PROJECT SUMMARY Aging is the major risk factor for multiple chronic diseases and two-thirds of individuals over the age of 65 suffer from multiple age-related conditions. Rather than trying to cure each individual disease, healthy aging can be promoted by targeting the biological pathways that regulate the rate of aging. The mTORC1 (mechanistic target of rapamycin complex I) signaling pathway promotes cellular growth and development when nutrients are abundant and its inhibition extends lifespan in a range of species. However, the promise of mTORC1 inhibition as an anti-aging therapeutic is limited by the associated negative side effects such as stunted growth, development, and fertility. The overarching goal of this project is to understand the mechanisms and key tissues through which mTORC1 specifically regulates aging in an effort to identify ways to target the mTORC1 pathway that can uncouple longevity from adverse health effects. Previous work in C. elegans found evidence that mTORC1 regulates aging through the neurons. In a long-lived mutant with decreased mTORC1 signaling throughout its entire body, restoring mTORC1 signaling only in the neurons suppressed the lifespan back to wild type. However, this neuronal mTORC1 rescue had no effect on the impaired growth or development of the null mutant, suggesting that targeting mTORC1 in key tissues may be a strategy to uncouple aging regulation form other mTORC1 functions. Lastly, this work found that restoring neuronal mTORC1 signaling induced changes in the expression of multiple neuropeptide genes and altered the shape of the mitochondrial network in peripheral tissues. Building on these findings, we have recently generated new data showing that neuron-specific mTORC1 inhibition in C. elegans extends lifespan without impairing growth or development. Thus, the central hypothesis of this proposal is that mTORC1 regulates aging, independently of other functions, through the neurons by modulating neuronal signaling and inducing metabolic changes cell-nonautonomously in peripheral tissues. We will use a suite of tissue- specific tools to investigate this hypothesis and probe the mechanisms of aging regulation by mTORC1 with unprecedented specificity. In Aim 1, we will assess how neuronal mTORC1 inhibition affects phenotypes associated with whole-body mTORC1 inhibition – such as growth, development, reproduction, and stress resistance – and test whether there are changes to the mitochondrial network in peripheral tissues. We will also identify downstream biological pathways that are required for neuronal mTORC1 longevity. In Aim 2, we will identify the specific neuronal signaling molecules and types of neurons through which mTORC1 acts to regulate aging. Altogether, this work will deepen our understanding of how metabolic pathways regulate aging and allow us to design strategies to target these pathways in a manner that promotes healthy longevity.