# Genetic and Molecular Basis of Longevity

> **NIH NIH R56** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $344,400

## Abstract

Project Summary/Abstract:
C. elegans surveils the mitochondrion for deficits and couples to an endocrine system of detoxification,
innate immunity, and longevity control. This coupling of immunity and detoxification pathways to lifespan
regulation has been observed in mice as well. Our analysis of immune responses triggered by
mitochondrial dysfunction in C. elegans has revealed that the RNA interference antiviral axis is strongly
induced by a variety of mitochondrial defects. The mitochondrial MAVS to RNA helicase system is highly
integrated into mammalian NF-kB antiviral cascades; we discovered that in C. elegans mitochondrial
dysfunction is coupled to the RNAi antiviral system used by most fungi and plants, and some animals
such as C. elegans. Our discovery that protein N-glycosylation by PNG-1/NGLY1 mediates the
deamidation of N-glycosylated asparagine residues from ER-localized proteins to aspartic acid has
important implications for viral immunity. Many viral proteins are N-glycoyslated, including 22 such
modifications on the Covid Spike protein, and our informatic analysis shows a strong signature of
NGLY1-mediated protein editing for some Spike protein N-glycosylations. Viral immunity emerged in this
past year as one of the major differences between the elderly and young adults: the death rate from
Covid is 10x higher than the relative increase in death rate from any cause in over 65 year old adults
compared to young adults. Thus a study of the molecular basis of viral immunity intersects the biology of
aging. Our genetic analysis of how C. elegans surveils its mitochondria and other core cellular
components for attacks to activate longevity programs as well as to innate immune and detoxification
responses is a very non-standard view of innate immunity and aging. But the intersection with for
example the use of rapamycin as an anti-aging drug is profound. We continue to focus on C. elegans in
this proposal. Over the past five years, C. elegans classical genetic analysis, screening for mutant
phenotypes and deducing the molecular defect that causes the phenotype by genome sequencing, has
been transformed by low cost full genome sequencing of newly isolated mutants. All of the genes we
propose to study have strong orthologues in humans, and are likely to function in humans in an ancient
conserved pathway for detection of microbial assaults and control of the aging process by such
surveillance. 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 trigger. Such variation may also be the cause of diseases as diverse as anorexia nervosa, migraine,
and autoimmunity, which, along with lifespan itself, are highly gender biased. 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:** 10490496
- **Project number:** 2R56AG016636-23
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** GARY B RUVKUN
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $344,400
- **Award type:** 2
- **Project period:** 1999-09-30 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10490496

## Citation

> US National Institutes of Health, RePORTER application 10490496, Genetic and Molecular Basis of Longevity (2R56AG016636-23). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10490496. Licensed CC0.

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