Our overarching goal is to understand how aging influences the epigenome, and in return, how modulation of the epigenome can influence the aging process. We want to understand how this interaction is modulated in response to environmental stimuli (e.g. dietary restriction) and in the context of specific endogenous factors, specifically sex, across vertebrates. Aging is accompanied by striking changes in chromatin and gene expression across cell types and species. Yet, how chromatin landscapes change with age and regulate transcription, and how epigenomic changes in turn influence aging in response to external or internal cues, is largely unknown. Such knowledge will be critical to counteract the functional decline associated with physiological aging, and its exacerbation in age-related disease.
Our main cell model of study are key components of the innate immune system and the inflammatory response: macrophages, which accomplish key tasks such as phagocytosis, antigen presentation and cytokine production. Consistently, aging is associated with increased macrophage infiltration into tissues. Macrophages have two main origins: tissue-resident macrophages differentiate from specific embryonic progenitors, whereas monocyte-derived macrophages differentiate from bone-marrow progenitors throughout life. Resident macrophage populations exist across tissues (e.g. microglia in the brain, Kupffer cells in the liver, osteoclasts in the bone matrix, etc.). Because of their key role in inflammation and damage repair, macrophages are a key cell type in age-related inflammatory diseases.
A critical aspect of research in the Benayoun lab is the use of multiple vertebrate model organisms. The short lifespan of non-vertebrate model systems (e.g. yeasts, worms, and flies) makes their use in experimental aging research very attractive, and they have been widely used to explore genetic and environmental underpinnings of aging. However, as a result of this experimental pragmatism, our understanding of mechanisms that regulate vertebrate aging, including the role of vertebrate-specific genes, organs, and tissues (e.g. bones and blood), and physiological processes (e.g. adaptive immunity), significantly lags behind. These considerations led us to spearhead the de novo sequencing, assembly, and annotation of the African turquoise killifish genome, the shortest-lived vertebrate that can be bred in captivity. Despite this compressed lifespan, the African turquoise killifish display all key age-related phenotypes, including age-related cognitive decline. Our work has transformed the use of this organism as a vertebrate model, and we now are able to leverage this powerful new model organism in conjunction to established traditional models to rapidly identify novel pathways regulating aging and longevity in vertebrates.
Specific ongoing research directions in the Benayoun lab focus on (i) identifying transcriptional and epigenomic changes with age and upon interventions which extend vertebrate longevity, (ii) dissecting transcriptional regulation changes throughout life , as well as underlying molecular mechanisms for these changes, and (iii) understanding the regulation of aspects of aging by sex, an important, yet very much understudied, factor in aging and longevity.
Our research currently focuses on the following questions:
1. How is remodeling of chromatin landscapes during aging and in response to longevity interventions determined and regulated?
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, liver, pancreas) and across vertebrate models (i.e. mouse, African turquoise killifish). These maps will help provide a comprehensive picture of vertebrate-conserved age-related changes, which can be strong therapeutic targets in the study of aging.
2. How are specific aspects of transcriptions regulated and impaired during aging?
In this research direction, we aim at dissecting the impact of aging on key features of the transcriptional landscape and understanding the underlying molecular mechanisms. Indeed, accumulating evidence suggests that loss of transcriptional precision contributes to aging, through decreased integrity of transcriptional networks, increased transcriptional noise, disrupted splicing patterns, or the acquisition of aberrant transcription of previously repressed genes. Using the epigenomic signature of transcriptional consistency that we previously identified, we are characterizing age-related changes in transcriptional consistency, and studying underlying molecular mechanisms that could play a role during aging and longevity. We are also interrogating changes to transcriptional landscape with age beyond the traditional protein-coding gene expression levels, including transposable element reactivation.
3. What role does sex, an important yet understudied factor in aging and longevity, play in the regulation of aging?
The final aspect of our research involves characterizing the functional impact of the sex-specific regulation of the transcriptional and epigenetic landscape during aging. Women life expectancy exceeds that of men, while many age-related diseases are more prevalent in post-menopausal women. Sex-dimorphic responses to pro-longevity drugs or genetic manipulations have been observed in mice, including a larger effect in females for rapamycin treatment. Additionally, emerging evidence suggests that clear differences exist between male and female chromatin profiles in matched cell types. However, the effect of sex on chromatin and transcription during aging remains largely unknown. 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 effects of sex-steroid hormones. As an important model, we are leveraging the inducible Foxl2 mouse knock-out, which displays adult female-to-male hormonal (but not karyotypic) sex reversal.
The response to these questions could ultimately be leveraged to improve human health through the restoration of ‘youthful’ chromatin states.