# Rejuvenating Aging Human Cells through Transcriptional Reprogramming

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $161,500

## Abstract

Aging is a major risk factor for many chronic diseases such as cardiovascular disease,
neurodegenerative disease, and cancer. As the global population progressively ages, age-related diseases
have become some of the world’s most prominent health problems. The established medical practice has thus
far focused on treating each disease independently as it arises. With this conventional approach, age-related
diseases are quickly becoming unmanageable collectively, as alleviating one disease for an individual does not
prevent the inevitable rise of another one. A fundamental shift of paradigm in treatment and prevention would
be to target the root cause of aging, instead of its “symptoms”. Under this new paradigm, rejuvenation of aging
human tissues and organs represents a promising and fundamentally new direction. Here we propose an
unconventional approach to tackle one of the grandest challenges of our time – to systematically identify
strategies for rejuvenation.
 Our proposal is based on a novel concept: rejuvenating aging human cells through transcriptional
reprogramming. This was inspired by Yamanaka’s success in deriving induced pluripotent stem cells from
differentiated cells through transcriptional reprogramming. The fundamental hypothesis is that both “young”
and “old” are different states of the cell defined by specific gene expression programs, and that by introducing
appropriate combinations of transcription factors (TFs) into the old cells, it is possible to directly rejuvenate the
old cells and bring them back to the youthful state.
 To test this hypothesis and to identify such transcriptional programs, we will develop a novel approach
that combines the CRISPR technology for targeted gene regulation, single cell RNA sequencing for gene
expression profiling, and state-of-the-art bioinformatic analysis. Using established human cell culture models
for aging study, we will systematically identify combinations of TFs that, when introduced to old cells, are able
to reverse the gene expression program of the old cells to that of the young cells. Positive hits from the high
throughput screening will be followed by detailed cellular and molecular phenotyping to confirm the effect of
rejuvenation. The identification of combinations of TFs capable of rejuvenation will set a unique stage for
discovering combinations of small molecule drugs that can achieve the same effect. Drugs that activate each
individual TF can be screened using transcriptional reporters, and positive hits for different TFs can be
combined. This reduce the impossible problem of searching for combination drugs for cell rejuvenation to a
much more manageable problem of searching for a single drug that activates a specific TF.

## Key facts

- **NIH application ID:** 10145567
- **Project number:** 5R21AG064357-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** HAO LI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $161,500
- **Award type:** 5
- **Project period:** 2020-05-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145567

## Citation

> US National Institutes of Health, RePORTER application 10145567, Rejuvenating Aging Human Cells through Transcriptional Reprogramming (5R21AG064357-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10145567. Licensed CC0.

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