Modulation of the nutrient sensing pathway governed by the protein TOR (target of rapamycin) leads to lifespan extension in various organisms. This discovery has outstanding potential health benefits for humans. However, failure to understand its mechanisms of action has slowed down its application for clinical healthspan benefits. The mammalian TOR complex 1 (mTORC1) can be pharmacologically inhibited with the compound rapamycin. Rapamycin inhibits a particular subset of TOR activity, mainly through S6 Kinase 1 and 2 (S6K1 and S6K2). Rapamycin extends lifespan of male and female mice, but also has negative effect on health via unknown mechanisms. S6K1-deficient female mice, but not male mice, have an extended lifespan suggesting a role for the other kinase, S6K2, in the lifespan extension by rapamycin. Also, no data is available regarding the lifespan of S6K2-deficient mice. Interestingly, S6K2 has been link to protect cells against apoptosis. Another, tumor suppressor mechanism is cellular senescence (a permanent cell growth arrest program). It is possible that cells expressing S6K2 favor senescence rather than apoptosis as a mechanism to protect against tumor apparition. Cellular senescence accumulation with age is widely seen as a contributor of aging phenotypes. These cells secrete proinflammatory cytokines a phenotype termed SASP for senescence- associated secretory phenotype and, therefore, their accumulation in an aging organism could contribute to chronic inflammation known to stimulate the apparition of age-related pathologies. Recently, it was shown that clearance of senescent cells alleviates age-related phenotypes in the progeroid mouse model. My preliminary data show that, in senescent cells in culture, rapamycin decreases the production of these proinflammatory cytokines and that similar results are obtained by downregulating S6K2, but not S6K1. My hypothesis is that reduction of S6K2 activity extends health- and lifespan by alleviating the senescent phenotype in aging mice. My research proposal will test the hypothesis that dampening complex activity by rapamycin or other means decreases the SASP, particularly its pro-inflammatory arm, by suppressing S6K2 activity. I will further test the hypothesis that suppression of S6K2 activity results in extension of both lifespan and healthspan in mice. Further, I will explore the mechanisms by which S6K2 acts and identify its major substrates. I will accomplish these aims by evaluating cells, tissues phenotypes and the physiology of S6K2 deficient cells and mice, as well as S6K2-expressing or -depleted human fibroblasts. I will examine the cells, tissues and animals for the relevant phenotypes using advanced biochemical and cell biological techniques. This award will serve me as a springboard to achieve my career goal for being professor and my scientific goals of developing strategies to ameliorate human healthspan. The mentored portion of the award will provide me with the necessary skills to achieve scientific independence and accomplish my short-term scientific goal. To achieve that I will received the help of numerous collaborators but also from two mentors experts in the two respective fields (senescence with Dr. Judith Campisi and mice healthspan with Dr. Richard Miller). My two mentors will also help for my preparation to become an assistant professor in the field of aging both at the scientific and personal level. In addition during the mentored phase I will take an intensive histology class from UC Davis. I will then be fully armed to embrace the independent portion of the award where I will continue studying the effects that S6K2 depletion on cellular senescence in vivo and its role on mice healthspan.
Health and lifespan extension strategies have been achieved in model organisms. Our knowledge on how these interventions work is currently limited and therefore cannot be translated to humans. Finding the mechanisms and the targets of these interventions can clear the way for clinical applications for healthspan extension.
|Jahrling, Jordan B; Laberge, Remi-Martin (2015) Age-Related Neurodegeneration Prevention Through mTOR Inhibition: Potential Mechanisms and Remaining Questions. Curr Top Med Chem 15:2139-51|
|Laberge, Remi-Martin; Sun, Yu; Orjalo, Arturo V et al. (2015) MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat Cell Biol 17:1049-61|