# Inositol signaling in C. elegans Senescence and Diapause

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $473,668

## Abstract

Project Summary Abstract:
 During the last 20 years, the insulin-like/daf-2 signaling pathway has emerged from genome-wide RNAi
screens as the most potent regulator of lifespan in C. elegans; it is a significant aging axis in mammals as
well. Our full genome screens for lifespan regulatory processes have also revealed that the second rank of
longevity regulation surveils core components of cells, for example, the ribosome, and if deficits are detected,
couples to an endocrine system of immunity and longevity control that is distinct from the insulin-like pathway.
In fact, detoxification pathways are coupled to lifespan regulation in mice as well. The remarkable ability of
rapamycin to extend the lifespan of mice is likely to be based on its ability to engage this
surveillance/longevity control system. Eukaryotes live in microbe-rich environments and are continuously
challenged by microbial attacks. In the past grant cycle we have greatly expanded our genetic analysis of
how C. elegans, and we believe that eventually this will be shown to apply across all eukaryotes, surveils its
core cellular components, most especially in this grant, the ribosome, for attacks and signals such attacks to
innate immune and detoxification responses as well as to longevity programs. We were initially drawn to
these experiments by our work on regulation of longevity and our finding that gene inactivations of core
cellular processes such as translation potently induce increased longevity. The major activity of this grant
proposal is to test whether the many mutants we have isolated which either inappropriately activate
detoxification pathways or fail to activate such pathways have consequences on the lifespan and measures
of aging of the animal. The coupling of longevity control to detoxification and immunity provides a satisfying
explanation for why human females live longer than males: we hypothesize that females have a higher set
point for detoxification to protect the fragile developing fetus. Variation in these same pathways will reveal
how humans respond appropriately and inappropriately to drugs or bacterial pathogens, or activate drug
detoxification pathways in the absence of a triggering drug, perhaps inducing a false endocrine state of
poisoning. Our proposal to study how the microbial flora attempt to subvert these pathways will also reveal
how variation in the microbiome may underlie variation in human longevity.

## Key facts

- **NIH application ID:** 10134171
- **Project number:** 5R01AG043184-25
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** GARY B RUVKUN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $473,668
- **Award type:** 5
- **Project period:** 2012-08-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134171

## Citation

> US National Institutes of Health, RePORTER application 10134171, Inositol signaling in C. elegans Senescence and Diapause (5R01AG043184-25). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10134171. Licensed CC0.

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