TOR-mediated regulation of metabolism in aging

Abstract

Cellular metabolism is regulated by the mTOR kinase, a key component of the molecular nutrient sensor pathway that plays a central role in cellular survival and aging. The mTOR pathway promotes protein and lipid synthesis and inhibits autophagy, a process known for its contribution to longevity in several model organisms. The nutrient-sensing pathway is regulated at the lysosomal membrane by a number of proteins for which deficiency triggers widespread aging phenotypes in tested animal models. In response to environmental cues, this recently discovered lysosomal nutrient-sensing complex regulates autophagy transcriptionally through conserved factors, such as the transcription factors TFEB and FOXO, associated with lifespan extension. This key metabolic pathway strongly depends on nucleocytoplasmic compartmentalization, a cellular phenomenon gradually lost during aging. In this review, we discuss the current progress in understanding the contribution of mTOR-regulating factors to autophagy and longevity. Furthermore, we review research on the regulation of metabolism conducted in multiple aging models, including Caenorhabditis elegans, Drosophila and mouse, and human iPSCs. We suggest that conserved molecular pathways have the strongest potential for the development of new avenues for treatment of age-related diseases.

Keywords: mTOR; aging; autophagy; lysosomal clearance; metabolism.

Figure 1

Transcriptional Regulation of Autophagy, Lysosomal, and Proteasomal Biogenesis through Lysosomal mTORC1. The so‐called lysosomal nutrient‐sensing (LYNUS) complex composed of vATPase, Ragulator, and the Rags (A/B and C/D) tether mTORC1 proximal to Rheb which activates the kinase complex. Membrane‐tethering of mTORC1 is regulated by the KICSTOR‐bounded GATOR complexes and the leucine‐sensing Sestrin 1/2 and arginine‐sensing CASTOR1 proteins. Active mTORC1 directly phosphorylates and inhibits the function of TFEB and FOXO while promoting Nrf‐1 activity associated with expression of proteasomal subunit. During starvation, mTORC1 dissociates from the lysosome and is rendered inactive. Under these conditions, TFEB and FOXO enter the nucleus to bind to their target promoters to promote lysosomal and autophagosomal gene expression, thereby restoring lysosomal activity through molecular clearance.

Figure 2

Regulation of Cellular Metabolism by Receptor‐Mediated Signaling, Tuberous Sclerosis (TSC) Complex, and mTORC1. The TSC complex is substrate to kinases and/or mediators regulated by incoming cellular signals ranging from hypoxia, DNA damage, and low energy levels to growth factors, Wnt, and TNF signals. Once phosphorylated, TSC complex dissociates from the lysosomal membrane to be degraded (Potter et al., 2002; Inoki et al., 2006; Demetriades et al., 2014; Menon et al., 2014), resulting in activating of Rheb. Active mTORC1 promotes pyrimidine synthesis (Yang et al., 2013a), ribosomal biogenesis (Thoreen et al., 2012), lipogenesis (Porstmann et al., 2008; Peterson et al., 2011), adipogenesis (Zhang et al., 2009), protein translation (Fonseca et al., 2015), and inhibition of lysosomal biogenesis (Sardiello et al., 2009) and autophagy (Kim et al., 2011; Settembre et al., 2011; Nazio et al., 2013).