Tiku, Varnesh et al. (2015) International Worm Meeting "NCL-1; an important player in Dietary Restriction mediated longevity in C. elegans."

Heestand, Bree N., Antebi, Adam, Tiku, Varnesh, Shen, Yidong

[International Worm Meeting, 2015]

Dietary restriction (DR) extends lifespan in many organisms ranging from simple invertebrates to complex mammals. A number of lifespan extending DR regimens have been described in diverse organisms, but it is still not clear if there are universal or overlapping mechanisms that modulate longevity by DR. In C. elegans, there are many ways to induce DR and different methods elicit varied downstream responses, revealing a complex process. Although a handful of important regulators have been identified, the molecular basis of DR mediated longevity still remains poorly understood, and additional players are likely to be involved.From a genetic screen for DR longevity mediators, we identified the RING finger protein NCL-1 to be required for DR induced longevity. ncl-1 is known to regulate the nucleolar size in worms and the loss of ncl-1 leads to increased nucleolar size and also increased translation. Our data suggest that nucleolar size is reduced under DR conditions and that the loss of ncl-1 abrogates DR longevity as well as the longevity conferred by the inhibition of the TOR pathway. The TOR pathway is known to be involved in DR mediated longevity and it also regulates translation. Global translation levels are low under DR conditions. So we speculate ncl-1 loss might be altering the translational rates thus abrogating longevity under DR and TOR inhibition. We are now investigating how ncl-1 interacts with nutrient sensing pathways and its detailed role in influencing lifespan extension. These studies should provide greater molecular insights into DR mediated longevity and a link between TOR signaling, translation and longevity under DR conditions. .

Webster, R. et al. (2019) International Worm Meeting "The Eternal Worm: Feedback Mechanisms in the Regulation of C.elegans Cell Size and Lifespan."

Tan, C., Anzi, S., Derry , W. B., Patel, N., Liu, S., Blutrich, R., Kafri, R., Dor, Y., Ginzberg, M., Webster, R.

[International Worm Meeting, 2019]

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.