Ageing and death

Ageing and short-lived cells

If cells from young humans are cultured they seem to be capable of about 50 cell divisions, but cells from older individuals are capable of progressively fewer cell divisions. The maximum number in each species is called the Hayflick limit, and differs between species: small and short-lived mammals have low Hayflick limits, and larger and long-lived species have high limits. Coupled with the observation that many organisms appear to have a finite length of life (humans, for example, even with ideal living conditions, rarely live beyond 10 decades), this has tempted some to believe that we need look no further for a comprehensive understanding of ageing, but direct translation of in vitro findings into in vivo observations has not been possible. The Hayflick limit has been ascribed to the shortening of telomeres with each successive cell division, though actual lifespans of organisms correlate poorly with lifespans calculated from in vitro determinations of telomere length. The idea that death is inevitable because telomere shortening is inevitable is no longer tenable.

Ageing and long-lived cells

Stem cells and progenitor cells, as well as short-lived cells such as enterocytes and circulating white cells, will divide any cytoplasmic debris between the daughter cells at each division, thus minimising their deleterious effect. This solution is not available to long-lived cells, and accumulated debris will have detrimental effects on function. Of course, there are intracellular mechanisms for ridding cells of this debris, and were these mechanisms perfect, then such cells might function well for ever. They clearly do not, though the precise nature of the damaging debris remains a matter for study. Early theories suggested that DNA mutations would lead to the accumulation of defective proteins, but these proteins have not been found in significant quantities, apart from a few specific examples such as the abnormally folded proteins of Alzheimer disease. Cytoplasmic proteins may be broken down by proteases within the cytoplasm, or following autophagy, whereby they are broken down after the autophagosome fuses with endosomes or lysosomes. This fusion allows degradation of defective macromolecules, and thus reutilisation of their sugars, amino acids, nucleotides and fatty acids. This degradation is rapid and efficient, but not entirely effective: peroxidation of lipids leads to the accumulation of indigestible lipofuscin, easily identifiable on light microscopy of long-lived cells such as hepatocytes and cardiac myocytes. There may also be intracellular aggregates of defective proteins that are resistant to autophagocytosis, and defective mitochondria may be accumulated.

Evidence for genetic factors

The processes of embryogenesis, infancy, adolescence and maturity are genetically programmed, although the individual experience of these stages may be modified by environmental conditions. Ageing, also, seems to have a genetic component: members of the same family tend to live to a similar age and age at a similar rate, although even this ‘limit’ might be modified by the environment: for example, by calorie restriction in childhood. Subjects with rare genetic conditions (progerias) such as Werner syndrome show premature ageing and die from old-age diseases such as advanced atheroma while still chronologically young. Similarly, people with Down syndrome age rapidly; their cultured fibroblasts are capable of fewer cell divisions than those from age-matched controls. Natural selection gives primacy to reproduction rather than longevity, and ageing can be seen as the passive result of a lack of genetic drive to optimise or prolong lifespan; genes involved in enhancing reproduction may even have deleterious effects on longevity.

The mechanisms responsible for the genetic component of ageing are complex. It was once believed that longevity was a maternal trait, inherited through mitochondrial genes, but genomic studies refute this idea. There is a well-established statistical association between longevity and certain alleles, but the total variation in longevity explained by these variants is small; it is also not clear whether they confer a positive benefit, or simply reflect the absence of deleterious variants. For instance, the ε4 allele of apolipoprotein (APO)- E is associated with both Alzheimer disease and cardiovascular illness. Extreme old age is associated with certain genetic variations in the human telomerase reverse transcriptase gene, and centenarians and their offspring maintain longer telomeres than controls.

Interaction with environmental factors

Social correlations with ageing and death are more difficult to interpret. Many diseases are more common in people from lower socioeconomic groups; these individuals exhibit ageing changes and die earlier than age- and sex-matched people from higher socioeconomic 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. Dutch children who survived chronic starvation in World War II eventually lived longer than populations not starved, a finding experimentally reproducible in calorie-restricted laboratory rats.

Role of free radicals

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