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The brain–body energy conservation model of aging

Nature Aging volume 4, pages 1354–1371 (2024)Cite this article

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Abstract

Aging involves seemingly paradoxical changes in energy metabolism. Molecular damage accumulation increases cellular energy expenditure, yet whole-body energy expenditure remains stable or decreases with age. We resolve this apparent contradiction by positioning the brain as the mediator and broker in the organismal energy economy. As somatic tissues accumulate damage over time, costly intracellular stress responses are activated, causing aging or senescent cells to secrete cytokines that convey increased cellular energy demand (hypermetabolism) to the brain. To conserve energy in the face of a shrinking energy budget, the brain deploys energy conservation responses, which suppress low-priority processes, producing fatigue, physical inactivity, blunted sensory capacities, immune alterations and endocrine ‘deficits’. We term this cascade the brain–body energy conservation (BEC) model of aging. The BEC outlines (1) the energetic cost of cellular aging, (2) how brain perception of senescence-associated hypermetabolism may drive the phenotypic manifestations of aging and (3) energetic principles underlying the modifiability of aging trajectories by stressors and geroscience interventions.

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Fig. 1: Overview of the BEC model of aging.
Fig. 2: The BEC cascade.
Fig. 3: Accumulating molecular damage triggers stress responses, cellular senescence and systemic signals of hypermetabolism.
Fig. 4: Brain energy sensing and regulation of aging physiology.
Fig. 5: Target sites of action for protective geroscience interventions and stressors that accelerate phenotypic and functional aging.

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Acknowledgements

We are grateful to the members of the Mitochondrial Psychobiology Laboratory, M. Yousefzadeh, J. Wanagat, R. Musci, J. McNamara, J. Carroll, D. Leake and the Columbia Science of Health group for input on parts of the manuscript. Our research is supported by NIH grants R01MH119336, R01MH122706, R01AG066828 and RF1AG076821, the Wharton Fund and the Baszucki Group (to M.P.).

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Authors and Affiliations

  1. Department of Psychiatry, Division of Behavioral Medicine, College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA

    Evan D. Shaulson & Martin Picard

  2. Robert N. Butler Columbia Aging Center, Columbia University Mailman School of Public Health, New York, NY, USA

    Alan A. Cohen & Martin Picard

  3. Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY, USA

    Alan A. Cohen

  4. Department of Neurology, H. Houston Merritt Center for Neuromuscular and Mitochondrial Disorders, Columbia Translational Neuroscience Initiative, College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA

    Martin Picard

  5. New York State Psychiatric Institute, New York, NY, USA

    Martin Picard

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  1. Evan D. Shaulson
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  2. Alan A. Cohen
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  3. Martin Picard
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Contributions

E.D.S., A.A.C. and M.P. contributed to the literature review and revised the final version of the figures and manuscript.

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Correspondence to Martin Picard.

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Nature Aging thanks Felipe Sierra and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Shaulson, E.D., Cohen, A.A. & Picard, M. The brain–body energy conservation model of aging. Nat Aging 4, 1354–1371 (2024). https://doi.org/10.1038/s43587-024-00716-x

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