# Project 1

> **NIH NIH U19** · WASHINGTON UNIVERSITY · 2020 · $3,321,692

## Abstract

The Long Life Family Study (LLFS) has enrolled 4,953 participants in 539 pedigrees in the USA and Denmark
that are enriched for exceptional longevity, and has measured them longitudinally in two extensive in-home visits
measuring key healthy aging phenotypes in all of the major domains of the aging process. We have
demonstrated through many publications that selecting on longevity in the first (proband) generation, results in
the second (offspring) generation being much healthier than average in many key phenotypes. However, the
pedigrees are heterogeneous by phenotype, with different families showing familial clustering of protection in
cognition, grip strength, pulmonary function, blood pressure, etc. Further, comprehensive linkage analysis of
the LLFS sample identifies extremely strong genetic linkage peaks for cross-sectional as well as longitudinal
trajectory rates of change phenotypes for a wide variety of healthy aging domains such as exceptional cognitive
performance and lack of Alzheimer’s disease. These peaks are NOT explained by GWAS SNPs (or those that
can be imputed by GWAS). Pedigree specific LODs and preliminary deep sequencing suggests that these peaks
are driven by rare, protective variants running in selected pedigrees. We propose to do Whole Genome
Sequencing on this unique cohort, to identify the rare protective variants driving these strong linkage peaks. We
propose to continue longitudinal assessment of the cohort with a third in-person visit, which will allow us to
assess potential non-linear patterns of aging, and adding formal assessment of dementia diagnosis for
Alzheimer’s Disease and other dementia types, which will increase specificity and power to discover and follow-
up on protective variants against Alzheimer’s Disease and other dementia diagnoses. For pedigrees driving
multiple strong linkage peaks, we also propose to phenotypically measure the third generation (grandchildren),
as these are likely to carry more copies of the rare protective alleles running in these families, which will
exponentially increase our power to resolve them. Preliminary evidence from the Danish Medical Registry
suggests that, at least in Denmark, the protection persists into this third generation, with significantly lower rates
of medical conditions across the disease spectrum. We also propose to do extensive transcriptomics,
methylomics, and proteomics on these selected high linkage pedigrees, to begin to move from “statistically
associated variants/loci” to the biological genes of action, since we expect most of the driving variants will be
regulatory and non-coding. It is critical to find the modes of action of these rare protective variants. We also
propose to do metabolomics on the entire LLFS cohort, longitudinally, with the goal of identifying novel
biomarkers of healthy aging and resistance to diseases such as Alzheimer’s in this unusually heathy cohort.
Combined with a systems biology/network approach to data integration of the ...

## Key facts

- **NIH application ID:** 9987435
- **Project number:** 5U19AG063893-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Michael A. Province
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $3,321,692
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987435

## Citation

> US National Institutes of Health, RePORTER application 9987435, Project 1 (5U19AG063893-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9987435. Licensed CC0.

---

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