# Targeting Cellular Senescence and RAGE in Type 2 Diabetes

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2024 · $355,756

## Abstract

PROJECT SUMMARY
Type 2 diabetes (T2D), a major risk factor for poor bone quality and fractures, is associated with the premature
accumulation of senescent cells and advanced glycation endproducts (AGEs; activators of the receptor for
AGE [RAGE] pathway) in multiple tissues, including bone. Intuitively, senescent cells and RAGE could act
independently or interact via cross-talk to contribute substantially to skeletal fragility in T2D, yet this concept
has not been rigorously tested. This proposal is founded on innovative concepts, technology, and approaches
to test our central hypothesis that targeting cellular senescence or RAGE can improve T2D-related skeletal
fragility. To test our hypothesis, we will use novel transgenic mice and innovative technology, including mass
cytometry as well as advanced histological and molecular tools. The interplay among bone, energy
metabolism, and T2D has been a topic of research for years, yet few in vivo studies have rigorously
interrogated the contributions of senescent cells or RAGE signaling to skeletal dysfunction in T2D. From a
translational perspective, better understanding of the cross-talk between senescence and RAGE in bone will
yield impactful advances and may reveal novel strategies to ameliorate accelerated skeletal aging in T2D. To
this end, in Aim 1 we will identify, locate, and characterize bone-resident senescent cell populations in mice
with T2D and define their T2D-specific senescence-associated secretory phenotype (SASP). In Aim 2, using
mice harboring transgenes that enable the selective elimination of p16Ink4a+ or p21Cip1+ senescent cells, we will
test the hypothesis that senescent cell clearance in mice with established T2D will normalize bone remodeling
and quality. Thus, we will distinguish the causal roles of p16Ink4a and p21Cip1 in mediating skeletal dysfunction in
T2D using our global p16- and p21-ATTAC mouse strains by comparing the effects of systemic clearance of
p16Ink4a+ vs p21Cip1+ senescent cells. In addition, we will assess the relative impact of clearing senescent
osteocytes, using our novel Cre-LoxP lines – p16-LOX-ATTAC and p21-LOX-ATTAC. Global and osteocyte-
specific clearance of senescent cells will be compared with pharmacological elimination using “senolytics”.
Finally, in Aim 3, using our novel Cre-loxP mouse that inhibits RAGE signal transduction via cell-specific
cytosolic-domain deficient dominant-negative RAGE (DN-RAGE) expression, we will define the effects of
inhibiting RAGE signaling in the osteoblast/osteocyte and myeloid/osteoclast lineages on skeletal fragility in
mice with T2D. Collectively, these studies will rigorously test whether cellular senescence and RAGE signaling
underlie T2D-related skeletal fragility. We will address these questions by leveraging our unique resources and
expertise. We will build upon compelling preliminary data and innovative approaches, including novel
analytical, transgenic, and pharmacological tools that we anticipate will sig...

## Key facts

- **NIH application ID:** 10839759
- **Project number:** 5R01DK128552-04
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Joshua Nicholas Farr
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $355,756
- **Award type:** 5
- **Project period:** 2021-05-01 → 2024-08-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10839759

## Citation

> US National Institutes of Health, RePORTER application 10839759, Targeting Cellular Senescence and RAGE in Type 2 Diabetes (5R01DK128552-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10839759. Licensed CC0.

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