Physical work involves oxygen consumption and waste product removal from the
involved muscles. It demands the integrated activity of a number of body systems,
cardiovascular, respiratory, muscular, nervous and , probably, endocrine. Delivery of
oxygen is facilitated by opening up ofthe capillary bed, increase in heart rate, blood
pressure, and cardiac output. Carbon dioxide has to be removed via the lungs and
excess acid neutralized by the buffer system of the blood aided by the kidneys. Heat
production is eliminated by sweating; adrenaline, released by the adrenal medulla,
increases glucose available to muscle by releasing glycogen stores from the liver and
by increasing the utilization of free fatty acids. The maximum work which the
individual, young or old, can achieve is thus seen to be the interplay of many factors
which must be adequately co-ordinated by the central nervous system.
Such complex controlling mechanisms become more sluggish with age, There is
good evidence of cellioss from the brain and changes occur in those that remain, such
as accummulation of lipofuscin in neuronal cells and the development of plaques,
tangles and areas ofsoftening (Tomiinson, Blessed & Roth, 1968). As a result ofthese
changes, cerebral function deteriorates in parallel with changes in all other systems.
Cell-mediated immunity declines with age as Weksler, Innes & Goldstein (1979)
have indicated. In mice lymphoid preparations, graft versus host reactivity,
generation of cytotoxic T-Iymphocytes and proliferation of T-Iymphocytes are all
impaired. 50% ofthe elderly have developed immune complexes, and the incidence
ofmonoclonal gammopathy increases with age. Burnett (1970) has suggested that the
early atrophy ofthe thymus gland may playa critical role in determining the timing
How are these widespread results of ageing initiated or controlled? Rosenberg
(1980) believes that our genetic make-up influences the process and cites three types
I) The constancy and species specific nature oflife-span.
2) Cell culture studies in which the same strains consistently survive for the same
3) Twin studies which demonstrate a consistently much closer association of age at
death in uniovular compared with binovular pairs.
Bullough (1973) believes that the key to an anirnal's life-span lies in its tissues
which, no matter how they vary in detailed structure and function , are controlled
throughout life by a common plan. He postulates that every tissue has to be
maintained at a mass which is constant relative to the total mass of the body and
must preserve a rate offunction which is appropriate to the body's needs at any given
moment. The former control is achieved through varying the rate of mitosis in tissues
consisting of cells retaining this potential. Bullough (1973) studied a number of
tissues including epidermis, sebaceous glands, me1anocytes, lung alveoli, kidney,
liver, granulocytes, erythrocytes and lyphocytes. In all cases, these cells synthesize a
tissue-specific antimitotic messenger molecule called a chalone which controls new
cell production. Every tissue which consists of cells capable of mitosis is constantly
changing, because as new cells are created , old cells are dying. After a certain period ,
which varies from tissue to tissue, 14-21 days for epidermal cells, but only 2 days for
those of duodenal mucosa , they lose the capacity for division and become ageing and
postmitotic. This process is achieved through the chalone antimitotic messenger
agent acting at point A to block further mitosis and move the cell metaphorically on
the road to point B (Figure 4a). Its demise at that point, signals the arrival of a new
cell into the mitotic circle. The faster the rate of mitosis, the shorter the life-span of
the cell, allowing the balanced size and function ofthe tissue to be maintained. The
time of death of the cell is dictated by the antimitotic messenger molecule which is
controlling affairs at its birth . Mitotic tissues are, therefore , theoretically at least,
Figure 48 Diagram of the chalone control mechanism in a typ ical mitotic tissue such as
epidermis. Chalone action is strengthened in the presence of the two stress hormones from the
adrenals. An inhibition of mitosis at point A is accompanied by an inh ibition of cell ageing at
Figure 4b Diagram of the situation in a typ ical non-mitotic tissue. With mitosis permanently
blocked all the cells pass very slowly along the ageing pathway to their death. It is suggested that
point B of th e chalone mechanism rem ains operative. (Reproduced by permission: Bullough,
Neurons and muscle cells, which, during embryonie development, are mitotic, lose
their ability to replicate at birth. Because the process of mitosis has been complete1y
blocked off, the ageing and death of cells is considerably slowed down (Figure 4b) but,
throughout life, and particularly after reaching maturity there is loss ofboth neurons
Why should there be potentially immortal, mitotic cells in our bodies on the one
hand and non-replicating tissues on the other? Bullough (1973) suggests that the
reasons may be to set a limit on the life-span of the animal, because this has an
ultimately beneficial effect on the species. If an evolutionary process is to continue,
there must be a continuous discarding to encourage recreating. If this is the purpose
of our nonmitotic tissues, then it is probable that they have a critical role to play in
determining one's life-span and the brain with its many controlling and regulating
functions is the most probable site ofits determination.
To prevent ageing has been man's dream for centuries in his search for the elixir of
life and eternal youth . In asking whether this is a realistic hope , one needs to
examine why we age. The answer is that we age and die for the benefit ofthe species.
Without death, no improvement to the latter could occur. We are indeed dispensible
'Iittle grains ofsand in the ocean of'time '.
For millions of years, man has been extending his maximum life-span potential
until today it is at least twice as long as most closely related mammals. This process
may, however, have reached its peak. Maximum Life-Span Potential (M.L.P .), which
is one way of measuring life, is the length of life of the last survi ving member of a
given population. Cutler (1979) has shown that M.L.P . is related to the weight ofthe
bra in relative to the body, the greater this is, the longer the life-span . The
mammalian species arrived on the scene 150 million years aga and hominids or their
immediate predecessors about fifteen million years ago. Since manl ike Homo first
appeared, the rate of increase of his longevity increased exponentially reaching a
peak between 200,000 and 100,000 years aga (Figure 5). During that period it
increased by fourteen years, but since then it has remained stationary.
Mi 11 ions 0 f yeors before presenl
Figure 5 Extension ofmaximum life-span potential ofspecies Hom o between 1.5 million years
ago and the present. M.L.? (0); Rate of change of M.L.? (0). (Reproduced by permission :
With the development of the brain, however, came an increase in time taken to
reach reproductive maturity. Improved cerebral function means greater ability to
communicate and think, which, in turn, results in the need for a more protracted
initial period of dependency to allow education of this advanced organ . Hence man
has a longer pre-pubertal phase than any other anima!. Within the past 100 years,
however, the average age at puberty has been falling. It is interesting to speculate on
the reasons and likely outcome ofthese two changes, the halting of exponential gain
in man's longevity and the reduction in the years of pre-reproductive life. Have we
Throughout our Iives, from a biological standpoint, we are constantly changing.
The genetic impulse which gives us our initial developmental thrust almost certainly
influences the pace of ageing and length oflife. Growth and development achieves its
peak as we reach maturity in the early twenties. Biologically speaking, that is the
point at which all of our bodily functions have the greatest potential, the greatest
reserve of function and their optimum capacity. Thereafter, the detrimental effect of
biosenescence takes over . Figure 6 represents the general pattern as it affects both the
human individual as a whole or each system of his or her body. During the first
twenty to thirty years beyond the point of optimum maturity, deterioration in
biological systems is slow and gradual, but beyond that period, it speeds up.
Figure 6 Representation ofrelationshipbetween function and age.
In youth and maturity, there is a range of function between individuals which
slowly widens during senescence. As a result, there are individuals at age 90 years
who constitute a biologically elite group, still within 10%oftheir optimum function,
while others of the same age have lost more than half of it. If one relates this idea to
brain function one can explain most ofthe awkward problems that are seen in elderly
Cerebral function involves sensory input and its translation into intellectual,
motor, and neuro-regulating activity. The brain achieves its optimum potential
between the ages of 16 and 20 years, after which there is a slow decline in its
capabilities. This decline is more rapid beyond the age of 75 years. Paralleling the
rapid development of the brain during childhood there is a considerable reversal
during the geriatric years. 1fthis is true, one might postulate that:-
1) The loss of agility and increasing c1umsiness of the failing motor system would
lead to an increasing number ofaccidents and falls - and so it does.
2) It is likely that failing receptors - visual , auditory, and cognitive - will lead to
misunderstandings and confüsion - and so it does.
3) The more eomplex of the nervous systern's regulating meehanisms will be most
suseeptible to the deteriorating efficiency of the ageing brain, and eontrol of
mieturition or defaeeation ean be expeeted to break down - and so it does.
4) Finally, reaetion to sudden stress - physical, mental, or emotional- aetivated by
the brain's hypothalamie eontrol ofhomeostasis may eollapse - and so it does.
Falling, confusion, ineontinenee and homeostatie disturbanee form a geriatrie
quartet and will be found separately or together in almost every aeute or long-term
problem posed by the elderly. They eonstitute an interrelated eomplex of old age
syndromes that are the essenee of clinieal geriatrie medieine (Cape, 1978) . The older
the patients, the more eommon the problems. To these ean be added iatrogen ie
illness, beeause many of the ageing ehanges whieh have been described, loss of lean
body mass, depleted elimination eapability and altered funetioning of tissues, will
inevitably eomplieate the use ofdrugs in elderly patients.
Andres, R. (1971). Aging and diabetes. Med. Clin. North Am.. 55, 835-846.
Bullough, W. S. (1973). Ageing ofMammals. Z. Alternsforsch., 27,247-253.
Burnet, F. M. (1970). An immunological outlook approach to ageing. Lancet, 2,358-360.
Cape, R. D. T. (1978). Aging: its complex management. New York: Harper & Row, Publishers,
Cutler, R. G. (1979). Evolution of human longevity: a critical overview. Mech. Ageing Dev.. 9,
Davies, D. F. & Shock, N. W. (1950). Age changes in glomerular filtration rate, effective renal
plasma flowand tubularexcretory capacity in adult males. J. clin./nvest.. 29,496-507.
Dunnill, M. S. & Halley, W. (1973). Some observations on the quantitative anatomy of the
kidney. J. Pathol..1l0, 113-121 .
Garn , S. M. (1978). Bone loss and ageing. In N utrition ofthe aged, ed. Hawkins, W. W., pp.
73-90. Proceedings ofa Symposium , The Nutrition Society ofCanada.
Holland , J., Milic-Emili, J., Macklem, P. T. & Bates, D. V. (1968). Regional distribution of
pulmonary ventilation and perfusion in elderly subjects. J. clin. Invest., 47, 81-92.
Novak, L. P. (1972). Aging, total body potassium , fat-free mass, and cell mass in males and
females between ages 18and 85 years. J. Gerontol., 27,438-443 .
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