# Dietary Restriction, GH/IGF-1 & Mechanisms of Cellular Protection and Regeneration

> **NIH NIH P01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $412,061

## Abstract

Abstract of Supplement
Alzheimer's disease (AD) is a devastating condition affecting millions and costing hundreds of billions of dollars
in caregiving expenses, for which no effective therapy exists. The pathophysiology of AD is complex and not fully
understood, but nutrition and exercise represent the most significant lifestyle determinants of AD risk.
Mitochondria have been linked to neurodegeneration on many levels; however, their DNA has not been carefully
studied in the context of Alzheimer's disease risk. Our lab characterized humanin, a mitochondrial-derived
peptide encoded from the 16S rRNA region of the mtDNA, which has shown to be a potent neuroprotective
factor. We recently showed that humanin administration prevents age-dependent cognitive decline in mice, and
others have shown that it slows the progression of amyloid beta (Aβ)-driven neurodegeneration in AD mouse
models. In recent unpublished data presented in this grant, separately, we recently identified a SNP in the
humanin ORF that is associated with lower circulating humanin levels and with more rapid cognitive decline in
individuals followed in the Health and Retirement Study (HRS). We now propose to expand this paradigm to the
entire mitochondrial genome to discover novel peptides that modulate AD and purpose the hypotheses that:
1) mitochondrial genetic variants interact with nutritional factors to modify ADRD risk and
2) the mitochondrial peptide transcriptome is dramatically affected by high-fat diet in aged mice.
We will center our focus by conducting cutting-edge genetic analyses to first see if certain mtSNPs attenuate or
synergize with diet to affect ADRD risk. This project will engage a team of scientists to address variation in
mitochondrial DNA (Aim 1) and mitochondrial RNA (Aim 2) with diet using the Health and Retirement Study
cohort and RNASeq data on brain samples from mice fed a high-fat diet, respectively.
Altogether, this supplement will identify mtDNA variants and potential peptides that interact with diet to modify
ADRD risk byusing two independent approaches (well characterized large human databases and state-of-the-
art novel transcriptomic approaches). If successful, findings from this project could lead to new target
identification of peptides with therapeutic potential.

## Key facts

- **NIH application ID:** 10123512
- **Project number:** 3P01AG055369-03S1
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Pinchas Cohen
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $412,061
- **Award type:** 3
- **Project period:** 2018-02-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123512

## Citation

> US National Institutes of Health, RePORTER application 10123512, Dietary Restriction, GH/IGF-1 & Mechanisms of Cellular Protection and Regeneration (3P01AG055369-03S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10123512. Licensed CC0.

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