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 for many 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-term goal 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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Aging Systems and Geriatrics Study Section (ASG)
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Moro, Manuel H
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University of Texas Health Science Center
Other Basic Sciences
Schools of Medicine
San Antonio
United States
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Salmon, Adam B; Dorigatti, Jonathan; Huber, Hillary F et al. (2018) Maternal nutrient restriction in baboon programs later-life cellular growth and respiration of cultured skin fibroblasts: a potential model for the study of aging-programming interactions. Geroscience 40:269-278
Sills, Aubrey M; Artavia, Joselyn M; DeRosa, Brian D et al. (2018) Long-term treatment with the mTOR inhibitor rapamycin has minor effect on clinical laboratory markers in middle-aged marmosets. Am J Primatol :e22927
Lee, Hak Joo; Feliers, Denis; Barnes, Jeffrey L et al. (2018) Hydrogen sulfide ameliorates aging-associated changes in the kidney. Geroscience 40:163-176
Weiss, Roxanne; Fernandez, Elizabeth; Liu, Yuhong et al. (2018) Metformin reduces glucose intolerance caused by rapamycin treatment in genetically heterogeneous female mice. Aging (Albany NY) :
Zhou, Jin; Chong, Shu Yun; Lim, Andrea et al. (2017) Changes in macroautophagy, chaperone-mediated autophagy, and mitochondrial metabolism in murine skeletal and cardiac muscle during aging. Aging (Albany NY) 9:583-599
Salmon, Adam B; Kim, Geumsoo; Liu, Chengyu et al. (2016) Effects of transgenic methionine sulfoxide reductase A (MsrA) expression on lifespan and age-dependent changes in metabolic function in mice. Redox Biol 10:251-256
Strong, Randy; Miller, Richard A; Antebi, Adam et al. (2016) Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an ?-glucosidase inhibitor or a Nrf2-inducer. Aging Cell 15:872-84
Salmon, Adam B (2016) Moving toward 'common' use of the marmoset as a non-human primate aging model. Pathobiol Aging Age Relat Dis 6:32758
Salmon, Adam B (2016) Beyond Diabetes: Does Obesity-Induced Oxidative Stress Drive the Aging Process? Antioxidants (Basel) 5:
Lelegren, Matthew; Liu, Yuhong; Ross, Corinna et al. (2016) Pharmaceutical inhibition of mTOR in the common marmoset: effect of rapamycin on regulators of proteostasis in a non-human primate. Pathobiol Aging Age Relat Dis 6:31793

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