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The brain, sirtuins, and ageing

Nature Reviews Neuroscience volume 18, pages 362–374 (2017)Cite this article

Subjects

Key Points

  • Various cellular and molecular changes occur in the constituents of the brain (for example, neurons, microglia, astrocytes and oligodendrocytes) during the ageing process.

  • Functional alterations, such as cognitive decline, mental deficits, sleep disruption and circadian dysfunction, are induced by these cellular and molecular changes.

  • Sirtuins have crucial roles in the regulation of brain function during the ageing process.

  • Activation of microglia, possibly caused by reduced sirtuin activity, induces prolonged neuroinflammation, resulting in synaptic damage and neuronal death.

  • Age-associated decline in hypothalamic function, which is probably due to reduced SIRT1 activity, mediates ageing at a systemic level and ultimately affects longevity in mammals.

  • Peripheral tissues communicate with the brain via a range of hormones and circulating factors, which have been characterized by parabiosis experiments, thus affecting the pathophysiology of brain ageing.

Abstract

In mammals, recent studies have demonstrated that the brain, the hypothalamus in particular, is a key bidirectional integrator of humoral and neural information from peripheral tissues, thus influencing ageing both in the brain and at the 'systemic' level. CNS decline drives the progressive impairment of cognitive, social and physical abilities, and the mechanisms underlying CNS regulation of the ageing process, such as microglia–neuron networks and the activities of sirtuins, a class of NAD+-dependent deacylases, are beginning to be understood. Such mechanisms are potential targets for the prevention or treatment of age-associated dysfunction and for the extension of a healthy lifespan.

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Figure 1: Cellular, histological and functional changes in normal brain ageing.
Figure 2: Exacerbation of brain ageing through the activation of microglia.
Figure 3: Communication between the brain and peripheral tissues.

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Acknowledgements

The authors apologize to those whose work is not cited owing to space limitations. The authors thank members of the Imai laboratory, Cynthia S. Brace in particular, for stimulating discussions and critical reading of the manuscript. This work was supported by grants from the National Institute on Aging (AG037457 and AG047902) to S.I. and from the American Sleep Medicine Foundation to A.S., and by the Glenn Foundation for Medical Research and grants from the National Institutes of Health to L.G.

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Authors and Affiliations

  1. Department of Developmental Biology, Washington University School of Medicine, Campus Box 8103, 660 South Euclid Avenue, St. Louis, 63110, Missouri, USA

    Akiko Satoh & Shin-ichiro Imai

  2. Department of Biology, The Paul F. Glenn Center for the Science of Aging, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Bldg 68–280, Cambridge, 02139, Massachusetts, USA

    Leonard Guarente

  3. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Kendall Square, Cambridge, 02139, Massachusetts, USA

    Leonard Guarente

  4. National Center for Geriatrics and Gerontology, Sleep and Aging Regulation Research Project Team, 7–430 Morioka-cho, Obu, 474–8511, Aichi, Japan

    Akiko Satoh

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Correspondence to Leonard Guarente.

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Competing interests

L.G. is a founder of Elysium Health and consults for GSK, Chronos (Oxford) and Segterra. A.S. and S.I. declare no competing interests.

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Glossary

Myokines

Biologically active peptides produced and secreted by muscle cells that mediate a range of biological effects in both original and remote tissues and organs.

Hepatokines

Biologically active peptides produced and secreted by hepatocytes that mediate a range of biological effects in both original and remote tissues and organs.

Adipokines

Biologically active peptides produced and secreted by adipocytes that mediate a range of biological effects in both original and remote tissues and organs.

Cytokines

General terms for small-size cell signalling peptides such as lymphokines, monokines, chemokines and interleukins (cytokines produced by lymphocytes, monocytes, chemocytes and leukocytes, respectively).

Brain atrophy

Shrinkage of the brain described as a loss of neurons and connections between neurons.

Circadian clock

Central mechanisms that drive circadian rhythm.

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Satoh, A., Imai, Si. & Guarente, L. The brain, sirtuins, and ageing. Nat Rev Neurosci 18, 362–374 (2017). https://doi.org/10.1038/nrn.2017.42

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