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Mitochondrially Targeted Antioxidant SS-31 Reverses Some Measures of Aging in Muscle – Article by Reason

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Categories: Science, Technology, Transhumanism, Tags: , , , , , , , , , , , , , , , ,

The New Renaissance Hat
Reason
May 26, 2013
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Originally published on the Fight Aging! website.

Antioxidants of the sort you can buy at the store and consume are pretty much useless: the evidence shows us that they do nothing for health, and may even work to block some beneficial mechanisms. Targeting antioxidant compounds to the mitochondria in our cells is a whole different story, however. Mitochondria are swarming bacteria-like entities that produce the chemical energy stores used to power cellular processes. This involves chemical reactions that necessarily generate reactive oxygen species (ROS) as a byproduct, and these tend to react with and damage protein machinery in the cell. The machinery that gets damaged the most is that inside the mitochondria, of course, right at ground zero for ROS production. There are some natural antioxidants present in mitochondria, but adding more appears to make a substantial difference to the proportion of ROS that are soaked up versus let loose to cause harm.

If mitochondria were only trivially relevant to health and longevity, this wouldn’t be a terribly interesting topic, and I wouldn’t be talking about it. The evidence strongly favors mitochondrial damage as an important contribution to degenerative aging, however. Most damage in cells is repaired pretty quickly, and mitochondria are regularly destroyed and replaced by a process of division – again, like bacteria. Some rare forms of mitochondrial damage persist, however, eluding quality-control mechanisms and spreading through the mitochondrial population in a cell. This causes cells to fall into a malfunctioning state in which they export massive quantities of ROS out into surrounding tissue and the body at large. As you age, ever more of your cells suffer this fate.

In recent years a number of research groups have been working on ways to deliver antioxidants to the mitochondria, some of which are more relevant to future therapies than others. For example gene therapies to boost levels of natural mitochondrial antioxidants like catalase are unlikely to arrive in the clinic any time soon, but they serve to demonstrate significance by extending healthy life in mice. A Russian research group has been working with plastinquinone compounds that can be ingested and then localize to the mitochondria, and have shown numerous benefits to result in animal studies of the SkQ series of drug candidates.

US-based researchers have been working on a different set of mitochondrially targeted antioxidant compounds, with a focus on burn treatment. However, they recently published a paper claiming reversal of some age-related changes in muscle tissue in mice using their drug candidate SS-31. Note that this is injected, unlike SkQ compounds:

Mitochondrial targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice

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Mitochondrial dysfunction plays a key pathogenic role in aging skeletal muscle resulting in significant healthcare costs in the developed world. However, there is no pharmacologic treatment to rapidly reverse mitochondrial deficits in the elderly. Here we demonstrate that a single treatment with the mitochondrial targeted peptide SS-31 restores in vivo mitochondrial energetics to young levels in aged mice after only one hour.

Young (5 month old) and old (27 month old) mice were injected intraperitoneally with either saline or 3 mg/kg of SS-31. Skeletal muscle mitochondrial energetics were measured in vivo one hour after injection using a unique combination of optical and 31 P magnetic resonance spectroscopy. Age-related declines in resting and maximal mitochondrial ATP production, coupling of oxidative phosphorylation (P/O), and cell energy state (PCr/ATP) were rapidly reversed after SS-31 treatment, while SS-31 had no observable effect on young muscle.

These effects of SS-31 on mitochondrial energetics in aged muscle were also associated with a more reduced glutathione redox status and lower mitochondrial [ROS] emission. Skeletal muscle of aged mice was more fatigue resistant in situ one hour after SS-31 treatment and eight days of SS-31 treatment led to increased whole animal endurance capacity. These data demonstrate that SS-31 represents a new strategy for reversing age-related deficits in skeletal muscle with potential for translation into human use.

So what is SS-31? If look at the publication history for these authors you’ll find a burn-treatment-focused open-access paper that goes into a little more detail and a 2008 review paper that covers the pharmacology of the SS compounds:

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The SS peptides, so called because they were designed by Hazel H. Sezto and Peter W. Schiler, are small cell-permeable peptides of less than ten amino acid residues that specifically target to inner mitochondrial membrane and possess mitoprotective properties. There have been a series of SS peptides synthesized and characterized, but for our study, we decided to use SS-31 peptide (H-D-Arg-Dimethyl Tyr-Lys-Phe-NH2) for its well-documented efficacy.

Studies with isolated mitochondrial preparations and cell cultures show that these SS peptides can scavenge ROS, reduce mitochondrial ROS production, and inhibit mitochondrial permeability transition. They are very potent in preventing apoptosis and necrosis induced by oxidative stress or inhibition of the mitochondrial electron transport chain. These peptides have demonstrated excellent efficacy in animal models of ischemia-reperfusion, neurodegeneration, and renal fibrosis, and they are remarkably free of toxicity.

Given the existence of a range of different types of mitochondrial antioxidant and research groups working on them, it seems that we should expect to see therapies emerge into the clinic over the next decade. As ever, the regulatory regime will ensure that they are only approved for use in treatment of specific named diseases and injuries such as burns, however. It’s still impossible to obtain approval for a therapy to treat aging in otherwise healthy individuals in the US, as the FDA doesn’t recognize degenerative aging as a disease. The greatest use of these compounds will therefore occur via medical tourism and in a growing black market for easily synthesized compounds of this sort.

In fact, any dedicated and sufficiently knowledgeable individual could already set up a home chemistry lab, download the relevant papers, and synthesize SkQ or SS compounds. That we don’t see this happening is, I think, more of a measure of the present immaturity of the global medical tourism market than anything else. It lacks an ecosystem of marketplaces and review organizations that would allow chemists to safely participate in and profit from regulatory arbitrage of the sort that is ubiquitous in recreational chemistry.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries.  

This work is reproduced here in accord with a Creative Commons Attribution license.  It was originally published on FightAging.org.

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Ending the War on Kidneys – Article by Sanford Ikeda

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Categories: Economics, Politics, Tags: , , , , , , , , , , , , , , , , ,

The New Renaissance Hat
Sanford Ikeda
October 13, 2012
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The war on drugs can be dated to 1914, although the phrase “war on drugs” was coined in 1972 during the presidency of Richard Nixon.  The war on kidneys began in 1984.

It’s an oft told tale how drug prohibition has led to the promotion of organized crime, skyrocketing violence here and abroad, and a simultaneous increase in potency and decrease in safety.  (See here and here for examples.)  The solution to these perhaps unintended but predictable negative consequences is legalization.  So it is, too, with the sale of organs–kidneys in particular.

Meanwhile in Iran…

Since 1984, under the leadership of Senator Al Gore, the United States government has made it illegal to buy or sell kidneys and in so doing has effectively launched a “war on kidneys.”  Again, the consequences, unintended but predictable, are mostly if not wholly bad.

According to the Human Resources and Services Administration there are currently over 93,000 persons in the United States on the waiting list for a donated kidney.  Another source estimates that the list grows by 3,000 to 4,000 candidates a year.  Between 1988 and 2008 yet another source reports that the number of kidney transplants performed in the United States has ranged from 8,873 (in 1988) to a high of 17,091 (in 2006) for an average of about 13,847 per year.  While that may indicate a dwindling list of candidates, the reality is that the number who die each year still runs into the thousands.

The United States Department of Health and Human Services, for instance, claims that 18 people die each day waiting for a kidney donor.  That’s 6,570 deaths a year, and though their figure for the waiting list is considerably higher than the HRSA’s, they are in the same ballpark.

Kidney sales are legal in Iran, which offers a mix of private and government financing for kidney transplants.  Not surprisingly, waiting lists there are practically nonexistent (because of a larger supply), and so is the number of people dying while waiting for one.

Moreover, the incidence of black markets and of “medical tourism”—in which relatively wealthy foreigners travel to relatively poor countries to buy local kidneys or have other procedures performed at lower cost than in the United States—would probably fall, much as legalization of alcohol after Prohibition saw the downfall of speakeasies and bathtub booze.

What’s the Downside?

And although some estimate that the cost of a kidney may be as high as $100,000—which would make the total cost of the transplant procedure around $350,000—keep in mind that in addition to the value of the lives saved, the savings from unnecessary kidney dialysis is about $70,000 per person per year.  (See also this article from The Economist.)

Some argue that only the rich would get organs and only the poor would die giving them up.  Existing black markets and medical tourism already reinforce any such tendency by keeping prices high.  Would a free market in organs mean that the relatively poor would supply the relatively rich?  Perhaps.  More generally, would abuses occur?  Yes, they would, just as they do in other aspects of organ transplantation—such as in shabby hospitals or lousy medical care. Nobody suggests banning hospitals or doctors because some hospitals and some doctors occasionally screw up.  The cure lies largely in greater competition, the prerequisite of which is making organ sales legal.

Some are put off by the very idea of a market in kidneys, and many who aren’t might have some reservations about extending the list to other parts of our bodies.  Some of this can be attributed to a socio-ethical resistance to “commoditizing the human body.”  Perhaps this is a valid concern.  Interestingly, there is a legal market for cadavers, so it seems to be OK to pay for bodies but not for organs.

What about other organs or body parts?  The thing about kidneys—or eyes, ears, hands, and feet—is that removing them from our bodies does not entail death or, in the case of kidneys, any significant decline in the quality of life to the donor.  But what about selling something vital such as a heart, which would spell certain death?  That’s a difficult question that we may not have to settle just yet.  Let’s start with kidneys.

The Moral Alternative

I confess to being uncomfortable with the thought of selling off body parts. In the same way, I would never recommend to anyone, including myself, taking cocaine for fun.  But I would stop short of banning cocaine, and my qualms about selling body parts doesn’t keep me from staunchly supporting legalization, especially when a strong case can be made (as in this video by Professor James Stacey Taylor) that banning it would itself be immoral.  Selling body parts for money should be no more illegal than letting people make a living fishing for crabs on the high seas or give up their lives for a cause they believe in.  I may disapprove of a practice that harms the practitioner, but that by itself doesn’t give me the right to stop it, especially if it harms no one else.

Finally, today it’s considered perfectly legal and moral to allow husband A to give up his kidney to his wife B without compensation.  Or, if A’s kidney is not a match for B, it’s okay for A to donate to C, whose husband D could then donate to B.  That is like trading a goat to Jack to get a pile of bricks to trade to Jill for a sack of grain, which is what you wanted for your goat in the first place.  While the Internet and creative websites have made organ bartering of this kind easier than in the past, humans long ago developed another institution that gets the job done much more easily:  buying and selling for money.

Crimalizing activities—whether  drugs, prostitution, or organ sales—typically generates consequences that are usually unintended but, with the aid of some basic economic knowledge, mostly predictable.  After decades and over a trillion dollars spent and countless lives ruined, a summit of Latin-American politicians earlier this year declared that “the war on drugs has failed,” a sentiment echoed around the world.

It’s time that our government ended the war on kidneys, too.

Sanford Ikeda is an associate professor of economics at Purchase College, SUNY, and the author of The Dynamics of the Mixed Economy: Toward a Theory of Interventionism.

This article was published by The Foundation for Economic Education and may be freely distributed, subject to a Creative Commons Attribution United States License, which requires that credit be given to the author.