Stem Cell Aging, Tissue Maintenance and Tumorigenesis
One of the most fundamental questions in biology is why we age. The past decade has witnessed a significant revision of a traditional view that aging is simply a random and passive process that is solely driven by entropy. In fact, the aging process is regulated genetically and lifespan can be extended by single gene mutations. Our research aims to understand signal transduction that regulates the aging process and explore therapeutic targets to slow down aging. The most intriguing aspect of pharmaceutical intervention that targets the aging pathways is that, instead of targeting a specific disease, it has the potential of ameliorating a wide array of seemingly unrelated diseases associated with aging, such as cancer, tissue degeneration, metabolic syndrome and immune dysfunction.
Calorie restriction (CR) is the most effective dietary intervention to extend lifespan in a wide spectrum of species. In mammals, this dietary regiment also prevents diseases of aging. One important concept that emerges from aging research is that, while degenerative changes associated with aging are complex and difficult to integrate, the molecular mechanism of CR comprises regulated pathways amenable to study and provides an entry point to decipher how we age. The molecular mechanisms underlying these biological processes are currently being studied using systemic genome-wide screens, cell culture studies, and genetics.
Sirtuins are a highly conserved protein family with unique NAD-dependent protein deacetylase activity. Sirtuins are the prime candidates for the mediators of CR response, because they may sense the availability of nutrients via the concentration of NAD, a major metabolite in the cell, and elicit profound CR response by deacetylating a variety of downstream targets. Many protein targets of sirtuins have been identified, which turn out to be the key regulators of diverse biological pathways associated with CR response, such as stress resistance, glucose and fat metabolism. While it still remains to be elucidated whether sirtuins are linked to longevity in mammals, increased dose of sirtuins or small molecule activators of sirtuins extend lifespan in model organisms including yeast, worms and flies. In mammals, there are seven sirtuins, SIRT1 -7, which are expressed in different tissues with different cellular localizations. We are testing the hypothesis that these seven sirtuins sense nutrients, coordinate with each other, and regulate aging related biological pathways in various cellular compartments.
The functional studies of sirtuins in aging will have direct pharmaceutical implications. Small molecule SIRT1 activators are currently in clinical trials for metabolic diseases associated with aging, in which the function of SIRT1 has been intensively investigated. Our studies open up the possibility of using sirtuin activators as potential pharmaceutical interventions for other diseases of aging. Understanding how sirtuins regulate various biological pathways at the molecular level will provide the basis for testing the drugs.