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SkQ1: A mitochondrially targeted antioxidant that extends lifespan

Mitochondria produce reactive oxygen species (ROS) as a byproduct of metabolism. These ROS are implicated in the mitochondrial free radical theory of aging (MFRTA) as the major cause of aging phenotypes. If the MFRTA is true, one could delay aging by removing these mitochondrially-produced ROS with enzymes or antioxidants. Although many antioxidant therapies for cancer and other age-related diseases have proved fruitless, these studies did not specifically target antioxidants to the mitochondria. One group recently did just that in mice with catalase, an antioxidant enzyme normally found in peroxisomes. By translocating catalase to the mitochondria, the scientists expanded the lifespan of the animals by five months.

Such genetic manipulations such as these are not in the cards when it comes to preventing human aging. Therefore, other mitochondrial targeting strategies must be employed. Accordingly, Vladamir Skulachev’s group synthesized an antioxidant attached to a positively charged ion, which they call SkQ1. This compound can readily pass through the cell membrane and travel to the mitochondrial intermembrane space, the only negatively charged region in the cell. There, SkQ1 will soak up any ROS formed by the electron transport chain. SkQ1 works similarly to the popular MitoQ, but does not have the pro-oxidant properties MitoQ is known to have at higher concentrations. SkQ1 is also better than MitoQ at inhibiting apoptosis induced by hydrogen peroxide. Studies by the group also showed that SkQ1 proved beneficial for heart and cardiovascular disease , tumor growth, and cataracts .

Anisimov et al found that SkQ1 increases the lifespan of several species of animals. The median and maximum lifespan of the fungus P. anserina was significantly increased with treatment of SkQ1. In the crustacean C. affins, the mean lifespan of SkQ1-treated animals was doubled compared to controls. In Drosophila, SkQ1 treatment significantly increased median lifespan in both males and females. Additionally, the researchers investigated the timing of SkQ1 treatment using Drosophila. Flies treated with SkQ1 during only their first week of life had the same survival curve as flies treated throughout their lives. There was no effect on survival in flies treated with SkQ1 for one week starting at 30 days of age, but, for flies treated constantly from 30 days of age, there was a reversion to the lifespan curve of flies treated constantly from day one. These results are reminiscent of Michael Rose’s experiments on the timing of calorie restriction in Drosophila.

In mice, the optimal dose of SkQ1 increased median lifespan by about 90%, with a maximum lifespan for both control and treated mice between 800- 850 days. It would be interesting to see if the mouse strain they used or husbandry conditions had any effect on the results, as a 800 days is an entire year shorter than the reported maximum lifespan for mice.

SkQ1 treatment had its largest effect on preventing death from non-cancerous diseases, with SkQ1-treated mice actually having a higher incidence of a certain kind of cancer, mammary gland adenocarcinoma. This might have to do with the fact that SkQ1 prevents the disappearance of estrus in female mice. Finally, fibroblasts treated with SkQ1 were more resistant than controls to hydrogen peroxide treatment, and expressed almost no β-galactosidase activity, a marker of senescence.

Notably, SkQ1 treatment is the only anti-aging treatment other than calorie restriction that has been shown to be effective across such a wide range of species. These results suggest that SkQ1 or other methods of chemical targeting of antioxidants to mitochondria hold promise as a novel means of intervening in the aging process.

(For more on SkQ1, see the coverage at Longevity Meme.)

11 comments

  2. For the uninitiated, the “Sk+” ions are triphenylphosphonium ions (TPP+), i.e. exactly the same functional group as Murphy used on MitoQ. Skulachev has long held the view that he should be credited for the discovery of this method of drug delivery to mito’s. Arguably he did get there first, with a paper in the 70’s using methyl-TPP+ to measure mito’ membrane potential, but then it took another 25 years for Murphy to come along and tack a useful cargo onto the TPP+ moiety (an antioxidant). Thus, the old adage that “you can’t own an idea if you don’t follow through on it” applies. Throughout much of the ’90s, Skulachev tried to slam Murphy’s compounds, talking up their toxicity. Funny that now he’s come up with his own version (SK stands for Skulachev), he’s happy to join the bandwagon.

    His rationale for the Q derivative on SkQ is quite interesting… the logic goes that plants are exposed to a much higher level of oxidative stress (because they make oxygen), so their antioxidants will be “better”. Thus he chose plastoquinone instead of ubiquinone. The latter is in mito’s, which consume oxygen and thus will be subject to less oxidative stress.

    The Murphy/Skulachev saga will be interesting to watch as these compounds get further into the clinical trials process.

  3. Thanks very much for the background, Virgil.

    On a related note: Chargaff (who discovered the A:T and C:G equivalencies in DNA but didn’t follow the trail to base-pairing) was similarly bitter about the people who did follow through, Watson and Crick. He famously said:

    “That in our day such pygmies throw such giant shadows only shows how late in the day it has become.”

  5. This work by Vladamir Skulachev’s group and others is fascinating. So encouraging to read the results suggest that SkQ1 or other methods of chemical targeting of antioxidants to mitochondria hold promise as a novel means of intervening in the aging process since I am 71.

  7. These results are trully interesting! Makes me wander why they haven’t been published in a “better” journal… Is the choice of a russian journal just nationalism or are those results can be contested in a way that i haven’t noticed?

  8. Yeah, too bad the russians are 55 years too late! Romanian dr.academician(the generals of scientists), Ana Aslan discovered someting called GH3 or Gerovital over 55 years ago and thousands of movie stars, heads of state and millions of regualar people have benefited from it! Stalone is 64, you know why he looks so good? 3 trips a year to romanian clinics for treatment or taking pills and injections! And so millions of others! FDA with the help of big Med money, has been trying to ban it in US ever since!! But you can buy it in Mexico and anywhere in the world! Just google it for Gods sake, and stop fawning over the russians so much for over 60 years!
    By the way, Dr Aslan died at ..92, no wrinkles, no gray hair, using her own product! She broke her hip and never recovered, otherwise…

    You already getting that antioxidants benefit if you eat the proper fruits and vegies(google it) and stop eating crap! a pill will not give any extra benefit, as the reaserch showed about vitamins! they actually can harm you!! Dr Aslan changed all that from a simple vitamin B, called paba! Check it out!! Even insuline was invented by a romanian dr, and many more other things and Im tired of the russians to get so much credit for nothing! Americans, germans, french, etc are doing this antioxidant research for as long as the russian! same conclusion!

    To Francois: By the way, you’re right, they would not publish my comment or anything negative!! its called RT!

  11. I’d like to know that myself. More on the chemical structure is available in Wikipedia’s plastoquinone article (SkQ1 is plastoquinonyl-decyl-triphenylphosphonium). I can’t find a commercial source. Skulachev and co-workers may be making it themselves.

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