We are delighted to announce that we are working with Dr. Brad Stanfield to launch human trials of rapamycin to see if it can slow down aging in a meaningful way.
The trial will include low-dose rapamycin combined with exercise to see if there is synergy between the two. When we are young, exercise alone is enough to trigger a cellular waste disposal system called autophagy. However, as we age, and our metabolisms become dysfunctional, we struggle to trigger autophagy.
This is where Dr. Stanfield believes that rapamycin can help. Evidence from multiple studies has suggested that rapamycin in low periodic doses may help get our metabolism back on track and restore the benefits of exercise when we are older.
Positive results would demonstrate a meaningful impact on the quality of life and ability of older people to function. This would be firm ground upon which to potentially get rapamycin approved as a drug to combat frailty caused by aging.
Dr. Stanfield has created this video to explain the reasoning behind this trial and how it will work. If you would like to support this trial, you can find out how by visiting the video below and donating to the fundraiser on Youtube.
We had the opportunity to speak with Dr. Stanfield about the proposed trial.
We hypothesize that periods of time where the mechanistic target of rapamycin (mTOR) pathway is activated via exercise, combined with alternate periods of time where mTOR is inhibited using Rapamycin, will result in greater muscle performance in older adults compared with just exercise alone.
Human skeletal muscle inevitably undergoes remarkable changes with aging, characterized by a decline in muscle mass and strength of about 1% per year from the age of around 40 years. A growing body of evidence suggests that muscular strength is inversely and independently associated with all-cause and cardiovascular mortality even after adjusting for cardiorespiratory fitness. Ultimately, muscle wasting contributes significantly to weakness, disability, increased hospitalization, immobility, and loss of independence.
mTOR complexes 1 and 2 (mTORC1 and mTORC2) both play vital roles in cellular regulation, and, therefore, dysregulation of this signalling pathway disrupts cell homeostasis and may lead to pathologies associated with aging. mTORC1 is a nutrient-sensing protein kinase that can activate protein synthesis, drive lipid and nucleotide synthesis, and represses catabolism and autophagy.
Given its capability of blocking mTORC1 signalling, Rapamycin could be used to restore the mTORC1 balance and thereby improve exercise performance in older adults. Overactivation of mTORC1 has been observed in aged human muscles, but this overactivation of mTORC1 in aged muscles does not induce protein synthesis. Instead, chronic mTORC1 activation in old muscle leads to muscle atrophy mainly due to the inability to induce autophagy, suggesting the importance of mTOR-induced regulation of autophagy in aged muscle. Therefore, intermittent dosing with Rapamycin may restore the mTORC1 balance, whereby there are periods of mTORC1 activation and therefore protein synthesis, but also periods of mTORC1 inhibition with Rapamycin leading to autophagy. Plausibly, this approach may lead to an improvement in muscle performance of older adults. Furthermore, with a low and intermittent dosing regime, we aim to inhibit primarily mTORC1, thereby reducing the potential of adverse events.
To investigate this idea, we propose an initial proof-of-concept study designed to assess the safety, tolerability, feasibility, and trial design of weekly rapamycin or placebo dosing over a three-month period, in combination with thrice-weekly group exercise programs. The target population is 60-70 year old adults with either no co-morbidities or a well controlled chronic condition, that do not already perform weekly, strenuous exercise, and the primary outcome is the 30-second (30-s) Chair Stand Test. This will enable an appropriate power calculation to be conducted to inform the number of participants required for a superiority clinical trial.
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