Lifelong voluntary aerobic exercise-mediated preservation of physical function is related to changes in the plasma metabolome in aged mice
Authors: Maurer Grace , Murray Kevin , Gioscia-Ryan Rachel , Justice Jamie , Zigler Melanie , D'Alessandro Angelo , Reisz Julie , Rossman Matthew , Seals Douglas , Clayton Zachary 
Published: May 2023

Declines in physical function with aging (i.e., grip strength, endurance, and coordination) are strongly linked to age-related diseases, and the plasma metabolome can predict the progression of healthy aging. A single bout of aerobic exercise induces changes in plasma metabolites that are implicated in healthy aging and lifespan (e.g., tRNA biosynthesis is required for protein synthesis; arginine biosynthesis contributes to nitric oxide production and skeletal muscle function; TCA cycle metabolites aid in cellular energy production). Moreover, lifelong voluntary aerobic exercise (VAE) preserves physical function with aging, but its relation to the plasma metabolome is unknown. Hypothesis: Lifelong VAE-mediated preservation of physical function is related to changes in the plasma metabolome. Design: We performed a secondary analysis of data from a lifelong study in male C57BL/6 mice, in which mice that engaged in voluntary wheel running (model of VAE; initiated at 3 mo) were compared to sedentary age-matched controls (SED) (n=8-9/group). Grip strength, endurance, and coordination were assessed at 6 and 18 mo. The plasma metabolome was measured at 19 mo by mass spectrometry. Group differences in metabolites were identified using independent t-tests (p<0.05) following a Shapiro-Wilk test of normality. Then, KEGG pathway analyses (Metaboanalyst) were used to identify metabolic pathways changed with VAE (p<0.05; false discovery rate<0.20). Finally, simple linear regressions were used to assess the relation between the magnitude of change in grip strength, endurance, and coordination from 6 to 18 mo and plasma metabolite concentrations (all p<0.05). Results: At 19 mo, VAE mice ran 3.2±0.1 km/day (mean±SE). Physical function was preserved from 6 to 18 mo (% decline) with VAE vs SED: grip strength, 0.4±1.7% vs 12±4.0% (p<0.05); endurance, 1±15% vs 61±5% (p<0.05); coordination, 10±4% vs 73±10% (p<0.05). Group-related differences in plasma metabolites were identified at 19 mo: 23 single metabolites (p<0.05) and 7 metabolic pathways. The top altered metabolic pathways are implicated in healthy aging (e.g., tRNA and arginine biosynthesis) and exercise metabolism (e.g., TCA cycle). Metabolomic differences in the VAE mice were associated with preservation of physical function: spermidine and DHA omega-3 fatty acid correlated with the change in grip strength, spermidine and L-ornithine correlated with the change in endurance, and 9 metabolites (e.g., citrate and spermidine) correlated with the change in coordination. Conclusions: We show associations between the preservation of physical function with lifelong VAE and plasma metabolite abundance. Plasma metabolomic differences in aged mice following lifelong VAE are consistent with observations of corresponding changes in response to acute exercise in young endurance trained adults. Changes in the plasma metabolome reflect preserved physical function with lifelong VAE. NIH T32 DK007135, R01 HL107120, K99 HL159241 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.