# Cross-Species and Evolutionary Biology

> **NIH NIH U19** · TRANSLATIONAL GENOMICS RESEARCH INST · 2024 · $1,512,540

## Abstract

PROJECT SUMMARY - PROJECT 2
There exists a vast diversity of observed lifespans across species. However, our understanding of the genetic,
molecular, and mechanistic underpinnings of aging differences between species remains largely unknown.
Within mammalian lineages alone, exceptional long and short lifespans have evolved multiple times. This
homoplasy renders evolution a powerful tool to identify mechanisms within humans and other species that
underlie lifespan differences. Furthermore, by understanding which aspects of human longevity are conserved
or divergent from other species at the molecular level,biologically relevant information is elucidated that can
influence our use of model organisms to test geroprotective therapies. However, identifying the individual
phylogenetic changes responsible for lifespan differences across species and linking them to phenotypic
effects at scale has remained a challenge for the field. This is due to both the complexity of cross-species
phylogenetic analysis and the difficulty in surveying gene regulatory elements at-scale which are known to be a
primary driver of evolutionary change. To address this The Longevity Consortium Cross Species and
Evolutionary Biology (CSEB) Project will integrate sophisticated evolutionary algorithms, high-throughput
functional genomics tools, and advanced phenotype-relevant neuronal models, to uncover the genetic basis of
longevity across species.
 First, we will leverage and expand on a large collection of multiomic data from hundreds of mammalian
species to construct a curated genomic database that is combined with longevity data. Using state-of-the-art
algorithms, many developed by members of the CSEB, we will identify genes, regulatory elements, and
pathways associated with differences in longevity across species. Second, we will deploy high-throughput
CRISPR screens to systematically perturb hundreds of longevity-associated loci in neurons and fibroblasts of 8
species. This allows us to build longevity gene-regulatory networks and assess their divergence across
species. Across these same species and cell types, we will use massively parallel reporter assays to
interrogate cis-regulatory elements and genetic variation within these elements to uncover the precise genetic
mechanism underlying longevity difference both across species and within the human population. Together,
these assays will (i) validate associations from our phylogenetic analysis and from findings from across the
consortium, and (ii) allow the construction of comprehensive gene regulatory models across multiple species
for use by the integrative analysis core. Lastly, we will extend the legacy cross-species fibroblast resource by
developing an iPSCs collection of 20 species allowing the functional characterization in differentiated cell
types.

## Key facts

- **NIH application ID:** 11022977
- **Project number:** 2U19AG023122-16
- **Recipient organization:** TRANSLATIONAL GENOMICS RESEARCH INST
- **Principal Investigator:** Ryan Tewhey
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,512,540
- **Award type:** 2
- **Project period:** 2004-09-30 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11022977

## Citation

> US National Institutes of Health, RePORTER application 11022977, Cross-Species and Evolutionary Biology (2U19AG023122-16). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11022977. Licensed CC0.

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