# Tissue-specific pharmacology to enhance healthspan

> **NIH NIH R56** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $331,075

## Abstract

PROJECT SUMMARY/ABSTRACT
Aging-related diseases are among the greatest public health challenges. To allow a healthier aging society,
healthspan-extending drugs are critically needed. Development of such drugs will likely be vastly more effective
for an aging population than attempting to treat aging-related diseases individually. Inhibition of mechanistic
Target Of Rapamycin (mTOR) is an evolutionarily conserved strategy for slowing aging and extending lifespan.
Perhaps the most promising and clinically translatable approach for healthspan extension is mTOR inhibition
caused by the small molecule Rapamycin. But understanding of the role of mTOR in age-related cellular
deterioration at the systems level is lacking, which prevents development of safer and more effective Rapamycin
analogs (Rapalogs). Specifically, because of the lack of methods to target Rapamycin to specific cell types, it is
not known how Rapamycin’s activity in particular cell types contributes to anti-aging effects at the organismal
level. The broad implication for this fundamental gap in knowledge is that crucial opportunities for development
of therapeutics for safe and effective healthspan extension may be missed. This provides a strong rationale for
elucidating how specific cell types affect net outcomes of pharmacological healthspan and lifespan extension
caused by Rapamycin. Our long-term goal is to determine which cell types are responsible for Rapamycin's
effects on healthspan extension, develop targeted mTOR inhibition pharmacology, and thus enable effective and
safe healthspan extension in humans in the longer term.
The central hypothesis of the proposed project is that pro-longevity effects of Rapamycin can be enhanced by
targeting the drug only to the specific tissues that are responsible for these effects. To test this hypothesis and
to advance toward our long-term goal, we propose the following specific aims: (1) Develop a chemical-genetic
approach for programmable, cell-type-specific targeting of Rapamycin; (2) Establish a chemical-genetic, in vivo
platform for cell-type-specific pharmacological mTOR inhibition; and, (3) Determine if healthspan and lifespan
benefits of systemic, pharmacological mTOR inhibition can be improved by selective sparing of Rapamycin's
inhibition of mTOR in skeletal muscle. The proposed project is significant because it will use innovative,
multidisciplinary approaches to address a major area of unmet medical need. The proposed study is expected
to yield new chemical-genetic tools and Rapalogs enabling tissue-specific, pharmacological mTOR inhibition,
and comprehensive analysis of healthspan metrics and lifespan. We expect the proposed study will open the
door to more effective approaches for pharmacological extension of healthspan via generation of tissue-specific
mTOR inhibitors with improved clinical efficacy and safety.

## Key facts

- **NIH application ID:** 10445523
- **Project number:** 1R56AG071857-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** KEVAN M. SHOKAT
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $331,075
- **Award type:** 1
- **Project period:** 2021-08-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445523

## Citation

> US National Institutes of Health, RePORTER application 10445523, Tissue-specific pharmacology to enhance healthspan (1R56AG071857-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10445523. Licensed CC0.

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