# Using geroscience to understand and treat Alzheimer's disease

> **NIH NIH R01** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2020 · $843,328

## Abstract

Abstract:
There are no effective treatments for age-dependent neurodegenerative conditions such as Alzheimer's
disease (AD). To address this major public health crisis, the National Alzheimer's Project Act (NAPA) was
passed to “find effective interventions to treat and prevent AD and related dementias by 2025.” To achieve
this goal in 5 years one or more effective drugs are required, likely sourced from repurposed drugs that are
the basis of this application. Dementias are diseases that occur with age. Therefore, aging must be
incorporated into the drug target validation strategy to ensure that the target mechanism remains active in
aged individuals and to facilitate an understanding of the interaction between aging and AD. The recognition
of this fact led to the NOT-AG-18-051 initiative with one goal of “employing a lifespan approach to understand
the mechanisms of protective and risk factors” for AD. In this application, we formally address the goals of
both initiatives by integrating lifespan studies with an age-related phenotypic screening platform that has
yielded compounds that extend lifespan (geroprotectors), one of which is now in AD clinical trials.
 During the last decade a novel phenotypic screening platform based upon 5 toxicities associated with the
aged brain was used to identify compounds that have therapeutic efficacy in multiple models of
neurodegeneration and dementia. Surprisingly, these new synthetic compounds as well as their precursors
slow aging in mice, keeping them younger at both the gene transcription and metabolomics levels and extend
lifespan in other model organisms. The molecular target of one compound, J147, is identical to the target of a
compound that extends lifespan in C. elegans. J147 has since been used in a 'chemical biology' approach to
understand fundamental aspects of aging itself, for it engages essentially all of the known molecular
pathways associated with the geroprotectors metformin and rapamycin as well as caloric restriction. Because
of these new observations, we reasoned that by integrating lifespan studies in C. elegans with our novel
phenotypic screening platform we could efficiently identify additional new aging pathways as well as AD
drugs and drug targets. To accelerate the time needed to bring any discoveries to the clinic we will screen the
ReFRAME library. This unique library consists of 12,000 compounds developed by the pharmaceutical
industry, including nearly all that have ever been in man and those registered as investigational drug
candidates. These drugs will initially be screened in the neurotoxicity assay used as our primary screen in
previous drug discovery efforts. Positive hits will then be assayed for longevity in C. elegans. When
necessary, target identification will be carried out as we have done in the past. Finally, pathway validation
studies will be done in two very distinct mouse models of aging and dementia. This collaborative effort
between three laboratories uses a ne...

## Key facts

- **NIH application ID:** 10054924
- **Project number:** 1R01AG069206-01
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** Pamela Anne Maher
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $843,328
- **Award type:** 1
- **Project period:** 2020-09-30 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10054924

## Citation

> US National Institutes of Health, RePORTER application 10054924, Using geroscience to understand and treat Alzheimer's disease (1R01AG069206-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10054924. Licensed CC0.

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