With the global aging population, Alzheimer’s disease, Parkinson’s disease and mild cognition
impairment are increasing in prevalence. The success of rapamycin as an agent to extend lifespan
in various organisms, including mice, brings hope that chronic mTOR inhibition could also refrain
age-related neurodegeneration. Here we review the evidence suggesting that mTOR inhibition -
mainly with rapamycin - is a valid intervention to delay age-related neurodegeneration. We discuss the
potential mechanisms by which rapamycin may facilitate neurodegeneration prevention or restoration
of cognitive function. We also discuss the known side effects of rapamycin and provide evidence to
alleviate exaggerated concerns regarding its wider clinical use. We explore the small molecule alternatives to rapamycin
and propose future directions for their development, mainly by exploring the possibility of targeting the downstream effectors
of mTOR: S6K1 and especially S6K2. Finally, we discuss the strengths and weaknesses of the models used to determine
intervention efficacy for neurodegeneration. We address the difficulties of interpreting data using the common
way of investigating the efficacy of interventions to delay/prevent neurodegeneration by observing animal behavior while
these animals are under treatment. We propose an experimental design that should isolate the variable of aging in the experimental
design and resolve the ambiguity present in recent literature.
Keywords: Aging, Healthspan, Intervention, mTOR, Neurodegeneration, Prevention, Rapamycin.
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