Our research focuses on, comparative genomics, gene regulation, networks of gene, protein and metabolite interactions in cellular aging and age-related diseases and linking composition of nutrition to molecular mechanism of aging. More specifically we try to understand the molecular and cellular basis for aging with the goal to identify novel molecular targets in aging pathways that will provide targets for clinical intervention in the future. Our work explores hypotheses that are best addressed through high-throughput assays and necessitate significant computational efforts to understand cellular processes that drives 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 a 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 experimental framework (Figure 1) for aging research to;
(i) Select candidate molecular determinants of aging (gene, protein, metabolite sets) through systems-level studies and generate hypotheses based on the findings from yeast model,
(ii) and validate lifespan extension and characterize mechanistic models for selected gene/protein orthologs and identified yeast cell metabolites in worm, fly and cell culture model,
(iii) translate these findings into mouse model to identify genes/metabolites conferring desired biological effects, i.e. lifespan extension (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 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 human 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).
With the power of these model organisms, combined with next generation sequencing technologies and computational platforms, we are;
(1) aiming to understand the effect of life history trajectories on (a) lifespan variation and (b) DR responses.
(a)The question of why some species or individuals within a population live longer than others is among the most important biological problems. With the current knowledge, it is safe to say that interaction between genetic and environmental factors, which influence longevity, varies between and within species. Genetic studies have found that longevity of laboratory animals can be extended by environmental, dietary, pharmacological and genetic interventions.
However, laboratory mutants characterized by extended lifespan are often unable to compete in the natural setting, and their ecological fitness in the wild may be questionable. To capture the experiment of nature that modifies the genotype arriving at different lifespans and natural selection interact to shape aging, we aim to utilize hundreds of ecologically diverse wild yeast isolates (Figure 2) with wide diversity of lifespan among them (Figure 3). We seek to identify genetic networks causally associated with natural variation in replicative lifespan across these wild yeast isolates, find genes, macromolecules and pathways that corralate with longevity, and discover the mechanisms through which dietary restriction (DR) and mitochondrial respiration extend lifespan.
(b) DR is a straightforward, non- invasive and highly promising nutritional regimen that can be extended to humans, but yet suffers from inconsistency and ranges of effects that sometimes lead to lifespan reduction in various genetic backgrounds. We will develop tools for predicting DR responses across genetic diversity (Figure 2) aiming to identify genotype-dependent and independent mechanisms of DR regulation in yeast, thereby accelerating applicability of DR to other genetically diverse species like ourselves.
(3) and planning a unique approach to rewire cellular metabolic state by turning off energy production pathways by supplying energy from outside in the form of pure ATP. Since much of the cellular damage is produced during the process of generating energy (in the form of ATP) from nutrients, we will test how aging is modulated when energy in the form of ATP is provided directly to cells, reducing the need for central catabolic processes and remodel the metabolism (Figure 4).