# Elucidating and targeting beta-cell senescence and its SASP

> **NIH DK R01** · JOSLIN DIABETES CENTER · 2026 · $427,500

## Abstract

Abstract
This proposal seeks to elucidate the mechanisms of β-cell senescence, an aging hallmark, as a contributor to
type 2 diabetes (T2D) and identify optimal therapeutic targets. Pancreatic insulin secreting β-cells, crucial to
glucose homeostasis, are heavily secretory cells, equipped to respond to small changes in blood glucose
levels and highly susceptible to stress by nutrient overload. My work has identified that mouse and human β-
cells undergo senescence in response to insulin resistance (IR), leading to loss of cellular identity, impaired
function and secretion of a unique senescence-associated secretory phenotype (SASP). Additionally, I showed
that senolysis improved blood glucose levels and recovery of β-cell function and identity. I hypothesize that
cellular senescence and its SASP are targetable drivers of β-cell dysfunction and loss. My goals are to
understand the mechanisms behind β-cell senescence and identify the optimal therapeutic strategy. Aim 1.
Identify the cell autonomous driver(s) of β-cell senescence and its functional effects. Based on our
models of IR and DNA damage, we hypothesize that cyclin-dependent kinase inhibitor p21Cip1 is upregulated
early in β-cell senescence and is followed by p16Ink4a. Genetic gain- and loss-of-function strategies will be used
to compare the effects of p21Cpi1 and p16Ink4a on mouse and human β-cell function, identity and SASP.
Additionally, the functional changes of senescent cells will be pinpointed. This aim will define the cell
autonomous molecular mechanism(s) that drive β-cell senescence and its functional consequences. Aim 2.
Elucidate the non-cell autonomous effects of the β-cell SASP. The hypothesis is that β-cell senescence
can be driven by a non-cell autonomous mechanism through SASP factors, capable of impairing the function
and gene identity of neighboring cells and precipitating their entry into senescence. To evaluate the effects of
SASP upon neighboring β-cells, we will test the effects of the 

## Key facts

- **NIH application ID:** 11324927
- **Project number:** 5R01DK132535-05
- **Recipient organization:** JOSLIN DIABETES CENTER
- **Principal Investigator:** Cristina  Aguayo-Mazzucato
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** DK
- **Fiscal year:** 2026
- **Award amount:** $427,500
- **Award type:** 5
- **Project period:** 2022-05-10T00:00:00 → 2027-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11324927

## Citation

> US National Institutes of Health, RePORTER application 11324927, Elucidating and targeting beta-cell senescence and its SASP (5R01DK132535-05). Retrieved via AI Analytics 2026-07-09 from https://api.ai-analytics.org/grant/nih/11324927. Licensed CC0.

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