# Obesity-induced mesenchymal stem cell senescence

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2020 · $641,587

## Abstract

ABSTRACT/SUMMARY
 The prevalence of obesity is rising to epidemic proportions. Obesity often leads to endocrine and metabolic
derangements, and reduction in its complications could diminish morbidity and mortality, and produce large
cost savings. Currently, bariatric surgery is considered the most effective treatment for sustainable weight loss.
 Obesity triggers cellular damage in multiple organs, partly via induction of premature senescence. This
cellular program is characterized by a permanent cell-cycle arrest and altered cellular function, which prompts
cells to acquire a senescence-associated secretory phenotype (SASP), a distinctive secretome that involves
secretion of inflammatory cytokines and chemokines. Aberrant accumulation of senescent cells exhibiting the
SASP phenotype exerts noxious effects on neighboring cells, and drives tissue injury and the aging phenotype.
 Mesenchymal stem cells (MSC), a ubiquitous cellular repair mechanism, may be injured by ambient risk
factors. In obesity adipose tissue-derived MSC might develop cellular senescence (CS) and acquire a SASP
phenotype, suggesting that obesity may impede endogenous cellular repair capacity. However, the effects of
obesity on CS in human MSC, and the impact of MSC CS on their reparative capacity, remain unknown.
 Our hypothesis is that obesity evokes senescence in human MSC, which interferes with their capacity
to repair injured kidneys. We hypothesize that this impaired MSC function is partly mediated by a
phenotype shift in MSC-derived extracellular vesicles (EV) that drive their paracrine effects, but would
be reversible upon senolytic pre-treatment of MSC, or following patient weight loss. We will use unique and
novel model systems and techniques to pursue specific aims showing that: Specific Aim 1: In human
subjects, obesity induces CS in adipose tissue MSC, and interferes with their repair capacity in injured mouse
kidneys. Specific Aim 2: The functional impairment in adipose tissue MSC from obese human subjects is
partly mediated by a phenotype shift in their membrane-derived EV. Specific Aim 3: MSC-CS and SASP in
obese human subjects would be reversible upon bariatric surgery.
 The proposed studies may uncover novel mechanisms, involving impaired circulating and tissue cellular
repair systems, which underlie complications of human obesity. Furthermore, they may establish a novel
strategy to blunt this injurious cellular senescence, and thereby boost endogenous kidney repair capability.

## Key facts

- **NIH application ID:** 9843124
- **Project number:** 5R01DK120292-02
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Lilach O Lerman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $641,587
- **Award type:** 5
- **Project period:** 2018-12-27 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843124

## Citation

> US National Institutes of Health, RePORTER application 9843124, Obesity-induced mesenchymal stem cell senescence (5R01DK120292-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9843124. Licensed CC0.

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