# Effects of leptin modulation on health span and lifespan

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $669,958

## Abstract

Project Summary/Abstract
The overall objective of the research proposal is to explore the impact of leptin modulation on healthspan and
lifespan. Aging is associated with a dramatic increase in visceral adiposity that contributes to elevated circulating
leptin and leptin resistance. Our recent publications in Science Translational Medicine, Diabetes, Cell
Metabolism and Molecular Metabolism have clearly indicated hyperleptinemia is a driving force for diet or
antipsychotic drug-induced obesity and its associated metabolic disorders, and partial leptin reduction protects
the mice from obesity and tissue dysfunction. Furthermore, our preliminary results suggest that chronic
hyperleptinemia drives cellular senescence in cultured preadipocytes, proving a potential mechanism for
increased inflammation and reduced capacity to differentiate into mature adipocytes. In addition, reducing
circulating leptin, achieved by a genetic approach, significantly extend both median and maximum lifespan.
Based on these observations, we proposed our central hypothesis that leptin modulation is a new means to
regulate both healthspan and lifespan via leptin-driven cellular senescence. With our newly generated mouse
models and customized leptin neutralizing antibody, along with numerous resources at San Antonio Nathan
Shock Center, we will assess the effect of leptin modulation in healthspan and lifespan with three Specific Aims.
Aim 1 is to test whether aging-associated hyperleptinemia accelerates cellular senescence and impairs
healthspan and lifespan; Aim 2 is to access the effects of reducing leptin on cellular senescence, healthspan,
and lifespan; Aim 3 will elucidate the underlying mechanism(s) mediating leptin-driven cellular senescence. All
three Specific Aims work together to establish
a novel mechanism for metabolic aging and set the stage for trials
of leptin-based therapeutics in humans to reduce age-related diseases and extend healthspan and lifespan.

## Key facts

- **NIH application ID:** 10981998
- **Project number:** 1R01AG084646-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Shangang Zhao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $669,958
- **Award type:** 1
- **Project period:** 2024-09-22 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981998

## Citation

> US National Institutes of Health, RePORTER application 10981998, Effects of leptin modulation on health span and lifespan (1R01AG084646-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10981998. Licensed CC0.

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