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.

Fig. 1 The number of cell divisions that a culture of normal human fibroblasts can undergo before experiencing cell replicative senescence declines, on average, with the age of the cell donor, as shown by the fitted line. Each data point is for cells cultured from a different donor. The circles correspond to normal subjects. The 3 diamonds show results for cells grown from individuals with Werner's syndrome, a genetic condition of accelerated ageing

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, Archie Young

Bibliography

• Concar, D. (1996). Death of old age. New Scientist, 150(2035), 24-9.
• Kennie, D. C., Dinan, S., and Young, A. (1998). Health promotion and physical activity. In Textbook of geriatric medicine and gerontology, (ed. J. Brocklehurst, R. Tallis and H. Fillit). Churchill Livingstone, London.
• Kirkwood, T. B. L. (1996). Human senescence. BioEssays, 18(12) 1009-16.
• Kirkwood, T. B. L. (1999). Time of our Lives: the Science of Human Ageing. Weidenfeld and Nicolson, London; Oxford University Press, New York.
• Woodhouse, K., Williams, R., Macmahon, D., Archer-Jones, P., Kennedy, R., and Main, A. (ed.) (1997). Services for people who are elderly: addressing the balance. An NHS Health Advisory Service Thematic Review. HMSO, Norwich

1. As wines age, they develop bouquet and a smooth mellow flavour, associated with slow oxidation and the formation of esters, as well as losing the harsh yeasty flavour of young wine.

2. The ageing of meat by hanging in a cool place for several days results in softening of the muscle tissue, which stiffens after death (rigor mortis). This stiffening is due to anaerobic metabolism leading to the formation of lactic acid when the blood flow ceases.

3. Ageing of wheat flour for bread making is due to oxidation, either by storage for some weeks after milling or by chemical action. Freshly milled flour produces a weaker and less resilient dough, and hence a less ‘bold’ loaf, than flour which has been aged.

As we grow older, we tend to become physically weaker, bones become more brittle and break more easily (see osteoporosis), reaction times are slower, and fitness declines. The desire and ability to exercise often diminishes, so the tendency to put on body weight (especially in the form of fat) increases. Consequently, the body mass index will also increase. The US National Research Council states that the desirable body mass index range increases with age (from 19 to 24 for a 20-year-old to 24-29 for a 65-year-old). Nevertheless, it is usually difficult for older people to maintain their desirable body mass index because basal metabolic rate decreases as muscle mass declines with age and lack of exercise. After the age of 60 years, metabolism slows down at a rate of up to three per cent a year. Even if activity levels remain the same, energy intake must drop to avoid excessive weight gain. A lower energy intake (and therefore total food intake) makes it more difficult to ensure adequate supplies of vitamins and minerals. Thus, it is very important that elderly people eat a well-balanced diet, rich in these nutrients.

Although you cannot change all of the ageing processes, many authorities believe that several of them are actually caused by other factors, such as inactivity. This type of ageing (called acquired ageing) is not inevitable and can be avoided or delayed by taking regular aerobic exercise, eating a balanced diet, and reducing stress. Gerontologists generally agree that poor physical fitness is one of the greatest problems of the elderly, and that a well-designed programme of exercise could help to reduce the effects of ageing, and improve both physical and mental well-being. Ageing curves of exercisers and sedentary people indicate that a steady deterioration in fitness occurs with each decade, but the deterioration is much less in active people than in those who are inactive.

You are never too old to benefit from exercise. Regular exercise three times a week, consisting of strength training sandwiched between stretching and cycling for the warm up and cool down, can improve strength by over 90 per cent in men and women aged between 56 and 80. This type of exercise will increase total energy expenditure by up to 15 per cent per day, even if the workout uses less than 250 calories. So, regular exercise can increase the strength and fitness of older exercisers, and enable them to control their weight more easily than non-exercisers. Diet may also affect the ageing process. Laboratory mice and rats kept on a calorie-restricted diet live longer and have less age-related diseases than animals fed on unrestricted diets. The applicability of these results to humans is questionable, but there is a growing body of evidence to support the notion that a well-balanced, calorie-controlled diet can delay ageing. There is also a strong suggestion that many foods are potential carcinogens (even glucose may react with amino acids to form mutagens) and that too much food increases the risk of harmful mutations. On the other hand, foods rich in antioxidants (e.g. vitamins A, C, and E) may slow down the ageing process by mopping up the free radicals that many scientists believe are the underlying cause of ageing.

You cannot halt ageing. It starts at conception and ends at death. But you can increase your chances of maintaining a high level of health throughout your life by taking regular aerobic exercise and eating sensibly.

British variant of aging.

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Performance at many types of task studied in the laboratory rises to a peak somewhere between the late teens and late thirties, and then gradually declines into old age. It used to be assumed that the declines were due either to age effects in sense organs, muscles, and joints, or to older people being uninterested in, or out of practice at, the kinds of tasks set by laboratory experiments. Research since the 1940s has shown that, while peripheral changes may be important in later old age, central brain functions account for the main trends of performance in middle and early old age. The trends are by no means all adverse: certain kinds of 'mental agility', such as indicated by scores on typical intelligence tests, decline from the early twenties — it has been estimated that by the age of 60 they have returned to their level at the age of 10 — but the decline is offset, at least partly and sometimes more than fully, by increased knowledge gained in the course of experience. The age of peak performance is thus usually in the thirties, forties, or fifties rather than in the twenties, and varies with the balance between demands for 'mental agility' and for knowledge: for example, it comes relatively early among mathematicians, and relatively late among historians and philosophers.

It must be emphasized that these statements are of average trends and that some individuals achieve their peak performance much earlier or later than the majority. Indeed, the extent and rate of changes differ widely between individuals, so that performances tend to become more variable with age — some people in their seventies or eighties perform some tasks in a manner similar to that of people half a century younger, whereas others show profound differences. It is thus all too easy for ideas about old age to be coloured, for better or worse, by a few striking examples who are not typical of their contemporaries.

Psychological studies of ageing made during the last thirty years or so may be broadly divided into three areas:

1. Speed of performance
2. Memory and learning
3. Personality

1. Speed of performance

Perhaps the most characteristic age change is that performance becomes slower. The extent to which it does so is not, however, uniform for all tasks. For simple, aimed movements the change is comparatively slight — a loss of less than 10 per cent between the twenties and seventies. Slowing in sensory motor tasks is mainly in the making of decisions about what action to take — in other words, in cognitive and intellectual rather than in motor functions. When the relationships between signals for action and the corresponding responses are straightforward, as, for example, when the signals are a row of lights and response is by pressing a button under whichever comes on, the time to react increases typically by about 25 per cent from the twenties to the seventies. When the relationships are more complex, as, for instance, when lights on the right have to be responded to by pressing buttons on the left, and vice versa, increases of 50 per cent or more have been found between these ages. Slowing with age is also greater in continuous tasks, where each response immediately brings on the signal for the next, than in discontinuous tasks, where responses and ensuing signals are separated by an interval of a second or more. The reason appears to be that older people tend more than younger to have their attention diverted to monitoring the response they have just made, so that they cannot attend immediately to any fresh signal.

Much if not all slowing with age can be explained by the fact that signals from the sense organs to the brain and from one part of the brain to another become weaker, while at the same time random neural activity in the brain tends to increase. The latter blurs the former and leads to errors. The blurring can, however, be at least partly overcome by taking a longer time. This allows data to be accumulated, making the signals stronger and averaging out some of the random activity. As a result, older people, although slower, may be as accurate or more so than younger people. With some highly complex tasks, however, such compensation is incomplete, so that older people tend not only to be slower but also to make more errors.

The laboratory findings accord well with studies of real-life situations. In industry, operatives tend to move before retiring age not only from physically strenuous work such as coal mining, but also from lighter jobs where there is pressure for speed, such as on assembly lines. Industrial accidents sustained by older people tend to involve either being hit by moving objects or tripping and falling — in other words, slowness either in getting out of the way or in recovering balance — whereas younger people's accidents tend to be the result of either rashness or lack of experience. The same is true of road accidents and traffic offences: older people fail to react in time to rapidly changing situations, while younger people take undue risks. The problem of complexity is shown in difficulties often found by older industrial operatives with complex machinery and elaborate working drawings. It is also epitomized in the finding that some older people can no longer read a map while travelling south without turning it upside down.

2. Memory and learning

A six- or seven-digit number heard once can be recalled immediately about equally well by people of all ages from the twenties to the sixties. With more items than this, older people recall less than younger. The reason appears to be that they have difficulty in transferring material from a limited and ephemeral short-term memory to a more enduring long-term memory: some of the material is lost, and the traces of what is transferred are weaker. The strength of the traces can be increased by repetition, and with enough additional practice recall by older people can equal that by younger. Once material has been learnt, older people do not forget more rapidly than younger. Well-learnt facts, familiar events, and thoroughly practised motor skills such as riding a bicycle or driving a car are, therefore, retained well in old age even if there is difficulty in learning new facts and acquiring new skills.

Failure to register material in long-term memory probably accounts for many difficulties in problem-solving and other tasks in which data have to be 'held in mind' while other data are gathered: for example, when multiplying, say, 57 by 38, the product 57 × 3 × 10 has to be held while 57 × 8 is obtained. Calculating the second product will destroy the short-term memory of the first, so that it will be lost unless it has been transferred to long-term memory.

Probably the most successful method of training older people in industry has been the 'discovery method' whereby the trainee is given just enough information to enable him to discover accurately for himself how to perform his task. The active decisions required have the effect of facilitating registration in long-term memory, and the fact that the trainee can learn at his own pace means that he has time to sort out difficulties. It is fair to suggest that insufficient time devoted to mastering new facts and ideas is a reason why thinking often becomes hidebound in later middle age among those hard pressed by day-to-day activities and responsibilities, and that time set aside to acquaint themselves with new developments would be well repaid.

3. Personality

This often appears to change with age, yet scores on personality tests show small, if any, trends. The apparent changes seem instead to represent reactions to altered circumstances in old age which are not measured by the usual tests. For example, on the one hand, retirement brings increased leisure and opportunities, while, on the other, changing capacities may restrict interests and activities and in extreme cases lead to dependency. The ways in which individuals adjust to these circumstances vary greatly. Some welcome the new opportunities and accept the restrictions. Others find little use for leisure, resent restrictions, and become self-centred. This last reaction is well illustrated in many who complain of being lonely. Older people are understandably lonely for a time following bereavement: however, complaint typically comes from those who are surrounded by relatives, neighbours, and others, but whose self-centredness makes normal social intercourse unrewarding. In all cases the manner of adjustment seems to have little relation to economic or material circumstances or, within limits, to health: it depends upon personality traits that have been present throughout life but which may not have had the opportunity to show earlier because of the exigencies of work or bringing up a family.

The changes in personality can perhaps be summed up by saying that old age is a revealing time, when the best and worst in us stand out in bold relief. As a recipe for contentment, we may cite a remark by Maurice Chevalier: 'Growing old is inevitable for all of us. The clever thing is to accept it and always plan your next move well in advance.'

See also ageing: sensory and perceptual changes.

— A. T. Welford

Bibliography
• Birren, J. E., and Schaie, K. W. (eds.) (1977). Handbook of the Psychology of Aging.
• Bromley, D. B. (1974). The Psychology of Human Ageing (2nd edn.).
• Charness, N. (ed.) (1985). Aging and Human Performance.
• Welford, A. T. (1958). Ageing and Human Skill.

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