# Molecular mechanisms by which mild elevation of mitochondrial superoxide extends lifespan

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2021 · $313,575

## Abstract

ABSTRACT
As the world's population ages, there is an increasingly urgent need to understand the aging process and its
role in age-onset disorders. While aging is the greatest risk factor for the development of neurodegenerative
disease, the role of aging in these diseases is not well defined. Our recent work suggests that targeting
pathways involved in aging may be an effective strategy in the treatment of Parkinson's disease, as well as
other neurodegenerative diseases. As the biology of aging is still poorly understood, the goal of the current
proposal is to gain insight into the aging process by defining the molecular mechanisms involved in one
specific pathway of lifespan extension. We have shown that in C. elegans mild elevation of reactive oxygen
species (ROS) levels through deletion of the mitochondrial superoxide dismutase gene sod-2, or directly
through treatment with the superoxide-generating compound paraquat, extends lifespan. Importantly,
increasing ROS has also been shown to extend lifespan in yeast and mice, indicating conservation across
species. However, the mechanism by which ROS increase lifespan is currently unknown.
 The long-term goal of this work is to advance our understanding of the aging process and to use that
knowledge to promote healthy aging and to develop treatments for age-onset neurodegenerative diseases. In
the current proposal, the objective is to define the molecular mechanisms by which ROS act to increase
lifespan. Our preliminary data demonstrates that the effect of ROS on lifespan is dependent on the precise
conditions under which ROS are altered. Increasing mitochondrial superoxide extends longevity, while
cytoplasmic superoxide decreases lifespan. Similarly, within the mitochondria, mild increases in superoxide
levels increases lifespan, while higher levels of superoxide are toxic. Accordingly, the current proposal will
define the conditions required for ROS to increase lifespan, and use this information to elucidate the
underlying mechanisms through the completion of three Specific Aims: 1) Determine the mechanism by
which elevated mitochondrial superoxide is detected in the cytoplasm; 2). Define the tissues in which mild
elevation of mitochondrial superoxide is necessary or sufficient to increase lifespan; and 3) Identify cellular
changes induced by elevated mitochondrial superoxide, but not cytoplasmic superoxide, that contribute to
longevity.
 The expected outcome of this project is the elucidation of the mechanism by which mild elevation of
mitochondrial superoxide levels extends lifespan. This research is innovative in addressing deficiencies in
conventional aging theories by investigating the poorly explored beneficial effect of ROS on lifespan. The
work is significant in advancing our molecular understanding of the aging process. This work has the
potential to impact public health through the identification of targets for the promotion of healthy aging and
treatment of neurodegenerative disease.

## Key facts

- **NIH application ID:** 9843503
- **Project number:** 5R01GM121756-04
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Jeremy Michael Van Raamsdonk
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $313,575
- **Award type:** 5
- **Project period:** 2017-01-01 → 2022-10-21

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843503

## Citation

> US National Institutes of Health, RePORTER application 9843503, Molecular mechanisms by which mild elevation of mitochondrial superoxide extends lifespan (5R01GM121756-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9843503. Licensed CC0.

---

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