# Modeling DR and mRNA translation to understand adaptive mechanisms that promote health

> **NIH NIH R01** · MOUNT DESERT ISLAND BIOLOGICAL LAB · 2021 · $373,500

## Abstract

PROJECT SUMMARY
 Dietary restriction (DR) without malnutrition protects against age-related decline. Part of the response to
DR involves restricting and redirecting translation to promote survival. On its own, genetically restricting
translation increases lifespan and resistance to cellular stress, but little is known about the downstream
mechanisms of regulation. The conserved nutrient sensing pathway governed by the target of rapamycin
(TOR) positively regulates translation through the cap-binding complex (CBC) when nutrients are plentiful.
We recently reported that restricting CBC activity increases survival during protein unfolding stress by
upregulating the heat shock response (HSR), which maintains cellular health by regulating protein folding and
turnover. Activation of the HSR involves upregulation of genes controlled by the transcription factor HSF1. One
of these genes encodes the chaperone HSP90, which inhibits HSF1 at the protein level in a negative feedback
loop. HSP90 translation and protein levels are downregulated during CBC restriction in C. elegans as well as
during TOR inhibition in mouse tissue culture. We discovered that DR involving food dilution similarly
suppresses synthesis of HSP90 relative to other cellular proteins. The HSR is universally recognized as critical
to adaptation and survival, but the precise nature of its relationship to DR has been elusive. Translational
regulation of HSP90 may act as a circuit in adaptation to DR involving the HSR. Our preliminary studies also
show that increased survival to unfolded protein stress is driven by restricting the CBC in neurons or germ
cells, which also limits reproduction. Interestingly, low CBC in these tissues upregulates the only Myogenic
Response Factor (MRF) in C. elegans, HLH-1, which activates genes encoding structural components and
chaperones in body muscle, the analog of skeletal muscle. Surprisingly, low CBC in muscle does not
upregulate HLH-1 or provide robust protection from unfolded protein stress in that tissue but does increase
reproduction. We propose that muscle is protected during DR to preserve function required for foraging and
that low translation in muscle is a signal of inactivity associated with nutrient abundance. We will determine
how low CBC activity associated with DR influences the HSR in different tissues and whether physical
inactivity recapitulates the effects of low translation with respect to reproduction. We will also investigate the
relationship between CBC activity and myogenic expression changes with respect to body muscle function,
integrity, protection from protein unfolding stress, and lifespan. Finally, we will test the role of HSP90 in DR
responses and in coordinating cross-talk between different tissues.

## Key facts

- **NIH application ID:** 10153619
- **Project number:** 5R01AG062575-03
- **Recipient organization:** MOUNT DESERT ISLAND BIOLOGICAL LAB
- **Principal Investigator:** ARIC N ROGERS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $373,500
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10153619

## Citation

> US National Institutes of Health, RePORTER application 10153619, Modeling DR and mRNA translation to understand adaptive mechanisms that promote health (5R01AG062575-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10153619. Licensed CC0.

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