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Four anti-aging drugs and calorie-restricted diet produce parallel effects in fat, brain, muscle, macrophages, and plasma of young mice

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Abstract

Average and maximal lifespan can be increased in mice, in one or both sexes, by four drugs: rapamycin, acarbose, 17a-estradiol, and canagliflozin. We show here that these four drugs, as well as a calorie-restricted diet, can induce a common set of changes in fat, macrophages, plasma, muscle, and brain when evaluated in young adults at 12 months of age. These shared traits include an increase in uncoupling protein UCP1 in brown fat and in subcutaneous and intra-abdominal white fat, a decline in proinflammatory M1 macrophages and corresponding increase in anti-inflammatory M2 macrophages, an increase in muscle fibronectin type III domain containing 5 (FNDC5) and its cleavage product irisin, and higher levels of doublecortin (DCX) and brain-derived neurotrophic factor (BDNF) in brain. Each of these proteins is thought to play a role in one or more age-related diseases, including metabolic, inflammatory, and neurodegenerative diseases. We have previously shown that the same suite of changes is seen in each of four varieties of slow-aging single-gene mutant mice. We propose that these changes may be a part of a shared common pathway that is seen in slow-aging mice whether the delayed aging is due to a mutation, a low-calorie diet, or a drug.

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Acknowledgements

We thank Lori Roberts, Natalie Perry, Roxann Alonzo, Jacob Sheets, and Ilkim Erturk for expert assistance in animal care. The work was supported by a grant from the Glenn Foundation for Medical Research, and by NIH grants AG023122 and AG024824.

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Authors and Affiliations

  1. Department of Pathology, University of Michigan School of Medicine, BSRB, 109 Zina Pitcher Place, RoomAnn Arbor, MI, 316048109-2200, USA

    Xinna Li & Richard A. Miller

  2. College of Literature, Science, & the Arts, University of Michigan, Ann Arbor, MI, 48109, USA

    Madaline McPherson, Mary Hager, Michael Lee & Peter Chang

  3. University of Michigan Geriatrics Center, Ann Arbor, MI, 48109, USA

    Richard A. Miller

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  1. Xinna Li
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  2. Madaline McPherson
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  3. Mary Hager
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  4. Michael Lee
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  6. Richard A. Miller
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Contributions

X.L. designed and did the experiments and wrote the manuscript. M.M., M.L., M.H., and P.C. helped with experiments. P.C. did western blotting experiments. R.A.M. helped design the experiments and to edit the manuscript.

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Correspondence to Xinna Li.

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Li, X., McPherson, M., Hager, M. et al. Four anti-aging drugs and calorie-restricted diet produce parallel effects in fat, brain, muscle, macrophages, and plasma of young mice. GeroScience 45, 2495–2510 (2023). https://doi.org/10.1007/s11357-023-00770-0

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