MSGID: 1:317/3 64acdaf7   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
   production in mitochondria prevents and treats metabolic syndrome in mice   
    A potential therapeutic for one of the major chronic diseases of aging   
      
      
     Date:   
         July 10, 2023   
     Source:   
         Buck Institute for Research on Aging   
     Summary:   
         The free radical theory of aging is back in play after falling   
         out of favor decades ago. (Remember when people were taking   
         massive doses of various vitamins and minerals? Mopping up free   
         radicals with antioxidants compromised beneficial metabolic   
         signaling pathways leading to bad side effects). What brings the   
         theory back? Researchers at the Buck discovered that they could   
         specifically block free radical production in mitochondria. An   
         elegant solution replaces an indiscriminate and messy mop up. These   
         scientists developed a bioavailable compound -- available in a pill   
         form -- that blocks free radical production. The compound both   
         prevented and treated metabolic syndrome in mice. 'We think that   
         mitochondrial radical production drives many chronic diseases of   
         aging, and that blocking the production of free radicals is a viable   
         disease- treating and anti-aging intervention,' said Martin Brand,   
         Ph.D., Buck Professor Emeritus and senior investigator of the study.   
      
      
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   Mopping up free radicals with antioxidants was the rage in the 1970's;   
   people were taking large, sometimes massive doses of various general   
   antioxidants, including vitamins and minerals, to try to remove harmful   
   byproducts of energy metabolism. The method was supposed to blunt the   
   effects of aging and stave off chronic disease. The strategy didn't work,   
   and in some cases, it caused harm because untargeted antioxidants also   
   compromised beneficial cellular signaling pathways. Over time, this area   
   of research went on the shelf as mitochondrial theories of disease and   
   aging fell into disfavor.   
      
   But research at the Buck offers a new way to deal with free radicals:   
   rather than mop them up, take a pill that selectively keeps them from   
   being produced in the first place. Building on this work, collaborative   
   research between the Buck and Calico Labs, recently published in Free   
   Radical Biology and Medicine shows that specifically inhibiting free   
   radical production at a particular mitochondrial site prevents and   
   treats metabolic syndrome in mice, by preventing and reversing insulin   
   resistance.   
      
   "We think that mitochondrial radical production drives many chronic   
   diseases of aging, and that blocking the production of free radicals   
   is a viable disease- treating and anti-aging intervention," said   
   Martin Brand, Ph.D., Buck Professor Emeritus and senior investigator   
   of the study. "We've found a way to selectively keep problematic free   
   radicals in check without compromising normal energy production in the   
   mitochondria. These compounds act like a cork in a wine bottle. They   
   plug a specific site so that it doesn't produce free radicals, without   
   hindering the mitochondria's critical function of energy metabolism. We   
   look forward to continuing this groundbreaking area of research."   
   The orally bioavailable compound that has been developed, S1QEL1.719   
   (a new "S1QEL" -- Suppressor of site IQ Electron Leak), was given   
   both prophylactically and therapeutically to mice fed a high-fat diet   
   that causes metabolic syndrome. Treatment decreased fat accumulation,   
   strongly protected against decreased glucose tolerance and prevented or   
   reversed the increase in fasting insulin levels by protecting against   
   the development of insulin resistance.   
      
   Acting on mitochondrial complex I highlights potential interventions for   
   other conditions S1QEL1s act on site IQin mitochondrial complex I. (The   
   mitochondrial electron transport chain consists of four protein complexes   
   integrated into the inner mitochondrial membrane. Together they carry   
   out a multi-step process, oxidative phosphorylation, through which cells   
   derive 90% of their energy.)  First author and Buck staff scientist Mark   
   Watson, Ph.D., says current literature strongly implicates complex I in   
   a number of different diseases, from metabolic syndrome to Alzheimer's,   
   fatty liver disease, and noise-induced hearing loss, as well as the   
   underlying aging process itself.   
      
   "S1QELs don't sequester oxidants or radicals. Rather, they specifically   
   inhibit radical production at the IQ site on complex I without interfering   
   with other sites," Watson said. "So the normal redox signaling that   
   we require in our cells will continue. S1QELs just modulate that one   
   site. They are very clean, very specific, and do not disrupt mitochondrial   
   functioning like inhibitors of mitochondria do."  Brand says the data   
   shows that free radical production from complex I is an essential driver   
   of insulin resistance and metabolic syndrome, a major disease of poor   
   lifestyle choices and of aging. He says this feature is a strong reason   
   to revisit the mitochondrial theory of aging. "These compounds fine-tune   
   mitochondrial production of free radicals," he said. "And it's really   
   interesting; just inhibiting this specific site improves the whole redox   
   environment and prevents metabolic disease, and that is amazing."   
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   Journal Reference:   
      1. Mark A. Watson, Harmanmeet Brar, Edwin T. Gibbs, Hoi-Shan Wong,   
      Pratiksha   
         A. Dighe, Bryan McKibben, Stephan Riedmaier, Amy Siu, James S.   
      
         Polakowski, Jason A. Segreti, Xiaoqin Liu, SeungWon Chung, Y. Marina   
         Pliushchev, Nathan Gesmundo, Zhi Wang, Timothy A. Vortherms,   
         Martin D.   
      
         Brand. 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. Free Radical Biology and Medicine,   
         2023; 204: 276 DOI: 10.1016/j.freeradbiomed.2023.05.022   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/07/230710113857.htm   
      
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