# Regulation of age-associated DNA damage

> **NIH NIH R56** · CEDARS-SINAI MEDICAL CENTER · 2021 · $342,350

## Abstract

PROJECT SUMMARY
 DNA damage response (DDR) and repair pathways are attenuated with aging. Accumulated damaged DNA,
if left unrepaired, may disrupt tissue homeostasis, enabling an aging milieu favoring tissue degeneration, cancer,
and metabolic dysfunction. Unrepaired DNA damage may also result in cell senescence, with senescence-
associated secretory phenotype (SASP) promoting DNA damage and cell proliferation in neighboring cells, or in
apoptosis. Non-pituitary growth hormone (npGH), synthesized locally in peripheral tissues, is recognized by
widely expressed GH receptors (GHR), and acts through autocrine/paracrine mechanisms. Our preliminary
results show that, in aged human tissues with high DNA damage, aged induced pluripotent stem cell (iPSC)-
derived human colon 3D organoids, hypophysectomized rats lacking endocrine GH, and senescent cells, npGH
is induced and npGH suppresses DDR, further reinforcing DNA damage. We propose a novel hypothesis
supporting the role of local epithelial GH as an adverse determinant of age-associated DNA damage
accumulation and as a marker of aging.
 We will assess npGH induction and DNA damage in aged normal human colon cells and aged colon
organoids. We will explore mechanisms of npGH induction and assess DDR activity, senescence pathways, and
DNA damage repair by blocking GHR signaling in vitro with pegvisomant, JAK2 inhibitor, and metformin, and
in hypophysectomized rats devoid of pituitary GH. We will assess npGH actions in aged tissues derived from
colon-specific and universal GHR knockout, and in GH overexpressing transgenic mice, and also assess colon
epithelial copy number variation (CNV) and genes affected by CNV mutations in mice overexpressing the GH
transgene. We will examine npGH expression in human colon tissue specimens derived from age-determined
cohorts and assess spatial genomic profiles in conjunction with cells expressing npGH. We will study whether
npGH is expressed in senescent cells, and whether it affects DNA damage and proliferation of adjacent cells. We
will determine whether npGH, as a component of SASP, may serve as a specific marker of DNA-damage–induced
senescence. We will test paracrine npGH effects on senescence in human Colon Intestine-Chip microfluidic
devices co-cultured with human colon fibroblast npGH transfectants, and will confirm in vitro results in
transgenic models overexpressing GH or in GHR knockout mice.
 We largely focus on validated human colon epithelial models, yet experiments in this proposal are designed
to elucidate a universal mechanism whereby local npGH reinforces epithelial age-associated DNA damage
leading to tissue degeneration.

## Key facts

- **NIH application ID:** 10490214
- **Project number:** 1R56AG070211-01A1
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** SHLOMO MELMED
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $342,350
- **Award type:** 1
- **Project period:** 2021-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10490214

## Citation

> US National Institutes of Health, RePORTER application 10490214, Regulation of age-associated DNA damage (1R56AG070211-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10490214. Licensed CC0.

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