Chapter 12 Ageing and death
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.
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
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Inbuilt genetic mechanisms (clonal senescence)
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.
These observations reveal that at least some features of ageing are genetically based.
Wear and tear (replication senescence)
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
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).
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.
CLINOPATHOLOGICAL FEATURES OF AGEING
![image](https://i0.wp.com/basicmedicalkey.com/wp-content/uploads/2017/06/x25B8-79.jpg?w=960)
There are also other situations in which diseases may be associated with old age but are not related to the causes of old age. Any individual who has lived for 60 years has had more opportunities for accidents than an individual who has lived for only 10 years so far. But this does not mean that accidents are part of the ageing process, although elderly individuals may be more prone to accidents because of failing eyesight and decreased agility. So we should attempt to distinguish between the process of ageing and accompaniments of ageing, and this proves very difficult to do (Fig. 12.4).
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