# Mechanisms of the cell non-autonomous dietary restriction pathway

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $383,185

## Abstract

PROJECT SUMMARY/ABSTRACT
Our understanding of the molecular and genetic mechanisms of aging has grown exponentially in the past 25
years. Groundbreaking studies in invertebrate models such as the nematode Caenorhabditis elegans have
been at the forefront of many breakthroughs, including the discovery of the first genes that control longevity.
Despite these important studies, there are many aspects of the genetic and molecular mechanisms of aging
that are still not well understood. One of these mechanisms is the cell non-autonomous control of aging by
small subsets of cells (frequently neurons) in an organism. Multiple highly regarded publications have
identified individual genes and neurons at the origin of signaling pathways that eventually modify genetic and
metabolic responses in peripheral tissues. These studies provide substantial evidence that cell non-
autonomous control of aging is common to multiple longevity pathways, but they lack in detail as to the specific
signals, receptors, neural circuits, and downstream effectors involved. Our preliminary data show that the
most well-studied longevity intervention, dietary restriction (DR), acts in part through a cell non-autonomous
signaling pathway that is inhibited by the smell of food in C. elegans. We further find that DR and fasting each
lead to induction of an intestinal protein, flavin-containing monooxygenase-2 (fmo-2), that is both necessary
and sufficient to improve healthspan, stress resistance, and longevity. We also observe that induction of fmo-2
and extension of lifespan both depend on the serotonergic signaling and can be recapitulated by the serotonin
antagonist drug, mianserin. This project will map the cell non-autonomous pathway initiated by removal of
food that eventually leads to intestinal fmo-2 induction and extension of lifespan. Aim 1 will identify and
epistatically relate the neurons involved in this neural circuit, answering important questions about which
specific cell(s) initiate the signal, which cell(s) propagate the signal, and ultimately, which cell(s) integrate the
signal into a system-wide response. The results will define a neural circuit led by food sensing and utilizing
serotonin that may overlap with other longevity pathways. The second aim will focus on the signals involved in
inter-neuronal and tissue to tissue communication by identifying small peptides, synaptic transport
mechanisms, and receptors involved in the pathway. The resulting data will fill out the neural circuit model
from aim 1 with the key signals and receptors beyond serotonin, and could lead to future studies designed to
mimic/block these signals. The third aim will identify the major receptors and transcription factors necessary to
induce fmo-2 in the intestine. We will use a forward genetic screen, a targeted RNAi approach, and existing
ChIP-SEQ data to define the major intestinal genes involved with DR-mediated fmo-2 induction. Together,
these aims will act independently and synergis...

## Key facts

- **NIH application ID:** 10149892
- **Project number:** 5R01AG059583-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** SCOTT F LEISER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $383,185
- **Award type:** 5
- **Project period:** 2018-08-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10149892

## Citation

> US National Institutes of Health, RePORTER application 10149892, Mechanisms of the cell non-autonomous dietary restriction pathway (5R01AG059583-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10149892. Licensed CC0.

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