Researchers develop a compound that blocks the production of free radicals in the mitochondria

In 1956, Denham Harman suggested that aging results from the accumulation of oxidative damage to cells, and that this damage is caused by free radicals that were produced during aerobic respiration. [1]. Free radicals are unstable atomWhich have a non-paired electron, which means that free radicals are constantly looking for an atom that has an electron that it can squeeze into to fill the space. This makes them very reactive, and when they steal atoms from your body’s cells, it’s very harmful.

Longevity Technology: In addition to being generated in the normal metabolism of cells, free radicals can be obtained from external sources (pollution, cigarette smoke, radiation, drugs, etc.) While the free radical theory of aging has been highly debated [2]Understanding the danger posed by free radicals increased the public’s interest in superfoods, vitamins and minerals that were antioxidants—substances with a spare electron they would be happy to give up to pass free radicals, thus removing them from the danger equation.

But before you get to the blueberries, it’s important to know that the story, as it often is in biology, isn’t black and white. Like a misunderstood cartoon villain, free radicals also have a beneficial side – albeit in moderation. Free radicals generated by cell mitochondria are useful in wound healing, and others act as important signaling substances. Free radicals are used as weapons by the body’s defense system, destroying invading disease-causing microbes to prevent disease.

Cells need a certain basic level of control from free radicals because they are signaling molecules, activating protective pathways. So if they are all flushed with antioxidants, the natural, protective and homeostatic role of radicals in the cell is also removed.

The yin-and-yang nature of free radicals is why subtlety is key—and now researchers at the Buck Institute for Aging Research and Calico Laboratories have come up with a new way to deal with them: Instead of flushing them out with antioxidants, take a pill that selectively prevents them from being produced in the first place. .

Researchers have found that they can specifically block the production of free radicals in mitochondria, the powerhouses of our cells, which, when they become dysfunctional with age or damage, begin to decrease cellular energy production and increase free radical production.

Posted in Free Radical Biology and MedicineIn this study, the researchers showed that specifically inhibiting the production of free radicals in a specific mitochondrial site prevents and treats metabolic syndrome in mice by preventing and reversing insulin dependence. [3].

“We believe that mitochondrial radical production leads to many chronic diseases of aging, and that blocking free radical production is an effective disease-fighting and anti-aging treatment,” said Martin Brand, PhD, Buck Professor Emeritus and lead investigator on 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 corks in a wine bottle. They plug a specific site so that free radicals aren’t produced, without impeding the critical function of the mitochondria in energy metabolism. We We look forward to continuing this pioneering area of ​​research.”

The bioavailable compound developed, S1QEL1.719 (“New S1QEL” – IQ Electron Leak Site Blocker), was administered preventively and therapeutically to mice fed a high-fat diet causing metabolic syndrome. The treatment reduces fat accumulation, strongly protects against decreased glucose tolerance and prevents or reverses the increase in fasting insulin levels by protecting against the development of insulin resistance.

Today, Mitochondria Complex I; Tomorrow the world

S1QEL1 acts on IQ in situ in mitochondrial complex I (The mitochondrial electron transport chain consists of four protein complexes embedded in the inner mitochondrial membrane. Together, they carry out a multistep process by which cells derive 90% of their energy.)

The current literature strongly implicates compound I in a number of different diseases, from metabolic syndrome to Alzheimer’s disease, fatty liver disease, and noise-induced hearing loss, as well as to the underlying aging process itself, says first author and Buck team scientist Mark Watson, PhD.

“S1QELs do not scavenge oxidants or radicals. Instead, they specifically inhibit radical production at the IQ site in complex I without interfering with the other sites,” Watson said. “So the normal redox signaling that we need in our cells will continue. S1QELs only modify that site. They are very clean, very specific and don’t disrupt mitochondria like mitochondrial inhibitors do.”

Brand says the data shows that the production of free radicals from compound 1 is a primary driver of insulin resistance and metabolic syndrome, a major disease related to poor lifestyle choices and aging. He says this feature is a strong reason to reconsider the mitochondrial theory of aging.

“These compounds regulate mitochondrial production of free radicals,” he said. “And this is really interesting; just inhibiting this specific site improves the whole redox environment and prevents metabolic disease, which is amazing.”

[1] https://escholarship.org/content/qt3w86c4g7/qt3w86c4g7.pdf
[2] https://www.sciencedirect.com/science/article/abs/pii/S0531556505002032
[3] https://www.sciencedirect.com/science/article/pii/S0891584923004458

Feature image: Julee Ashmead/Vecteezy.
Additional images: Buck Institute for Research on Aging