# AgRP neurons promote the effects of calorie restriction on lifespan

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $441,823

## Abstract

Calorie restriction has been show to extend lifespan. A key aspect of calorie restriction is a shift in systemic
metabolism from carbohydrate to lipid metabolism. The hypothalamus is a crucial regulator of systemic
metabolism and has been directly implicated in the aging process of mice. We uncovered that cell-selective
impairment of hypothalamic Agouti-related peptide (AgRP)-expressing neuronal circuitry, part of the
hypothalamic melanocortin system, in ad libitum fed mice, results in accelerated aging phenotype of many
tissues, including the immune system and bone. We also found that males of mice strains with impaired AgRP
neuronal circuitry have shorter mean lifespan when ad libitum fed. Taken together these results gave
impetus to the central hypothesis of this proposal, which is that the AgRP system is key mediator in
calorie restriction-induced extension of lifespan. We will test our hypothesis through the following specific
aims: Specific Aim 1. To test the hypothesis that calorie restriction prevents declining functioning of
hypothalamic AgRP neurons in chronological aging. In our preliminary studies we found that AgRP neurons
manifest aging associated decline in mitochondrial integrity in ad libitum fed mice. We also observed that
calorie restriction promotes AgRP mRNA expression and suppression of POMC mRNA levels. We showed that
the input organization of the melanocortin system is shifted by calorie restriction to a constellation that
enhances AgRP neuronal activity and suppresses POMC cells. We hypothesize that calorie restriction
suppresses deterioration of AgRP neurons during chronological aging, and that this effect is mediated by
intracellular pathways regulating mitochondrial dynamics and ROS generation. We will test this hypothesis by
analyzing the effect of calorie restriction on AgRP neuronal activity, mitochondrial dynamics and ROS
production in control and transgenic mice, in which specific processes of mitochondrial fission, fusion or ROS
control is cell-selectively down or up-regulated. Specific Aim 2. To unmask if hypothalamic AgRP neurons are
critical for lifespan promotion by calorie restriction. We will utilize multiple lines of transgenic animals in which
AgRP neuronal function is selectively up- or down-regulated. Groups of animals will be maintained for lifespan
assessment and whole body necropsy will be carried out at the time of death in each. In other control and
experimental cohorts, we will analyze the effect of calorie restriction on systemic metabolism and behavior of
mice. We will also assess pancreatic beta cell-, adipose-, liver, muscle and immune system parameters of
control and experimental animals. The execution of these studies will shad new light on integrative physiology
and molecular principles of calorie restriction-induced alterations in heath- and lifespan.

## Key facts

- **NIH application ID:** 10174641
- **Project number:** 5R01AG052005-05
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** TAMAS L HORVATH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $441,823
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10174641

## Citation

> US National Institutes of Health, RePORTER application 10174641, AgRP neurons promote the effects of calorie restriction on lifespan (5R01AG052005-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10174641. Licensed CC0.

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