Researchers develop compound that prevents free radical production in mitochondria

Buck Scientists develop specific, bioavailable compound that prevents and treats metabolic syndrome in mice – and they’ve put it in a pill.

Back in 1956, Denham Harman proposed that the aging is caused by the build up of oxidative damage to cells, and that this damage is caused by free radicals which have been produced during aerobic respiration [1]. Free radicals are unstable atoms that have an unpaired electron, meaning a free radical is constantly on the look-out for an atom that has an electron it can pinch to fill the space. This makes them highly reactive, and when they steal atoms from your body’s cells, it is very damaging.

Longevity.Technology: As well as being generated in normal cell metabolism, free radicals can be acquired from external sources (pollution, cigarette smoke, radiation, medication, &c) and while the free radical theory of aging has been the subject of much debate [2], the understanding of the danger free radicals pose led to an increase in the public’s interest in superfoods, vitamins and minerals that were antioxidants – substances that have a spare electron which they are happy to give away to passing free radicals, thus removing them from the danger equation.

But before you reach for the blueberries, it is important to know that, as so often in biology, the story is not black and white. Like a misunderstood cartoon villain, free radicals have a beneficial side, too – albeit in moderation.  Free radicals generated by the cell’s mitochondria are beneficial in wound-healing, and others elsewhere act as important signal substances. Used as weapons by the body’s defense system, free radicals destroy invading pathogenic microbes to prevent disease.

Cells need a certain basal, control level of free radicals because they are molecules that signal, they activate protective pathways. So if they are all scavenged by antioxidants, the normal, protective, homeostasis-governing role of radicals in a cell is removed, too.

This yin and yang nature of free radicals is why precision is key – and now researchers at the Buck Institute for Research on Aging and Calico Labs have come up with a new way to deal with them: rather than mop them up with antioxidants, take a pill that selectively keeps them from being produced in the first place.

The researchers found they can specifically block free radical production in mitochondria, the powerhouses of our cells, which as they become dysfunctional with age or damage, begin to dial down the production of cellular energy and dial up the production of free radicals.

Publishing in Free Radical Biology and Medicine, the researchers show that specifically inhibiting free radical production at a particular mitochondrial site prevents and treats metabolic syndrome in mice by preventing and reversing insulin dependence [3].

“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, PhD, Buck Professor Emeritus and senior investigator of the study.

Researchers develop compound that prevents free radical production in mitochondria
Martin Brand, PhD, 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.

Today, mitochondrial complex I; tomorrow, the world

S1QEL1s act on site IQ in 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 through which cells derive 90% of their energy.)

First author and Buck staff scientist Mark Watson, PhD, 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.

Researchers develop compound that prevents free radical production in mitochondria
Mark Watson, PhD, First author and Buck staff scientist

“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.”


Main photograph: Julee Ashmead/Vecteezy.
Additional images: Buck Institute for Research on Aging