Author(s): JOHNSON, A., BEVINGTON, R., JABILE, T., WANG, D., STEINBERG, G., PARISE, G., Institution: MCMASTER UNIVERSITY, Country: CANADA, Abstract-ID: 914

INTRODUCTION:
Age-related functional decline in skeletal muscle leads to increased risk of falls, frailty, and other diseases, therefore developing countermeasures against the underlying mechanisms of aging is crucial. Senescence is a hallmark of aging and is also associated with impaired wound healing and chronic inflammation. Senolytics are a class of drugs that selectively eliminate senescent cells and have potential to be used as anti-aging therapeutics. Currently the most common treatment to mitigate the adverse effects of sarcopenia is exercise. However, the use of senolytics and exercise to mitigate age-related functional decline in muscle has yet to be investigated. We hypothesized that combining senolytics and exercise would have the most beneficial effects in preserving skeletal muscle function and quality.
METHODS:
12-month-old male and female mice (n=20/group) were randomly assigned to four groups: (a) naturally aged (VEH), (b) 2x/week treadmill training (EX), (c) biweekly senolytic treatment using Dasatinib + Quercetin (5mg/kg + 50mg/kg) (SEN), or (d) both treadmill training and senolytic treatment (SENEX) for 9 months. A young (n=10, 3-month) group served as young healthy controls. Functional measurements were evaluated every 3 months and in metabolic cages at 6 and 9 months of treatment. Muscles were collected for biochemical analysis.
RESULTS:
After 9 months of intervention, SENEX had a lower frailty index compared to VEH and SEN (p<0.05). EX, SENEX, and young had higher endurance stress test times, distance travelled, and rearing times suggesting higher muscle function and activity levels. There were no changes in cross-sectional area or satellite cell number (Pax7+) between groups. VEH mice (17±3.9) had significantly higher macrophage numbers (F4/80+) compared to young (4.08±1.1), EX (7.39±1.5) and SENEX (5.62±1.2). EX had higher Il1b gene expression compared to SENEX and young mice (p<0.05) as well as higher Cxcl12 gene expression compared to all groups (p<0.05). VEH mice had higher proportion of p21+ senescent cells compared to young mice (VEH: 1.16±0.3, Young: 0.25±0.1, p<0.05) with no significant changes in p16 or yH2AX nuclei.
CONCLUSION:
These findings suggest that exercise and senolytics could be strategies to mitigate sarcopenia by improving muscle function, activity levels, and inflammatory processes. However, there were no additive benefits of senolytics and exercise in improving skeletal muscle function or quality. This study included one of the longest treatment periods of senolytics, starting at mid-age, however, further research is needed to fully understand the optimal treatment regime for senolytics. Results from this study will contribute to improved treatment strategies for sarcopenia.