Hallmark 1 of 12

Genomic instability

Every cell repairs its DNA around the clock. A small share of damage escapes control and remains as a permanent change. Over decades this produces a patchwork of cells carrying different genomes. Genomic instability describes exactly this process, and it comes first in the López-Otín taxonomy because it precedes many other ageing processes.

Scientific term: Genomic instability
Group: Primary causes
Hallmarks of Aging: Described in 2013

The hallmarks of aging are a research framework, not a diagnostic tool. They describe processes that occur during ageing, but they do not prove causation and are not a basis for medical decisions.

What lies behind it

DNA damage arrives from two directions. From within through reactive oxygen species produced by metabolism, through spontaneous chemical decay and through replication errors. From outside through UV light, ionising radiation and reactive chemicals. Estimates for the number of lesions per cell per day run into the tens of thousands, although the exact magnitude is methodologically hard to pin down.

Against this stands a layered repair system. Base excision repair removes individual chemically altered bases, nucleotide excision repair cuts out larger distortions of the double helix, mismatch repair corrects mispairings after replication. Double-strand breaks are either repaired precisely via homologous recombination or closed quickly, but more error-prone, via non-homologous end joining.

Whatever these systems fail to catch remains: point mutations, losses or duplications of whole segments, misdistributed chromosomes, reactivated retrotransposons. This affects not only nuclear DNA but also the mitochondrial genome, which lacks histones and has limited repair machinery. Disturbances of the nuclear envelope add to the picture: in Hutchinson-Gilford progeria a mutation in the LMNA gene produces a defective lamin A and thus an unstable nuclear architecture.

A particularly well documented human example is clonal haematopoiesis. A blood-forming stem cell acquires a mutation, frequently in DNMT3A, TET2 or ASXL1, and subsequently expands preferentially. With rising age more and more people carry such clones without developing leukaemia.

How robust is the evidence

Robust evidence

Consistent human data and mechanistic animal models point in the same direction.

The evidence is unusually broad for a hallmark because it comes from three independent directions. First, human genetics: inherited conditions with defective DNA repair, such as Werner syndrome or Cockayne syndrome, show features of accelerated ageing. Second, cross-species comparison: work from the Sanger Institute analysed somatic mutation rates across sixteen mammalian species and found an inverse relationship with lifespan. Long-lived species accumulate fewer mutations per year but reach a similar total by the end of life.

Third, sequencing of healthy tissue. Normal human skin already carries a high number of somatic mutations in middle age, including driver mutations in cancer genes, without any tumour being present. The same holds for oesophagus, liver and blood. That shifts the interpretation: mutations are not the exception in diseased tissue but the normal state in ageing tissue.

The clinically most robust single finding is clonal haematopoiesis. In large cohorts its presence was associated with increased all-cause mortality, and in a follow-up analysis with roughly a doubling of coronary heart disease risk. This is one of the few points where a hallmark connects directly to a hard clinical endpoint.

Findings in humans

Inherited conditions with impaired DNA repair, such as Werner or Cockayne syndrome, show features of premature ageing.
Healthy skin already carries a high somatic mutation load in middle age, including driver mutations in cancer genes.
Clonal haematopoiesis increases markedly with age and was associated with higher mortality in cohort studies.
In a follow-up analysis, clonal haematopoiesis was associated with roughly a doubling of coronary heart disease risk.
Across sixteen mammalian species, the annual somatic mutation rate falls as lifespan rises.

What of this is measurable at YEARS

Partly, via adjacent markers

There is no routine test for genomic instability itself. The mutation burden of healthy tissue can only be determined through elaborate single-cell or deep sequencing, and reliable reference ranges do not exist. Three elements of YEARS diagnostics touch on the topic, but each measures something different.

Whole-genome and whole-exome sequencing

Captures the germline, meaning the genome you were born with. This says something about inherited risk, for example in repair genes such as BRCA1 and BRCA2, but nothing about the mutations your cells have accumulated over a lifetime.

Liquid biopsy (TruCheck)

Looks for circulating tumour cells in blood. The method therefore targets a possible consequence of genomic instability, not the process itself. It is flagged as experimental in the YEARS panel and does not replace guideline-based cancer screening.

Whole-body MRI

Imaging finds space-occupying lesions above a certain size. That too is a late consequence, not a marker of mutation burden. Also listed as experimental.

Context

None of these findings measures genomic instability. They capture either inherited risk or consequences that have already occurred. Anyone offering to determine your somatic mutation burden as an ageing marker is operating outside what is currently validated.

Limits of this hallmark

The strongest objection concerns the direction of causality. That mutations increase with age is uncontested. That they cause ageing is not. For cancer the link is clear. For muscle weakness, cognitive decline or frailty there is no direct demonstration that mutation burden is the driving factor rather than an accompanying phenomenon.

Progeroid syndromes are frequently cited as proof but serve that purpose only partly. They reproduce some features of ageing and omit others. People with Hutchinson-Gilford progeria, for example, develop neither dementia nor elevated cancer risk. Such a phenotype is a model, not a miniature version of normal ageing.

There is also a fundamental criticism of the hallmark concept itself. The categories were derived from existing literature and describe what stands out. Gems and de Magalhães have pointed out that such a catalogue remains descriptive and risks conflating observation with explanation. Genomic instability is well documented as a phenomenon. As an explanation of ageing it remains one hypothesis among several.

Frequently asked questions

What does genomic instability mean?→

Genomic instability describes the growing accumulation of changes in the genome of individual body cells over a lifetime. This includes point mutations, lost or duplicated DNA segments, misdistributed chromosomes and reactivated jumping genes. The starting point is damage that occurs in large numbers every day, partly through your own metabolism, partly through external influences such as UV radiation. Repair systems catch most of it, but not all. What remains is permanent and is passed on at every cell division. In the hallmarks of aging taxonomy, genomic instability counts as a primary cause because it precedes other ageing processes in time.

Can genomic instability be measured?→

Not as a routine investigation. The somatic mutation burden of healthy tissue can only be determined through single-cell or very deep sequencing, and no clinical reference ranges exist for the results. What is available measures something else: genome sequencing shows the germline, meaning the predispositions you were born with. A liquid biopsy looks for signs of an existing tumour. A blood test for clonal haematopoiesis is established in research but is not standard in preventive care. Offers promising to measure your genomic instability should be examined critically.

Does DNA damage cause ageing, or merely accompany it?→

This is open. For cancer, causality is well established: mutations in certain genes lead to uncontrolled growth. For other age-related changes the picture is less clear. Inherited conditions with impaired DNA repair do show features of accelerated ageing but never reproduce the full picture. Cross-species comparison provides a strong indication: long-lived mammals accumulate fewer mutations per year than short-lived ones. An indication, however, is not proof. It remains possible that mutation burden and ageing share a common cause. The honest answer is that genomic instability is a very well documented accompanying phenomenon whose causal contribution to ageing has not been quantified.

What is clonal haematopoiesis and why is it mentioned so often?→

Clonal haematopoiesis means that a single blood-forming stem cell has acquired a mutation and subsequently expands more than its neighbours. A growing share of blood cells then descends from that one clone. The genes DNMT3A, TET2 and ASXL1 are frequently affected. The condition is rare in young people and becomes markedly more common with age. It is notable for two reasons. First, it can be detected in blood, making it one of the few directly observable examples of genomic instability in humans. Second, in large cohorts it was associated not only with blood cancer but also with increased mortality and with coronary heart disease.

Sources

López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The Hallmarks of Aging. Cell. 2013;153(6):1194–1217.
López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023;186(2):243–278.
Vijg J, Suh Y. Genome instability and aging. Annual Review of Physiology. 2013;75:645–668.
Cagan A, Baez-Ortega A, Brzozowska N, et al. Somatic mutation rates scale with lifespan across mammals. Nature. 2022;604:517–524.
Martincorena I, Roshan A, Gerstung M, et al. Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science. 2015;348(6237):880–886.
Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. New England Journal of Medicine. 2014;371(26):2488–2498.
Jaiswal S, Natarajan P, Silver AJ, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. New England Journal of Medicine. 2017;377(2):111–121.
Gems D, de Magalhães JP. The hoverfly and the wasp: A critique of the hallmarks of aging as a paradigm. Ageing Research Reviews. 2021;70:101407.

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Hallmark 2 of 12