The role and mechanisms of mTOR inhibition in ameliorating immune ageing features in humans

Large-scale studies demonstrate that skeletal muscle mass and functional capacity are fundamentally important for healthy ageing. With ageing, approximately 30% of an individual's peak skeletal muscle mass is lost by age 80-years. This age-associated muscle loss (sarcopenia) is of significant relevance to the maintenance of good health, with reduced muscle mass and function associated with increased cancer-related deaths, delayed post-operative recovery and reduced independence, amongst others. At present, other than weight-lifting exercise, no effective strategies exist to counteract sarcopenia.

A potential intervention is to use a compound which has already been shown in animal models to improve skeletal muscle preservation with ageing. One such compound acts by inhibiting mechanistic target of rapamycin (mTOR), a molecule which is involved in the maintenance of healthy muscle; in older muscle, this molecule becomes overactive and there is evidence that this hyper-activity becomes harmful. This research will determine proof-of-concept for the potential of mTOR inhibition in relation to ameliorating human frailty.

In this study, the compound (rapamycin/Sirolimus) used to inhibit mTOR is an antibiotic derived from bacteria found in the soil of Easter Island. At low doses, the drug has been shown to have many benefits unrelated to its antibiotic properties. Crucially, this compound is safe to provide to older humans, although its use in relation to human ageing remains unexplored from a scientific and clinical perspective. The compound will be administered to older people and evidence of "anti-ageing" properties in relation to human muscle will be interrogated. This research will be conducted alongside exercise training to determine interactions with muscle activity.

Finally, in collaboration with Prof Lynne Cox, we aim to investigate the impacts of rapamycin administration upon aspects of immune cell ageing, including secretion of factors that drive inflammation, as well as assessing whether mTOR inhibition can reduce signs of immunosenescence (age-related loss of immune function) in older adults. This is important for several reasons: older people's immune systems are less effective than those of younger people at fighting off infection, and immune cell senescence is thought to play a major part in this. This has been seen very clearly with COVID-19; excitingly, treatments that remove senescent cells and/or inhibit mTOR are looking promising in preventing deaths from coronavirus infection in preclinical studies and in very preliminary human trials. Determining whether rapamycin can help support older people's immune systems is therefore very important for overall health in later life. Older adults also have elevated levels of chronic inflammation even in the absence of infection, and this inflammation can damage cells and tissues, contributing to a number of different age-related diseases. Exercise can reduce this inflammation, and from our lab-based studies we know that mTOR inhibition can also lower levels of damaging inflammatory factors. In this study, we will be able to test whether rapamycin also does this in older adults.

The scientific objectives are to:

1. Determine the impacts of rapamycin upon human muscle mass by investigating:

   Whole body muscle mass by DXA and MRI;
   Whole body muscle mass by D3 creatine tracer;
   Ultrasound of thigh muscles.

2. Determine the impacts of rapamycin treatment on muscle function by investigating:

   Muscle strength as MVC/1-RM;
   Muscle power;
   Muscle performance as short performance physical battery testing;
   Muscle-nerve cross-talk.

3. Determine the impacts of rapamycin treatment on muscle metabolism by investigating:

   Effects on muscle protein synthesis;
   Effects on muscle protein breakdown;
   Regulatory pathways of muscle protein turnover.

4. Determine the impacts of rapamycin treatment on immune ageing

   Effects on lymphocyte senescence;
   Effects on inflammation by proteomics analysis of blood

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