# Genetic and Molecular Basis of Longevity

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $431,960

## Abstract

Project Summary/Abstract:
Our discovery that the NGLY1/PNG-1 deglycosylation enzyme mediates the protein editing of N-
glycosylated asparagines to aspartic acid of the SKN-1A transcription factor to increase proteasomal
capacity is highly relevant to protein aggregation diseases, such as Alzheimer’s disease and ADRD.
NGLY1 N to D editing of SKN-1A also mediates the up-regulation of proteasome biogenesis in face of
protein aggregation challenges including to human Ab, a key trigger of AD and ADRD. Precisely the
same PNG-1/NGLY1, DDI-1, SKN-1A pathway acts in human tumor cells to mediate responses to the
protein assembly and degradation challenges of aneuploidy. Our informatic analysis shows a strong
signature of NGLY1-mediated protein editing in the SARS-CoV-2 Spike protein, motivating our genetic
analysis of anti-viral response defects in C. elegans png-1, ddi-1, and skn-1a mutants. We also explore
how decreased mitochondrial function increases longevity and antiviral defense in C. elegans. C.
elegans uses a system homologous to the mammalian mitochondrial MAVS to RNA helicase system that
is coupled to NF-kB antiviral cascades in mammals and to RNA interference in C. elegans to activate
antiviral defense. Mutations in C. elegans drh-1,the orthologue of mammalian MDA5 RNA helicase, a
key player in mammalian mitochondrial to interferon antiviral defense, suppress the enhanced RNAi and
suppress the lifespan extension of mitochondrial mutants, supporting the model that enhanced antiviral
defense as a key anti-aging output from mitochondrial mutations. The dramatic increases in C. elegans
longevity that are observed in C. elegans insulin-signaling mutants also induce enhanced RNAi, an
antiviral response. This intersects with the dramatically increased vulnerability to viruses in the elderly,
especially for Sars-Cov2, where the vast majority of deaths were over 75 years old. We hypothesize that
the striking increase in AD and ADRD during aging may be caused by the sum of late onset viral
infections that challenge proteasomal capacity. Our genetic analysis discovered that the activation of the
CMTR-1 RNA methylase suppresses the hyperoxia lethality of complex I mutants. The phylogenetic
profile of CMTR-1 shows that it is very similar to the C. elegans cat-2 tyrosine dioxygenase that mediates
dopamine synthesis. We will test if CMTR-1 RNA methylates the cat-2 and other mRNAs that encode
dopamine production and whether this RNA methylation is responsive to oxygen. The mitochondrion is
implicated in Parkinson’s disease by the human mitochondrial Parkin ubiquitin ligase and PINK1 kinase,
and we will test whether C. elegans mutations in the orthologues of these mitochondrial Parkinson’s
genetic risk genes pdr-1 (Parkin) or pink-1 interact with the CMTR-1 RNA methylase to cat-2 mRNA
regulatory interaction.

## Key facts

- **NIH application ID:** 10451193
- **Project number:** 2R01AG016636-23A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** GARY B RUVKUN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $431,960
- **Award type:** 2
- **Project period:** 1999-04-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10451193

## Citation

> US National Institutes of Health, RePORTER application 10451193, Genetic and Molecular Basis of Longevity (2R01AG016636-23A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10451193. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*