35 replies to this topic

[eldras]

"5) SkQ, a Mitochondrially Targeted Ingested Antioxidant

A Russian researcher has demonstrated a form of antioxidant that can be targeted to the mitochondria even though ingested. Per the mitochondrial free radical theory of aging, anything that can reduce the damage mitochondria do to themselves via the free radicals they generate in the course of their operation should extend life span. Indeed, SkQ seems to boost mouse life span by about 30%:"

from:

http://nextbigfuture...y-progress.html

[niner]

I'd guess one problem is that since these are synthetic chemicals not found in nature, they don't fall under the usual supplement rules. It's still kind of curious why nobody sells them anywhere, not even on the dodgy far extremes of the net.

[Sillewater]

Biochim Biophys Acta. 2009 May;1787(5):437-61. Epub 2008 Dec 29.
An attempt to prevent senescence: a mitochondrial approach.
Skulachev VP, Anisimov VN, Antonenko YN, Bakeeva LE, Chernyak BV, Erichev VP, Filenko OF, Kalinina NI, Kapelko VI, Kolosova NG, Kopnin BP, Korshunova GA, Lichinitser MR, Obukhova LA, Pasyukova EG, Pisarenko OI, Roginsky VA, Ruuge EK, Senin II, Severina II, Skulachev MV, Spivak IM, Tashlitsky VN, Tkachuk VA, Vyssokikh MY, Yaguzhinsky LS, Zorov DB.

A. N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Vorobyevy Gory 1, Moscow, Russia. skulach@belozersky.msu.ru
Abstract
Antioxidants specifically addressed to mitochondria have been studied to determine if they can decelerate senescence of organisms. For this purpose, a project has been established with participation of several research groups from Russia and some other countries. This paper summarizes the first results of the project. A new type of compounds (SkQs) comprising plastoquinone (an antioxidant moiety), a penetrating cation, and a decane or pentane linker has been synthesized. Using planar bilayer phospholipid membrane (BLM), we selected SkQ derivatives with the highest permeability, namely plastoquinonyl-decyl-triphenylphosphonium (SkQ1), plastoquinonyl-decyl-rhodamine 19 (SkQR1), and methylplastoquinonyldecyltriphenylphosphonium (SkQ3). Anti- and prooxidant properties of these substances and also of ubiquinonyl-decyl-triphenylphosphonium (MitoQ) were tested in aqueous solution, detergent micelles, liposomes, BLM, isolated mitochondria, and cell cultures. In mitochondria, micromolar cationic quinone derivatives were found to be prooxidants, but at lower (sub-micromolar) concentrations they displayed antioxidant activity that decreases in the series SkQ1=SkQR1>SkQ3>MitoQ. SkQ1 was reduced by mitochondrial respiratory chain, i.e. it is a rechargeable antioxidant. Nanomolar SkQ1 specifically prevented oxidation of mitochondrial cardiolipin. In cell cultures, SkQR1, a fluorescent SkQ derivative, stained only one type of organelles, namely mitochondria. Extremely low concentrations of SkQ1 or SkQR1 arrested H(2)O(2)-induced apoptosis in human fibroblasts and HeLa cells. Higher concentrations of SkQ are required to block necrosis initiated by reactive oxygen species (ROS). In the fungus Podospora anserina, the crustacean Ceriodaphnia affinis, Drosophila, and mice, SkQ1 prolonged lifespan, being especially effective at early and middle stages of aging. In mammals, the effect of SkQs on aging was accompanied by inhibition of development of such age-related diseases and traits as cataract, retinopathy, glaucoma, balding, canities, osteoporosis, involution of the thymus, hypothermia, torpor, peroxidation of lipids and proteins, etc. SkQ1 manifested a strong therapeutic action on some already pronounced retinopathies, in particular, congenital retinal dysplasia. With drops containing 250 nM SkQ1, vision was restored to 67 of 89 animals (dogs, cats, and horses) that became blind because of a retinopathy. Instillation of SkQ1-containing drops prevented the loss of sight in rabbits with experimental uveitis and restored vision to animals that had already become blind. A favorable effect of the same drops was also achieved in experimental glaucoma in rabbits. Moreover, the SkQ1 pretreatment of rats significantly decreased the H(2)O(2) or ischemia-induced arrhythmia of the isolated heart. SkQs strongly reduced the damaged area in myocardial infarction or stroke and prevented the death of animals from kidney ischemia. In p53(-/-) mice, 5 nmol/kgxday SkQ1 decreased the ROS level in the spleen and inhibited appearance of lymphomas to the same degree as million-fold higher concentration of conventional antioxidant NAC. Thus, SkQs look promising as potential tools for treatment of senescence and age-related diseases.

PMID: 19159610 [PubMed - indexed for MEDLINE]

[okok]

thanks, this looks promising.

[rwac]

Ultraviolet radiation at 300-400 nm, specific of sunlight near the Earth’s surface, causes DNA damage due to ROS generation [23]. As shown by our experiments, SkQ1 at 1 nM concentration practically completely inhibits the genotoxicity of this kind of radiation for E. coli. No studied natural or synthetic antioxidant exhibited an equivalent effect in a similar system [8, 24]. Minimal effective dose for the thiazine dye methylene blue, that showed the best result, was 10 nM. It is interesting that this compound, like SkQ1, is a lipophilic cation capable of in vivo formation of an oxidation/reduction cycle [25].

http://protein.bio.m...l/75030331.html

Interesting. Methylene Blue is the next best spin trap to SkQ1, at 10x the concentration.
SkQ1 is more mitochondria specific.

Edited by rwac, 21 April 2010 - 12:15 AM.

[Sillewater]

Yea, I saw that too. So what kinds of in vivo concentrations are people getting with 60mcg?

[rwac]

Yea, I saw that too. So what kinds of in vivo concentrations are people getting with 60mcg?

MB is generally only found in intracellular water which is about 25 liters of 40 liters body water of a normal person.
So

((60 mcg) / (25 liters)) / 319.85 ~ 7.5 nM

MB has a half life of around 5.25 hrs, so you would either use multiple doses/day or larger doses.

Caveat: Concentration may be higher in regions of higher metabolism like the brain. This may generate a higher concentration in the brain.

Edited by rwac, 21 April 2010 - 01:26 AM.

[rwac]

I just looked at the MB paper, again. The strongest antioxidant effect of MB likely occurs around 100nM.

So they might actually have handicapped MB somewhat here, or maybe they just didn't check 100nM.

[okok]

Ultraviolet radiation at 300-400 nm, specific of sunlight near the Earth’s surface, causes DNA damage due to ROS generation [23]. As shown by our experiments, SkQ1 at 1 nM concentration practically completely inhibits the genotoxicity of this kind of radiation for E. coli. No studied natural or synthetic antioxidant exhibited an equivalent effect in a similar system [8, 24]. Minimal effective dose for the thiazine dye methylene blue, that showed the best result, was 10 nM. It is interesting that this compound, like SkQ1, is a lipophilic cation capable of in vivo formation of an oxidation/reduction cycle [25].

Would these make a good addition to a sunscreen then?

[clairvoyant]

As to SkQ ions, these substances increase life span several times not 30% . They are tested on higher mammals such as rabbits, horses and dogs. They can restore blind horse vision and lift almost dead dog. Even the inventor (Skulachev over 75 year old now) has cured himself from cataract. The laboratory animals die YOUNG, can have sex until the end of their prolonged life. Actually, they die of shortening of the cell telomere. This might be the NECTAR OF IMMORTALITY.

They are patented and pat # can be found in Google. Can anybody find or synthesize them?

[niner]

I've heard that SkQ wasn't so good, and that the reported 30% might be due to it compensating for poor mouse husbandry, a typical problem. The stuff's been knocking around for what, ten years now? If it was the NECTAR OF IMMORTALITY, it seems like we might have seen some evidence of that by now.

At any rate, the structures are known. SkQ1 is a plastoquinone hooked to a triphenylphosphonium ion with a decyl linker. Any synthetic organic chemist with a lab and access to commercially available precursors should be able to make it.

[xEva]

I don't believe that Skulachev shyster. I have no proof, just a strong hunch.

The laboratory animals die YOUNG, can have sex until the end of their prolonged life. Actually, they die of shortening of the cell telomere.

please.

[niner]

This may be interesting to many of us- There is a large consortium of mostly Russian scientists, along with some international participants, that appears to be aimed at developing a commercial drug of the Skulachev Ion class. They have a very informative web site. Check it out.

[niner]

Here is where the "tripling of lifespan" nonsense comes from. Apparently SkQ1 is really good at squaring the mortality curve. Nothing wrong with that. From the Skulachev Ions site I mentioned in the previous post:

Another set of long-term experiments was performed by the group of V.N. Anisimov (the Petrov Institute of Oncology, St. Petersburg). The effect of SkQ1 on aging of normal outbreed mice was investigated. Lifetime administration of SkQ1 with drinking water at 5 nmol/kg dose considerably reduced age-related mortality of normal animals. The effect on the death rate for the first 20% of deceased animals (Fig. 2) was especially significant resulting in 2.5−fold increase of life span. For 50 % of deceased animals a 30% effect was documented. Finally for long-lived mice (the last 20 % of the cohort) there was approximately 10 % extension of lifespan. In other words, SkQ1 caused so-called rectangularization of the mortality curve of mice. The same trend was revealed in experiments with fungi (podospora, Fig. 3) and invertebrates (insect − drosophila, Fig. 4; crustacean − daphnia Fig. 5) whose life spans were also increased by the lifetime SkQ1 treatment. Lifetime SkQ1 treatment not only prolonged the lifespan of animals but also resulted in an improvement in the “quality of life”. For example, normally the majority of aged female mice have irregular estrous cycles by the age of 22 months. In V.N. Anisimov’s experiments, namely SkQ1-treated mice rather than control animals retained regular cycles similar to young animals (Fig. 6).

[steampoweredgod]

SkQ1=SkQR1>SkQ3>MitoQ.

The mentioned mitoq has had some success in model alzheimers. Though I'd like to see that comparison with skq1 from a third party or those behind mitoq to see if there's agreement with such statement or if bias affected the outcome.

Now, a study by researchers in the University of Georgia College of Pharmacy has shown that an antioxidant can delay the onset of all the indicators of Alzheimer's disease, including cognitive decline. The researchers administered an antioxidant compound called MitoQ to mice genetically engineered to develop Alzheimer's. The results of their study were published in the Nov. 2 issue of the Journal of Neuroscience.

"MitoQ selectively accumulates in the mitochondria,"


In their study, mice engineered to carry three genes associated with familial Alzheimer's were tested for cognitive impairment using the Morris Water Maze, a common test for memory retention. The mice that had received MitoQ in their drinking water performed significantly better than those that didn't. Additionally, the treated mice tested negative for the oxidative stress, amyloid burden, neural death and synaptic loss associated with Alzheimer's.-sciencedaily

MitoQ appears to be a lipophilic antioxidant that accumulates in the mitochondria and protects its membrane. In other species membrane composition changes to resist oxidation have been one of the factors behind an order of magnitude increase in lifespan.

MitoQ^® is targeted to mitochondria by covalent attachment to a lipophilic triphenylphosphonium cation.

Because of the large mitochondria membrane potential, the cations accumulate within cellular mitochondria up to 1,000 fold, compared to non-targeted antioxidants such as Coenzyme Q or its analogues. This accumulation enables the antioxidant moiety to block lipid peroxidation, and maintain the integrity of the mitochondria membrane by protecting it from oxidative damage.-link

Edited by steampoweredgod, 17 January 2012 - 04:24 PM.

[VidX]

This may be interesting to many of us- There is a large consortium of mostly Russian scientists, along with some international participants, that appears to be aimed at developing a commercial drug of the Skulachev Ion class. They have a very informative web site. Check it out.

I see there are some updates, nice.
Talking about /quackery/, well, I can read russian.. I've researched this scientis quite a lot in the past and if he is a /quack/, than anyone could be one. I mean - he's a very respected person in the serious science circles, he was actually in my country like a year ago and gave a lecture, I didn't make it there, but plenty of respectable people from universities and such attended that lecture, media was putting lighht on it and so on.. That is a very interesting project and he has his point, the question is - whether it will turn out to be true to some extent.

[Anthony_Loera]

Hi folks,

anyone you reccomend to create it to have it tested?
https://www.opencure...rotocol_outline

IM me, as I would be interested to have Dr. Valenzuela test it in some donor blood samples.

Thanks

A

[xEva]

He does not sound legit to me. In Russian, his site and what is said there is called развод на деньги. Don't try to translate it through a dictionary. It means making up sleek appearances with aim of soliciting money from unsuspecting wide-eyed victims.

Here are some things that make no sense to me:

First, he repeatedly claims that aging and death are genetically programmed, and then goes on to fix this program with one tiny molecule, his ion.

Second, he fixes mitochondrial ROS production via a molecule that is more likely to harm mitochondria instead, by damaging their membranes. Here is why:

1. Small positively charged organic molecules, also called antimicrobial peptides (AMPs), are produced by all eukaryotes as part of their innate immunity. They kill bacteria by damaging their negatively charged membranes.

2. It is well-known that mitochondria arose hundreds of millions years ago from an engulfed bacterium, and one of the key similarities between bacteria and mitochondria is in the structure of their membranes.

3. It recently became known that, as a side effect, AMPs harm host mitochondria in a similar way as they harm invading microbes for whom they were intended, i.e. they depolarize, rupture and otherwise damage their membranes.

IMO, recycling mitochondria via mitophagy, a form of autophagy that specifically targets defective mitochondria, is what fixes the problem of damaged mitochondria known for their uncontrolled ROS production. Adding more positively charged molecules to the brew should only aggravate rather than fix the problem.

Based on all this, it is my belief that "Skulachev ions" act as antimicrobial peptides and it is their antimicrobial peoperties what may have some positive physiological effects, if any. I am willing to speculate that addition of these ions frees epithelial cells from the necessity to produce their own AMPs, much closer to their own mitochondria, which may affect them negatively (hehe, actually, those are positively charged ions but their effects on the mitochondrial membranes are negative... in non-chemical meaning... well, I'm sure you understand).

Edited by xEva, 17 January 2012 - 06:24 PM.

[VidX]

The whole project may turn out to be "non legit" (but it has been up for 10years or so.. I don't know if it's a good timing for a scam huh?) but Skulachev is legit (as a scientist). Let's wait and see.

[eighthman]

Do a Google and see that this SKQ-1 was supposed to be on sale before the end of 2011. Came. Went. Ain't Here.

[VidX]

Do a Google and see that this SKQ-1 was supposed to be on sale before the end of 2011. Came. Went. Ain't Here.

Maybe because they are really trying to make it work?

[xEva]

VidX, yes Skulachev is/was a legit scientist, but his current ways of getting funds for his research/living are deceptive and the claims are clearly overblown. I don't know what sort of funding he gets after the fall of the Soviet Union. I know that Russian intelligentsia has traditionally lived in abject poverty, that he is old now, and that pensions there are miserly.

And regarding my hypothesis that his ions may have some beneficial physiological effects due to their antimicrobial properties, did you see on his site mention that half of the mice in the control group were dead at day 300? That speaks of appalling husbandry, and any farmer will tell you that adding antibiotics to the feed will improve the survival of animals raised in such conditions. Antimicrobial peptides are a sort of antibiotics. Did his ions show benefit for animals raised under decent care?

Edited by xEva, 18 January 2012 - 10:48 AM.

[VidX]

VidX, yes Skulachev is/was a legit scientist, but his current ways of getting funds for his research/living are deceptive and the claims are clearly overblown. I don't know what sort of funding he gets after the fall of the Soviet Union. I know that Russian intelligentsia has traditionally lived in abject poverty, that he is old now, and that pensions there are miserly.

And regarding my hypothesis that his ions may have some beneficial physiological effects due to their antimicrobial properties, did you see on his site mention that half of the mice in the control group were dead at day 300? That speaks of appalling husbandry, and any farmer will tell you that adding antibiotics to the feed will improve the survival of animals raised in such conditions. Antimicrobial peptides are a sort of antibiotics. Did his ions show benefit for animals raised under decent care?

He was financed by Deripaska (russian /oligarch/) for some time, later some initiative, similar to SENS, joined the funding, I'm not sure about the current state of affairs.
Regarding mice - death is not important in that experiment (according to him) as a mortality curve that squared, what means that these mice were "young" till their last day..

[eighthman]

I think Skulachev is real and doing the best he can but the 2011 statement still stands and a hopeful update would be appreciated

[manofsan]

Regardless of whether it's MitoQ, or SkQ, or whateverQ - this seems to be about targeting the mitochondria with anti-oxidants.

What about the idea of using Ubiquinone to trigger mitochondrial turnover, while targeting the non-defective mitochondria with an agent that protects them from the Ubiquinone?

[niner]

Regardless of whether it's MitoQ, or SkQ, or whateverQ - this seems to be about targeting the mitochondria with anti-oxidants.

What about the idea of using Ubiquinone to trigger mitochondrial turnover, while targeting the non-defective mitochondria with an agent that protects them from the Ubiquinone?

What do you mean by 'protects' them from ubiquinone? Ubiquinone triggers mitochondrial turnover? As in destroying mitochondria and creation of new ones? Or do you mean turnover of the redox cycle? I don't get it.

[manofsan]

I remember speaking with a Dr Daniel Klionsky once, and if I recall correctly, he told me that ubiquinone receptors have been linked to turnover of various cellular organelles, including the mitochondria. When I say 'turnover', I am referring to the destruction of mitochondria and creation of new ones.

[steampoweredgod]

Remembered gingko biloba mitochondria antiaging article connection

A Ginkgo biloba extract (EGb 761) prevents mitochondrial aging by protecting against oxidative stress.



Abstract

The effect of aging on indices of oxidative damage in rat mitochondria and the protective effect of the Ginkgo biloba extract EGb 761 was investigated. Mitochondrial DNA from brain and liver of old rats exhibited oxidative damage that is significantly higher than that from young rats. Mitochondrial glutathione is also more oxidized in old than in young rats. Peroxide formation in mitochondria from old animals was higher than in those from young ones. According to morphological parameters (size and complexity), there are two populations of mitochondria. One is composed of large, highly complex mitochondria, and the other population is smaller and less complex. Brain and liver from old animals had a higher proportion of the large, highly complex mitochondria than seen in organs from young animals. Treatment with the Ginkgo biloba extract EGb 761 partially prevented these morphological changes as well as the indices of oxidative damage observed in brain and liver mitochondria from old animals.-link

in an old article it was indicated preservation of youthful morphology of mitochondria population into advance age was possible via such extract exposure i think in mice

Edited by steampoweredgod, 18 April 2012 - 10:51 PM.

[clairvoyant]

Ok, ok. Some offers one antioxidant other does another. Could anybody of you, especially with scientific background, make A LIST

of anti aging supplements a healthy man should take on a daily, long term basis.

[xEva]

SkQ is an uncoupling protein (UCP). Yeah, I had a different idea about it last time I posted here, and in fact it occurred to me that it's an uncoupling protein just an hour after I made that post, and we can't edit posts. Anyway,

http://www.fightagin...-for-humans.php

Substantial evidence suggests that the ability of UCPs to reduce ROS and regulate energy utilization underpins the ability of UCPs to promote lifespan in various experimental models.

A short list of uncoupling proteins: metformin, BHT, ... DNP...

It was found that CR increases the natural production of UCPs, and I think cold adaptation should also boost endogenous UCP production.