ageing

ageing

Why ageing occurs

Ageing affects all parts of the body and leads to increasing frailty, a declining capacity to respond to stress, increasing incidence of age-related diseases, and eventually, death. Why the body should undergo this spectrum of degenerative changes, when it is equipped with sophisticated mechanisms for self-maintenance and repair, is a question that has long puzzled biologists.

Animals in the wild do not usually live long enough to show obvious signs of ageing; they tend to die young from extrinsic hazards such as infection, starvation, or being killed by a predator. Because Darwinian fitness is strongly governed by the survival and reproductive success of young animals, genetic factors that promote growth and fecundity in early life are favoured by natural selection, even though these same factors may bring deleterious consequences later on. Thus, ageing is thought to result from trade-offs. In effect, late survival is sacrificed for reproduction.

An important trade-off is that which concerns the allocation of metabolic resources, especially energy, between activities of growth, maintenance, and reproduction. Each of these activities is metabolically expensive. Natural selection requires only enough maintenance for the body remain in sound condition through the normal life expectancy in the natural (‘wild’) environment. This concept is known as the ‘disposable soma’ theory, the soma consisting of all those parts of body which do not form a part of the reproductive cell lineage, or germ-line (the germ-line must of course be maintained to a high standard, else the reproductive lineage would die out over successive generations).

Evolution theory therefore supports the view that ageing arises principally through the gradual accumulation of random (or stochastic) faults in somatic cells and tissues. This is not to deny the importance of genetic factors in specifying longevity. Genes determine the levels of action of key maintenance systems, like DNA repair, and genes affect hereditary predisposition to a wide range of age-related diseases. However, it is no longer thought plausible that ageing, such as occurs in a species like Homo sapiens, is programmed through mechanisms which exist for the specific purpose of causing death.

Ageing at the cellular level

Our understanding of cellular aspects of ageing is focused on how cells change during the course of the life span, on the mechanisms that underly these changes, and on how changes at the cell level may affect the functions of tissues and organs. As yet our knowledge of these matters is far from complete.

Cell replicative senescence

Much research on cell ageing has concerned the phenomenon of cell replicative senescence. Cells from many tissues can be propagated in vitro (in culture outside the body) and normal cells grown in this way have finite replicative life spans. The cell type most commonly studied is the fibroblast, a constituent of connective tissue, which grows readily in culture. After as many as 60 cell divisions, the growth rate of fibroblast cultures slows down, the cells stop dividing, and eventually they will die.

This phenomenon has been widely regarded as a manifestation of ageing at the cell level. Three lines of evidence support this view: (i) a negative correlation has been reported between the number of cell divisions that a culture can achieve, and the age of the cell donor (Fig. 1); (ii) cells from short-lived mammalian species undergo fewer divisions in culture than cells from long-lived species; (iii) cells from human subjects with Werner's syndrome, a genetic condition showing an approximately two-fold acceleration of many features of ageing, undergo markedly fewer divisions than cells from normal age-matched controls (Fig. 1).

Intriguingly, cells grown from malignant tumours or cells treated with cancer-causing chemicals or viruses often grow without limit. Such cultures are said to have been ‘immortalized’. Because of this connection between cell immortalization and cancer, some suggest that cell replicative senescence may be primarily an anti-cancer mechanism, a ‘fail-safe’ device to arrest the growth of abnormal cells. However, this hypothesis remains controversial.

Ageing of cells

in vivo Within the living body, cells age in very different ways, associated with the proliferative status of the tissues in which they are found. Some cells such as neurons and muscle cells are ‘post-mitotic’ from birth, meaning that they can no longer divide. Ageing changes lead either to loss of cell function or even to cell death. By the time that such changes affect significant numbers of cells within an organ they will have important and probably irreversible effects on its function. Other tissues such as the covering and lining layers (epithelia) in skin and gut, or the blood-forming (haemopoietic) system, depend upon rapid cell proliferation and turnover for their proper function. In these highly proliferative systems, the responsibility for maintenance of homeostasis can be traced to small numbers of pluripotent stem cells. Stem cells themselves divide at a low rate but they give rise to rapidly dividing, differentiated cells which undergo considerable clonal expansion. The ageing of stem cells has so far been little studied because of the intrinsic difficulty of working with these cells. Recently, however, it has been found that epithelial stem cells in the small intestine of the mouse show important functional changes with age, being more likely to undergo cell death (apoptosis) when subjected to low doses of ionizing radiation, and less able to regenerate the tissue after damage.

Between the extremes of post-mitotic organs (e.g. the brain) and highly proliferative tissues (e.g. the gut wall), there are many tissues where cell division occurs when and where it is required for ongoing homeostasis. It is from these kinds of tissues that cells are most easily grown in culture. However, in spite of the evidence (see above) that cell replicative senescence is a manifestation of ageing at the cell level, the normal ageing of these tissues in vivo is not thought to be caused directly by the exhaustion of cell replicative capacity. Even cultures from centenarians are capable of ample proliferation. Nevertheless, it is possible that, with advancing age, growing numbers of individual cells do reach the end of their capac-ity for division and may contribute to a decline in cell renewal. A biochemical marker known as senescent b-galactosidase, which characterizes cells that have reached the end of their replicative capacity in vitro, can be detected in small numbers of cells in vivo, and the number of such cells increases with age.

Mechanisms of cell ageing

There are many kinds of damage that might affect a cell and contribute to its ageing. Chief among these are (i) damage and mutation affecting genetic information (DNA); (ii) accumulation of aberrant proteins due to errors in protein synthesis or processing, heat denaturation, or other damage; (iii) damage to subcellular organelles, particularly mitochondria; (iv) damage to membranes. The mechanisms responsible for these kinds of damage include a variety of intrinsic and extrinsic stressors such as reactive oxygen species (including free radicals) and heat, as well as mistakes in the synthesis and processing of macromolecules. Cell ageing is likely to be due to a combination of all of these processes, with the cell being protected by a network of defence and repair mechanisms.

A special mechanism implicated in the replicative senescence of cultured cells is the progressive shortening of telomeres (structures at the ends of chromosomes), which is due to the shutting off of the enzyme telomerase in somatic tissues. Telomerase acts in germ cells to maintain telomeres at a constant length, and the enzyme is often found to be reactivated in immortal cell lines and in cancers. The extent to which telomere shortening contributes to cell ageing as a causal factor in vivo remains to be determined.

Physiological functions

Ageing and ‘normality’

In adulthood, increasing age is accompanied by a progressive decline in the function of most physiological systems. Contrary to the uniformity implied by the expression ‘the elderly’, however, there are considerable differences between elderly individuals, as a result of the broad age range, interindividual differences in the rate of deterioration, and a rising prevalence of chronic diseases. For example, some elderly people have exceedingly limited physical abilities whereas others are capable of performances which are better than those of many young adults.

Subject selection is thus a crucial issue in any gerontological study. Some investigations will require subjects who are representative of their contemporaries, with a typical complement of chronic disorders and medication. Other studies might require highly selected subjects who, although atypical, are free of disease, free of risk factors for subclinical disease, and free of medication.

The rising prevalence of chronic pathologies complicates any attempt to determine the rate (or the cellular mechanism) of the age-related decline in a physiological function. It is not even clear how often it is valid to distinguish between ‘ageing’ and diseases associated with old age. (In osteoporosis, for example, the boundary between ageing and disease is especially indistinct.) Nevertheless, it is clear that in many organs the loss of function is largely attributable to the loss of functioning cells, even in the absence of overt disease.

Physiological decline and loss of safety margins

As one ages, the decline in physiological functions may not be immediately apparent, the individual living successfully without testing the function of any system to its limit. All the time, however, the safety margins between maximal function and critical threshold levels of function are being eroded.

Examples include the decline of bone mineral content (towards a threshold for likelihood of fracture), of glomerular filtration rate (towards a threshold for susceptibility to clinical renal failure), of renal tubular function (towards a threshold for clinically important susceptibility to dehydration), of hepatic function (towards a threshold for toxic accumulation following conventional ‘young adult’ doses of common medications), or of lower limb strength (towards a series of thresholds for aspects of independent everyday mobility). These changes in function are mainly due to an age-related loss of functioning cells, the residual tissue continuing to function normally. Some others, however, are due more to qualitative changes, such as increasing stiffness of the chest wall (increasing the rate at which oxygen must be consumed just to meet the needs of the respiratory muscles) or decreas-ing sensitivity of tissues to circulating catecholamines (reducing maximal heart rate, for example).

The loss of spare capacity also lowers the maximal extent to which an individual can respond to an environmental or situational challenge, and thus limits their ability to meet that challenge. Such impairments of homoeostasis are usually the result of effector organs functioning less successfully. In some cases, however, it seems to be the control mechanisms which are affected. For example, after water deprivation, older people are less thirsty and drink less than young adults. Similarly, some elderly people appear to show a blunted sense of thermal discomfort in a cold environment.

The ability to balance this precarious situation is central to the skills of the physician specializing in the management of illness in elderly people. The geriatric physician recognizes that, in an elderly person, an apparently minor illness must often be treated with great urgency, before it suddenly becomes life-threatening. Similarly, an elderly patient demands much greater precision in prescribing, as the margin between the wanted and unwanted effects of medications becomes narrower.

Muscle and physical performance

The loss of muscle (muscular cachexia, or sarcopenia) is a good example of the age-related loss of functioning cells and of the resulting loss of functional safety margins. Sarcopenia is central to the declining physical ability, increasing fatiguability, and progressive frailty of old age. It begins in middle age, proceeds at approximately 1% per year, and impairs all aspects of muscle function. Much of the loss is due to the loss of contractile muscle cells (muscle fibres) — probably resulting from a slowly progressive and incompletely compensated denervation — and is unrelated to habitual activity. The loss of muscle fibres may also be due to impaired regeneration of muscle after damage. A variable degree of shrinkage of some of the surviving muscle fibres also contributes to the loss of active muscle tissue and may reflect individual variation in habitual activity. Although most of the weakness is directly attributable to the reduced muscle mass, older muscle may also be weak for its size.

The age-related loss of muscle performance is greater than the loss of body weight. This has important implications for gait and mobility, especially for women, as they have a lower percentage of their body weight as muscle than men of the same age. In the English National Fitness Survey, nearly half of all women (compared with 15% of men) aged 70 to 74 had a power/weight ratio below the value at which they could still be confident of managing a 30 cm step without using a hand rail. The loss of muscle, together with changes in cardiovascular function, also limits the ability to perform endurance (aerobic) exercise, so that many elderly people (especially women) are unable to perform some everyday activities in comfort and without fatigue. For example, in the English National Fitness Survey, 80% of women (but only 35% of men) aged 70 to 74 had an aerobic power/weight ratio such that they would be unable to walk comfortably at 3 miles per hour.

Muscle also acts as a crucial, dynamic metabolic store during severe illness. If the acute event is severe or prolonged, the elderly person's greatly diminished muscle mass may no longer be adequate as a source of materials for tissue repair and of cellular fuels for immune competence.

An octogenarian's remaining muscle, how-ever, still shows a normal response to physical training. The improvements are equivalent to 10–20 years' ‘rejuvenation’. Strength training may also provoke valuable enlargement of remaining muscle fibres although the underlying, progressive, age-associated reduction in the number of muscle fibres appears to continue.

Tom Kirkwood, and Archie Young

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