New roles for old lipids – sphingolipidome in aging and disease

Abstract: Lipids are particularly known for their role in cardiovascular disease as causative agents and useful biomarkers. In addition to circulating lipids in the blood, the role of intracellular lipids participating in cellular signaling presents as an emerging field. Sphingolipids are best known as blood biomarkers in cardiovascular disease. Here, we discover a new role for sphingolipids in severe skeletal muscle diseases, and we extend our findings to skeletal muscle aging. We show that sphingolipid accumulation disrupts cellular protein homeostasis through mitochondrial signaling, leading to dysfunctional and gerastenic muscles and stem cell function. Therapeutic interventions blocking sphingolipid biosynthesis improve age-related fitness in aged mice, and alleviate symptoms associated with muscular dystrophies. Using genetically homogenous aging cohorts from Finland, and diverse cohorts from the UK biobank, we demonstrate that genetic variants associated with reduced sphingolipid synthesis are also associated with improved age-related fitness in humans. In summary, our research identifies novel role for sphingolipids in aging and disease, and reinforces the concept of bioactive lipids in cellular physiology, independent of circulating blood lipids.

Speaker Bio: Pirkka-Pekka Laurila, MD, received his PhD from the University of Helsinki, Finland in the laboratory of Leena Peltonen-Palotie, on genome-wide studies on lipid levels and identification of USF1 as a novel transcription factor regulating brown adipose tissue activity. He studied aging at the laboratory of Johan Auwerx in Switzerland, identifying sphingolipid metabolism as a key pathway in the pathogenesis of muscle diseases and aging. Currently, he works as a research scientist and attending physician at the lipid clinic of Helsinki University Central Hospital, finalizing his specialty in internal medicine. He has received young investigator awards from the American Heart Association, European Atherosclerosis Society, and International Atherosclerosis Society, and can be reached at pplaurila@gmail.com