What ultimately determines lifespan? Several processes have been identified to have causal influences on longevity, however work with our collaborators has uncovered a striking trend: cell size is negatively correlated with lifespan in mammals (Anzi et al., 2018). This suggests that not only are these seemingly unrelated traits likely governed by a single pathway, but that this coupling is highly conserved throughout evolution. From a screen of small compounds that selectively target specific protein kinases, we uncovered a network of signaling pathways that control cell size, including mTOR. mTOR has emerged as both a master regulator of cell growth and a strong determinant of lifespan. From yeast to mice, genetic and pharmacological inhibition of mTOR complex 1 (mTORC1) consistently causes an increase in longevity. Curiously, from yeast to humans this inhibition leads to a reduction in cell size. In fact, a number of mTORC1-mediated processes correlate with lifespan, including ribosomal biogenesis and protein translation. Work by us and by others has shown that cell size and lifespan additionally correlate with nucleolus size, the primary site of ribosome biogenesis (Tiku et al., 2017; Uppaluri et al., 2016). This raises the question: why has evolution linked these traits - cell size and lifespan - to a common pathway? We seek to understand the cellular processes that mediate mTORC1 activity in cell size and longevity, and to ask if the lifespan of an organism is dependent on cell size, or whether the traits are coincidentally linked. To do this we have established an experimental system in C. elegans, an ideal model based on the strong conservation of longevity pathways, and the transparency of the organism which makes cell and nucleolar size measurements easy to perform in vivo. Assaying for lifespan upon knock-down of homologs to our identified cell size regulators has uncovered a novel potential lifespan phenotype of
kin-20, a kinase involved in the regulation of circadian rhythm. In addition, we are using 3D imaging and live video tracking to monitor cell and nucleolar size as well as healthspan metrics throughout the life of a worm. This approach will allow us to gain a deeper understanding of how the regulation of each trait is coordinated, and where this regulation diverges downstream of mTORC1.