Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice

Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice

Metabolism and aging are tightly connected. Alpha-ketoglutarate is a key metabolite in the tricarboxylic acid (TCA) cycle, and its levels change upon fasting, exercise, and aging. Here, we investigate the effect of alpha-ketoglutarate (delivered in the form of a calcium salt, CaAKG) on healthspan an...

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Published in:Cell metabolism Vol. 32; no. 3; pp. 447 - 456.e6
Main Authors: Asadi Shahmirzadi, Azar, Edgar, Daniel, Liao, Chen-Yu, Hsu, Yueh-Mei, Lucanic, Mark, Asadi Shahmirzadi, Arash, Wiley, Christopher D., Gan, Garbo, Kim, Dong Eun, Kasler, Herbert G., Kuehnemann, Chisaka, Kaplowitz, Brian, Bhaumik, Dipa, Riley, Rebeccah R., Kennedy, Brian K., Lithgow, Gordon J.
Format: Journal Article
Language:English
Published: United States Elsevier Inc 01-09-2020
Subjects:
alpha-ketoglutarate
frailty
healthspan
IL-10
inflammation
lifespan
longevity
SASP
frailty
inflammation
alpha-ketoglutarate
lifespan
longevity
healthspan
SASP
IL-10
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Summary:Metabolism and aging are tightly connected. Alpha-ketoglutarate is a key metabolite in the tricarboxylic acid (TCA) cycle, and its levels change upon fasting, exercise, and aging. Here, we investigate the effect of alpha-ketoglutarate (delivered in the form of a calcium salt, CaAKG) on healthspan and lifespan in C57BL/6 mice. To probe the relationship between healthspan and lifespan extension in mammals, we performed a series of longitudinal, clinically relevant measurements. We find that CaAKG promotes a longer, healthier life associated with a decrease in levels of systemic inflammatory cytokines. We propose that induction of IL-10 by dietary AKG suppresses chronic inflammation, leading to health benefits. By simultaneously reducing frailty and enhancing longevity, AKG, at least in the murine model, results in a compression of morbidity. [Display omitted] •A CaAKG-supplemented diet extends lifespan of middle-aged female mice•AKG supplementation extends healthspan of both female and male mice•AKG compresses morbidity. Reduction in frailty is more dramatic than lifespan extension•AKG reduces chronic inflammation and induces IL-10 in T cells of female mice Asadi Shahmirzadi et al. report that an alpha-ketoglutarate-supplemented diet extends lifespan of middle-aged female mice and increases healthspan in both sexes. With simultaneous reduction in frailty and increase in longevity, the intervention compresses morbidity. AKG suppresses chronic inflammation and induces secretion of IL-10 in T cells of female mice.
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AUTHOR CONTRIBUTIONS
G.J.L. and B.K.K. supervised the study. D.E., Azar Asadi Shahmirzadi, G.J.L., and B.K.K. designed experiments. Azar Asadi Shahmirzadi, D.E., C.-Y.L., Y.-M.H., and G.G. investigated the healthspan data. Azar Asadi Shahmirzadi and Arash Asadi Shahmirzadi undertook the formal analysis. C.-Y.L., R.R.R., Y.-M.H., G.G., and Azar Asadi Shahmirzadi investigated the mouse samples. B.K. performed the metabolic studies. Azar Asadi Shahmirzadi and H.G.K. investigated the immune phenotype with H.G.K. undertaking the flow cytometric assays. C.D.W. and C.K. provided primers and C.D.W. helped with senescent-related experiments. D.E.K. and Azar Asadi Shahmirzadi performed the hair follicle melanocyte experiments. Azar Asadi Shahmirzadi, B.K.K., and G.J.L. wrote the paper with input from all authors.
ISSN:1550-4131
1932-7420
DOI:10.1016/j.cmet.2020.08.004