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

ofthe ageing process.

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

of evidence. These are:-

I) The constancy and species specific nature oflife-span.

2) Cell culture studies in which the same strains consistently survive for the same

number of doublings.

94 R.D. T.CAPE

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,

potentially immortal.

(a)

I •

•

(b)

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

point B.

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,

1973).

BIOLOGICAL AGEING 95

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

and muscle cells.

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.

V>

90

g

80

"0

0-

§ 70 0-

V>

60

E

=>

E

'x 50 o

::<

H. neondertholensis eoropaeus

H. europaeus pre -Würm

1.4 1.2 1.0 0.8 0.6 0.4 0.2 0

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 :

Cutler, 1979).

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,

96 R.D. T.CAPE

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

perhaps passed our zenith?

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.

100

Level

of

Function

50

(percentage

of optimum)

I

Ili

20 30 40 50 60 70 80 90

Age in Years

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

patients.

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.

BIOLOGICAL AGEI NG 97

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.

References

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,

Inc.

Cutler, R. G. (1979). Evolution of human longevity: a critical overview. Mech. Ageing Dev.. 9,

337-354.

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 .