# Age-dependent SKN-1/NRF cytoprotection at the cost of metabolic homeostasis

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2022 · $338,250

## Abstract

Abstract
SKN-1/NRF2 is a conserved cytoprotective transcription factor that plays established dose dependent roles in
response to diverse cytotoxic stressors. As such, the degree of SKN-1/NRF2 activity can impact survival and
physiological responses to environmental toxins. Although it makes sense that increased SKN-1/NRF2 activity
could be protective, it remains possible that the NRF2 response itself contributes to disease pathology. As
such, a major question is whether SKN-1/NRF2 activation is universally helpful or if it can also drive pleiotropic
consequences over the lifespan. We have uncovered the existence of a conserved signature, defined by metabolic
dysregulation, in worms and mice with activated SKN-1/NRF2. These metabolic defects mask the potentially positive
cytoprotective effects of SKN-1/NRF2 activation later in life. The central hypothesis driving our proposal is that animals
with activated SKN-1/NRF2, have enhanced resistance to stress, but also increased incidence of metabolic disorders
that compromise health later in life; this ultimately diminishes life expectancy. To test our hypotheses, we propose two
interconnected specific aims. In Aim 1, we will biochemically define the age-related depletion of somatic lipids when
SKN-1/NRF2 is activated, which ultimately leads to reduced health later in life. We will also examine the lifespan and
healthspan of animals that where the somatic lipid depletion phenotype is suppressed, by genetic or nutritional
interventions, while SKN-1/NRF2 activation is maintained. This will functionally uncouple the positive and negative
effects of SKN-1/NRF2 activation on healthspan and lifespan. In Aim 2, we will define the mechanisms underlying
the metabolic and stress resistance phenotypes resulting from activated SKN-1/NRF2 by elucidating the molecular,
and spatial determinants of these responses, whose capacity is governed by age. Finally, in Aim 3, we will define a
new mechanistic link between lipid metabolism and immune activation that is governed by activated SKN-1/NRF. The
successful completion of the proposed research will inform strategies to capitalize on the health promoting benefits of
molecules like SKN-1 and NRF2 while avoiding pleiotropic outcomes over the lifespan.

## Key facts

- **NIH application ID:** 10436150
- **Project number:** 5R01AG058610-04
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Sean P CURRAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $338,250
- **Award type:** 5
- **Project period:** 2019-08-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436150

## Citation

> US National Institutes of Health, RePORTER application 10436150, Age-dependent SKN-1/NRF cytoprotection at the cost of metabolic homeostasis (5R01AG058610-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10436150. Licensed CC0.

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