# Targeting Aging to prevent Alzheimer's Disease: the Geroscience Approach

> **NIH NIH R01** · BUCK INSTITUTE FOR RESEARCH ON AGING · 2021 · $581,874

## Abstract

PROJECT SUMMARY
Alzheimer’s disease (and related dementias ADRDs) are the leading cause of dementia in those over the age
of 65. Attempts to develop therapeutics to treat the condition have, to date, yielded disappointing results in
clinical trials. Neuropathologies associated with the disease include increased levels of proteotoxic species of
both beta-amyloid (Aβ) and tau. Aβ and tau have both independently been hypothesized to be the primary
agent driving ADRD-related neurodegeneration, although it is not clear that these “proteinopathies” are the
cause of these disorders. Neurotoxic proteins are certainly associated with intracellular and extracellular
protein aggregates in the form of tangles and plaques. These pathological features contain other insoluble,
aggregated cellular proteins. We and others have shown that increased protein insolubility is a feature of
normal aging. The proteins that enter the “insolublome” are enriched for lifespan determining functions, but it is
not clear how normal aging processes and the ADRD disease processes are related. “Geroscience” is a
concept that unites research on normal aging processes and research on chronic progressive diseases such
as AD. Integral to the Geroscience approach is that aging is a likely cause of multiple human chronic diseases.
It follows that interventions that target aging will provide novel therapeutic avenues for distinct diseases
including ADRDs. We have previously identified scores of chemical compounds that extend the lifespan of the
nematode C. elegans and have preliminary data that some of these compounds promote general protein
homeostasis and suppress aspects of neurological disease. Here we propose to exploit this resource to better
understand the relationship between normal aging and ADRDs but also to develop new potential therapies. We
propose to initially test the efficacy of aging interventions in C. elegans models of Aβ and tau neurotoxicity and
in human cell-based models of ADRDs. We will then screen for effects on age-related protein insolubility in
these models. We will use the powerful genetics of the worm and biochemical techniques to determine
pathways and mechanisms in a subset of lead compounds. Finally, we will utilize mouse models of ADRDs, to
gauge the effectiveness of aging intervention in the top 1-2 lead compounds. By undertaking such a
“Geroscience approach”, we aim to develop new methods to targeting the very earliest proteostatic changes
that lead to AD.

## Key facts

- **NIH application ID:** 10140261
- **Project number:** 5R01AG067326-02
- **Recipient organization:** BUCK INSTITUTE FOR RESEARCH ON AGING
- **Principal Investigator:** Gordon J Lithgow
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $581,874
- **Award type:** 5
- **Project period:** 2020-04-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140261

## Citation

> US National Institutes of Health, RePORTER application 10140261, Targeting Aging to prevent Alzheimer's Disease: the Geroscience Approach (5R01AG067326-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10140261. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*