate-to-severe depression requires a specific mental-health assessment and treatment plan, including assessment of self-harm risk.
  treatment_term:
    preferred_term: Stepped Psychological Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: It is recommended to apply a stepped care approach , starting with a self-help low-intensity intervention (stress management) and monitoring symptoms and provision of further interventions, in case of no improvement or worsening.
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 10.4 recommends stepped care, with separate management of established moderate-to-severe depression.'
  target_mechanisms:
  - target: Depressive symptoms
    treatment_effect: MODULATES
    description: Assess depressive symptoms, severity and underlying stressors; offer stress management, psychoeducation and, when needed, structured psychological interventions. Moderate-to-severe depression requires a specific mental-health assessment and treatment plan, including assessment of self-harm risk.
    evidence:
    - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
      reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: It is recommended to apply a stepped care approach , starting with a self-help low-intensity intervention (stress management) and monitoring symptoms and provision of further interventions, in case of no improvement or worsening.
      explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 10.4 recommends stepped care, with separate management of established moderate-to-severe depression.'
- name: Cognitive Assessment and Rehabilitation
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  description: Investigate delirium, medication effects, vascular and other causes of cognitive loss. Consider cognitive stimulation, training and rehabilitation within an individualized plan; people with dementia may need a specific pathway. Cognitive decline alone is not an indication for anti-dementia medication.
  treatment_term:
    preferred_term: Cognitive Assessment and Rehabilitation
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Cognitive stimulation therapy, cognitive training, CBT, and referral to rehabilitation services
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 5.4 lists interventions to consider alongside management of underlying conditions.'
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Prescription of anti-dementia medicines for cognitive decline without diagnosis of dementia is not recommended.
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 5.4 explicitly separates domain impairment from a dementia diagnosis.'
  target_mechanisms:
  - target: Cognitive Capacity Decline
    treatment_effect: MODULATES
    description: Investigate delirium, medication effects, vascular and other causes of cognitive loss. Consider cognitive stimulation, training and rehabilitation within an individualized plan; people with dementia may need a specific pathway. Cognitive decline alone is not an indication for anti-dementia medication.
    evidence:
    - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
      reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: Cognitive stimulation therapy, cognitive training, CBT, and referral to rehabilitation services
      explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 5.4 lists interventions to consider alongside management of underlying conditions.'
- name: Integrated Multidomain Care in Multimorbid Older Adults
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  description: An ancillary TIGER randomized-trial analysis in 398 community-dwelling adults aged 65 or older with at least three chronic conditions found greater improvement in measured IC during a 12-month integrated multidomain program than usual care, mainly in locomotion and cognition. Biomarker changes were associated with IC changes but do not establish mediation or efficacy of an isolated component.
  treatment_term:
    preferred_term: integrated multidomain lifestyle intervention
    term:
      id: NCIT:C15900
      label: Lifestyle Therapy
  target_mechanisms:
  - target: Composite Intrinsic Capacity Decline
    treatment_effect: MODULATES
    description: Improved the measured composite in this selected multimorbid population.
  evidence:
  - reference: PMID:37949432
    reference_title: 'Enhancing Intrinsic Capacity and Related Biomarkers in Community-Dwelling Multimorbid Older Adults Through Integrated Multidomain Interventions: Ancillary Findings From the Taiwan Integrated Geriatric (TIGER) Trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The intervention arm had greater improvement in IC than the usual care arm (overall difference 1.5; 95% CI 0.5-2.5; P = .005)
    explanation: Ancillary analysis of 398 randomized participants; the result is tied to the study-specific IC instrument.
diagnosis:
- name: WHO ICOPE Basic and In-Depth Assessment
  description: Use brief domain questions/tests as the first assessment, followed by locally validated confirmatory measures for affected domains. In-depth assessment also reviews diseases, medication, the person’s goals, and social and physical environments. Examples include cognitive testing, nutritional assessment, SPPB and vision/hearing assessment; instruments and cutoffs require local adaptation. No single composite cutoff defines all affected people.
  evidence:
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: There are three key elements to an in-depth assessment; investigating and confirming impairment of intrinsic capacity; evaluating underlying diseases and risk factors; and assessing the person’s social and physical environment.
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 3.2 specifies the content of assessment.'
  - reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    reference_title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: A potential impairment of intrinsic capacity needs to be confirmed by applying the tools/tests, that are locally available and validated.
    explanation: 'WHO ICOPE handbook, second edition (source copyright and suggested citation: 2024). Section 3.2.1 separates potential loss on basic assessment from confirmation.'
animal_models:
- name: Four-performance-criterion frailty model in aged mice
  species: Mouse
  genotype: Naturally aged C57BL/6 mice
  publication: PMID:24336799
  description: The Liu study assessed weakness, walking performance, activity and endurance in 27- to 28-month-old mice. Each criterion used a cutoff 1.5 standard deviations below the cohort mean; three low criteria defined frailty and two mild frailty. This is a performance-based frailty classification, not a 31-deficit index.
  notes: The small initial cohort and cohort-relative cutoffs limit transportability. The source does not validate a five-domain human IC equivalent or measure cognitive, psychological and sensory capacity.
  modeled_mechanisms:
  - target: Locomotor Capacity Decline
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: Captures selected physical performance limitations that overlap with locomotor capacity.
    limitations: Frailty classification rather than an IC-specific mechanism or five-domain instrument.
    readouts:
    - name: Inverted-cling, rotarod, wheel-running and derived endurance performance
      target: Locomotor Capacity Decline
      direction: DECREASED
      interpretation: Low performance on multiple cohort-relative criteria identifies physical frailty in this model.
      evidence:
      - reference: PMID:24336799
        reference_title: Clinically relevant frailty index for mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        snippet: The criteria in mice were evaluated by the inverted-cling grip test, rotarod test, voluntary wheel running, and derived endurance scores.
        explanation: These are four performance criteria in 27- to 28-month-old C57BL/6 mice, not the separate 31-item deficit-accumulation instrument.
    evidence:
    - reference: PMID:24336799
      reference_title: Clinically relevant frailty index for mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: The criteria in mice were evaluated by the inverted-cling grip test, rotarod test, voluntary wheel running, and derived endurance scores.
      explanation: These are four performance criteria in 27- to 28-month-old C57BL/6 mice, not the separate 31-item deficit-accumulation instrument.
  evidence:
  - reference: PMID:24336799
    reference_title: Clinically relevant frailty index for mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: The criteria in mice were evaluated by the inverted-cling grip test, rotarod test, voluntary wheel running, and derived endurance scores.
    explanation: These are four performance criteria in 27- to 28-month-old C57BL/6 mice, not the separate 31-item deficit-accumulation instrument.
- name: Clinical deficit-accumulation frailty index in mice
  species: Mouse
  publication: PMID:28463656
  description: The reviewed Whitehead clinical mouse frailty index scores 31 observations across integumentary, musculoskeletal, auditory, ocular and other systems, together with body weight and temperature. It measures accumulated deficits and should not be conflated with the Liu performance criteria.
  notes: Observer characteristics, testing conditions and strain-specific deficits can influence scoring. Sensory observations are included, but comprehensive cognition and the human psychological IC domain are not established by this tool. The source evaluates frailty, not validation of the WHO IC composite.
  evidence:
  - reference: PMID:28463656
    reference_title: Implementation of the mouse frailty index.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: REVIEW_SYNTHESIS
    snippet: It assesses 31 different deficits across a range of domains including the in tegument, musculoskeletal system, vestibulocochlear/auditory systems, ocular and nasa l systems, digestive system, urogenital system, respiratory system, signs of discomfort, as well as the body weight, and body surface temperature.
    explanation: The review describes the Whitehead clinical frailty index, including auditory and ocular observations. This instrument is distinct from the four-performance-criterion model.
    directness: INDIRECT
clinical_trials:
- name: NCT02582138
  phase: NOT_APPLICABLE
  status: UNKNOWN
  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: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  - preferred_term: Gait disturbance
    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.
    quote_role: PRIMARY_RESULT
    reference_title: 'Sarcopenia and Physical fRailty IN Older People: Multi-componenT Treatment Strategies (SPRINTT)'
  notes: Registry status and phase checked through ClinicalTrials.gov APIv2 on 2026-09-21. Registry status is retained separately from completed published analyses. The live registry currently marks status UNKNOWN because its record is stale; the cited paper reports a completed trial analysis. Participant totals in the description follow the published randomized cohort; the stale registry retains an earlier estimated enrollment.
- name: NCT03243422
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: ACHIEVE randomized 977 adults aged 70–84 with untreated hearing loss to hearing intervention or health education. Recruitment included 238 ARIC participants and 739 newly recruited volunteers; the primary outcome was three-year global cognitive change.
  target_phenotypes:
  - preferred_term: Age-related hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  - preferred_term: Cognitive impairment
    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 registry identifies the hearing-intervention study. The overall null cognitive result and prespecified subgroup finding are described with publication evidence in treatments.
    quote_role: PRIMARY_RESULT
    reference_title: Aging and Cognitive Health Evaluation in Elders (ACHIEVE) Randomized Trial
  notes: Registry status and phase checked through ClinicalTrials.gov APIv2 on 2026-09-21. Registry status is retained separately from completed published analyses.
- name: NCT01041989
  phase: NOT_APPLICABLE
  status: UNKNOWN
  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
    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.
    quote_role: PRIMARY_RESULT
    reference_title: Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability
  notes: Registry status and phase checked through ClinicalTrials.gov APIv2 on 2026-09-21. Registry status is retained separately from completed published analyses. The live registry currently marks status UNKNOWN because its record is stale; the cited paper reports a completed trial analysis. Participant totals in the description follow the published randomized cohort; the stale registry retains an earlier estimated enrollment.
- name: NCT00672685
  phase: NOT_APPLICABLE
  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
    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.
    quote_role: PRIMARY_RESULT
    reference_title: Assessment of the Efficacy of Omega-3 Fatty Acids Supplementation, Multi-domain Intervention or Their Combination on the Change of Cognitive Functions in Frail Elderly Subjects
  notes: Registry status and phase checked through ClinicalTrials.gov APIv2 on 2026-09-21. Registry status is retained separately from completed published analyses.
- name: NCT04224038
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: INSPIRE-T is an observational longitudinal bio-resource platform, not a randomized treatment trial. The registry describes recruitment from age 30 upward; published cohort analyses include adults from age 20. It supports investigation of IC trajectories and biomarkers.
  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.
    quote_role: PRIMARY_RESULT
    reference_title: The Inspire Bio-resource Research Platform for Healthy Aging
  notes: Registry status and phase checked through ClinicalTrials.gov APIv2 on 2026-09-21. Registry status is retained separately from completed published analyses. The registry still reports RECRUITING with a last update in 2023; this is a recorded status, not confirmation that enrollment is open today.
- name: NCT03528005
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: TIGER randomized 398 community-dwelling older adults with multimorbidity to integrated multidomain care or usual care. The ancillary IC analysis reports study-specific composite and domain outcomes over 12 months.
  notes: Status, phase and actual enrollment verified through ClinicalTrials.gov APIv2 on 2026-09-21. Published outcome evidence is cited in treatments.
  evidence:
  - reference: clinicaltrials:NCT03528005
    reference_title: 'Effectiveness of Integrated Care Network for Community-living Older Adults: a Randomized-Controlled Trial'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    snippet: This project aims to examine the effectiveness of the community-based integrated care service model , based on a multi-domain intervention program, among community-dwelling older adults
    explanation: Registry summary identifies the registered intervention; it does not by itself establish efficacy.
- name: NCT05828043
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: ENHANCE randomized 102 community-dwelling older adults in urban and rural Taiwan. Its published functional and MRI outcomes use smaller per-protocol samples, not all randomized participants.
  notes: Status, phase and actual enrollment verified through ClinicalTrials.gov APIv2 on 2026-09-21. Published outcome evidence is cited in treatments.
  evidence:
  - reference: clinicaltrials:NCT05828043
    reference_title: 'Brain Aging: Muscle-to-brain Axis Modulates Physio-cognitive Decline'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    snippet: The primary goal is to develop a multidomain intervention program focused on preserving global or regional brain volume and functions while simultaneously improving physical mobility and cognitive functions in older individuals with mobility frailty
    explanation: Registry summary identifies the registered intervention; it does not by itself establish efficacy.
discussions:
- discussion_id: gap_ic_hallmark_causality
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Which ageing mechanisms causally contribute to changes in measured intrinsic capacity?
  attaches_to:
  - pathophysiology#Mitochondrial Bioenergetic Decline
  - pathophysiology#Chronic Low-Grade Inflammation
  rationale: The curated human biomarker, genetic and methylation studies provide associations. General ageing reviews supply plausible mechanisms, but neither evidence type establishes mediation of the clinical composite. Studies combining validated repeated IC measures, tissue-specific functional measurements and interventions are needed to test the candidate links. The absence of such evidence in this curated set is not a claim that no relevant human study exists.
  evidence:
  - reference: PMID:38145874
    reference_title: 'From biological aging to functional decline: Insights into chronic inflammation and intrinsic capacity.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    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 review describes association rather than an intervention establishing causation, and reports inconsistent biomarker findings.
  - reference: PMID:40467932
    reference_title: A blood-based epigenetic clock for intrinsic capacity predicts mortality and is associated with clinical, immunological and lifestyle factors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Also, despite identifying a strong association between IC and the immune system, it is unclear whether causal relationships underlie this association
    explanation: The primary methylation study states the causal uncertainty.
- discussion_id: gap_pain_management_and_capacity
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Does treating pain improve intrinsic capacity?
  attaches_to:
  - pathophysiology#Psychological Capacity Decline
  - pathophysiology#Locomotor Capacity Decline
  rationale: A cross-sectional INSPIRE-T study of 971 adults aged 20–102 associated pain during the previous eight days with lower IC. It did not establish chronic pain, direction of causation, inflammatory-clock moderation or an effect of pain treatment. This clinical association is not classified as a proven external environmental cause of ageing-associated IC decline.
  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.
    quote_role: PRIMARY_RESULT
  - 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 call for future investigation of pain management; the cross-sectional association does not establish that treating pain improves IC.
    quote_role: PRIMARY_RESULT
- discussion_id: controversy_icope_screening_tool_structure
  kind: CONTROVERSY
  status: OPEN
  prompt: Which IC instruments are suitable for triage, repeated measurement and prediction in each population?
  attaches_to:
  - definitions#WHO ICOPE Step 1 screening for decline in intrinsic capacity
  rationale: The original ICOPE screen, its local adaptations, factor-derived research scores and the expanded second-edition basic assessment serve different purposes. INSPIRE-T reported vision sensitivity 97.2% but specificity 2.7%, with sensitivity 42.0–69.6% for the other evaluated domains. The adapted Toledo composite added no statistically significant prognostic information over its domains in that sample. Hong Kong validation data also contain denominator and diagnostic-table inconsistencies. These findings require population- and instrument-specific interpretation, not a universal endorsement or rejection of all IC measurement.
  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
    quote_role: PRIMARY_RESULT
    snippet: High specificity (>70%) was observed for all the IC domains, except for vision (2.7%).
    explanation: The low vision specificity is necessary context for its high sensitivity.
  - 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
    quote_role: PRIMARY_RESULT
    snippet: The IST included as a composite in a model with the individual domains showed no statistically significant associations with any of the outcomes  # codespell:ignore-line
    explanation: The adapted Toledo instrument had no added composite association in the specified outcome models.
- discussion_id: gap_ic_no_mondo_class
  kind: CURATION_TODO
  status: OPEN
  prompt: Should a MONDO term be requested for this ICD-11-anchored clinical construct?
  attaches_to:
  - disease#Ageing Associated Decline in Intrinsic Capacity
  rationale: This entry retains its ICD-11 Foundation mapping without substituting a MONDO term for frailty or sarcopenia. Any future MONDO request should address the distinction between a functional-capacity construct and an aetiological disease and should be checked against the then-current ontology. The unresolved mapping is not evidence that related concepts are equivalent.
  evidence:
  - reference: PMID:31275941
    reference_title: 'Frailty and Intrinsic Capacity: Two Distinct but Related Constructs.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: IC should not be seen as the mere opposite of frailty.
    explanation: The conceptual review cautions against equating these related constructs.
references:
- reference: PMID:23746838
  title: The hallmarks of aging.
- reference: PMID:24336799
  title: Clinically relevant frailty index for mice.
- reference: PMID:25771249
  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.'
- reference: PMID:26520231
  title: 'The World report on ageing and health: a policy framework for healthy ageing.'
- reference: PMID:28463656
  title: Implementation of the mouse frailty index.
- reference: PMID:29408961
  title: Evidence for the Domains Supporting the Construct of Intrinsic Capacity.
- reference: PMID:30312372
  title: 'Sarcopenia: revised European consensus on definition and diagnosis.'
- reference: PMID:31275941
  title: 'Frailty and Intrinsic Capacity: Two Distinct but Related Constructs.'
- reference: PMID:31678933
  title: The structure and predictive value of intrinsic capacity in a longitudinal study of ageing.
- reference: PMID:35545258
  title: 'Multicomponent intervention to prevent mobility disability in frail older adults: randomised controlled trial (SPRINTT project).'
- reference: PMID:35569785
  title: 'Defining and assessing intrinsic capacity in older people: A systematic review and a proposed scoring system.'
- reference: PMID:36098317
  title: 'Implementation of the WHO integrated care for older people (ICOPE) programme in clinical practice: a prospective study.'
- reference: PMID:36356628
  title: WHO working definition of vitality capacity for healthy longevity monitoring.
- reference: PMID:37478886
  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.'
- reference: PMID:37517058
  title: 'Exploring the natural history of intrinsic capacity impairments: longitudinal patterns in the 10/66 study.'
- reference: PMID:37620614
  title: Association between aging-related biomarkers and longitudinal trajectories of intrinsic capacity in older adults.
- reference: PMID:37960903
  title: 'The icope Intrinsic Capacity Screening Tool: Measurement Structure and Predictive Validity of Dependence and Hospitalization.'
- reference: PMID:38029399
  title: 'Multi-Trajectories of Intrinsic Capacity Decline and Their Impact on Age-Related Outcomes: A 20-Year National Longitudinal Cohort Study.'
- reference: PMID:38145874
  title: 'From biological aging to functional decline: Insights into chronic inflammation and intrinsic capacity.'
- reference: PMID:38251736
  title: 'Implementation and impact of the World Health Organization integrated care for older people (ICOPE) program in China: a randomised controlled trial.'
- reference: PMID:38396729
  title: Mitochondrial Quantity and Quality in Age-Related Sarcopenia.
- reference: PMID:38616369
  title: 'The Impact of Exercise and Cognitive Stimulation Therapy on Intrinsic Capacity Composite Score in Pre-Frail Older Adults: A Pre-Post Intervention Study.'
- reference: PMID:38676323
  title: 'Predictive Capacity of the Integrated Care for Older People Screening Tool for Intrinsic Capacity Impairments: Results From the INSPIRE-T Cohort.'
- reference: PMID:38945130
  title: 'Association of intrinsic capacity with functional decline and mortality in older adults: a systematic review and meta-analysis of longitudinal studies.'
- reference: PMID:39088112
  title: 'Prevalence of intrinsic capacity decline among community-dwelling older adults: a systematic review and meta-analysis.'
- reference: PMID:39702725
  title: Cohort trends in intrinsic capacity in England and China.
- reference: PMID:40060276
  title: The Biological Rationale for Integrating Intrinsic Capacity Into Frailty Models.
- reference: PMID:40188489
  title: 'Exercise effects on intrinsic capacity in acutely hospitalised older adults: a pooled analysis of two randomised controlled trials.'
- reference: PMID:40464147
  title: 'Enhancing Neurocognitive Health via Activity, Nutrition and Cognitive Exercise (ENHANCE): A Randomized Controlled Trial.'
- reference: PMID:41066301
  title: A genome-wide association study identified 10 novel genomic loci associated with intrinsic capacity.
- reference: PMID:41360071
  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.'
- reference: clinicaltrials:NCT00672685
  title: Assessment of the Efficacy of Omega-3 Fatty Acids Supplementation, Multi-domain Intervention or Their Combination on the Change of Cognitive Functions in Frail Elderly Subjects
- reference: clinicaltrials:NCT01041989
  title: Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability
- reference: clinicaltrials:NCT02582138
  title: 'Sarcopenia and Physical fRailty IN Older People: Multi-componenT Treatment Strategies (SPRINTT)'
- reference: clinicaltrials:NCT03243422
  title: Aging and Cognitive Health Evaluation in Elders (ACHIEVE) Randomized Trial
- reference: clinicaltrials:NCT04224038
  title: The Inspire Bio-resource Research Platform for Healthy Aging
- reference: PMID:40467932
  title: A blood-based epigenetic clock for intrinsic capacity predicts mortality and is associated with clinical, immunological and lifestyle factors.
- reference: PMID:37949432
  title: 'Enhancing Intrinsic Capacity and Related Biomarkers in Community-Dwelling Multimorbid Older Adults Through Integrated Multidomain Interventions: Ancillary Findings From the Taiwan Integrated Geriatric (TIGER) Trial.'
- reference: clinicaltrials:NCT03528005
  title: 'Effectiveness of Integrated Care Network for Community-living Older Adults: a Randomized-Controlled Trial'
- reference: clinicaltrials:NCT05828043
  title: 'Brain Aging: Muscle-to-brain Axis Modulates Physio-cognitive Decline'
- reference: url:https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
  title: https://iris.who.int/server/api/core/bitstreams/7516b015-e205-43d1-883f-01f2c31af261/content
mechanistic_hypotheses:
- hypothesis_group_id: geroscience_contributors
  hypothesis_label: Candidate contributions from ageing biology
  status: EMERGING
  description: General ageing biology supports possible contributions from muscle mitochondrial dysfunction and senescence-associated secretion. The clinical evidence curated here does not establish that these mechanisms explain the composite, that they occur in every affected person, or that modifying them improves IC.
  evidence:
  - reference: PMID:38396729
    reference_title: Mitochondrial Quantity and Quality in Age-Related Sarcopenia.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Mitochondrial dysfunction has been indicated as a key contributor to skeletal myocyte decline and loss of physical performance with aging.
    explanation: The review synthesizes human associations and experimental muscle biology. It supports a candidate contribution to physical performance, not a demonstrated cause of the five-domain IC composite.
    directness: INDIRECT
  - reference: PMID:23746838
    reference_title: The hallmarks of aging.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: senescent cells manifest dramatic alterations in their secretome, which is particularly enriched in pro-inflammatory cytokines and matrix metalloproteinases
    explanation: This synthesis describes the senescence-associated secretory phenotype in general ageing biology; it does not show that this is the principal inflammatory source in people with low IC.
    directness: INDIRECT

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