The Role of Mtor Inhibition on Longevity and Healthy Aging in a Non-Human Primate

The mechanistic target of rapamycin (mTOR) signaling pathway has been identified as an important and evolutionary conserved determinant of longevity in invertebrate models and mice. Rapamycin, a small molecule inhibitor of mTOR signaling, has been demonstrated as the first pharmaceutical capable of extending longevity in mice and also delaying or abrogating several age-related diseases in pre-clinical mouse models. Despite the excitement raised by these studies, their potential translational relevance in terms of preventing age-related disease in humans remains unclear. Clarifying the role of mTOR signaling in human aging is challenging for several reasons and assessing its effect on human longevity is ostensibly impossible. We propose that a major step towards bridging this knowledge gap regarding translation potential can be made by testing whether inhibition of mTOR extends longevity in a non-human primate model. In the context of aging studies, the common marmoset (Callithrix jacchus) offers many advantages other commonly utilized non- human primates, foremost of which is that their normal lifespan is the shortest of any anthropoid primate and amenable to testing effects on longevity within the funding period of a single R01 grant. In our preliminary studies, we used rapamycin as a pharmaceutical tool to chronically inhibit mTOR signaling in marmosets. We found that rapamycin treatment in healthy marmosets was well-tolerated by all subjects, inhibited mTOR signaling in vivo, and did not increase risk formany effects that have been associated with its use clinically. Thus, our laboratory is in the unique position to test for the first time the hypothesis that inhibition of mTOR will both extend lifespan and improve healthspan in a non-human primate. In aim 1, we directly assess the effect of chronic mTOR inhibition on both lifespan and pathology in marmosets. Because longevity is the 'gold-standard' for measuring effects on aging, if positive, the results from this aim will provide the most conclusive evidence that inhibition of mTOR can slow aging in primates. In aim 2, we test the long-term effects of mTOR inhibition on functional markers of healthy aging in the marmoset. An overarching goal of aging research is to define means to promote healthy aging, and extension of lifespan without improving or maintaining health could be viewed as detrimental. We determine function using longitudinal assessments of minimally-invasive assays targeting five physiological systems shown to be affected by rapamycin in mice: muscle, brain, cardiac, glucose metabolism and inflammation. In aim 3, we define what role autophagy plays in mediating the effects of mTOR inhibition in marmosets. While autophagy, a cellular process by which proteins and organelles are degraded in the cell, is an important target of mTOR signaling, the role of this process in primate longevity is largely unknown. Overall, our long-termgoal is to determine whether inhibiting mTOR promotes healthy aging in primates to build the foundation for targeting mTOR-based therapies to improve health in humans. PUBLIC HEALTH RELEVANCE: Inhibition of the mTOR signaling pathway has been shown to extend both lifespan and healthspan in mice, but the implications of these findings for improving normal, healthy aging in humans is largely unknown. To bridge this knowledge gap, we propose testing whether mTOR inhibition through chronic administration of rapamycin delays aging in a non-human primate, the common marmoset, as an important step towards translational approaches to delay age-related disease in humans.