# Does Necroptosis Play a Role in Inflammation and Aging

> **NIH VA I01** · OKLAHOMA CITY VA MEDICAL CENTER · 2020 · —

## Abstract

Chronic, low-grade inflammation (inflammaging) is a hallmark of aging and is a major risk factor for both
morbidity and mortality in the elderly humans. In addition, inflammation is a major risk factor for a variety of
age-related diseases, e.g. type 2 diabetes, cardiovascular disease, cancer, neurodegenerative diseases,
frailty, etc. Despite the link between inflammation, aging, and age-associated diseases, we do not know the
molecular mechanism(s)/pathway(s) responsible for the chronic, low-grade inflammation seen in old animals
and whether the increase in chronic inflammation is a causative factor in aging and age-related diseases.
Necroptosis is a recently identified pathway of programmed necrosis that induces cell death through the lysis
of cells, resulting in the release of damage-associated molecular patterns (DAMPs) from the dead cells.
DAMPs are potent inducers of inflammation, and circulating DAMPs have been shown to increase with age in
humans and to be strongly correlated to the level of inflammation in the individual. 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, improved healthspan, and
reduced age-related pathology. We will use genetically modified mouse models and a pharmacological
intervention to block/reduce apoptosis by targeting the receptor-interacting protein kinases (RIPK) 1 or 2 and
mixed lineage kinase domain like (MLKL) protein, which are involved in the initiation of necroptosis.
Aim1. Determine the role of necroptosis in chronic inflammation that occurs with age and the types of
cells undergoing necroptosis. We will determine the effect of reducing necroptosis either genetically (using
Ripk3+/-, Ripk3-/-, Mlkl+/-, and Mlkl-/- mice) or pharmacologically (treating with necrostatin-1s, a RIPK1 inhibitor)
on inflammation. We will also identify the cell type(s) that undergo necroptosis in selected tissues of old mice.
Based on our hypothesis, we predict that those tissues showing an up-regulation in necroptosis with age will
show an increase in production of proinflammatory cytokines and reducing/blocking necroptosis will decrease
inflammation in these tissues as well as circulating levels of proinflammatory cytokines.
Aim2. Identify the pathways that increase necroptosis with age and determine the mechanism(s) that
mediates the age-related increase in inflammation arising from necroptosis. TNFα, oxidative stress, and
mTOR signaling have been proposed to initiate necroptosis, and these pathways increase with age. In Aim 2,
we determine the role of these pathways play in the age-related increase in necroptosis using specific
inhibitors to each of the pathways. DAMPs released by necroptotic cells induce inflammation through
activation of three pathways: the IKK-NF-κB, MAPK-AP1 and inflammasome pathways. In Aim 2, we will also
assess the effect of age on the activation of these pathwa...

## Key facts

- **NIH application ID:** 9913983
- **Project number:** 5I01BX004538-02
- **Recipient organization:** OKLAHOMA CITY VA MEDICAL CENTER
- **Principal Investigator:** ARLAN G. RICHARDSON
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9913983

## Citation

> US National Institutes of Health, RePORTER application 9913983, Does Necroptosis Play a Role in Inflammation and Aging (5I01BX004538-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9913983. Licensed CC0.

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