New Approach to Free Radicals Holds Promise for Treating Metabolic Syndrome

In the 1970s, the use of antioxidants to combat free radicals was popular, with people taking high doses of various general antioxidants in the hopes of countering the effects of aging and preventing chronic diseases.

However, this approach proved ineffective and even harmful, as untargeted antioxidants disrupted important cellular signaling pathways. As a result, research in this area waned, and mitochondrial theories of disease and aging lost favor.

But now, scientists at the Buck Institute for Research on Aging offer a fresh perspective on dealing with free radicals. Instead of trying to mop them up, they have developed a pill that selectively prevents the production of free radicals in the first place. Collaborating with Calico Labs, the team recently published a study in the journal Free Radical Biology and Medicine, demonstrating that inhibiting free radical production at a specific site in mitochondria can prevent and treat metabolic syndrome in mice, including the reversal of insulin resistance.

“We believe that mitochondrial radical production underlies many chronic aging-related diseases, and blocking the generation of free radicals can serve as a viable intervention for disease treatment and anti-aging,” explains Martin Brand, Ph.D., Buck Professor Emeritus and senior investigator of the study. “We have found a way to selectively control problematic free radicals without compromising the mitochondria’s essential function of energy metabolism. These compounds act like corks in a wine bottle, plugging a specific site to prevent the production of free radicals while allowing the mitochondria to perform their critical energy-related tasks. We are excited to continue this groundbreaking research.”

The compound developed in the study, S1QEL1.719 (a new “S1QEL” or Suppressor of site IQ Electron Leak), was administered both prophylactically and therapeutically to mice fed a high-fat diet that induces metabolic syndrome. The treatment resulted in decreased fat accumulation, strong protection against decreased glucose tolerance, and prevention or reversal of increased fasting insulin levels by safeguarding against the development of insulin resistance.

The action of S1QEL1s specifically targets site IQ in mitochondrial complex I. This complex plays a significant role in various diseases, including metabolic syndrome, Alzheimer’s, fatty liver disease, noise-induced hearing loss, and the aging process itself. According to Mark Watson, Ph.D., first author and Buck staff scientist, S1QELs do not sequester oxidants or radicals but instead selectively inhibit radical production at the IQ site, while leaving other sites unaffected. This means that essential redox signaling in cells continues uninterrupted, as S1QELs solely modulate the targeted site without disrupting overall mitochondrial function like traditional mitochondrial inhibitors.

Brand emphasizes that the data reveals free radical production from complex I as a crucial driver of insulin resistance and metabolic syndrome, both linked to poor lifestyle choices and aging. These findings provide a compelling reason to revisit the mitochondrial theory of aging. “These compounds fine-tune the mitochondrial production of free radicals,” Brand explains. “Interestingly, inhibiting this specific site not only improves the overall redox environment but also prevents metabolic disease, which is truly remarkable.”

The study involved additional Buck researchers, including Harmanmeet Brar, Edwin T. Gibbs II, Hoi-Shan Wong, and Pratiksha A. Dighe. Collaborators from AbbVie, such as Bryan McKibben, Stephan Riedmaier, Amy Siu, James S. Polakowski, Jason A. Segreti, Xiaoquin Liu, Seung Won Chung, Y. Marina Pliushchev, Nathan Gesmundo, Zhi Wang, and Timothy A. Vortherms, also contributed to the research.

The research received support from Calico Life Sciences, LLC, located in South San Francisco, CA.

Citation: Suppression of superoxide/hydrogen peroxide production at mitochondrial site IQ decreases fat accumulation, improves glucose tolerance, and normalizes fasting insulin concentration in mice fed a high-fat diet. DOI: https://doi.org/10.1016/j.freeradbiomed.2023.05.022