Key proteins and pathways that regulate lifespan

Abstract

Here, we review three sets of key proteins and their corresponding downstream pathways that have been linked to extending lifespan and promoting health span in a wide range of organisms. In particular, we review the biology of the sirtuin family of proteins, the insulin/insulin-like growth factor (IGF) signaling (IIS) pathway, and the mechanistic target of rapamycin (mTOR). Using insights derived from simple model organisms, mice, and humans we discuss how these proteins and pathways may potentially alter the rate of aging. We further describe how knowledge of these pathways may lead to the rational design of small molecules that modulate aging and hence alter the propensity for a host of age-related diseases.

Keywords: IGF-1; aging; insulin-like growth factor (IGF); lifespan; mammalian target of rapamycin (mTOR); mouse genetics; sirtuin; sirtuins.

Figure 1.

Environmental or pharmacological strategies to slow aging. Drugs such as rapamycin and STACs, and lifestyle interventions such as fasting or caloric restriction, alter the activity of the IIS, mTOR, and sirtuin pathways. This alteration induces a complex web of functional alterations that individually or collectively might slow the aging process.

Figure 2.

mTORC1 and its downstream effectors. The molecular components of the mTORC1 complex as well as some of the downstream effectors are shown. See text for further details.

Figure 3.

Interaction between sirtuins, mTOR, and IIS signaling. Various points of interaction between these three signaling pathways have been described, some of which are depicted here. See text for details. P, phosphorylation site; Ac, acetylation site.