Accumulating DNA Damage
trigger
Somatic cells are continuously exposed to endogenous and environmental sources of DNA damage - reactive oxygen species, spontaneous replication errors, UV and ionizing radiation, and environmental mutagens - that introduce a very large number of chemical lesions into the genome each day. This continuous genotoxic burden is the initiating input of the hallmark.
Downstream
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Declining Genome Maintenance and Erroneous Repair
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"Somatic cells are continuously exposed to various sources of DNA damage, from reactive oxygen species to UV radiation to environmental mutagens."
Enumerates the continuous endogenous and environmental sources of DNA damage that constitute the genotoxic input modeled here. Evidence source is OTHER because this is a review.
"To cope with the tens of thousands of chemical lesions introduced into the genome of a typical cell each day, a complex network of genome maintenance systems acts to remove damage and restore the correct base pair sequence."
Quantifies the daily lesion burden and introduces the genome-maintenance network that normally counters it, framing the trigger and the next node. Evidence source is OTHER because this is a review.
Declining Genome Maintenance and Erroneous Repair
central effector
Genome-maintenance and DNA-repair capacity is normally sufficient to remove damage and restore the correct sequence, but with age this capacity declines while damage continues to accrue, and repair is sometimes erroneous (as is replication during division). The failure to fully and faithfully repair accumulating damage is the central effector that disease-specific genome-maintenance defects converge upon.
Downstream
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Accumulation of Somatic Mutations and Genomic Damage
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"Occasionally, however, repair is erroneous, and such errors, as well as the occasional failure to correctly replicate the genome during cell division, are the basis for mutations and epimutations."
Establishes erroneous repair and replication failure as the source of mutations and epimutations, the failing-maintenance effector modeled here. Evidence source is OTHER because this is a review.
Accumulation of Somatic Mutations and Genomic Damage
effector
Unrepaired and misrepaired lesions leave a rising burden of somatic mutations, epimutations, and persistent DNA damage that accumulates in various organs and tissues over the lifespan. This is the conserved measure of genomic instability in the aging frame, upstream of its cellular consequences.
Downstream
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DNA-Damage-Driven Cellular Dysfunction and Aging
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"There is now ample evidence that mutations accumulate in various organs and tissues of higher animals, including humans, mice, and flies."
Documents accumulation of somatic mutations across organs and tissues with age, the genomic-damage burden modeled in this node. Evidence source is OTHER because this is a review.
"These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication."
Enumerates genomic instability as a hallmark of aging, framing this module. Evidence source is OTHER because this is a review.
DNA-Damage-Driven Cellular Dysfunction and Aging
consequence
In the aging frame, the accumulated DNA damage and mutation burden drives cellular dysfunction, senescence, and cell loss - affecting most aspects of the aging phenotype and acting as a potentially unifying cause of aging. This is the conserved consequence that distinguishes the aging arm from the cancer arm (mutator phenotype and clonal evolution); the specific organ or disease phenotype is supplied by the conforming disorder, and targeting DNA damage is a rationale for anti-aging intervention.
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"Here we synthesize accumulating evidence that DNA damage affects most, if not all, aspects of the ageing phenotype, making it a potentially unifying cause of ageing."
Establishes DNA damage as affecting most aspects of the aging phenotype and a potentially unifying cause of aging, the consequence modeled here. Evidence source is OTHER because this is a review.
"Targeting DNA damage and its mechanistic links with the ageing phenotype will provide a logical rationale for developing unified interventions to counteract age-related dysfunction and disease."
Frames DNA-damage targeting as a rationale for anti-aging intervention, the intervention angle of this outcome node. Evidence source is OTHER because this is a review.