TOR signaling never gets old: aging, longevity and TORC1 activity

Abstract

The target of rapamycin (TOR) signal transduction network monitors intra- and extracellular conditions that favor cell growth. Research during the last decade has revealed a modular structure of the TOR signaling network. Each signaling module senses a particular set of signals from the cellular milieu and exerts regulatory control towards TOR activity. The TOR pathway responds to growth factor signals, nutrient availability, and cellular stresses like hypoxia and energy stress. The signaling modules and their molecular components constituting the TOR network are remarkably conserved in both sequence and function across species. In yeast, roundworms, flies, and mice, the TOR pathway has been shown to regulate lifespan. Correspondingly, genetic, dietary or pharmacological manipulation of individual signaling modules as well as TOR activity itself extends lifespan in these model organisms. We discuss the potential impact of manipulating TOR activity for human health and lifespan.

Box 1. Power for survival analysis

Power is calculated for the log-rank two-sided test under different hazard ratios assuming equal numbers in the experimental and control groups and no censoring, alpha=0.05, and no accrual period (Schoenfeld, 1981). The size of the experimental group is shown along the X-axis. The dashed line indicates power of 0.80.

Figure 1. The Tor signaling network

The signaling core of the Tor pathway integrates the activity of growth factor signaling like insulin and wnt, hypoxia, energy stress and amino acid sufficiency to regulate translation initiation. The individual signaling modules survey the intra- and extracellular environment for their particular stimuli, and relay their signal to key components of the Tor signaling core, Tsc2 and the Tor complex 1 (TORC1). Among other processes, Tor regulates the biosynthetic capacity of the cell by controlling translational initiation. For species-dependent differences, please see main text.