Author(s): PUUMALAINEN, V., HUTZ, B., KORHONEN, M., KORHONEN, T.M., LEHTI, M., KARVINEN, S., Institution: UNIVERSITY OF JYVÄSKYLÄ, Country: FINLAND, Abstract-ID: 2417

INTRODUCTION:
Regular endurance exercise is linked to longer healthy life expectancy. One proposed mechanism is reduced accumulation of senescent, nonfunctional cells via enhanced senolytic processes. However, how lifelong endurance exercise affects senescence markers in blood and skeletal muscle is unclear. Systemic signaling particles – extracellular vesicles (EVs) and high density lipoprotein (HDL) – transport microRNAs (miRs) that regulate many biological pathways, including aging, making them compelling for endurance exercise research. While aging and endurance exercise are known to impact EV miRs, the role of HDL miRs is poorly understood. Here we examined how lifelong endurance exercise affects senescence markers in blood and skeletal muscle, and whether these correlate with HDL miRs.
METHODS:
Participants were aged (>70 y) and young (<35 y) male Masters endurance athletes (runners, n=10/group). Aged athletes had >40 years of competitive running history on average. Controls were age‑matched healthy non‑runners (n=10/group). V. lateralis biopsies and blood samples were collected. Serum senescence markers were measured (qPlex). Skeletal muscle senescent cells (γH2AX+) were quantified (confocal microscopy). Plasma HDL particles were isolated for miR profiling, and correlations between HDL miRs and muscle senescence were assessed.
RESULTS:
Lifelong running tended to reduce senescent muscle cells, yet not reaching statistical significance. Serum analyses showed independent effects of age and exercise on matrix metalloproteinases (MMPs): aged runners had higher MMP-2 levels than young runners (p=0.005), and MMP-2 was affected by both age and exercise (p≤0.004). Age increased MMP-7 (p=0.018). Age*exercise interaction affected MMP-13 (p=0.020).
Two HDL miRs differed between aged runners and aged controls: miRs 1-3p and 206 were upregulated in aged runners (p≤0.008). Compared with young controls, aged runners showed upregulated miR-1-3p and downregulated miR-451a (p≤0.008). These miRs are linked to senescence regulation: miR-1-3p and miR-206 have anti-senescence roles, while miR-451a promotes senescence.
Across all groups, miRs let-7f-5p, let-7i-5p, 182-5p, and 30d-5p positively correlated with senescent cell number (r≥0.446, p≤0.048). In cell models, miR-30d-5p is shown to promote senescence by suppressing TIA-1 protein, a regulator of mitochondrial dynamics, and let-7f is shown to induce senescence via increased oxidative stress. However, muscle-specific studies are lacking.
CONCLUSION:
This study shows for the first time that age and lifelong endurance exercise affect the HDL miR cargo. Correlations between HDL miRs and skeletal muscle senescence suggest a link between systemic HDL signaling and tissue-level cellular aging. Age and lifelong exercise also affected serum MMPs, key regulators of extracellular matrix turnover linked to functional decline. Further research is needed to clarify tissue-level mechanisms, the role of MMPs in aging, and how lifelong exercise modifies these processes.