With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging

Abstract

Target of rapamycin (TOR) is an evolutionarily conserved nutrient-sensing protein kinase that regulates growth and metabolism in all eukaryotic cells. Studies in flies, worms, yeast, and mice support the notion that the TOR signaling network modulates aging. TOR is also emerging as a robust mediator of the protective effects of various forms of dietary restriction (DR), which can extend life span and slow the onset of certain age-related diseases across species. Here we discuss how modulating TOR signaling slows aging through downstream processes including mRNA translation, autophagy, endoplasmic reticulum (ER) stress signaling, stress responses, and metabolism. Identifying the mechanisms by which the TOR signaling network works as a pacemaker of aging is a major challenge and may help identify potential drug targets for age-related diseases, thereby facilitating healthful life span extension in humans.

Figure 1. Schematic of the TOR signaling network

TORC1 integrates intra- and extracellular environmental cues through discrete signaling modules that sense and relay diverse inputs to a central “signaling core” (in green). This figure summarizes biochemical evidence from various studies that have identified the inputs and outputs of TORC1. Various outputs (in grey) that keep cellular growth in balance with the environment are regulated by TORC1. See main text for details.

Figure 2. TOR pathway, a conserved mediator of lifespan extension in multiple species

The diagram represents the genetic interactions in the TOR signaling network that execute lifespan extension in yeast, worms, flies and mice. The diagram summarizes the lifespan data for genes in the TOR signaling pathway or those that demonstrate a genetic interaction with mutants in the TOR pathway. The shaded area refers to components of the TOR pathway that show conserved effects on lifespan extension in different species. See main text for details.