Rapamycin -mTOR Antiaging in a pill

The mammalian target of rapamycin (mTOR) signaling pathway is a master regulator of cell growth and metabolism. Deregulation of the mTOR pathway has been implicated in a number of human diseases such as cancer, diabetes, obesity, neurological diseases and genetic disorders. Rapamycin, a specific inhibitor of mTOR, has been shown to be useful in the treatment of certain diseases. 

Rapamycin was initially discovered as an antifungal metabolite produced by Streptomyces hygroscopicusfrom a soil sample of Easter Island (also known as Rapa Nui). Subsequently, rapamycin was found to possess immunosuppressive and anti-proliferative properties in mammalian cells, spurring an interest in identifying the mode of action of rapamycin. Rapamycin was shown to be a potent inhibitor of S6K1 activation, a serine/threonine kinase activated by a variety of agonists and an important mediator of PI3 kinase signaling Concurrently, the target of rapamycin (TOR) was identified in yeast and animal cells (Laplante and Sabatini, 2012; Loewith and Hall, 2011). Rapamycin forms a gain-of-function complex with the 12-kDa FK506-binding protein (FKBP12), and this complex binds and specifically acts as an allosteric inhibitor of mammalian TOR (mTOR, also known as mechanistic TOR) complex 1 (mTORC1).

TOR signaling is an important player in longevity regulation. Genetic or pharmacological inhibition of mTOR signaling has been found to extend lifespan of invertebrates including yeast, nematodes and fruit flies (Lamming et al., 2013). In 2009, Harrison et al showed that rapamycin extends both median and maximal lifespan of male and female genetically heterogeneous mice when beginning treatment at 9 or 20-months of age (1.5–2 years duration) (Harrison et al., 2009), representing the first demonstration in mammals. Subsequent work by other groups confirmed the positive effect of rapamycin on lifespan in mice with different genetic backgrounds and other model organisms (Lamming et al., 2013). Two classes of explanations may account for these observations: 1). rapamycin increases lifespan by slowing aging; or 2). rapamycin inhibits detrimental metabolic diseases or lethal neoplastic diseases, independent of aging effects. To test the hypothesis that rapamycin might retard aging in mice, Wilkinson et al used a genetically heterogeneous mouse model and analyzed a number of age-related pathologies as well as age-dependent spontaneous activity of mice upon rapamycin treatment beginning at 9-months of age (1 year duration). Their results suggested that age-dependent changes occur more slowly in rapamycin-treated mice, including alterations in heart, liver, endometrium, adrenal gland, and tendon elasticity. Rapamycin was also shown to diminish age-related decline in spontaneous activity of mice (Wilkinson et al., 2012).

As rapamycin is known to have modest anti-proliferative properties in many forms of cancer, lifespan extension by rapamycin could also be caused by suppression of specific life-limiting pathologies (e.g., cancer). In a recent article by Neff et al 2013, several concerns were raised with regard to the previous reports on the effect of rapamycin in slowing aging. For example, cancer is the main cause of death in mice including the mice strain used in the study by Wilkinson et al. In addition, aging-independent effects by rapamycin were not examined previously. In the study by Neff et al 2013, the authors dosed male C57BL/6j mice with rapamycin or vehicle control for 1 year at 3 different treatment onsets: young adulthood (i.e., at 4 months), midlife (i.e., at 13 months), and late in life (i.e., at 20–22 months). After completing the treatment, they performed a large assessment of diverse structural and functional aging phenotypes in a variety of cell types, tissues and organ systems. Intriguingly, while rapamycin did extend lifespan in mice, age-related traits were largely unaffected. Although rapamycin was able to rescue a subset of aging-dependent phenotypes, such as spatial learning and memory impairments, as well as declined exploratory activity, similar positive effects on many of these attributes were also observed in young mice, indicating an age-independent effect. They reasoned that the discrepancy in findings could be due to different mouse models (genetic backgrounds) used in the studies or technical variations in the analysis (Neff et al., 2013), which, however were challenged by Blagosklonny (Blagosklonny, 2013). Clearly, future studies with other mouse strains and gender are warranted (Figure 2).?