# Using cellular co-biosis and age programmable mice to derive a global interaction map of aging hallmarks

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2024 · $453,583

## Abstract

PROJECT SUMMARY
Biological systems are presumed to fail over time based on nine “hallmarks of aging,” which somehow cause a
global decline in tissue function and health. Based on this paradigm, interventions, and combinations of them,
are being developed to attenuate each of the hallmarks and slow the aging process. Unfortunately, a lack of
insight into the interdependence among these aging hallmarks has made it difficult to develop universally
effective mitigation strategies. Our lab and others have provided evidence that a loss of stored information
impairs the function of cellular machinery and physical structures, leading to aging and age-related diseases.
We have developed the ICE system (Yang et al. 2022, provisionally accepted by Cell) which allows for spatial
and temporal control over epigenetic aging in mammals. We have also discovered that partial reprogramming
using the reprogramming factors, Oct4, Sox2, and Klf4 (OSK), allows cells to retrieve a “backup copy” of youthful
information that resets the epigenome, reverses multiple hallmarks of aging, and restores DNA methylation
patterns to their previous youthful state (Lu et al., 2020; Yang et al., 2022, provisionally accepted by Cell).
In this study, we leverage our ability to control the pace of aging in forward and reverse directions to test the
hypothesis that a loss of interconnectivity between cellular information and cellular machinery and physical
structures is a primary driver of the Hallmarks of Aging and a reversible cause of aging itself. To do this, we will
develop the first set of fluorescent hallmark reporters to monitor hallmark progression and interactions during
aging and discover ways to promote their co-reversal. This novel tool will be utilized along with advanced multi-
omic approaches in novel co-biosis systems and age-programmable mice in the heterogeneous UM-HET3
genetic background.
This study is important because it will provide valuable knowledge concerning the long-standing questions about
interconnectivity among the aging hallmarks, such as whether hierarchies exist and if the reversal of one hallmark
ensures the erasure of others. Together, this work will provide the field with a novel set of customizable tools to
track and study these hallmarks and test the hypothesis that many hallmarks intersect at the informational level
and are therefore co-reversible when information in the nucleus is reset to a youthful state.

## Key facts

- **NIH application ID:** 10923958
- **Project number:** 5R01AG082737-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** DAVID A. SINCLAIR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $453,583
- **Award type:** 5
- **Project period:** 2023-09-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10923958

## Citation

> US National Institutes of Health, RePORTER application 10923958, Using cellular co-biosis and age programmable mice to derive a global interaction map of aging hallmarks (5R01AG082737-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10923958. Licensed CC0.

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