Chemical Biology of Aging
Aging is a natural phenomenon that all living organisms are predisposed to. Since many pathological conditions including neurological disorders and cancer can be thought of as forms of premature aging, uncovering the mechanistic underpinnings of this multifaceted process can lead to new treatments, as well as a means for healthier living.
Reactive aldehyde species (e.g., formaldehyde, 4-HNE, MDA) are at the center of our investigations because they can induce epigenetic modifications, damage biomolecules via crosslinking events and adduct formation, and trigger chronic inflammatory states. We hypothesize these deleterious changes can lead to the decline of stem cell functionality which compromises our body's ability to replenish damaged or aged cells. To study aldehydes in this context, we have developed a plethora of new chemical biology tools and established bioanalytical assays. Representative examples include FP1, an imaging probe to detect formaldehyde in live cells (JACS 2015), fluorogenic substrates (Green-AlDeSense™) to monitor the activity of aldehyde processing enzymes (ACS Cent Sci 2018), and light-activatable aldehyde donors like photoFAD-3 and the corresponding assays to quantify their release (JACS 2020). Current research is focused on employing these tools in animal models of aging and to expand our chemical toolbox to investigate other aldehyde targets.
We are also interested in determining how mediators of the inflammatory response (e.g., Cox-2, nitric oxide) can drive aging and the progression of diseases such as cancer. Of note, in addition to the tools we develop in-house, we also utilize a broad range of chemical biology techniques for these projects. Our work has lead to the development of the CoxFluor™ assay, which features an isoform-selective probe for Cox-2, has allowed us to discover a dependency on oxygenation for enzyme activity (Angew Chem 2020). Moreover, we have developed a series of photoacoustic imaging probes to detect nitric oxide in vivo (JACS 2018, Chem Sci 2020, JACS 2021), as well as BL660-NO, a highly sensitive bioluminescent nitric oxide sensor (ChemRxiv 2021). Using BL660-NO, we revealed that high-fat diets promote breast cancer growth by establishing an inflammatory tissue microenvironment where nitric oxide production is elevated due to the recruitment of tumor associated macrophages and the overexpression of iNOS. Our current work is focused on examining the crosstalk between inflammation and the aberrant production of aldehydes.
Researchers working on projects in the 'Chemical Biology of Aging' area will learn synthetic chemistry, cell culturing techniques, genetic manipulation, proteomics, molecular imaging, and animal work.