# The Role of Necroptosis in Aging

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2022 · $321,393

## Abstract

Project Summary/Abstract
 The research objective is to characterize the role of necroptosis-induced inflammation on aging. Chronic,
low-grade inflammation (inflammaging) is a hallmark of aging and is one of the ‘seven pillars of aging’.
Inflammaging is a highly significant risk factor for both morbidity and mortality in the elderly people because a
variety of age-related diseases (e.g. type 2 diabetes, cardiovascular diseases, cancer, and neurodegenerative
diseases) share a strong inflammatory phenotype. Despite the link between inflammation, aging and age-
associated diseases, two major gaps currently exist in our understanding of the role inflammation plays in aging:
(1) the molecular mechanism(s)/pathway(s) responsible for the chronic, low-grade inflammation and (2) whether
inflammaging is a causative factor in aging or occurs secondary to aging. Damage-associated molecular patterns
(DAMPs) play a role in age-associated chronic inflammation and necroptosis is a newly identified pathway of
programmed necrosis that plays a major in the generation of DAMPs. Necroptosis is initiated when necroptotic
stimuli sequentially activate the receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase
domain like (MLKL) protein through phosphorylation. Phosphorylated MLKL binds to and disrupts the plasma
membrane of cells, releasing DAMPs. The DAMPs in turn trigger chronic low-grade inflammation through
increased production of inflammatory cytokines such as TNF by innate immune cells, which can activate RIPK1
in other cells in a positive feedback loop. Studies show that inhibiting necroptosis by knocking out Ripk3 reduces
necroptosis as well as inflammation in several mouse models. Our preliminary data provides the first evidence
showing that necroptosis might play a role in aging, i.e., necroptosis increases with age in wild type (WT) mice
and in a model of accelerated aging (Sod1-/- mice), and reducing/blocking necroptosis (both genetically and
pharmacologically) reduces inflammation in Sod1-/- mice. Based on our preliminary data, we hypothesize that
necroptosis plays a role in chronic, low-grade inflammation, which occurs with age, and preventing
necroptosis will attenuate inflammation, leading to increased lifespan and improved healthspan. To test
this hypothesis, in Aim1 we will determine the role of necroptosis in age-associated chronic inflammation by
identifying progression of necroptosis and inflammation in various tissues of young, middle-aged and old male
and female WT mice and determine the effect of reducing necroptosis either genetically (Ripk3+/- and Ripk3-/-
mice) or pharmacologically (necrostatin-1s, a RIPK1 inhibitor) on inflammation; in Aim2 we will determine the
mechanism by which necroptosis mediates age-associated inflammation by assessing the activation of
inflammatory pathways in tissues and cells of young and old WT mice and determine the effect of genetic
inhibition of necroptosis on inflammatory pathways; in Ai...

## Key facts

- **NIH application ID:** 10353386
- **Project number:** 5R01AG059718-04
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Deepa Sathyaseelan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $321,393
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10353386

## Citation

> US National Institutes of Health, RePORTER application 10353386, The Role of Necroptosis in Aging (5R01AG059718-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10353386. Licensed CC0.

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