I am interested in understanding the molecular basis of aging. Individual age is the primary risk factor for the majority of the top causes of death in the United States and other developed nations. As our population grows older, aging is increasingly a central problem for both individual quality of life and the economics of societal health. Understanding the molecular architecture that drives aging will reveal key intervention points to extend healthy human lifespan, simultaneously delay onset of multiple categories of age-associated disease, and develop targeted treatments for specific pathologies. In the Sutphin Lab, we use a combination of systems biology, comparative genetics, and molecular physiology to understand the molecular processes that underlie aging and drive age-associated disease.
Comparative Genetics of Aging
Virtually every cell and tissue type displays functional decline as we age. The aging process, in turn, is influenced by a wide range of molecular and physiological processes. Determining the range of genes and molecular processes that are capable of influencing aging and understanding how they interact in the context of an aging organism is an important step to identifying key intervention points to treat age-associated disease. To this end, a primary goal of our laboratory is to identify and characterize novel genetic determinants of longevity.
We use a combination of systems and comparative genetics to study evolutionarily conserved mechanisms of aging, leveraging the unique strengths of three model organisms: humans (Homo sapiens), mice (Mus musculus), and nematodes (Caenorhabditis elegans). We employ an experimental pipeline that (1) applies systems genetics to select candidate aging gene sets in humans and mice, (2) employs longevity screening in worms to select the subset of genes capable of directly affecting longevity or other age-associated phenotypes, and (3) uses molecular tools in worms and mice to characterize selected genes and build mechanistic models describing their interaction with aging. Ultimately, we will use these models to identify molecular targets to treat age-associated disease.
Targeting Kynurenine Metabolism in Age-Associated Disease
The first molecular process identified in our comparative genetics pipeline was the kynurenine pathway. The kynurenine pathway is the primary metabolic destination for ingested tryptophan and has been linked to multiple age-related pathologies, including neurodegeneration, kidney disease, and cardiovascular disease. In C. elegans, inhibiting multiple kynurenine pathway enzymes extends lifespan and improves healthspan. In ongoing work, we are using C. elegans to determine which of several kynurenine-associated molecular processes—oxidative stress, proteostasis, neuroreceptors regulation, NAD synthesis—mediates the observed effect on lifespan. We are also validating our C. elegans observations in mice by manipulating kynurenine enzymes and measuring lifespan and other age-associated phenotypes. We are particularly interested in the efficacy of kynurenine-based interventions at specifically treating cardiovascular, renal, and neurodegenerative disease.
Environmental Influences on Aging
Our environment has a profound impact on how long we live and how healthy we are as we age. Our individual genetic make-up substantively effects how our bodies respond to different environmental factors, such as temperature, stress, or diet. These interactions are important when considering individual risk factors and in designing personalized clinical strategies to treat disease. We are interested in understanding this interaction between genes and environment.
In C. elegans, temperature is a primary environmental determinant of longevity. Worms maintained at 15°C live nearly twice as long on average as worms at maintained at 25°C. Manipulating specific molecular processes, including many of the most commonly studied processes in aging—mTOR signaling, insulin signaling, the hypoxic response, sirtuins—affects longevity and healthspan differently when worms are maintained at different temperatures. In the most severe cases, an intervention will extend lifespan at one temperature and shorten lifespan at another temperature. We are working to define the range of genes that display an interaction with environmental temperature and identify the key molecular processes that regulate the molecular and cellular response to temperature in the context of aging.