Sean Curran, PhD, on the molecular genetics of longevity and the potential for clinical translation

Dr. Sean Curran’s research focuses on defining the molecular mechanisms utilized by novel homeostatic pathways, which influence animal physiology, metabolism, and ultimately lifespan. His research group utilizes a multidisciplinary approach that combines genetics, functional genomics, biochemistry, cell and molecular biology, and physiology. The ultimate goal of his research is to understand the molecules, genes, and cells that impact health over the lifespan, with his findings positioned to impact the development of therapies to reduce the prevalence and progression of multiple types of human disease that occur with age like cancer diabetes, obesity, and frailty.

We recently caught up with Dr. Curran to learn more about how AFAR has support this research career and the novel research he will discuss during his Cristofalo Award Lecture titled “Diet-based strategies, informed by genetics, to improve healthspan,” at The Gerontological Society of America’s 2020 Annual Scientific Meeting Online on November 5, 2:45-3:30 pm ET.

AFAR is proud to have awarded you at various points in your career, including the 2009 Diana Jacob Kalman/AFAR Research in Biology of Aging and your 2013 Glenn Foundation for Medical Research and AFAR Grant for Junior Faculty awards. How have these awards contributed to the research that you will present in your upcoming presentation at the GSA Annual Scientific Meeting Online?

I am grateful for the continued support I have received from AFAR. Funding received when I was first starting up my independent research group enabled me to acquire preliminary data that drove the successful acquisition of federal funding. Moreover, this early support allowed me to explore new ideas and research directions, which have laid a strong foundation for my research group.

Our early work on SKN-1 looked for genetic mutations that led to constant activation of this cytoprotective transcription factor. Remarkably, although these mutants were able to withstand acute exposures to oxidative stress, we found that constitutive activation resulted in shortened lifespan and diminished health. This told us that turning off transcriptional responses in a timely manner is perhaps just as important as turning them on.

Since this initial discovery, we have determined that physiological responses to SKN-1 activation in worms and Nrf2 activation in mammals, are tied to the organisms’ capacity to alter metabolism to meet current needs. Surprisingly, we found that we mask the impact of these genetic mutations that activate SKN-1 by simply changing the diet we feed to these animals. These diet-gene pairs, or genes that are only essential on certain diets, are critical to our understanding of how genetics impact overall health, particularly through what we eat.

How has your work on diet-gene pairs informed clinician's ability to prescribe a personalized diet?

This is still a new idea, but we suspect there are hundreds (if not thousands) of diet gene pairs in humans. Diet is perhaps one of the most variable factors that can impact health and these diet gene pairs might explain why one person will respond positively to a particular diet while another individual does not. As we continue to map these diet-gene pairs our ability to model what foods are healthy, benign, or disease-promoting for each person will become more sophisticated and we will move toward a period when clinicians will prescribe personalized diets for health just as they might prescribe dietary interventions for diabetes, cardiovascular disease and other age-related conditions.

You discovered approximately 60 highly conserved genes involved in development. How do these genes impact lifespan?

When I first entered geroscience research as a post-doctoral fellow, high-thourghput RNAi screens were a popular approach to study the genetics of aging. What was missing at the time was a study of how genes that are important for development could impact adult aging. Because RNAi can be initiated at any point over the lifespan, I allowed animals to develop normally into reproductive adults and then initiated the inactivation of all known genes that are important for early development. This led to the discovery of 60+ genes that when inactivated only in adulthood could significantly increase adult lifespan. Several of these gene inactiavtions results in the stimulation SKN-1 activity, which is how I became interested in studying this cytoprotective transcription factor.

What are important metrics, beyond lifespan, that you consider in your research on the molecular genetics of longevity?

Metabolic health is an important criterion to measure in any longitudinal study. Although several studies have noted the importance of lipid and fat levels, our work has noted that in addition to the quantitative measurement of total lipid level, the distribution of lipids is also important. In all conditions that we have studied where SKN-1 is activated (genetic mutants, dietary interventions, exposure to certain stressors), lipids are relocated from the somatic tissues to the germline. Although this reallocation drives reproductive output, the loss of somatic lipids impairs stress adaptations and diminishes overall lifespan. In obese individuals, the accumulation of fat in distinct areas can influence health outcomes, our studies suggest a molecular mechanism that can drive differential lipid storage between tissues, which is a byproduct of homeostatic responses to stress.

Has COVID-19 impacted your laboratory's focus or activity? If so, how?

It has! We recently reported that the redistribution of lipids when SKN-1 is activated is due to a perceived infection of the organism by bacterial pathogens. By dampening this pathogen response we could alleviate several of the metabolic consequences of SKN-1 activation. In light of this response to bacterial pathogens we are now investigating whether activation of innate immunity pathways by viruses evoke similar metabolic changes. With regard to COVID-19, we are testing if exposure to the SARS-coV-2 spike protein, in our worm and cultured cell models activates SKN-1/NRF2 and how that alters cellular metabolism. Because COVID-19 impact older adults more than younger populations we predict an age-related response in both of these models.