# Epigenetics of Aging and Age-Associated Diseases

> **NIH NIH P01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $2,150,681

## Abstract

OVERALL ABSTRACT
Epigenetics is a critical determinant of aging and longevity, and senescence is a key driver of age-associated
pathologies. Our program is leading efforts to understand the epigenetics of cell senescence and aging. Our
overall hypothesis is that the epigenome is inherently dynamic/plastic to provide for flexible regulation, and
during aging, this dynamic epigenome undergoes a loss of overall integrity. This loss of epigenome integrity, in
turn, contributes to a secondary cascade of cell and tissue signaling events that also exacerbate aging, for
example Senescence-Associated Secretory Phenotype (SASP) in senescent cells, a cause of “inflamm-aging”.
We have coined the term “chromostasis” for the process whereby cells and tissues attempt to manage their
dynamic/plastic epigenome to maintain epigenome integrity, transcriptional fidelity and, hence, promote healthy
aging and longevity. The current P01 grant period was highly successful, as measured by our publications (56
total), collaborative efforts (20 collaborative publications), and our contributions to the fields of aging and
epigenetics (104 publications since initial funding in 2008).
 Our specific major accomplishments in the current grant period are: (1) We uncovered dramatic
changes to the epigenomic landscape within senescent human cells, some of which also occur in aged and
diseased tissues. We discovered mechanisms underlying this altered epigenomic landscape, including
disruption heterochromatin and the first example of a nuclear substrate of autophagy. (2) We discovered new
mechanisms for activation of the SASP in senescent cells, and pioneered new small molecule/drug-based
approaches to inhibit the SASP and promote healthy aging, including MLL and HDAC inhibitors. (3) We
discovered a DNA methylation clock in mouse, and showed its slowing by diverse prolongevity interventions.
(4) We dissected the structure and function of the HUCA (HIRA/UBN1/CABIN1/ASF1a) histone chaperone
complex, a key mediator of histone dynamics in senescent cells, and defined the molecular basis of HUCA’s
histone H3.3 variant selectivity. (5) We found age-correlated alterations in conserved chromatin factors that
lead to inappropriate cryptic transcription from gene bodies, and showed this to be a novel cause of aging.
 In the renewal of this PO1, we will (1) leverage multi-disciplinary discovery platforms to uncover
mechanisms underlying deficient chromostasis, (2) determine relevance of altered chromostasis in
mouse/human aging, and (3) dissect mechanisms underlying the secondary pro-aging signaling events and
identify pharmacological approaches to block these processes to promote healthy aging.

## Key facts

- **NIH application ID:** 10174627
- **Project number:** 5P01AG031862-14
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** SHELLEY L BERGER
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $2,150,681
- **Award type:** 5
- **Project period:** 2008-03-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10174627

## Citation

> US National Institutes of Health, RePORTER application 10174627, Epigenetics of Aging and Age-Associated Diseases (5P01AG031862-14). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10174627. Licensed CC0.

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