# Targeting Biology of Aging Mechanisms Underlying Alzheimer's Disease Risk with Metformin

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2024 · $828,960

## Abstract

PROJECT SUMMARY/ABSTRACT
Age is the strongest risk factor for Alzheimer’s disease and related dementias (ADRD), with a doubling of disease
prevalence every five years after the age of 65 years. Nonetheless, the mechanisms linking biological aging with
ADRD remain elusive, impeding the development of therapeutics targeting these core processes. Advances in
the field of geroscience has led to the discovery of key biological aging pathways and hallmarks of aging,
including cellular senescence, mitochondrial dysfunction, epigenetic alterations, inflammation, and deregulated
nutrient sensing/metabolism, which act in concert to induce tissue degradation and ultimately, functional decline.
Emerging research indicates that the pace of aging is modifiable through interventions that act upon these key
aging pathways and hallmarks, which may serve to prevent or delay the onset of age-related disease such as
ADRD. Given the pleiotropic effects of metformin on multiple aging pathways and hallmarks, our team has been
conducting a randomized clinical trial of metformin vs. placebo for frailty prevention in prediabetic older adults
(R01AG052697), as well as a related project (R01AG069690) examining metformin-induced changes on aging
pathways and hallmarks in biospecimens collected from participants enrolled in the randomized trial.
In response to PAR-22-093 and aligned with NIA AD+ADRD Milestone 2.A, we propose to examine whether
biological aging pathways and hallmarks of aging, separately and collectively, contribute to indicators of ADRD
pathology and whether modulating biological aging processes with metformin improves indicators of ADRD
pathology. We will leverage data from our ongoing randomized trial of metforminvs. placebo for frailty prevention
in older adults without dementia at baseline (mean age 72±5 years, 49% female, 35% Hispanic), in which we
have performed comprehensive and longitudinal (24 month) assessments of hallmarks of aging (senescence,
inflammation, metabolism, mitochondrial function, and epigenetics) and key cellular pathways that control them
(AMPK, mTOR, NFκB). In Aim 1a, we will evaluate the hypothesis that that biological aging pathways and
hallmarks of aging will be linked with ADRD markersincluding indicators of neuronal/axonal injury (neurofilament
light chain), neuroinflammation (glial fibrillary acidic protein, YKL-40), vascular dysfunction (platelet-derived
growth factor), neuropathology (phosphorylated tau 217, amyloid beta (Aβ) 42/40). Under Aim 1b, we will
evaluate longitudinal trajectories in the pathways and hallmarks of aging and how they relate to changes in
cognition and plasma ADRD markers over 24 months. Under Aim 2, we will examine whether modulating the
biological aging pathways and hallmarks of aging with metformin relative to placebo alters ADRD markers.
The proposed project will expand our understanding of the role that biology of aging mechanisms exert on ADRD
pathology. In addition, we will experimentally assess...

## Key facts

- **NIH application ID:** 10992073
- **Project number:** 1R01AG089711-01
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Sara Elyse Espinoza
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $828,960
- **Award type:** 1
- **Project period:** 2024-09-30 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10992073

## Citation

> US National Institutes of Health, RePORTER application 10992073, Targeting Biology of Aging Mechanisms Underlying Alzheimer's Disease Risk with Metformin (1R01AG089711-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10992073. Licensed CC0.

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