# Succinate triggers gut dysbiosis and activates SUCNR1 to enhance inflammaging

> **NIH NIH R01** · NEW YORK UNIVERSITY · 2021 · $495,946

## Abstract

Abstract
 Inflammaging, the chronic low-grade inflammation that characterizes aging is a likely consequence of a
dysfunctional relationship between the imbalanced microbiota and their metabolites with the host's immune
system. Inflammaging plays an increasingly important role in the rate of aging and age-related diseases. We
have shown that the elevation of succinate, an intermediate metabolite in citric cycle, was associated with
aging in both human and mouse which altered the gut microbiome by increasing the relative abundance of
pathobionts. Succinate elevation also activates the SUCNR1 to augment myelopoiesis and inflammation.
Mechanistically we showed that succinate increased IL-1β and TNFα in the serum and bone marrow, and
induced a 30-fold increase of Interleukin-1 receptor-associated kinase 1 (IRAK1) expression and a 50%
increase of granulocyte macrophage progenitors in bone marrow. Our preliminary data provided new
mechanistic proof that the interplay among gut microbes, altered metabolites and myelopoiesis contributes to
inflammaging. We now seek to advance this project by testing the following over-arching hypothesis that
targeting the gut microbiome and extracellular succinate receptor activation alleviate inflammaging. In Aim 1
we will determine the impact of succinate elevation on gut dysbiosis and host response in young and old WT
C57/B6 and IRAK1 KO mice and how these alterations regulate IL-1β-IRAK1 signaling to promote
inflammaging. Then we will use gnotobiotic, antibiotic treatment and Fecal Microbiota Transplantation to
determine whether reprogramming the microbiome alters the course of inflammaging. In Aim 2 we will use WT
and myeloid lineage-specific SUNCR1 KO mice determine whether the myeloid lineage cells are the key
mediators of succinate-stimulated myelopoiesis and inflammation. Finally we will determine whether succinate-
stimulated inflammation and myelopoiesis is IRAK1-dependent by conducting bone marrow transplant in WT
and IRAK1 KO from young to old mice and monitor the reconstitution of myeloid and lymphoid cells.
 The proposed study on aging-related succinate elevation on gut dysbiosis and SUCNR1 activation will
enable us to understand the causative changes in the intrinsic mechanisms of inflammaging and provide novel
target to alleviate inflammaging.
 Impact: This project directly addresses the NIA's RFA-AG-20-030 on “Microbiome and Aging: Impact
on Health and Disease” and provides information on age-related changes in the gut microbiome and how a
cross-talk between the host immune system and microbiota correlates to the local and systemic immune
responses.

## Key facts

- **NIH application ID:** 10237290
- **Project number:** 5R01AG068857-02
- **Recipient organization:** NEW YORK UNIVERSITY
- **Principal Investigator:** Xin Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $495,946
- **Award type:** 5
- **Project period:** 2020-08-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10237290

## Citation

> US National Institutes of Health, RePORTER application 10237290, Succinate triggers gut dysbiosis and activates SUCNR1 to enhance inflammaging (5R01AG068857-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10237290. Licensed CC0.

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