Evidence for genetic factors

From a scientific point of view, few would deny that the processes of embryogenesis, infancy, adolescence and maturity are genetically programmed, although the individual experience of these stages in life may be very highly modified by environmental conditions; the current estimate is that the more complex and variable features such as behaviour are about 60% genetic and 40% environmental. The process of ageing seems to have a genetic component: members of the same family tend to live to a similar age and they age at a similar rate, leaving aside accident and disease.

The actual inherited mechanism(s) responsible for the genetic component of ageing is still unclear but it is worth noting that longevity appears to be inherited through the female line and that all mammalian mitochondria come from the egg and none is transmitted via the sperm. Cell culture experiments suggest that some gene(s) affecting human ageing are carried on chromosome 1, but, again, the way in which they influence ageing is unclear. There are also some remarkable ‘natural experiments’ in which some human subjects with rare genetic conditions (progerias) such as Werner’s syndrome show premature ageing and die from old-age diseases such as advanced atheroma while still chronologically in their teens or early adulthood. Similarly, Down’s syndrome patients generally age more rapidly; their fibroblasts are capable of fewer cell divisions in culture than those from age-matched controls.

Two related theories of ageing—the disposable soma and antagonistic pleiotropy—are related in that they reflect the priority given to reproduction in natural selection. The optimal deployment of genetic and metabolic resources gives primacy to reproduction rather than to ensuring longevity. Consequently, ageing is the passive result of a lack of genetic drive to optimise or prolong life-span. Indeed, some genes involved in enhancing reproduction are hypothesised to have later deleterious effects.

These observations reveal that at least some features of ageing are genetically based.

Interaction with environmental factors

Social correlations with ageing and death are more difficult to interpret. Many diseases are more common in people from lower socio-economic groups; these individuals exhibit ageing changes and die earlier than age- and sex-matched people from higher socio-economic groups. The most immediate interpretation of these phenomena is that people in these groups are disadvantaged in terms of diet, housing and social welfare generally.

Role of free radicals

The common pathway resulting in cellular deterioration is currently thought to be the generation of highly reactive molecular species called ‘free radicals’ (Ch. 6). Free radicals are created in neutrophils and macrophages, under carefully controlled conditions, to kill ingested infective organisms; if they are generated accidentally elsewhere there are numerous enzymatic and quenching processes in cells to dispose of them before they can do harm. However, the greater the exposure to free radical inducers (such as toxins in the diet, ionising radiation, etc.), the greater the chance that some damage will occur; these insults will accumulate until they become evident as the ageing process.

Defective repair

Natural experiments lend support to the wear and tear model. There are mechanisms in the cell that deal with damage, particularly DNA damage. These DNA repair mechanisms are numerous but very few deficiency states are well known; the best characterised of these is xeroderma pigmentosum. In this condition young children who are exposed to sunlight develop skin atrophy and numerous skin tumours that are more characteristic of elderly subjects with a long history of chronic sun exposure. This condition suggests that there are at least some mechanisms that hold many of the manifestations of ageing at bay; it is certainly possible that these mechanisms themselves could be susceptible to wear and tear, thus paving the way for more general decline.

Living systems are distinguished from most mechanical systems by their ability to regenerate. If the gastric mucosa is damaged, as it is every day by the simple process of eating, then unspecialised reserve cells at the base of the crypts divide and one of the progeny differentiates to become a new crypt cell; this mechanism is common to most tissues. However, the Hayflick phenomenon suggests that most cells have the capacity for only a limited number of divisions (unlike cancer cells which seem to be immortal) and that this is under genetic control. Therefore, in the final analysis, replicative senescence seems to be dependent upon some form of clonal senescence, and the modifications to the cell during its lifetime act upon an intrinsic life-span programme (Fig. 12.2).

Fig. 12.2 Suggested cellular mechanisms of ageing and death. There is direct or circumstantial evidence supporting each of the mechanisms illustrated. Some mechanisms interact with others; for example, free radicals may be responsible for DNA mutations.

Telomeric shortening

At the tip of each chromosome, there is a non-coding tandemly repetitive DNA sequence; this is the telomere. These telomeric sequences are not fully copied during DNA synthesis prior to mitosis. As a result, a single-stranded tail of DNA is left at the tip of each chromosome; this is excised and, with each cell division, the telomeres are shortened. Eventually the telomeres are so short that DNA polymerase is unable to engage in the subtelomeric start positions for transcription and the cell is then incapable of further replication. In human cells, it is only in germ cells and in embryos that telomeres are replicated by the enzyme telomerase. We might also expect telomerase to be active in cancer cells as these are immortal; recent studies have shown that this is true of many, but not all, cancers.

Telomeric shortening could explain the replication (‘Hayflick’) limit of cells. This is supported by the finding that telomeric length decreases with the age of the individual from which the chromosomes are obtained (Fig. 12.3). In progeria, there is premature telomeric shortening. Furthermore, short telomeres permit chromosomal fusion, and this correlates with the higher incidence of karyotypic aberrations in cells from elderly individuals and in senescent cells in culture.

Fig. 12.3 Telomeres, telomerase and replicative capacity. Telomeres are essential for chromosomal copying during the S phase of the cell cycle. However, most somatic cells lack telomerase (the enzyme that regenerates telomeres), so the telomeres shorten with each cell division until chromosomal copying becomes impossible. Germ cells and some neoplastic cells express telomerase and thereby have extended replicative capacity.