# Chromatin Regulation by Mammalian SIRT7 in Aging and Disease

> **NIH VA I01** · VETERANS ADMIN PALO ALTO HEALTH CARE SYS · 2021 · —

## Abstract

Aging is the single greatest risk factor for many chronic diseases and thus is a major contributor to
morbidity in the VA population. Our broad research goal is to understand how chromatin regulatory
mechanisms influence nuclear and epigenetic programs, and how de-regulation of these mechanisms
contributes to aging and disease. The work proposed here will focus on elucidating the functions of SIRT7,
a chromatin regulatory enzyme in the Sirtuin family of aging-regulatory factors. Inactivation of SIRT7 in mice
leads to shortened lifespan and phenotypes associated with aging, cancer, and metabolic disorders. Thus,
studying the molecular mechanisms and physiologic functions of SIRT7 promises to elucidate central
molecular pathways that impact on aging and health span.
 This project will study novel mechanisms of SIRT7 in protecting against genomic instability and
cellular senescence, fundamental aging mechanisms that are implicated in age-related diseases and
are a significant cause of tissue dysfunction. Recent studies indicate that elimination of senescent cells
in mice can prevent or reverse a wide range of aging-related pathologies, from cancer to fatty liver disease.
By elucidating the SIRT7 signaling pathways that control cellular senescence, the proposed work can
provide insights for developing therapeutic strategies for aging-related diseases that impact Veterans'
health.
 The central hypothesis of the study is that genomic instability at repetitive ribosomal DNA
(rDNA) sequences is a driver of senescence in mammalian cells, and that SIRT7 guards against
such instability by maintaining rDNA chromatin silencing via novel mechanisms. Molecular, cellular,
and genetic approaches will be taken to (1) study the molecular mechanisms and biological contexts of
SIRT7 in controlling rDNA chromatin dynamics; (2) elucidate the functional interplay of SIRT7 with a newly
described rDNA silencing pathway that is mutated in numerous cancers; and (3) characterize downstream
chromatin signaling mechanisms of SIRT7 at rDNA sequences.
 Accumulating evidence indicates that rDNA instability may be an oncogenic driver in many cancers, and
senescent cells can have pathogenic effects in tumor malignancy and myriad aging-associated pathologies.
By elucidating the SIRT7 signaling pathways that control rDNA instability and cellular senescence, our
proposed work can provide insights for developing therapeutic strategies for aging-related diseases that
impact Veterans' health.

## Key facts

- **NIH application ID:** 10043818
- **Project number:** 5I01BX000286-10
- **Recipient organization:** VETERANS ADMIN PALO ALTO HEALTH CARE SYS
- **Principal Investigator:** Katrin F. Chua
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2009-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10043818

## Citation

> US National Institutes of Health, RePORTER application 10043818, Chromatin Regulation by Mammalian SIRT7 in Aging and Disease (5I01BX000286-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10043818. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*