# Lowering Mitochondrial ATP Synthase Activity Slows Aging and Alzheimer's Disease

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $917,648

## Abstract

ABSTRACT
Aging is the biggest risk factor for Alzheimer's disease (AD) and related dementias (ADRD). However, the
underlying molecular mechanism that link mechanisms of aging to ADRDs are unknown. To develop
geroprotectors, drugs that target aging and could be used to treat ADRDs we developed a neuro-centric
geroscience platform to identify Gero-Neuro-Protectors (GNP), geroprotectors that extend lifespan and
simultaneously protect neurons from multiple age associated toxicities. GNPs should make ideal treatments
for ADRDs. Increasing lifespan alone, without treating dementia, will only delay disease onset or even prolong
disease duration, and thus worsen the ADRD problem, which is the consequence of ever increasing lifespans.
We present a proof of principle GNP, J147 and show that it extends lifespan, prevents memory loss, and even
restores memory when treatment is initiated in 20-24 month old wild type or symptomatic APPswe mice. We
propose a testable model in which J147 protects neurons from ongoing proteotoxic stress by lowering ATP
synthase activity, shifting energy metabolism towards glycolysis accompanied by accumulation of acetyl-CoA.
Accumulating acetyl-CoA leads to increased H3K9 histone acetylation and protects synapse related gene
expression from transcriptional drift -the age-associated deterioration of transcriptional programs- and
consequently from functional decline. In the following proposal we will test this model in detail by conducting
neuropathology, electrophysiology and behavioral assays in aged wild type mice and two mouse models of
ADRD. We show that these effects are evolutionarily conserved and that lowering ATP synthase activity
extends lifespan in M. musculus, D. melanogaster and C. elegans. As both, ATP synthase and the age-
associated transcriptional drift of synaptic genes are evolutionarily conserved from M. musculus to C. elegans
we will use C. elegans to identify the chromatin remodeling factor that controls synapse related gene
expression in aging and how it respond to mitochondrial insults. We will validate the role of the identified factor
in controlling chromatin on synaptic promoters in primary neurons, aged wild type mice and mouse models of
ADRD. Finally, we will expand our GNP concept to profile geroprotective compounds identified by the
intervention testing program (ITP) for their ability to protect neurons from different age-associated toxicities and
to identify combinations of geroprotectors that are complementary in their protective effects. Because ADRDs
are complex diseases with multiple pathological aspects that are unlikely to be addressable by a single drug,
we predict rationally designed combinations of geroprotectors to outperform individual geroprotectors.
Together these studies will provide deep insights into how aging and ADRDs compromise synapse function
and how this can be addressed by treatment with single GNPs or rational GNP combinations.

## Key facts

- **NIH application ID:** 9971297
- **Project number:** 1R01AG067331-01
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Michael Petrascheck
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $917,648
- **Award type:** 1
- **Project period:** 2020-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971297

## Citation

> US National Institutes of Health, RePORTER application 9971297, Lowering Mitochondrial ATP Synthase Activity Slows Aging and Alzheimer's Disease (1R01AG067331-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9971297. Licensed CC0.

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