Our research focuses on metabolism, comparative genomics, gene regulation, networks of gene, protein, and metabolite interactions in cellular aging and age-related diseases, and linking the composition of nutrition (interventions) to the molecular mechanism of aging. More specifically, we try to understand the molecular and cellular basis for aging with the goal of identifying novel molecular targets in aging pathways that will provide targets for clinical intervention for age-associated diseases such as Alzheimer's disease and cancer in the future. Our work explores hypotheses that are best addressed through high-throughput unbiased screenings in various aging models, including yeast, worms, mammalian cell culture, and mice, along with computational biology approaches to understand cellular processes that drive aging.
Current evidence suggests that many of the aging mechanisms and related genes are conserved among eukaryotes, from yeast to mammals. Each model system provides key advantages and challenges. Due to a variety of factors – notably including ease of genetic manipulation and physiology similar to that of humans – the mouse has become the pre-eminent mammalian model organism in aging biology. However, in light of the high housing costs and relatively long lifespan of mice, large-scale unbiased screening to identify anti-aging medicines is not feasible in this organism. With the realization that many aging-related pathways are evolutionarily conserved, even among widely divergent species, short-lived invertebrate models have instead been employed for such screening. The nematode C. elegans – with its short lifespan of ~3 weeks, and budding yeast S. cerevisiae – with its short chronological lifespan of ~4 weeks and replicative lifespan of ~40 divisions, ease of culture and genetic manipulation, and well-characterized aging biology – represents a very attractive model system to identify molecular determinants that modulate cellular aging and organismal age-related phenotypes. Accordingly, our research aims to develop an experimental framework (Figure 1) for aging research to;
(i) Select candidate molecular determinants of aging (gene, protein, metabolite sets) through systems-level studies/screenings and generate hypotheses based on the findings from invertebrate models,
(ii) validate life- and healthspan extension and characterize mechanistic models for selected gene/protein orthologs and selected metabolites with computational biology approaches
(iii) translate these findings into cell culture and a mouse model to identify genes/metabolites conferring desired biological effects (i.e., lifespan and healthspan (estimation of the age of most tissues and cell types will be performed based on recently developed methylation clocks, which will provide faster validation of the effect of molecular interventions on aging),
(iv) evaluate shorter-term surrogate phenotypes, such as molecular markers (i.e., DNA methylation changes) or age-associated defects in humans, such as cognitive function (i.e., processing speed), physical capability (i.e., strength, locomotion) and physiological and metabolic health (i.e., cardiovascular function, glucose metabolism).