A Conserved ModulaTOR of Aging

A key interest of our lab is the nutrient sensor and kinase TOR (Target Of Rapamycin). TOR is emerging as a key regulator of lifespan and healthspan, and the mechanism(s) by which TOR operates to affect organismal aging is currently under intense investigation. TOR regulates several important biological processes that could modulate aging (Figure 2). Two such TOR-regulated processes, protein synthesis and the cellular recycling process autophagy, have received particular attention and we and others have shown that these processes affect lifespan in a conserved fashion. Other processes such as metabolism and stress responses are also emerging to play critical roles. In our lab, we are investigating how TOR and TOR-regulated processes contribute to the aging process in C. elegans. You will find a couple of these interesting projects outlined below!
























Figure 2: Overview of TOR-regulated processes with conserved effects on aging. Inhibition of TOR extends lifespan of multiple model organisms by affecting several biological processes, including protein translation, the cellular recycling pathway autophagy, metabolism, and stress responses. This proposal focuses specifically on elucidating how protein translation (highlighted in orange) modulates aging. Protein translation has conserved effects on aging in organisms ranging from yeast to mice. Figure is modified from Hansen and Kapahi, The Enzymes, Vol 28, Chapter on TOR and Aging, 2010.

Autophagy
An important focus of the lab is to elucidate the role of the TOR-regulated process of autophagy in aging. Autophagy is a cellular process by which the cell can degrade and recycle cytoplasmic material (Figure 3), and we and others have shown that autophagy is important for the longevity effects of at least some long-lived C. elegans strains, including animals subjected to dietary restriction. Nutrient limitation is a potent environmental method of lifespan extension observed in a multitude of different model organisms, including monkeys. We have observed that dietary-restriction triggers autophagy, a cellular process by which the cell can degrade and recycle cytoplasmic components (Figure 3). In addition, genes with functions in this process are required for dietary-restricted animals to live long (Hansen et al., PLoS Genetics, 2008). However, the mechanisms by which autophagy modulates longevity are not yet understood. To address this critical question, we are using a combination of genetic and molecular approaches to understand how and where in the organism the autophagy process functions to modulate longevity. We also aim to identify the mechanisms by which the cytoplasmic material/cargo, yet to be characterized as non-specific or selective in nature, is degraded during the aging process.
















Figure 3: Model summarizing the (macro)autophagy process in C. elegans. Different steps of the autophagy process are highlighted. Inserts show the molecular components of complexes assembled in C. elegans during the steps of nucleation, including the Class III phosphatidylinositol-3-kinase Vps34 (VPS-34 in worms) as well as Atg6/Vps30/Beclin1 (BEC-1 in worms), and in vesicle nucleation, including Atg8/LC3 (worms have two orthologs of LC3, LGG-1 and LGG-2). To get stably associated with the autophagosomal membrane, LC3 undergoes post-translational processing, including proteolytic cleavage followed by conjugation to phosphotidyl-ethanolamine (PE). Adapted from Melendez and Levine, Wormbook, 2009.

Protein synthesis
Our lab also studies the TOR-regulated process of mRNA translation. We and others have found that inhibition of the translational machinery or of regulators of protein synthesis, including the ribosomal S6 kinase (S6K) and translation initiation factors (eIFs), can extend lifespan and improve healthspan (Hansen et al., Aging Cell, 2007), possibly in a conserved fashion. We are using biochemical and genomic approaches to elucidate the mechanisms by which reduced protein synthesis has effects on aging and age-related diseases, such as cancer.

New Genes with Effects on Aging

Previous work by us and others has identified many conserved genes with effects on lifespan, however, the mechanism by which these genes modulate longevity is not known. We are investigating the mechanism of action of several novel genes identified in a genome-wide RNAi screen (Hansen et al., PLoS Genetics, 2005), including proteins with roles in integrin signaling, an important signaling pathway important for cell adhesion and critically involved in tumor formation in mammals.