ECSS Paris 2023: OP-MH06
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.
Read CV Amanda JohnsonECSS Paris 2023: OP-MH06
INTRODUCTION: Functional decline and sarcopenia are major aging-related concerns. While protein intake is known to influence muscle health, its longitudinal impact on strength and physical function across age and gender remains underexplored. This study assessed whether low protein intake predicts future onset of low handgrip strength (HGS) and physical impairments in older adults using SHARE data. METHODS: We analyzed 38,073 adults aged ≥50 years from 27 European countries using SHARE Waves 8 (baseline) and 9 (follow-up). A protein intake index was derived from the frequency of consuming dairy, legumes/eggs, and meat/fish/poultry. Low intake was defined as the lowest decile. Logistic regression models, adjusted for age, gender, country, and baseline health, examined associations with low HGS and ten physical difficulties, stratified by age (50–65 vs. ≥66 years) and gender. RESULTS: Low protein intake significantly increased the odds of low HGS in men (OR = 1.39 for 50–65; OR = 1.35 for ≥66) and older women (OR = 1.21). It was also associated with higher odds of mobility-related limitations, including walking 100 meters (ORs = 1.25–1.53), stooping/kneeling (ORs = 1.20–1.19 in women), and reaching overhead (ORs = 1.19–1.33). Strength-related tasks, such as pushing/pulling large objects were more affected in men (ORs = 1.44 and 1.21). Notably, women aged 50–65 had over twice the odds of toileting difficulty (OR = 2.27) and significantly higher odds of difficulty shopping (OR = 1.65). These patterns highlight gender- and age-specific vulnerabilities. CONCLUSION: This study demonstrates that inadequate protein intake is linked with diminished muscle strength and functional ability among older European adults, with notable variations across gender and age groups. The results highlight the importance of promoting adequate, high-quality protein intake as a central component of healthy aging strategies. Future SHARE waves and experimental studies should aim to validate these findings using biomarker-based dietary measures and to explore whether targeted protein supplementation, when combined with structured physical activity, can prevent or reverse functional decline. In conclusion, low protein intake is a robust predictor of functional decline in older adults. Tailored nutritional strategies may mitigate age- and gender-specific risks to physical independence.
Read CV Shaea AlkahtaniECSS Paris 2023: OP-MH06
INTRODUCTION: Sarcopenia contributes to frailty, impaired mobility, and reduced quality of life. mTOR is prototypical positive regulator of muscle anabolism; however, its ‘hyperactivity’ in ageing may counterintuitively disrupt proteostasis e.g., preclinical evidence indicates mTOR inhibition unexpectedly attenuate sarcopenic phenotypes. We for the first time, investigated the effects of rapamycin therapy on human muscle physiology under rested and resistance-trained conditions. METHODS: Healthy male participants (n=22, 65.8 ± 7.7y, BMI: 26.4 ± 2.7 kg/m²; n.b. single sex initially due to funding constraints and unpredictable potential for sexual dimorphism) were included in this analysis following ethical approval (FMHS 90-0820) and clinical trials registration (NCT05414292). Participants were randomly assigned to either: ‘Rapamune’ (rapamycin) (n=11) receiving 1 mg (pill-form) daily, or placebo (n=11) (lactose pill). The intervention lasted 4-months, with participants undergoing unilateral resistance exercise training (3x/week, knee-extension with the dominant leg; 75% 1-repetition maximum). Muscle architecture of the vastus lateralis was assessed by ultrasonography (cross-sectional area (CSA) and muscle thickness (MT)) before and after the intervention. Strength was evaluated by maximum voluntary contraction (MVC) of the knee-extensors. Data were analysed by ANOVA, with p<0.05 considered significant. RESULTS: In the untrained-state, no changes in MT were seen in Rapamune (2,43 ± 0,19 vs 2,41 ± 0,16 cm, p=0.95) or placebo groups (2,06 ± 0,39 vs 1,98 ± 0,46 cm, p=0.39). However, CSA, better reflecting gross muscle architecture, increased in the Rapamune group (26,04 ± 2,17 vs 29,05 ± 2,11 cm², p<0.0001), despite no changes being observed in the placebo group (21,23 ± 4,86 vs 21,98 ± 4,84 cm², p=0.34). MVC increased in the Rapamune untrained-state (398 ± 87 vs 490 ± 124 N, p<0.0001), and also increased in the placebo group (382 ± 88 vs 421,05 ± 100 N, p=0.048. In the trained-state, there were no changes in MT in either the Rapamune (2,51 ± 0,16 vs 2,62 ± 0,14 cm, p=0.20) or placebo (2,15 ± 0,44 vs 2,09 ± 0,49 cm, p=0.62) groups. CSA increased in the Rapamune group (27,75 ± 3,46 vs 30,48 ± 4,13 cm², p=0.0004), with no changes being observed in the placebo group (21,79 ± 4,82 vs 23,05 ± 4,94 cm², p=0.11). MVC increased in the Rapamune group (384,00 ± 108,90 vs 505,91 ± 119,51 N, p=0.0001), with no changes in placebo (411,27 ± 124,41 vs 457,45 ± 122,41 N, p=0.13). CONCLUSION: Our findings represent the first to support the concept that dampening mTORC1 signalling could facilitate, not hinder, age-related neuromuscular declines in humans. In terms of muscle mass, discordance between MT and CSA via ultrasound requires MRI validation and ongoing work will address this. As will be probing molecular mechanisms, translational relevance in more diverse cohorts, and key clinical outcomes (e.g., mobility, balance, and physical function).
Read CV Harun MemisECSS Paris 2023: OP-MH06