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Genetic damage accumulates with ageing due to extrinsic (chemical, physical) and intrinsic (replications errors, reactive oxygen species) factors, and genomic instability results from an imbalance between DNA damage and repair.^17,18 This results in mutations, translocations, chromosomal aneuploidies, and telomere shortening in nuclear DNA, which may affect critical genes, cause cell dysfunction, and ultimately impair homeostasis. Of note, age‐related damage also affects mitochondrial DNA.¹⁹ Consequences of accumulated DNA damage are typically illustrated by Werner syndrome, caused by mutations in a genome caretaker (DNA helicase). Even if its relevance to the complex biology of ‘usual’ ageing may be discussed, this syndrome is an example of premature ageing or progeroid disease. As another clue to the role of genomic instability in ageing, an experimental increase in the activity of BubR1, a mitotic checkpoint that controls the segregation of chromosomes, reduces tumorigenesis and age‐related tissue deterioration and extends lifespan in mice.²⁰ Nevertheless, robust evidence is lacking that the burden of somatic mutations is associated with the usual human phenotypes of ageing.

Telomere shortening is a specific type of genomic damage: telomeres are repetitive DNA sequences capping chromosomes, which shortens at each cell division. At some point, telomere exhaustion limits the proliferative capacity of in vitro cultured cells, a phenomenon called replicative senescence.²¹ Telomere shortening is also seen during normal ageing in mice and humans,²² and experimental modification of telomere loss influences lifespan in mice.^23,24 In a recent meta‐analysis of 25 studies, telomere attrition was predictive of all‐cause mortality.²⁵ Nevertheless, longitudinal studies revealed erratic changes in telomere length over time, possibly due to measurement error. Therefore, despite associations with several age‐related diseases,²⁶ telomere length is not currently considered a biological age marker.²⁷

Table 1.1 Components of biological ageing.

Type	Description	Ref.
Genomic instability	Imbalance between DNA damage (mutations, translocation, chromosomal aneuploidies) and repair. Telomere shortening.	[17, 18, 20] [22–26]
Epigenetical changes	Modifications of the DNA methylation status of CpG islets. Epigenetical age can be calculated based on measures of methylation in key regions of the genome. These ‘epigenetic clocks’ provide hybrid estimations of chronological and biological age.	[28–32]
Mitochondrial dysfunction	Stress‐induced permeabilisation, reduced mitochondria biogenesis, and reduced quality control by autophagy. Dual role of reactive oxygen species: stress‐induced survival signals that become deleterious if antioxidant systems are overwhelmed.	[34–36]
Loss of proteostasis	Increased protein misfolding and/or failure of quality control mechanisms (refolding by chaperone proteins; degradation by the ubiquitin‐proteasome system and autophagy); misfolded proteins aggregates and accumulates.	[37–40]
Metabolic dysfunction	Insulin/IGF‐1 axis activity decreases during ageing. Dietary restriction and drugs that mimic it (e.g. rapamycin) were shown to increase lifespan in animal models (including mice) through an effect on the insulin/IGF‐1 pathway.	[41–45]
Cell senescence	Arrest of the cell cycle coupled to the production of matrix metalloproteases and pro‐inflammatory cytokines (senescence‐associated secretory phenotype). Triggered by DNA damage or excessive mitogenic signalling.	[48, 49, 52, 54–58]
Stem cell exhaustion	Decline in the capacity of resident stem cells to divide and replace damaged tissue.	[59, 60]
Immunosenescence	Production of chronic low‐grade inflammation. Decreased number of naïve cells available for new challenges, increased number of memory cells, and shrinkage of the antigenic repertoire of lymphocytes.	[61, 63–72]