Research Interests
Our overarching goal is to understand how aging influences ‘omic’ landscapes across key cell types and tissues, and in return, how modulation of such landscapes influences aging and susceptibility to age-related disease. Specifically, we are excited to explore understudied influences (specifically, biological sex and reproductive status) on gene regulation in key biological systems, with a focus on innate immune cells and the brain. We are also curious to understand how these biological inputs can lastingly influence vertebrate health. Although sex-dimorphic processes can have a major influence on somatic health throughout life, this exciting question remains dramatically understudied, with few studies looking at the influence of biological sex as a focal point of interest, thus ignoring a major contributor to health gaps with aging in humans (e.g. Alzheimer’s disease is twice as frequent in women than men, yet the biological drivers of that difference have not been elucidated).
In contrast, our lab has been investigating how lifelong sex-differences shape aging trajectories, most specifically in the innate immune system (i.e. peritoneal macrophages, neutrophils, microglia), in the brain (i.e. microglia), and integrating the role of the ovary (i.e. developing models of menopause and parity), using the power of big data.
Our research currently focuses on the following questions:
1. Mechanisms of genomic deregulation during vertebrate aging
With this research direction, we aim at understanding chromatin and transcriptional remodeling during aging and in response to pro-longevity interventions. Age-associated changes in expression levels and chromatin structure have been observed across cell types and species, but the genomic pattern of such changes is still largely unknown. Furthermore, how the remodeling of the epigenome during vertebrate aging influences transcriptional outputs and cellular functions remains unclear. To address these questions, we are extensively mapping epigenomic and transcriptional changes during aging at multiple levels (e.g. tissue, single cells), in multiple tissues (e.g. brain) and across vertebrate models (i.e. mouse, African turquoise killifish).
An important theme that emerged from our research is the widespread activation of inflammatory pathways. As a potential driver of such inflammation, we identified age-related transcriptional reactivation of transposable elements (TEs) across species . TEs are endogenous mobile genetic elements with viral-like properties, that can elicit inflammatory responses and promote genomic instability, which are in turn deleterious to cell health.
This work will help provide a comprehensive picture of vertebrate-conserved age-related changes, which can be strong therapeutic targets in the study of aging and age-related disease (e.g. Alzheimer’s).
2. Sex-dimorphism in the lifelong regulation of inflamm-aging
Accumulating evidence shows that biology is highly sex-dimorphic, including in the context of aging and age-related disease. In this research direction, we are investigating how biological sex impacts the mammalian immune system during aging and age-related disease (e.g. Alzheimer’s models) with a focus on macrophages/microglia and neutrophils.
We are studying molecular mechanisms driving sex-differences at the molecular, cellular, tissue and organismal level. Specifically, we are investigating two levels at which sex could influence aging: (i) the genetic level (i.e. sex chromosomes), through modulation of transcriptional and epigenomic identity, and (ii) the endocrine level, through the systemic effects of sex-steroid hormones. As an important model, we are leveraging the inducible adult Foxl2 mouse knock-out, which displays adult female-to-male hormonal (but not karyotypic) sex reversal. More recently, we have started to study the systemic impact of menopause-like hormonal states, as well as past reproductive history (both sex-specific life history event), on aging trajectories focusing on brain (e.g. microglia impacts), peripheral immune cells (e.g. macrophages, neutrophils), and metabolic compartments (e.g. liver, adipose).
Together, our work is providing unique insights into how sex-specific biology – both at baseline and in response to sex-specific life history events – can drive differential changes in molecular pathways of aging and age-related disease, and how longevity interventions (e.g. 17-alpha-E2 treatment) interact with sex-dimorphic aging biology.
3. Understanding the mechanisms and the health impact of reproductive aging
Mammalian female reproductive lifespan is limited by a fixed “ovarian reserve”, whose age-related attrition culminates in menopause in humans. Accumulating evidence indicates that ovarian failure contributes to aging and frailty, with post-menopausal women at higher risk for age-related disease (e.g. Alzheimer’s). However, due to limited tissue accessibility and a lack of reliable models, ovarian aging and its health impact remain poorly understood.
Although laboratory animals show age-related decreases in reproductive capacity, they lack key aspects of human menopause (e.g. low to absent estrogen in post-reproductive period). Thus, while age-at-menopause is a top predictor of women’s health and longevity, preclinical models to study the impact of menopause on health are severely limited. To enable better modeling of sex-specific influences on aging, we are spearheading systematic efforts to evaluate age-relevant models of menopause: (i) genetic models (e.g. Fshr +/-, Foxl2 +/-), (ii) chemical models (e.g. VCD, with a range of age-at-exposure).
Finally, we have been conducting foundational work to establish the impact of the gut microbiome on measures of ovarian aging in mice, establishing the lifelong impact of a bidirectional gut/ovary axis in the regulation of ovarian aging, with potential translational impact.
Together, this project has the potential to uncover novel biomarkers for female reproductive aging and molecular targets that may be used for alleviating the health impact of ovarian aging, provide new physiologically relevant preclinical models of menopause, and help better understand how envrionmental inputs regulate ovarian aging (and thus systemic health).
4 . The naturally short-lived African turquoise killifish: a new vertebrate model for aging research
Vertebrate aging research has been hindered by the relatively long lifespan of classical model organisms, such as the mouse (~3 years) or zebrafish (~5 years). Because of its short lifespan (~0.5 years), the African turquoise killifish (Nothobranchius furzeri) is a promising model for aging research. Our lab is playing a central role in developing new tools, datasets/resources, and protocols for the use of the turquoise killifish in experimental aging research.
An important tool in any model organism is a compendium of reliable cell type markers, that can be used to isolate cells or drive transgene expression. Consistently, we recently published a single-cell atlas of peripheral tissues in adult female vs. male turquoise killifish (>100,000 cells). Using this data, we identified robust cell type markers, and saw widespread sex-dimorphic gene expression. In addition to the intrinsic value of the atlas, it helped us identify interesting new biology, including sex differences in liver lipid storage. We are also currently leading a project to map ‘omic’ brain aging in this species at single-nucleus resolution as part of the SCPAB, in males vs. females in genetic strains with divergent lifespans. In addition, an unique feature of the African turquoise killifish is the TE-rich nature of its genome (~50%), on par with the human genome. The Benayoun lab is developing a toolkit to study TE biology in this species, including computational pipelines.
This work will have a transformative impact on the study of vertebrate aging by providing a standardized molecular and phenotypic blueprint for a naturally short-lived, powerful new model organism.
The response to these questions could ultimately be leveraged to improve human health through the restoration of ‘youthful’ ‘omic’ states, leading to functional rejuvenation.