Kane Lab Overview
“Aging is an incredibly heterogeneous process. Organisms of the same chronological age can have hugely different health status and function. Increasing our understanding of where this heterogeneity originates, and how we can predict and target it, will transform how we understand, treat and optimize diseases and health in aging.”
–Alice Kane, PhD, Ling/Obrzut Assistant Professor
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Despite the fact that aging is a universal process, the kinetics of aging are highly heterogeneous – a notion that is quantitatively captured by the concept of frailty. The Kane Lab is interested in identifying biological determinants of frailty in order to understand more about the molecular underpinnings of frailty and aging, to develop predictive biomarkers of frailty, and to identify targets to delay or prevent frailty. We use a combination of physiological, molecular and computational techniques across mouse models and human datasets.
Development of predictive aging clocks: The preclinical aging field has limited tools to measure, and more importantly predict, overall health in aging. Lifespan studies have become the standard, but these are expensive, time consuming, and do not give information about health status. There has been recent focus on the development of “clocks” in mice that model specific data to predict age or lifespan. These include epigenetic clocks, which accurately predict age based on the methylation at specific CpG sites in the genome, and frailty-based clocks, which predict both age and lifespan based on non-invasive frailty measures in mice. These tools are somewhat limited in their applicability, however, being developed mostly in older, male mice of a single species, and with limited interpretability of what the predictions mean in terms of health status. The Kane Lab aims to expand this work to develop interpretable machine-learning based clocks that combine functional, physiological and molecular measures from deeply phenotyped outbred mice of both sexes to accurately predict age, lifespan and frailty. These will be invaluable tools for the aging field, and help identify beneficial aging interventions without waiting years for complete lifespan data and reduce study duration and costs. Additionally, these studies will provide valuable clues about the mechanisms or determinants associated with frailty, accelerated aging or mortality risk, and similar approaches can ultimately be applied to the prediction of outcomes in humans.
Longitudinal studies for the identification of molecular determinants of frailty: Frailty quantitatively captures the heterogeneity of aging and can be considered a measure of biological – rather than chronological – age. Those who are frail are at increased risk of poor outcomes, including falls, institutionalization, hospitalization and mortality. However, little is known about the molecular mechanisms of frailty and whether they are distinct from or related to those of aging. Additionally, there are no clinically accepted frailty biomarkers to identify those at risk, or interventions to delay or prevent frailty. The Kane Lab aims to use longitudinal studies in mice and humans to identify molecular determinants and biomarkers of frailty. We will collect standard non-terminal samples such as blood, urine and feces, but also less-studied samples including vaginal swabs and skin, at regular intervals from mice that are also assessed for frailty, function and other clinically relevant outcomes. These samples will be used for molecular analyses of changes to the epigenome (histone marks, chromatin accessibility and DNA methylation), transcriptome, metabolome, proteome and microbiome. We will investigate the kinetics of the relationship between frailty and molecular changes over time in individual mice. This will allow us to identify underlying determinants and mechanisms of frailty, and to also potentially understand more about the underlying mechanisms of aging itself.
Investigation of mechanisms of sex differences in frailty: In humans, females are more frail than males at all ages despite having lower mortality risk, and the reasons for this paradox are not well understood. Mouse models of frailty provide ideal tools to specifically explore the biological basis for this sex difference, in the absence of social or behavioral factors. The Kane Lab aims to address the important question of how sex chromosomes, hormones or other factors may contribute to increased frailty and/or reduced mortality risk in females. We will characterize aging and frailty in genetically modified mouse models such as the “four core genotypes” mice, a novel series of transgenic mouse strains which have either XX or XY chromosomes with either testes or ovaries, in order to understand the effect of sex chromosomes and hormones on frailty and health during aging, and the interaction of this with lifespan. We will also explore in large-scale human datasets (including self-reported data, lab-based data and epigenetic clocks) whether sex differences change with different types of frailty or biological age assessments. We ultimately aim to identify underlying mechanisms that contribute to sex differences in frailty and mortality, to better understand mechanisms of aging, and to identify of targets for interventions to improve healthspan in both men and women.