Abstract
Declines in physiological function with aging are strongly linked to age-related diseases. Lifelong voluntary aerobic exercise (LVAE) preserves physiological function with aging, possibly by increasing cellular quality control processes, but the circulating molecular transducers mediating these processes are incompletely understood. The plasma metabolome may predict biological aging and is impacted by a single bout of aerobic exercise. Here, we conducted an ancillary analysis using plasma samples, and physiological function data, from previously reported studies of LVAE in male C57BL/6N mice randomized to LVAE (wheel running) or sedentary (SED) (n = 8–9/group) to determine if LVAE alters the plasma metabolome and whether these changes correlated with preservation of physiological function with LVAE. Physical function (grip strength, coordination, and endurance) was assessed at 3 and 18 months of age; vascular endothelial function and the plasma metabolome were assessed at 19 months. Physical function was preserved (%decline; mean ± SEM) with LVAE vs SED (all p < 0.05)—grip strength, 0.4 ± 1.7% vs 12 ± 4.0%; coordination, 10 ± 4% vs 73 ± 10%; endurance, 1 ± 15% vs 61 ± 5%. Vascular endothelial function with LVAE (88.2 ± 2.0%) was higher than SED (79.1 ± 2.5%; p = 0.03) and similar to the young controls (91.4 ± 2.9%). Fifteen metabolites were different with LVAE compared to SED (FDR < 0.05) and correlated with the preservation of physiological function. Plasma spermidine, a polyamine that increases cellular quality control (e.g., autophagy), correlated with all assessed physiological indices. Autophagy (LC3A/B abundance) was higher in LVAE skeletal muscle compared to SED (p < 0.01) and inversely correlated with plasma spermidine (r = − 0.5297; p = 0.054). These findings provide novel insight into the circulating molecular transducers by which LVAE may preserve physiological function with aging.
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Acknowledgements
We thank Jill Miyamoto-Ditmon for her assistance with data collection.
Funding
This work was supported by the National Institutes of Health Grants R01HL107120 (DRS), 5T32KD007135 (KOM & ZSC), F31AG047784 (RGR), K01DK115524 (MJR), F32HL167552 (KOM), and F32HL151022 & K99HL159241 (ZSC) and the American Heart Association grants 23POST1025630 (KOM) (https://doi.org/10.58275/AHA.23POST1025630.pc.gr.161298) and 23CDA1056582 (MJR) (https://doi.org/10.58275/AHA.23CDA1056582.pc.gr.168037).
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K.O.M., G.S.M., and Z.S.C. conceived and designed the research, performed experiments, analyzed data, interpreted results of experiments, prepared figures, drafted the manuscript, edited and revised the manuscript, and approved the final version of the manuscript. R.A.G. and M.C.Z. conceived and designed the research, performed experiments, analyzed data, interpreted results of experiments, edited and revised the manuscript, and approved the final version of the manuscript. K.R.L. performed experiments, edited and revised the manuscript, and approved the final version of the manuscript. A.D. and J.A.R. performed experiments, edited and revised the manuscript, and approved the final version of the manuscript. M.J.R. edited and revised the manuscript and approved the final version of the manuscript. D.R.S. conceived and designed research, acquired funding, interpreted the results of experiments, edited and revised the manuscript, and approved the final version of the manuscript.
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Kevin O. Murray and Grace S. Maurer are co-first authors.
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Supplemental Figs. 1 and 2, the complete list of assessed plasma metabolites (and fold change and FDR-adjusted p-values), and the supplemental methods can be found here: https://doi.org/10.6084/m9.figshare.23699265. (PDF 323 KB)
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Murray, K.O., Maurer, G.S., Gioscia-Ryan, R.A. et al. The plasma metabolome is associated with preservation of physiological function following lifelong aerobic exercise in mice. GeroScience 46, 3311–3324 (2024). https://doi.org/10.1007/s11357-024-01062-x
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DOI: https://doi.org/10.1007/s11357-024-01062-x