# Downregulation of Inflamm-aging for Protection Against Organ Damage in Sepsis

> **NIH VA I01** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2021 · —

## Abstract

Older adults make a large proportion of sepsis patients. Organ dysfunction is common in patients with
severe sepsis, and old septic patients often have more severe organ injury and longer-lasting organ
dysfunction. However, the mechanism underlying exacerbated organ injury/dysfunction in old septic
patients remain unclear. This proposal tests the central hypothesis that aging enhances and prolongs
inflammation to exacerbate organ injury and to impede the recovery of organ function following sepsis.
The central hypothesis is based on our novel findings in preliminary studies using an animal model of
sepsis. Specifically, we observed that old mice display enhanced and prolonged inflammation, as well as
more severe cardiac and renal dysfunction, mimicking the clinical manifestations of old septic patients.
Aging-related deficiency in anti-aging protein Klotho in the myocardium and kidney tissue is responsible
for the augmented inflammation, and such altered inflammation occupies a major role in organ injury and
dysfunction. Further, sepsis induces the over-production of pro-inflammatory mediator FGF23, and
Klotho has a novel function in down-regulation of FGF23 production and its pro-inflammatory activity.
More importantly, anti-inflammatory cytokine IL-37 up-regulates Klotho expression in old mice and
protects against organ dysfunction and mortality in sepsis.
We will pursue two interrelated Specific Aims to test the hypothesis that aging impedes the recovery of
organ function following sepsis by prolonging inflammation and to explore therapeutic approaches for
promotion of organ recovery from injury caused by sepsis. Proposed studies will address the role of
aging-related Klotho deficiency in the mechanism underlying the augmented inflammation and
exacerbated organ injury/dysfunction in old septic mice and will elucidate the mechanism by which
FGF23 augments inflammation. Further, the proposed studies will explore the therapeutic potential of
recombinant Klotho and IL-37 for protection of organs against injury/dysfunction.
Overall, the proposed studies will provide insights into the mechanisms underlying exacerbated organ
injury/dysfunction in old septic subjects and offer preclinical information for development of novel
therapeutic approaches for down-regulation inflamm-aging to protect organs in old people affected by
sepsis.

## Key facts

- **NIH application ID:** 10015500
- **Project number:** 1I01BX005163-01
- **Recipient organization:** VA EASTERN COLORADO HEALTH CARE SYSTEM
- **Principal Investigator:** XIANZHONG MENG
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10015500

## Citation

> US National Institutes of Health, RePORTER application 10015500, Downregulation of Inflamm-aging for Protection Against Organ Damage in Sepsis (1I01BX005163-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10015500. Licensed CC0.

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