TOR and ageing: a complex pathway for a complex process

Abstract

Studies in invertebrate model organisms have led to a wealth of knowledge concerning the ageing process. But which of these discoveries will apply to ageing in humans? Recently, an assessment of the degree of conservation of ageing pathways between two of the leading invertebrate model organisms, Saccharomyces cerevisiae and Caenorhabditis elegans, was completed. The results (i) quantitatively indicated that pathways were conserved between evolutionarily disparate invertebrate species and (ii) emphasized the importance of the TOR kinase pathway in ageing. With recent findings that deletion of the mTOR substrate S6K1 or exposure of mice to the mTOR inhibitor rapamycin result in lifespan extension, mTOR signalling has become a major focus of ageing research. Here, we address downstream targets of mTOR signalling and their possible links to ageing. We also briefly cover other ageing genes identified by comparing worms and yeast, addressing the likelihood that their mammalian counterparts will affect longevity.

The effect of resveratrol on longevity across species: a meta-analysis

“…Clearly, dietary restriction in higher-order animals involves more complex interactions than those upon which resveratrol acts. New research into different compounds may be more promising, with interest mounting in the antiageing effects of downregulating the target of rapamycin pathway [16].…”

Peroxiredoxins, gerontogenes linking aging to genome instability and cancer

“…CR, a practice that prolongs life span in taxonomically diverse organisms (Fontana et al 2010;Kenyon 2010;McCormick et al 2011), counteracts sulfinylation of Tsa1 during aging in an Srx1-dependent manner . Specifically, a CR-induced reduction in RAS-PKA signaling bolsters Gcn2-dependent translation of the SRX1 transcript (Fig.…”

“…Specifically, aging is decelerated by mutations reducing signaling through nutrient-responsive pathways, including insulin/insulin-like growth factor, mTOR, and RAS-PKA signaling (Cohen and Dillin 2008;Kenyon 2010;Bartke 2011;McCormick et al 2011). Such a reduced activity in nutrient-responsive pathways results in the altered expression of a large number of genes, and it is presently not clear which of all of these genes are the most crucial targets responsible for life span extension.…”

Targeting tissue-specific metabolic signaling pathways in aging: the promise and limitations

“…mTOR signaling: linking energy homeostasis to aging mTOR is a Ser/Thr protein kinase that integrates signals originating from changes in growth factors, nutrient availability, energy status, and various physiological stresses (Wullschleger et al, 2006;Liu et al, 2009). Convergence of these internal and external signals to the mTOR complex, in turn, triggers various downstream outputs such as mRNA translation, protein synthesis, autophagy, cell proliferation, growth, and survival, which are critical for the lifespan of organisms (Kennedy and Kaeberlein, 2009;McCormick et al, 2011;Zoncu et al, 2011). mTOR functions in cells by formation of two distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).…”

“…Pharmacological or genetic manipulations of key signaling pathways involved in the regulation of glucose and energy metabolism, such as the insulin and the mammalian target of rapamycin (mTOR) signaling pathways, have been shown to improve health-span and longevity in diverse model organisms such as yeast, worms, flies, and mammals (Kennedy and Kaeberlein, 2009;McCormick et al, 2011;Laplante and Sabatini, 2012). An interesting question remains to be answered is what are the underlying mechanisms by which altering the insulin/insulin-like growth factor 1 (IGF-1) or the mTOR signaling pathway suppresses or delays aging-associated diseases and extends lifespan.…”