# Neuronal Orchestration of Metabolic State and Longevity

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2022 · $561,924

## Abstract

PROJECT SUMMARY/ABSTRACT
Older adults will be disproportionately affected by the complications arising from metabolic diseases including
diabetes, heart disease and neurodegeneration, predicted to double between now and 2050. However, the
fundamental mechanisms that link obesity and metabolic disease with longevity remain poorly understood. The
central nervous system is a major driver of lipid metabolism and lifespan. However neuroendocrine signals that
specifically control metabolism and lifespan are poorly understood in any system, and cannot be modeled in
cell culture. The long-term goal of my laboratory is to decipher the neural circuits and neuroendocrine
mechanisms that regulate metabolism and lifespan, and to define the key regulatory principles that govern their
relationship. We have uncovered an integrated neuro-metabolic system that underlies communication between
the nervous system and the intestine in the C. elegans model system, in which ancient and conserved aspects
of neuroendocrine biology can be discovered with state-of-the-art molecular tools. We define two critical nodes
for the regulation of this neuroendocrine system: one neuronal, one metabolic. The neuronal node integrates
food and oxygen sensory information from the environment, and the metabolic node integrates fat loss with
mitochondrial stress. Our central hypothesis is that the neuronal and metabolic nodes counterbalance one
another to maintain the integrity of neuroendocrine homeostasis, and that disruption of this counterbalancing
mechanism at either node alters lifespan. The objective of this proposal is to determine the molecular
mechanisms that regulate the homeostatic balance between the neuronal and metabolic nodes, and to identify
the key drivers that protect longevity. Thus, our neuroendocrine pathway defines a unique and powerful model
to study the consequences of neuronally-stimulated lipid metabolism, on longevity. Aim 1 will define the neural
circuit mechanisms that integrate neuroendocrine signaling, fat metabolism and lifespan. Our goal is to scale
multiple levels of analysis from molecular, circuit-level and organismal properties to achieve mechanistic
insights how the activity of a multimodal neural circuit gives rise to coordinated physiological shifts in
metabolism and longevity. Aim 2 will identify the mechanistic interactions between neuronally-driven fat loss
and mitochondrial stress-sensing pathways in the intestine, which ultimately drive lifespan. Using molecular
genetic approaches, biochemical analyses, metabolic and lifespan assays, we will uncover the molecular
mechanisms that couple fat loss with stress-protective mechanisms that together determine longevity. A major
expected outcome of our proposed studies is that longevity is an emergent property, determined by the extent
to which mitochondrial stress in metabolic tissues can counterbalance the neuronal drive for fat loss. The
experiments proposed in Aims 1 and 2 are expected to pinpoint,...

## Key facts

- **NIH application ID:** 10372000
- **Project number:** 5R01AG056648-05
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Supriya Srinivasan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $561,924
- **Award type:** 5
- **Project period:** 2018-03-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372000

## Citation

> US National Institutes of Health, RePORTER application 10372000, Neuronal Orchestration of Metabolic State and Longevity (5R01AG056648-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10372000. Licensed CC0.

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