The Theories of Ageing

Theories of ageing

Introduction

The fundamental biological problem which all theories of ageing are seeking to explain was stated very elegantly in 1957 by Williams when he wrote, "It is indeed remarkable that after a seemingly miraculous feat of morphogenesis, a complex metazoan should be unable to perform the much simpler task of merely maintaining what is already formed".

The difficulty in attempting to establish an understanding of that ageing is that it is not a single physiological process. It is multifaceted and hierarchical in its expression with subtle changes occurring simultaneously at the molecular, cellular, tissue and organ levels. The considerable heterogeneity that characterises many species, particularly humans, and the complexity of environmental interactions and polygenic controls, results in an enormous phenotypic variability being associated with ageing. This variability is frequently confounded by the symptoms of underlying pathology and invariably increases between individuals with ageing.

It is therefore necessary to extract the essential attributes of the ageing process from this phenotypic complexity as a foundation on which to base an understanding of the biochemical processes involved. Strehler has attempted this and has identified four criteria to define the ageing process and to distinguish it from chronic pathology. Are these characteristics sufficient and adequate to distinguish ageing from morbidity?

Attributes of the Ageing Process

* Universal - the change occurs in all older members of the species;

* Intrinsic - ageing is a process which occurs even when all environmental influences are eliminated.

* Progressive - the onset of the process is gradual and the change accumulative.

* Deleterious - the change must shorten life.

Biochemical Theories of Ageing

In the scientific literature there are published over 300 theories seeking to explain the biochemical mechanisms of ageing. What conclusions can you draw from this statement? It is necessary and possible to simplify the issue by categorising the many disparate theories into two basic types; self-destructive genetic programme, or random chemical damage to proteins and DNA reducing the metabolic efficiency of the cell. Other schemes can also be used to provide a rationale approach to the literature. What other schemes can you suggest that could be used to categorise the theories of ageing?

The Program Theory of Ageing

The central idea of the programmed theory is that ageing is the result of a sequence of events encoded in the genome, just as the developmental sequence is controlled by gene expression. Ageing is considered to be programmed into the genome and genes exist whose function, when expressed, is to kill the organism. Clearly individual species have characteristic life-spans, and within a species genetically determined differences in life-span occur. It is assumed in this theory that there is some genetic program that determines the maximum life-span for each species. It has been suggested that the process of ageing and senescence may be under neural and endocrine control in a manner similar to development, growth and maturation.

Can you construct an argument from the available data in the literature to support/contradict this proposal?

Your approach to resolving this question could consider the following:

1. Studies on longevity in monozygotic and dizygotic twins, (McGue et al. 1993). In the classic study of Kallman and Sander, they reported that in a group of 59 pairs, the mean intra-pair differences in life-span for mono-zygotic twins was 36.9 months while in dizygotic twins it was 78.3 months. This finding was confirmed by later studies. This data has been reviewed by Jacquard (1982) who noted that although the difference in the life spans of monozygotic twins (36.9 months) is significantly less than the difference in the life spans of dizygotic twins (78.3 months), these differences decrease with age and finally disappear towards 80 years of age. Thus the contribution of genetic heterogeneity to the observed variability in life span seems to operate only during the early stages of life and strongly decrease with age.

What interpretation can you offer to explain this data?

Have recent studies confirmed or contradicted this interpretation of twin studies? What is the estimated contribution of genetics to eventual survival in the human?

2. Although human life expectancy has increased throughout recorded history, the rate of ageing has remained constant. What justification is there for this statement and if correct, does this statement support or contradict the program theory of ageing?

3. The program theory of ageing has been given some support by the work of Hayflick and others in studying cell mitotic potential under culture conditions. Prior to 1961 it was thought that animal cell populations could be propagated, apparently indefinitely in vitro. It is now known that normal cells derived from almost all vertebrate and most insect tissue can be cultured only for a finite number of generations. This has been interpreted as support for a programmed theory of ageing. Explain why you agree/disagree that this observation is evidence for a program theory of ageing (see Hayflick 1985).

4. Ageing may arise because of the pleiotrophic effect of some genes, i.e. genes may have more than one phenotype or be expressed at different times in the life span. Genes which are detrimental to survival will be eliminated from the genome if they are expressed early in the life span, but genes with detrimental effects late in the life span may not be eliminated so readily from the genome. Why should this be so? It is proposed that the total effect of detrimental,