NSF Project Summary

IISAGE is an NSF-funded Biological Integration Institute aimed at understanding the functional genomic basis of differences in lifespan and aging between sexes across a wide range of animals. We are comprised of 11 research laboratories spread across 9 institutions.


We have established a Biology Integration Institute to determine how genome architecture, organismal biology, and phenotypic plasticity contribute to sex-specific aging and its evolution. In many species across the animal kingdom, one sex ages faster or has a longer lifespan. This sex-specific aging has significant implications for conservation, agriculture, and human health. However, no unified model exists that reveals how mechanistic and evolutionary processes cause the diverse patterns of sex-specific aging seen in nature. Furthermore, current research on sex-specific aging has been siloed because researchers primarily use discipline-specific approaches without integration.

These four research themes will advance IISAGE research goals through interconnected project design and iterative multi-scale science,
revealing the rules that govern sex-specific aging.

The Integration Initiative: Sex, Aging, Genomics, and Evolution (IISAGE) will bring together expertise from evolutionary biology, molecular genetics, genomics, physiology, and computational biology to identify the molecular mechanisms generating sex differences in aging. Working with amniotes, fish, and insects, IISAGE will define the rules that govern sex-specific aging. Tightly integrated projects with common methodologies will test hypotheses focused on differences between the sexes in genome architecture, organismal biology, and phenotypic plasticity to understand sex-specific aging. Through an integrated, iterative process of data collection, modeling, and hypothesis testing, IISAGE will define how processes at the molecular, organismal, and population level interact to generate sex-specific aging and develop predictive models for how sex differences in aging arise. Scientific projects are organized into four themes:

  • Theme 1: Sex Determination (SD) & Genome Architecture. Determines how sex determination systems, sex chromosomes, dosage compensation, and heterochromatin content contribute to sex differences in aging.
  • Theme 2: Organismal Biology. Investigates how cellular stress responses, sexual size dimorphism, and sex reversal impact sex differences in aging.
  • Theme 3: Phenotypic Plasticity. Defines how phenotypic plasticity, or the changes in phenotype based on environmental conditions, impacts sex-specific aging.
  • Theme 4: Evolutionary Systems Biology. Identify pathways that drive sex differences in aging by integrating data from themes 1-3 using multi-omics Machine Learning in a phylogenetic comparative framework.

We will define commonalities and species-specific mechanisms of sex-specific aging.

Intellectual Merit

Sex differences in aging are common in many taxa but vary significantly, and the mechanisms that control them are not understood. Identifying rules that explain sex differences in aging is challenging because phenotypic sex is confounded with many other differences between males and females. IISAGE will determine how genome architecture, organismal biology, and phenotypic plasticity generate sex differences in aging and define evolutionarily conserved and taxon-specific mechanisms controlling sex differences in aging. By integrating across disciplines, approaches, and levels of biological organization, IISAGE will develop predictive models for how genome architecture, organismal biology, and phenotypic plasticity can interact and lead to sex-specific aging. IISAGE’s approach will include data from both wild species, laboratory manipulations, and citizen scientists to provide unprecedented insights into the mechanisms controlling sex differences in aging.

Broader Impacts

ISAGE will produce novel analysis tools and hundreds of matched datasets profiling expression and chromatin in dozens of species, providing new resources for the scientific community. In addition, the insights into sex differences in aging derived from IISAGE’s work will be of interest to scientists ranging from basic biologists to translational researchers and individuals in the medical and conservation fields. Integrated with its interdisciplinary scientific mission, IISAGE’s training, education, and outreach program will increase diversity in STEM and prepare trainees to work in diverse careers and in multidisciplinary teams. The IISAGE REU program will engage 50 students from groups underrepresented in STEM. Our citizen science project will engage pet hobbyists and K-12 students in afterschool programs to collect demographic data to support IISAGE scientific goals. IISAGE will integrate outreach and research activities while publicizing the importance of basic science.