Why demographic aging – i.e., the onset, rate, and duration of adult mortality trajectories – often differs between males and females is not understood. Equally perplexing is how sex-specific demographic aging is underpinned by sex-specific organismal senescence – i.e., the deterioration of biochemical and physiological processes leading to declining function with advancing age.

Stated simply, the why and how of sex-specific aging are questions without unifying answers – answers that have broad implications for conservation, agriculture, and human health. Mechanistic hypotheses for variation in sex-specific aging derive from genetics (Theme 1), organismal biology (Theme 2), quantitative genetics (Theme 3), and evolutionary biology (Theme 4).

THEME 1: How do sex chromosomes and sex determining mechanisms contribute to sex-specific aging?

Naturally occurring variation in sex-determining mechanisms is abundant (e.g., genetic sex determination vs. environmental sex determination (ESD)). Theme 1 leverages variation in sex-determining mechanisms, sex chromosomes, and species in which sex-specific genome features can be manipulated, to test their role in sex-specific aging.

Specifically, we are undertaking the following projects:

1.1 How does sex determining mechanism affect sex-specific aging phenotypes?
1.2 How does sex-specific aging respond to altered heterochromatin differences between the sexes?
1.3 How do sex differences in aging phenotypes respond to manipulations of dosage compensation?

Range of sex chromosome differentiation and regulation in species studied by IISAGE.

THEME 2: How does variation in physiology and morphology contribute to sex-specific aging?

Natural variation in sex-specific organismal biology is abundant – ranging from species where one sex has heightened cellular stress responses, or one sex has greater body size. Theme 2 leverages this variation and species in which sex differences can be manipulated, to test their impact on sex-specific aging phenotypes.

Specifically, we are undertaking the following projects:

2.1 How do sex, morphology, and physiology interact to impact sex-specific aging?
2.2 How does sex-specific aging respond to the induction of cellular stress responses?
2.3 Can we eliminate sex differences in aging phenotypes by experimentally evolving size monomorphism through selective breeding?

Sex differences in lifespan vary widely across animal taxa. Gray and black bars represent lifespan in females and males.

THEME 3: How does sex-by-environment plasticity contribute to sex-specific aging?

Sexes can respond differently to environmental perturbations, and can even change phenotypic sex. Theme 3 leverages long-term field studies, controlled laboratory studies, and novel sex-reversal studies to test for the contribution of phenotypic plasticity to sex-specific aging.

Specifically, we are undertaking the following projects:

3.1 Do sex-by-temperature interactions in wild populations sampled along thermal clines result in sex differences in aging phenotypes?
3.2 How do sex-by-temperature interactions in laboratory reciprocal transplant populations influence sex differences in aging phenotypes?
3.3 How does sex-reversal impact aging phenotypes, and does the mortality trajectory follow that of the genotypic sex or the phenotypic sex?

Phylogenies of species (purple) that will be subjected to multi-population sampling and laboratory
experiments under IISAGE. TSD: Temperature sex determination.

THEME 4: How repeatable, fixed, and/or labile are sex-specific mechanisms of aging across animal diversity?

Integrating across Themes 1-3, IISAGE will identify common vs. lineage-specific rules in sex-specific aging. These integrated interaction network analyses, spanning multiple disciplines and animal lineages, will distinguish between taxon-specific processes impacting sex differences in aging versus rules that apply across animal lineages.

Specifically, we are undertaking the following projects:

4.1 What are the universal mechanisms of sex-specific aging from species contrasts across a phylogeny, that correspond to gradients of sex determination and/or from the manipulations that alter sex differences in aging/lifespan?
4.2 What are the molecular pathways implicated in sex-specific aging that are conserved across species and environments?
4.3 What are the cellular and organismal factors that predict evolutionary change in sex-specific aging?

IISAGE will 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.