Associate Director, Center for Genomic Medicine, MGH
Associate Director, Boston Area Diabetes Endocrinology Research Center
Director, Metabolic Phenotyping Core, Nutrition Obesity Research Center of Harvard
Department of Medicine / Endocrine Division / Diabetes Unit
The Soukas Lab studies the genetic basis of aging, longevity, obesity and diabetes.
Aging is the single, greatest contributor to nearly every disease and condition that affects us after our youth. Diabetes, obesity, heart disease, stroke, cancer, osteoporosis, and dementia are all diseases of aging. In the Soukas Laboratory, we endeavor to figure out how things go wrong in the cells of the body in aging, and more excitingly, how to fix what goes wrong. Our findings have the ability to impact not one, but nearly every disease that impacts humankind. We have the major goal of identifying molecular “switches” that can be thrown to turn back the clock on the aging process, promoting healthy aging and staving off aging-associated diseases.
1. Promoting Healthy Aging with Metformin.
Metformin is the most commonly used medication for type 2 diabetes worldwide. In recent years, it has become clear that metformin also has anti-cancer properties and can prolong lifespan of humans and model organisms such as mice and C. elegans.
The Soukas Lab is exploring the biological mechanisms of how metformin has these beneficial effects. We published in Cell that metformin effects at mitochondria lead to alterations in nuclear transport, restricting nuclear access of the mTOR complex 1 activating protein RagC. When RagC is excluded from the nucleus, mTORC1 is inactivated, turning on the gene ACAD10, inhibiting cancer growth, and prolonging lifespan. Remarkably, this pathway is conserved from C. elegans to human.
The Soukas Lab continues to explore the health benefits of metformin and the mechanisms by which metformin blocks cancer growth, prevents certain cancers, increases health as organisms age, and lowers blood glucose in type 2 diabetes.
2. Mitochondria Spring a “Leak” in Aging.
Activation of autophagy, the process by which cells clear defective organelles and molecules, is required in almost every genetic, dietary, and pharmacologic manipulation that extends lifespan. However, elevated levels of autophagy under certain circumstances can also have negative effects. Our work demonstrates that mitochondrial permeability, or “leakiness” in our cells’ powerhouse, determines whether the effects of autophagy on health and longevity will be positive or negative. Remarkably, in every case tested, the longevity benefit of autophagy was reversed by triggering increased mitochondrial permeability (“leakiness”). Even in mammals, elevated autophagy causes greater tissue damage during ischemia-reperfusion injury when mitochondrial permeability is high. We put forth the idea that it is not autophagy levels per se rather the cellular context in which autophagy is activated that is the critical determinant of whether autophagy is beneficial versus detrimental. This work was published in Cell in April 2019. You can link to the paper by clicking here.
We continue to work on the processes that govern mitochondrial permeability and the consequences of mitochondrial permeability in aging. New evidence suggests that certain prolongevity paradigms extend lifespan by shutting down mitochondrial permeability. By deducing the mechanisms by which this occurs, we can put forth new strategies to promote healthy aging in humans.
3. Personalized Medicine for Obesity and its Complications.
Obesity is an epidemic public health problem in industrialized nations and developing nations alike. According to the World Health Organization (WHO), at present 1.9 billion people are overweight worldwide, and greater than 650 million are obese. Any rise above ideal body weight is associated with an increase in the risk of death from any cause, especially atherosclerotic cardiovascular disease and cancer. Thus the prevalence of obesity threatens poor health and early death of a group of epic proportions. The amount of body fat mass humans store is heavily determined by genetics. As such, understanding the human genes that govern energy balance is of the utmost importance to develop the next generation of therapies for obesity and to reduce the impact of its associated conditions such as heart disease, stroke, diabetes, and cancer.
We are collaborating with the Claussnitzer Lab at CGM and the MGH Weight Center to put forth a new paradigm of personalized medicine in obesity prevention and treatment. The bedrock of this program is elucidation of human genetic variation that predicts risk for obesity progression and its complications. Future versions of this effort will include use of personalized genetic information to guide therapy for obesity and its complications.