Blazing a trail for the clinical use of rapamycin as a geroprotecTOR
Adam R. Konopka, Dudley W. Lamming, RAP PAC Investigators & EVERLAST Investigators
GeroScience (2023) 06 October 2023
…Concerns over the risk of potentially serious side effects in humans, including immunosuppression and metabolic disruptions, have cautiously limited the translation of rapamycin and its analogs as a treatment for aging associated conditions. During the last decade, we and others have developed a working model that suggests that while inhibition of mTORC1 promotes healthy aging, many of the negative side effects of rapamycin are associated with “off-target” inhibition of a second mTOR complex, mTORC2. Differences in the kinetics and molecular mechanisms by which rapamycin inhibits mTORC1 and mTORC2 suggest that a therapeutic window for rapamycin could be exploited using intermittent dosing schedules or alternative rapalogs that may enable more selective inhibition of mTORC1. However, the optimal dosing schedules and the long-term efficacy of such interventions in humans are unknown.
Here, we highlight ongoing or upcoming clinical trials that will address outstanding questions regarding the safety, pharmacokinetics, pharmacodynamics, and efficacy of rapamycin and rapalogs on several clinically oriented outcomes. Results from these early phase studies will help guide the design of phase 3 clinical trials to determine whether rapamycin can be used safely to inhibit mTORC1 for the treatment and prevention of age-related diseases in humans.
Impact of rapamycin on select physiological outcomes in pre-clinical and clinical studies
Metabolic function
Cognitive function
Cardiac function
Physical function
Immune function
Potential risks and unknowns
Working model
Using genetic models, inhibition of mTORC1 signaling alone extends lifespan and healthspan [7, 8] while tissue-specific and whole body genetic depletion of mTORC2 has negative effects on metabolic health, frailty, and survival in mice [89,90,91,92,93]. Similarly, genetic inhibition of mTORC2 activity in the heart impairs cardiac function in flies, while genetically increasing mTORC2 activity preserves cardiac function with aging and extends the lifespan of flies [94, 95]. These data support a model shown in Fig. 2 in which rapalog-mediated inhibition of mTORC1 is geroprotective, while the “off-target” inhibition of mTORC2 may be responsible for many negative effects of rapamycin.
Therefore, to enhance translation of mTOR inhibitor-based therapies from pre-clinical models to human clinical trials and clinical practice, rapalog dosing strategies that preferentially inhibit mTORC1 rather than mTORC2 should be tested to potentially capitalize on healthspan extension while minimizing adverse side effects. …There is currently a lack of pharmacokinetic and pharmacodynamic (PK/PD) data in healthy older adults. Therefore, it remains unknown what dose or dosing schedule of rapamycin or rapalogs minimizes undesirable side effects in older adults and whether rapamycin can have a beneficial impact on proposed biomarkers of aging and human healthspan as it does in pre-clinical models. We also do not understand if the dose of rapamycin for geroprotection will differ between sex, the age-related condition(s), or impacted tissue(s). Furthermore, we do not know how rapamycin will interact with healthy lifestyle practices such as exercise and diet. To address this need for additional information, a number of new clinical trials at the University of Wisconsin-Madison and around the world have begun or will begin in the near future to better study the effects of rapamycin and its analogs on age-related conditions (Table 2). … These relatively small trials will be signal-generating and will be used to inform on future, well-powered phase 3 clinical trials that will be needed for more definitive assessments of the therapeutic potential of rapalogs for human aging-related conditions.
Table2LammingKonopka.pdf (242.0 KB)