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.

生理功能随衰老而下降与年龄相关疾病密切相关。终生自愿有氧运动（LVAE）可能通过增加细胞质量控制过程来保持衰老过程中的生理功能，但介导这些过程的循环分子传感器尚不完全清楚。血浆代谢组可以预测生物衰老，并受到单次有氧运动的影响。在这里，我们使用血浆样本和生理功能数据进行了辅助分析，这些数据来自先前报道的雄性 C57BL/6N 小鼠的 LVAE 研究，随机分配到 LVAE（轮式跑步）或久坐不动（SED）（n  = 8-9/组）确定 LVAE 是否改变血浆代谢组，以及这些变化是否与 LVAE 生理功能的保留相关。在 3 个月和 18 个月大时评估身体功能（握力、协调性和耐力）；19 个月时评估血管内皮功能和血浆代谢组。LVAE 与 SED（所有p  < 0.05）的物理功能得以保留（％下降；平均值±SEM）——握力，0.4 ± 1.7% vs 12 ± 4.0%；协调性，10±4% vs 73±10%；耐久性， 1 ± 15% 与 61 ± 5%。LVAE 的血管内皮功能 (88.2 ± 2.0%) 高于 SED (79.1 ± 2.5%；p  = 0.03)，与年轻对照组相似 (91.4 ± 2.9%)。与 SED 相比，LVAE 有 15 种代谢物不同（FDR  < 0.05），并且与生理功能的保存相关。血浆亚精胺是一种增强细胞质量控制（例如自噬）的多胺，与所有评估的生理指标相关。与 SED 相比，LVAE 骨骼肌中的自噬（LC3A/B 丰度）较高 ( p  < 0.01)，并且与血浆亚精胺呈负相关 (r = − 0.5297；p  = 0.054)。这些发现为循环分子传感器提供了新的见解，LVAE 可以通过该传感器在衰老过程中保持生理功能。