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Genetic links between diet and lifespan: shared mechanisms from yeast to humans

Nature Reviews Genetics volume 8, pages 835–844 (2007)Cite this article

Key Points

  • Dietary restriction — the limitation of available nutrients without malnutrition — can extend the lifespan of every species that has been tested, including mammals. Dietary restriction also reduces the incidence of and/or slows the progression of many age-related pathologies.

  • Dietary restriction has been modelled in yeast by reducing glucose concentration in the medium from 2% to 0.5% (moderate dietary restriction). Studies using this system have revealed a genetic pathway that controls dietary-restriction-induced longevity, which is dependent on increased mitochondrial respiration and sirtuin 2 (SIR2) genes.

  • A more severe form of dietary restriction in yeast, 0.05% glucose (severe dietary restriction), causes lifespan extension that is not dependent on SIR2 genes or on increased mitochondrial respiration. Instead, this form of dietary restriction may function through reduced target of rapamycin (TOR) and/or AKT signalling.

  • Few genes that mediate metazoan dietary restriction have been identified, but candidate genes that are known to be involved in both lifespan control and nutrient sensing include those encoding TOR, AMP-dependent protein kinase (AMPK), insulin signalling proteins and sirtuins.

  • Genes that have been clearly identified as required for metazoan dietary-restriction-induced longevity include skn-1 and pha-4 (in worms), Sir2 (in flies) and the growth hormone receptor gene (in mice).

  • Invertebrate studies have shown that neurons are crucial mediators of the dietary-restriction response in worms and flies.

  • A possible role of the mammalian hypothalamus in the response to dietary restriction is proposed in this Review. This is suggested by the clear demonstration of the importance of central neuronal signalling for dietary restriction in lower organisms and the many parallels between the genetics of invertebrate lifespan control and the genetics of hypothalamic energy sensing, as well as data suggesting that central hormonal axes under hypothalamic control have a role in mammalian dietary restriction.

Abstract

Caloric restriction is the only known non-genetic intervention that robustly extends lifespan in mammals. This regimen also attenuates the incidence and progression of many age-dependent pathologies. Understanding the genetic mechanisms that underlie dietary-restriction-induced longevity would therefore have profound implications for future medical treatments aimed at tackling conditions that are associated with the ageing process. Until recently, however, almost nothing was known about these mechanisms in metazoans. Recent advances in our understanding of the genetic bases of energy sensing and lifespan control in yeast, invertebrates and mammals have begun to solve this puzzle. Evidence is mounting that the brain has a crucial role in sensing dietary restriction and promoting longevity in metazoans.

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Figure 1: Conserved lifespan control pathways.
Figure 2: Responses to moderate and severe dietary restriction (DR) in yeast.
Figure 3: Potential parallel mechanisms of longevity control induced by dietary restriction (DR) in yeast and metazoans.
Figure 4: Homeostatic energy balance is maintained by the hypothalamus.
Figure 5: A neural basis for longevity induced by dietary restriction (DR).

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Acknowledgements

We thank members of the scientific community working on ageing and acknowledge support from the US National Institutes of Health and the Glenn Foundation.

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  1. Department of Biology, 77 Massachusetts Avenue, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Nicholas A. Bishop & Leonard Guarente

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Leonard Guarente is a founder of Elixir Pharmaceuticals.

Glossary

Feeding ad libidum

A feeding protocol in which an organism is allowed to eat as much as desired, given an unlimited food supply.

Hypothalamus

A region of the brain that regulates organismal homeostasis, in particular energy balance, by regulating behaviour and metabolism by endocrine and autonomic signalling.

Uncoupling proteins

A family of mammalian proteins that dissipate the proton gradient across the mitochondrial membrane, necessitating more rapid respiration to maintain the rate of ATP production.

Dauer

An alternative larval stage of Caenorhabditis elegans that is adapted to survive adverse conditions.

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Bishop, N., Guarente, L. Genetic links between diet and lifespan: shared mechanisms from yeast to humans. Nat Rev Genet 8, 835–844 (2007). https://doi.org/10.1038/nrg2188

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