# Metabolic Reprogramming and Regeneration in the Aged Epidermis

> **NIH NIH P01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $474,554

## Abstract

SUMMARY
Human skin is the largest and one of the most complex organs in the human body. It performs diverse functions,
ranging from protection, sensation, heat regulation, absorption of gases, excretion of sweat, and water
resistance. Skin structure and functions gradually deteriorate with age. While there is a substantial effort towards
understanding cellular mechanisms that cause cellular aging and influence the lifespan of model organisms, the
molecular mechanisms of age-related alterations in human skin in vivo are barely explored. The limited number
of studies on this subject conducted by bulk sequencing or metabolomics analyses of whole tissue lysates failed
to provide evidence on robust transcriptional, epigenetic or metabolic alterations that drive skin aging or generate
any reliable theory on the molecular determinates of these processes. We hypothesize that aging in the human
epidermis affects only the discrete populations of cells with stem and progenitor features and results in the
deterioration of their ability to drive self-renewal. Our preliminary data show that cycling stem cells maintain
epidermal homeostasis by undergoing a profound metabolic reprograming, which determines their ability to
differentiate and build the cornified barrier. We also found that the aptitude to initiate such metabolic adaptations
is progressively impaired in aging stem cells, which correlates with decreased expression of certain metabolic
enzymes. Consequently, we propose that exhaustion of metabolic reprogramming capacity is caused by aging
of the epidermal stem cells and is highly relevant for age-related alterations in the skin. We plan in aim 1 to
utilize our unique repository of primary human epidermal stem cells derived from donors of different ages and
further expose the metabolic failure of elderly progenitors. We will define the transcriptional alterations underlying
the defects in reprogramming from cytosolic glycolysis to mitochondrial oxidative phosphorylation. Aim two will
employ human artificial skin equivalents and a recently developed total thickness human skin regeneration
system as models of epidermal homeostasis and wound healing to address the functional significance of altered
metabolism-associated genes identified in Aim 1. Based on these findings, we will further explore the function of
the gene candidates in vivo in the mouse epidermis (in aim 3) using a highly efficient in utero gene-editing
system.

## Key facts

- **NIH application ID:** 10494658
- **Project number:** 1P01AG071463-01A1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Anna Mandinova
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $474,554
- **Award type:** 1
- **Project period:** 2022-09-30 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10494658

## Citation

> US National Institutes of Health, RePORTER application 10494658, Metabolic Reprogramming and Regeneration in the Aged Epidermis (1P01AG071463-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10494658. Licensed CC0.

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