(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] |
Epigenetic changes
Changes in DNA sequence are not the only age‐associated genomic alterations. DNA methylation, histone modification, and chromatin remodelling (collectively referred to as epigenetic modifications, known to influence gene expression) are also features of ageing.15 Several groups have observed high correlations between methylation status of CpG islets and chronological age in human and other species and thus described DNA methylations clocks that can predict donor age with an average error <5 years.28,29 Perhaps more interestingly, the difference between chronological age and age predicted by these clocks in older individuals (DNA methylation age or epigenetic age) was shown to be associated with cognitive and physical functions, frailty, and various age‐related diseases and to be an independent predictor of all‐cause mortality.30‐32 DNA methylation of selected key regions of the genome could thus reflect biological age rather than chronological age. Nevertheless, to date, biological causes and consequences of these epigenetic modifications during the ageing process remain unclear.33
Mitochondrial dysfunction
According to the historical mitochondrial free radical ‘theory’ of ageing,34 progressive mitochondrial dysfunction reduces energy availability and increases the production of reactive oxygen species (ROS) that damage macromolecules, contributing to ageing. Nevertheless, this theory has been reshaped in light of observations that (i) increased ROS may prolong lifespan in model organisms, (ii) increased ROS production and oxidative damage do not accelerate ageing in mice, and (iii) experimental mitochondrial dysfunction may accelerate ageing without ROS production.35 Therefore, ROS may be considered a stress‐induced survival signal response to ageing‐related damage, which will eventually aggravate the process if antioxidant systems are overwhelmed. ROS‐independent mechanisms of mitochondrial dysfunction include a propensity to stress‐induced permeabilisation, reduced mitochondria biogenesis, and reduced quality control by autophagy (see the following section).15
Interestingly, mitochondrial metabolic function can now be measured in vivo, and it has been shown to be associated with muscle strength and mobility in older people.36 Measures of mitochondrial physiology and function may thus be powerful markers of biological ageing but need careful standardisation.27
Loss of proteostasis
Several quality control mechanisms maintain intracellular protein homeostasis, or proteostasis: misfolded proteins can be refolded by chaperone proteins or degraded by the ubiquitin‐proteasome system and lysosomal pathways (the latter phenomenon being referring as autophagy). An increase in protein misfolding (due to cellular stress, for instance) and/or failure of quality control mechanisms is thought to contribute to ageing and age‐related diseases, typically Alzheimer’s and cataracts.37,38 Mice deficient in the CHIP co‐chaperone exhibit accelerated‐ageing phenotypes and reduced lifespan,39 and mice overexpressing Atg5 (a protein essential for autophagosome formation) have better motor function and increased lifespan. In humans, autophagy appears to be better maintained in offspring of individuals with exceptional longevity and is associated with higher effector functions of
