href="#fb3_img_img_98de302c-0430-56b1-a1ba-2bed38ffc216.jpg" alt="Graph depicts a Gompertz curve showing the increase in the incidence of death with age."/>
Figure 1.1 A Gompertz curve showing the increase in the incidence of death with age.
Figure 1.2 The ‘non‐Gompertzian’ curve of the incidence of death in the naked mole‐rat. Source: Ruby, Smith, and Buffenstein2.
The second important fact is the compression or rectangularization of the survival rate curve (see Figure 1.3). In practice, it shows that medicine delays the death of most individuals of a given generation until they are closer to maximum lifespan, but it does not change the maximum lifespan much. Fries, who introduced this notion 30 years ago, interpreted this ‘compression of mortality’ as the result of a ‘compression of morbidity’5: it follows from the facts that there is a maximum lifespan (be it intrinsic or extrinsic); that even without chronic disease, individuals would still die; and that chronic diseases can be prevented. Related to this fact is the emergence of the concept of healthspan, or duration of life in good health.
Figure 1.3 The rectangularization or compression of mortality (dotted line) that occurs with medical intervention.
The third fact is a change in our views on medical intervention in old age. Healthspan and cognate concepts such as ‘successful ageing’6 and ‘healthy ageing’ are intended to be descriptive. However, they remain biologically vague. Most healthy old people undergo low‐grade chronic inflammation, progressive endothelial dysfunction, decreased glomerular filtration rate, and other phenomena associated with particular diseases. The only difference may be that the progression is slower: it is therefore confusing to define successful ageing as being ‘healthy’. The right function for these concepts is not descriptive; rather, it is prescriptive of a consensual norm of intervention for medicine7: keep as many people as possible as healthy as possible for as long as possible. This is also the acknowledged goal of anti‐ageing intervention, which has recently gained traction and credibility.
The evolutionary roots of the phenomenon of ageing
All humans age, develop biological dysfunctions, and eventually die. If this process is universal, it is reasonable to assume that it is also necessary. But what kind of necessity is it? Since Gompertz, there has been a consensus that it is an intrinsic rather than extrinsic necessity. Indeed, the reduction of extrinsic challenges is known to translate the curve on the y‐axis (incidence of death), not on the x‐axis (time of death). Accidents, starvation, and extreme living conditions do not make a human population grow old more quickly; they only make the population extinct sooner, as a now‐famous study on the curve of incidence of death for a population of Australian prisoners in prisoner‐of‐war camps has shown.8
A different question is whether ageing is a biological or physical necessity. It is sometimes said that ageing is the necessary realisation of the second law of thermodynamics: i.e. the irreversible progress of any closed system toward maximum entropy, which (as Schrödinger originally put it) for the living, is death.9 However, Schrödinger mentioned no physical reason why a particular organism could not perpetually draw ‘negative entropy’ from its environment, as long as the Sun provides free energy. The reason why ageing is ineluctable must, therefore, be biological.
Many species undergo senescence, as evolutionary biologists call it (note that molecular biologists use the word in another sense). The dominant explanation of the ‘origin and evolution’ of senescence was first proposed by Medawar10 and then refined by Williams,11 Hamilton,12 Charlesworth,13 and Kirkwood.14
Imagine a population that does not undergo functional decline with age. It is not immortal, because of extrinsic causes of death, but the number of individuals in a generation will still decline with time. Mechanically, older individuals will have fewer offspring than younger generations, although they all have an equal chance of survival and reproduction, younger or older. If genetic variations produced deleterious effects that manifest themselves only after some time, they will be eliminated by natural selection only in proportion to the number of individuals that reach the age of appearance. In other words, deleterious traits appearing in an age class with few individuals cannot be eliminated as efficiently as in an age class with many individuals. A body organisation that does not lead to late functional decline is no fitter than one that does, when most individuals die before functional decline may occur. On the other hand, natural selection will tend to postpone all deleterious effects until an age when they do not make a difference to reproduction. Hence 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
