# Cell Biology and Functional Analysis

> **NIH NIH U19** · TRANSLATIONAL GENOMICS RESEARCH INST · 2024 · $1,332,008

## Abstract

PROJECT SUMMARY- PROJECT 5
The underlying mechanisms that drive resiliency or, conversely, rapid decline, remain unclear. Moreover, models
of human aging, longevity, and resilience to disease that allow for the functional testing of potential interventions
are virtually non-existent. To directly address these gaps in understanding, we propose to build and harness
novel, complementary, in vitro human cellular models created from the fibroblasts and/or Peripheral Blood
Mononuclear Cells (PBMCs) of healthy young and old subjects and those experiencing mild cognitive impairment
(MCI) or clinically verified Alzheimer's Disease and Related Dementias (ADRD). We will also study and compare
cells generated from individuals who display exceptional longevity (EL) and/or resistance to or resilience against
ADRD. First (1), in combinatorial efforts, fibroblasts and PBMCs will be reprogrammed into iPSCs and
differentiated into neurons (iPSC-derived neurons) while, in parallel, the same starting material will undergo
direct conversion into induced neurons (iNs) which retain aging-associated signatures. Using this approach, we
harness both the flexibility and unlimited cell source provided by iPSCs while also capturing potential epigenetic
drivers of longevity or resilience by using iNs. Next (2), we will exploit these complementary cell-based models
to identify mechanisms underlying prevention (iPSC model) or reversal (iN model) of aging-related decline
including studies and models of dynamic resilience, DNA repair hotspots, and metabolic functionality. Lastly (3),
we will leverage iPSCs and iNs in functional validation studies of the genes, genetic variants, proteins,
metabolites, and other analytes found to be associated with longevity or decline across all projects in the
Longevity Consortium. These overlapping strategies present a unique opportunity for the cross validation of the
functional results, identified pathways, and signatures observed across systems and laboratories, a major point
of concern in the rapidly emerging geroscience field. This work combines innovative, complementary human
cell-based models capable of recapitulating human development with next generation omics and functional
assays to identify and validate the transcription factors, signaling pathways, and protein interaction networks that
are linked to longevity and act to sustain cellular integrity and functionality during disease and in old age. The
described work, to be performed by a collaborative team of uniquely skilled individuals, has the potential to make
substantial and meaningful advances in the fields of regenerative medicine and aging while unlocking a detailed
roadmap to healthful living and longevity.

## Key facts

- **NIH application ID:** 11022980
- **Project number:** 2U19AG023122-16
- **Recipient organization:** TRANSLATIONAL GENOMICS RESEARCH INST
- **Principal Investigator:** FRED H GAGE
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,332,008
- **Award type:** 2
- **Project period:** 2004-09-30 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11022980

## Citation

> US National Institutes of Health, RePORTER application 11022980, Cell Biology and Functional Analysis (2U19AG023122-16). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11022980. Licensed CC0.

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