# Interrogation of the cellular and subcellular architecture of nutrient metabolism in conditions of dietary restriction

> **NIH NIH R56** · VANDERBILT UNIVERSITY · 2024 · $396,250

## Abstract

Project Summary/Abstract
The re-allocation of metabolic resources towards cell processes that promote somatic maintenance is a long-
held hypothesis to explain how diverse longevity paradigms promote healthier aging. One of the best models of
this hypothesis is dietary restriction (DR), which optimizes metabolic efficiency while maintaining animal fitness
and longevity. However, we possess surprisingly little insight into how specific nutrient resources are differentially
utilized at the cell level during DR. In addition to altering metabolic processes, DR promotes a dramatic
remodeling of organelle structures and functions. Increasingly we understand that not only is the structure of a
discrete organelle critical for its functional state, but also the spatial relationships and contact sites formed
between different organelle networks. The restructuring of the overall subcellular architecture thus plays a critical
role in determining metabolic performance. However, our preliminary data suggest that age-dependent
accumulation of molecular damage causes remodeling of the endoplasmic reticulum (ER), a hub of inter-
organellar communication. Our overarching hypothesis is thus that remodeling of inter-organelle interactions is
is both a key route by which aging cells lose functional resilience and an essential mechanism of DR-mediated
reprogramming of metabolism. To advance this hypothesis we propose to exploit new correlative electron
microscopy (EM) and stable isotope imaging technology in a combination of mouse and C. elegans models to
establish a framework for how DR restructures the organelle interactome and re-allocates nutrient flux between
organelles. Altogether this proposal aims to establish a framework for how DR remodels the organelle
interactome to promote healthy aging with a focus on the role of the ER.

## Key facts

- **NIH application ID:** 10932400
- **Project number:** 5R56AG082758-02
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Rafael Arrojo e Drigo
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $396,250
- **Award type:** 5
- **Project period:** 2023-09-20 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932400

## Citation

> US National Institutes of Health, RePORTER application 10932400, Interrogation of the cellular and subcellular architecture of nutrient metabolism in conditions of dietary restriction (5R56AG082758-02). Retrieved via AI Analytics 2026-07-03 from https://api.ai-analytics.org/grant/nih/10932400. Licensed CC0.

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