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Ageing

Mutant mice live longer

Nature volume 402, pages 243–245 (1999)Cite this article

Is there a way to extend mammalian lifespan without paying a cost? On page 309 of this issue, Migliaccio et al.1 describe mutant mice that seem to live almost one-third longer than wild-type animals. These mice, which have a single targeted mutation in the gene encoding the p66shc protein, develop and eat normally, and have a normal body weight. But the absence of p66shc confers a heightened cellular resistance to agents that cause oxidative damage. Although the conclusions must be regarded as provisional until larger groups of animals are studied, the results support the proposal2 that oxidative damage is involved in ageing. They also indicate that modification of the response to oxidative damage can have a considerable effect on lifespan, without apparent negative side effects.

This claim might seem surprising from the perspective of evolutionary biology, which argues that ageing results from the absence of selection in the germ line against mutations that cause a post-reproductive decline in cell-maintenance functions3. A specific version of this theory predicts that certain genes function positively while the animal is developing and reproducing, then act negatively in the post-reproductive period4. If this is the case, genetic strategies to slow ageing should extract a cost by harming normal development or fertility. In fact, previous strategies to extend lifespan in mice have shown such a cost. For example, calorie restriction can extend lifespan by 50% or more, yet the affected mice are less fertile and about 30% smaller than controls5. Likewise, Ames dwarf mice live longer than controls, but they also have deficiencies in size and fertility6.

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Figure 1: Possible mechanisms for the action of p66shc.
Figure 2: Cellular response to oxidative stress and DNA damage.

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  1. the Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Leonard Guarente

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  1. Leonard Guarente
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Correspondence to Leonard Guarente.

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Guarente, L. Mutant mice live longer. Nature 402, 243–245 (1999). https://doi.org/10.1038/46185

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