Brad Stanfield, Matt Kaeberlein, Brian Leroux, Julie Jones, Ruth Lucas, Bruce Arroll
28 August 2024, PREPRINT (Version 1) available at Research Square
Aging leads to a decline in muscle mass and strength, contributing to frailty and decreased quality of life. Sirolimus (Rapamycin), an mTOR inhibitor, has shown potential in preclinical studies to extend lifespan and improve healthspan. This study evaluates the safety and efficacy of once-weekly Sirolimus (Rapamycin) administration on muscle strength and endurance in older adults engaged in a 13-week exercise program.
Methods
This randomized, double-blind, placebo-controlled trial will enrol 40 participants aged 65–85. Participants will be randomly assigned to receive either Sirolimus (Rapamycin) 6 mg/week or placebo for 13 weeks, in conjunction with an at-home exercise program. The primary outcome measure is the change in muscle strength and endurance, assessed by the 30-Second Chair-Stand Test. Secondary outcome measures include adverse events, changes in muscle strength and endurance as measured by the 6-minute walk test, handgrip strength, and participant-reported outcomes using the SF-36 survey.
Assessments will be conducted at baseline, mid-intervention (week 6), and post-intervention (week 13). Blood samples will be collected for hematology and biochemistry analyses, including full blood count, urea and electrolytes, liver function tests, HbA1c, lipids, serum IGF-1, and hs-CRP. DNA methylation will be analyzed using TruDiagnostic™ to explore changes in biological age.
I wish they could do a larger study and use a better-validated epigenetic age test than TruDiagnostic, but it’s a great start, and will be an independent test of things also tested in EVERLAST.
When it comes to older average people, you always get an effect from exercise programs. Examining the effects on muscle due to an exercise program is a highly complex issue. At least if you are interested in what is causing the effect on a cellular level. Exercise programs for older people can sometimes produce increases of more than 100 % in strength/power. If this study has a few more hyper responders in one of the arms, then the results will not say as much as we would have liked.
I also would have liked the study to go on for longer than 13 weeks. There are many forms of adaptation taking place. For instance, in the early stages of an exercise program, improved neuromuscular recruitment of muscle cells will take place, (in other words, a neurological learning process). And yes, this is important for improved strength, power, and coordination, but this is most likely not what we want to study. Or? At least, I would want to know more about any differences seen inside the cells (in the intracellular milieu, related to sarcopenia). To “guess” that seen effects on strength come from intracellular changes, I think the study would benefit from being longer than 13 weeks.
But these are only my first thoughts. I wish the money would be enough for a larger study and a longer study, this so the effect seen of hyper responders and different learning processes would be more limited. I am glad that Brad got this going. This is a way to get initial results and lead the field to improve the coming studies.
“The effects of exercise on skeletal muscle are various and involve several molecular and metabolic players, which are activated to a larger or lesser extent depending on the modalities of training. The recent findings about the involvement of autophagy and reactive species, with their ambivalent effects, in adaptation to exercise demonstrate how this phenomenon is extremely complicated. Exercise’s physiological and therapeutic relevance to health justifies the efforts of the scientific community that are aimed at unraveling the complex network of signaling and metabolic pathways triggered by physical training on skeletal muscle.”