Ageing and death

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Chapter 12 Ageing and death

AGEING 260
Theories of ageing 260
DEATH 265
Dying and death 266
Clinical features of death 266
Biological mechanisms of death 267
Terminal events 268

 

Ageing and death are linked: as people age their death becomes more likely until, in extreme old age, we may be surprised more by continued life than by the event of death. In general we believe that the older an object is the more likely it is that some disaster will occur; old cars break down, old buildings fall down, many old trees succumb to storms. But this is not a universal phenomenon; in a sense, unicellular animals that reproduce by asexual division live for ever. Every amoeba alive today is in direct line of cytoplasmic and nuclear descent from the very first amoeba that ever lived. The single cells of multicellular animals do not behave like this. Some, such as neurones or heart muscle cells, stop dividing at around the time of birth and, if one cell dies, it is usually not replaced. Even those cells that can reproduce in the human body do so less efficiently with the passage of time (Fig. 12.1); thus, elderly individuals experience slower wound healing. If cells from young animals are cultured they seem to be capable of about 50 cell divisions, but cells from older individuals are capable of progressively fewer cell divisions.

image

Fig. 12.1 Ageing and the replicative capacity of cells. In cell cultures, the number of mitotic divisions of which cells are capable is inversely proportional to the age of the individual from which the cells were obtained. Thus, fetal cells have considerable growth potential, whereas those from an elderly person are capable of only a few divisions. This is the ‘Hayflick limit’.

AGEING

Let us consider some of the clinical features of old age. It is often said that we are as old as our arteries, suggesting that arterial disease, which certainly increases with old age, is the cause of all the clinical signs of old age. Arterial degeneration, particularly arteriosclerosis (most frequently due to atheroma), is the commonest cause of debility and death in developed countries (Ch. 2). It would seem logical to think that many diseases might also have their roots in a progressively diminishing supply of oxygen and nutrients. However, in autopsies it is not uncommon to see people who have apparently died from ‘old age’ without significant arterial disease; this shows that at least some cases of ageing are not due to arterial problems even though this is commonly associated with ageing. In many developing societies the elderly population is not particularly afflicted by atherosclerosis and yet such individuals show all of the classic bodily features of old age. There is also a significant difference between the diseases that patients die with and the diseases that they die from, but this difference is often very difficult to establish scientifically.

THEORIES OF AGEING

image Hypotheses include inbuilt genetic mechanisms (clonal senescence) and ‘wear and tear’ (replication senescence)
image Ageing is influenced by genetic and environmental factors
image Replicative life-span of untransformed cells is limited (Hayflick limit)
image Cumulative free radical-mediated intracellular injury may be important

Basically there are two main groups of ageing theories: inbuilt genetic mechanisms and environmental ‘wear and tear’ mechanisms. There is evidence to support both theories but like the nature/nurture arguments in other areas of biology, such as the development of intelligence or of sexual orientation, the two possibilities are not mutually exclusive.

Inbuilt genetic mechanisms (clonal senescence)

Common experience supports the idea that there is an inbuilt ‘allotted life-span’ for humans and other animals. For instance, each animal species seems to have a characteristic natural life expectancy ranging from one day for a mayfly to well over 100 years for some amphibia; not all individuals reach this—under natural conditions prevailing in the wild it may be that no individual reaches this natural limit because of the effects of predators, accidents and disease, or the younger individuals may actively drive out or kill aged members of the group or more passively neglect them when they are no longer useful or economically viable. If animals are kept under ideal conditions it does appear that they age and die at around the same time; barring accidents, there is a characteristic life-span. Most human societies reflect this in their belief that there is a natural life expectancy and that there are natural phases in life: infancy, adolescence, adulthood and ageing.

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.

Wear and tear (replication senescence)

The ‘wear and tear’ theories suggest that the normal loss of cells due to the vicissitudes of daily life and the accumulation of sublethal damage in cells lead eventually to system failure of sufficient magnitude that the whole organism succumbs. This theory provides a good explanation of why it is that cardiac and central nervous system failure are such common causes of death, as the functionally important cells in these crucial tissues have very limited ability to regenerate. This theory ultimately depends upon a statistical view of ageing, suggesting that we are all exposed to roughly the same amount of wear and tear and therefore have a narrow range of life expectancy that appears to give us a characteristic life-span.

The various cellular and subcellular mechanisms that have been suggested to cause cumulative damage include:

protein cross-linking
DNA cross-linking
true mutations in DNA making essential genes unavailable or functionally altered
damage to mitochondria
other defects in oxygen and nutrient utilisation.

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).

image

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.

image

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.

CLINOPATHOLOGICAL FEATURES OF AGEING

image Some features associated with ageing are merely accompaniments; others are directly involved in the ageing process
image Every organ changes with age, often with progressive functional impairment
image Multiple pathology and comorbidity are common in the elderly
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