# Premature aging disorders, metabolites, and atherosclerosis

> **NIH HL R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2026 · $691,393

## Abstract

Project Summary/Abstract
Premature senescence-triggered vascular diseases (PmSVD) induced by ionizing radiation (IR), as well
as Hutchinson-Gilford progeria syndrome (HGPS), are notably characterized by accelerating processes
of atherosclerosis (AthS) and coronary artery disease (CAD). Although endothelial dysfunction in PmSVDs is well
known, there is a paucity of available treatments to prevent PmSVD-induced CAD; hence, there is an urgent need to
fill this gap. Persistent senescence-associated secretory phenotype (PISP), provoked by TL dysfunction, plays a
central role in cancer recurrence and resistance, but its regulatory mechanisms and contribution to AthS remain
unknown. Our long-term goal is to determine the molecular mechanisms by which PmSVD induces PISP in
endothelial cells (ECs) and CAD. PmSVD significantly up-regulated TOP2β degradation via PKCζ activation. The
depletion of EC TOP2β instigated PARP activation and PISP; it also accelerated AthS. We showed the critical
role of mtROS in PKCζ activation, which is one of the initial steps for the Mt-nucleus feedback loop. Of note, the
crucial role of mtROS in both IR and HGPS has been well established. Lastly, by performing IC-MS analysis in both
IR and HGPS ECs, we also found that the following 3 metabolite-related pathways were regulated in IR and HGPS
ECs in common: 1) nucleotide sugars-glycosaminoglycans (GAGs) and sulfate, 2) glutamate, and 3) NAD+-
hydrogen sulfide (H2S). Although the contribution of all 3 metabolites pathways to CAD and aging has been
suggested, the exact role and mechanical insights in regulating PmSVD remain largely unknown. We propose the
novel hypothesis that PmSVD-induced mtROS activates the PKCζ-TOP2β module, followed by TOP2β
degradation, and instigates TL DNA damage. TL DNA damage promotes PARP activation, which induces mt
dysfunction and forms an mt-nucleus feedback loop, resulting in persistent metabolites changes, including
nucleotide sugars and NAD+-H2S pathways, causing PIS

## Key facts

- **NIH application ID:** 11228780
- **Project number:** 5R01HL163857-04
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Jun-Ichi  Abe; JOHN P COOKE; Nhat-Tu  Le; Bing  Yu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** HL
- **Fiscal year:** 2026
- **Award amount:** $691,393
- **Award type:** 5
- **Project period:** 2022-12-15T00:00:00 → 2026-11-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11228780

## Citation

> US National Institutes of Health, RePORTER application 11228780, Premature aging disorders, metabolites, and atherosclerosis (5R01HL163857-04). Retrieved via AI Analytics 2026-07-05 from https://api.ai-analytics.org/grant/nih/11228780. Licensed CC0.

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