Books and Arts

Nature 447, 262-263 (17 May 2007) | doi:10.1038/447262a; Published online 16 May 2007

A singular view of ageing

Linda Partridge1

BOOK REVIEWEDAging of the Genome: The Dual Role of DNA in Life and Death

by Jan Vijg

Oxford University Press: 2007. 372 pp. £70, $114.50 (hbk); £32.50, $65 (pbk)

There is no shortage of theories of ageing. Confronted by the terrifying realization of mortality, human ingenuity has created an interesting array of explanations, including toxins produced by gut bacteria (curable by eating yoghurt) and reduced secretions from the testicles (curable by transplants of testicular tissue from monkeys). There is now general agreement that ageing is caused by the accumulation of damage. Key issues are the exact types of damage responsible for functional impairment and death, and the processes that generate this damage and protect against it. Jan Vijg's excellent book Aging of the Genome makes no concession of equal space for the many candidates subject to current scrutiny. Rather, it critically examines the case for one — somatic mutation.

First formulated in the 1950s, this theory suggests a key role in ageing for the accumulation of random alterations to DNA in somatic tissues (all tissues other than the reproductive germline cells). DNA is being constantly bombarded with chemical and physical challenges that induce random alterations, including structural damage and changes in nucleotide sequence and organization. But unlike other biomolecules, such as proteins and lipids, the damaged DNA cannot be simply broken down completely and remade, because it holds unique information. Instead, cellular pathways detect alterations and, contingent on the type of cell and the nature of the changes, this variously leads to DNA repair, arrest of the cell cycle (preventing cell division), cellular senescence or death, or toleration of the change. In some cell types, some forms of DNA alterations accumulate with age, with evidence for genomic hotspots and considerable variation between individuals. Cancer is a clear case where DNA alterations can give rise to age-related pathology; their role in other aspects of functional decline is less clear, with the exception of mutations in DNA within mitochondria, the organelles that power cells. As well as leading to ageing directly, DNA alterations could lead to ageing as a result of cellular defence mechanisms, such as selective cell death, although there is little evidence for this.

Vijg gives a clear and thoughtful account of this complex, and potentially confusing, body of work and its limitations: little work has been done on non-dividing cells; most evidence has come from cells in dishes rather than in tissues; measuring DNA alterations is difficult; a net change in levels of DNA alterations can be attributable to several different events including cell death; and pinning functional decline to altered DNA is a major challenge.

How can we tell if a theory of ageing is correct? If one underlying process is key to loss of function and death, then slowing it down should also slow down ageing. Vijg points to excitement about one successful application of this approach. The trail-blazing work of Michael Klass, who isolated the first long-lived mutant animals in the nematode worm Caenorhabditis elegans, culminated in the discovery of evolutionarily conserved mechanisms for increasing healthy life span. A critical test of a key role for DNA alteration in ageing, would therefore be to reduce it, by increasing the activity of pathways that combat it. For biochemical reasons, this is going to be difficult, however. Vijg gives a fascinating account of single-gene mutations, such as those causing Werner's syndrome, that seem to accelerate some aspects of ageing in humans. Progerias such as Werner's syndrome involve lesions in pathways that sense and repair alterations in DNA, suggesting that these processes are crucial for assuring a normal life span. More telling evidence for a key role for DNA alterations in normal ageing comes from the finding that some types of change in DNA accumulate more slowly in mutant long-lived mice, or when life span is extended by dietary restriction.

If this clear and insightful text has a cloudy patch, it is the account of the evolutionary basis of ageing. Contrary to Vijg's account, a solid mathematical foundation in theoretical population genetics and dynamics has revealed that, despite the loss of fitness it causes, ageing can evolve, through just two routes. Germline mutations with deleterious effects at later ages in adulthood, such as Huntington's disease in humans, can accumulate in populations through mutation pressure. Mutations that cause a benefit earlier in life, such as high fecundity, but at the cost of a higher subsequent rate of ageing, can also enter populations, by natural selection. Vijg points out that detection and repair of DNA alterations is costly, potentially leading to a trade-off between reproduction and somatic maintenance. Mutation pressure could also be important; small, life-long effects on maintenance of the integrity of DNA could lead to variation in the rate of ageing.

This is a work of real scholarship, a critical account of a huge swathe of work with no fewer than 879 references. It will nonetheless be enjoyable for non-specialists, and the opening chapters are a brisk walk through much of modern biology. The sharp focus on one type of damage, the excellent writing style and the well argued, personal perspective of the author contrive to keep the reader going. As Vijg acknowledges, the jury is out on the role of alterations to DNA in ageing, and this text points the way to the kind of research that will be needed to resolve the issue.

  1. Linda Partridge is in the Department of Biology, University College London, Gower Street, London WC1E 6BT, UK.


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