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

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2022 · $336,270

## Abstract

Project Summary
 The initiative behind RFA-AG-20-013 was designed to understand the role of aging in the development and
etiology of Alzheimer's disease (AD) and related dementias (ADRD). Our work shows that the F1F0-ATP
synthase, the mitochondrial complex responsible for ATP synthesis, is a core component of the mechanisms
linking aging to ADRD. We found that the experimental Alzheimer's drug candidate J147 targets the F1 subunit
of ATP synthase to exert geroprotective and neuroprotective effects. Our most recent data, obtained under this
grant, shows that J147 robustly extends lifespan in C. elegans via chromatin remodeling in neurons. Our data
further suggest that J147 extends lifespan in C57BL6 mice, remodels lipid metabolism, and shows signs of
improving cognitive performance in very old animals (28 months of age). These additional data are consistent
with our central hypothesis that mitochondria are a pivotal link between aging and ADRD that is druggable.
Mitochondria control synaptic gene expression via epigenetics and are subject to deterioration by age-associated
toxicities such as protein misfolding or oxidative stress. Treatment with J147 stabilizes mitochondria against age-
associated toxicities and thus extends lifespan and protects from neurodegeneration by allowing the
mitochondria to maintain control of synapse-related gene expression.
 For this supplement, we ask for the funds to extend specific Aim 1 in the parent application which determines
how protecting mitochondrial function preserves and restores synapse function in aged mice. We propose to
determine how protecting mitochondria by treatment with J147 preserves or improves mitochondrial and synapse
integrity in very old (28 months) wild-type C57BL6 mice using cutting-edge 3-dimensional electron microscopy.
We will engage the National Center for Microscopy and Imaging Research to generate ultrastructures of
mitochondria and synapses using multi-scale - multi-modal quantitative 3D microscopies, new technologies that
became available since we submitted the original award. These advanced EM methods allow quantitative
comparisons of tissue changes, such as amyloid plaque sizes, locations, and numbers - as well as quantitative
analysis of cellular and sub-cellular elements like mitochondria or synaptic vesicles predicted to be influenced
by the main action of J147 as an ATP synthase inhibitor. Our preliminary data also show an interesting thickening
of the myelin sheath in very old (28 months) J147 treated animals that is most likely associated with the effect of
J147 on lipid metabolism.

## Key facts

- **NIH application ID:** 10653496
- **Project number:** 3R01AG067331-03S1
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Michael Petrascheck
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $336,270
- **Award type:** 3
- **Project period:** 2020-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10653496

## Citation

> US National Institutes of Health, RePORTER application 10653496, Lowering Mitochondrial ATP Synthase Activity Slows Aging and Alzheimer's Disease (3R01AG067331-03S1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10653496. Licensed CC0.

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