there will be an accumulation of deleterious effect toward the end of life.
Medawar refers to one particular form of this general phenomenon: pleiotropy (the multiplicity of effects of the same gene). Williams made it the main explanation of ageing under the label of the ‘antagonistic pleiotropy theory of ageing’. If a gene had a very small positive effect on survival in the first period of life but a very dramatic negative effect later, it would be fitter and would be selected during evolution. According to Williams, but not to Medawar, this is probably the primary explanation for the apparition of ageing during evolution.
According to Kirkwood’s hypothesis of the ‘disposable soma’, a more general reason is that organisms inevitably make errors that they cannot correct perfectly. Indeed, they have to invest the free energy they draw from their environment either in functioning or in control and reparation. Species settle on the best trade‐off for them in given circumstances. The more challenging the environment, the more necessary are early reproduction and a high level of functioning, and the less necessary is a very efficient control/reparation system. Maintenance of the soma is necessary only until the germline is passed on.
The evolutionary biology of ageing is a very important basic theory for biogerontology. So far, however, the consequences for geriatric medicine have been very limited. Answering the question why we age is somewhat independent of answering the question how we age. Only the latter is particularly relevant to geriatrics. However, this is only the beginning for this theory: it is likely to improve and gain explanatory force by taking into account the results of the molecular biology of ageing.
The components of biological ageing
Although there is no universal ‘programme’ of ageing, there are common themes as to how organisms age when one looks across species. These have led scientists to propose various components of biological ageing over the years, based on experimental observations. They each describe some aspect of biological ageing that has been recognised as a hallmark or pillar of ageing15,16 because it occurs during normal ageing and experimental modification of molecular/cellular pathways has an impact on healthspan and/or lifespan (see Table 1.1). These components seek to describe how we age, whereas evolutionary concepts seek to describe why we age.
Genomic instability
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] |
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