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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FULL STORY
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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
==========================================================================

Link to news story:
https://www.sciencedaily.com/releases/2023/07/230710113857.htm

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