Fight Aging!

Actually, there are now some mitochondrially targeted antioxidants available in stores - online stores, anyway:

http://en.wikipedia.org/wiki/MitoQ

I've been taking them for several months.

@Kay Aych: I discount MitoQ as an uninteresting part of the background noise from the supplement industry. I don't see life span studies in normal animals for MitoQ or indeed any studies other than the normal class of papers that you can find for even prosaic items such as Vitamin E or Coenzyme CoQ10. All of these supplements marketed to the masses have associated studies showing a modest improvement here or there in animal models of some diseases. That doesn't mean it is worth anything for a normal healthy individual.

Certainly there's nothing as impressive out there in terms of replicated results for MitoQ as exists for plastiquinones, and as I point out here and elsewhere even those most promising mitochondrially targeted antioxidants are only capable of what are minor, trivial adjustments to aging in the grand scheme of things. They are not the path to any sort of meaningful extension of life span in humans, and focusing on them might be rewarding because you feel like you are accomplishing something, but in truth it is a waste of time and energy. You have a much greater certainty of a larger beneficial outcome by exercising, eating less, and donating the funds you would have spent on supplements to medical research.

Thank you for cutting through the bollocks that surrounds a lot of longevity science Reason.

The anti-oxidant people seem to have been flogging a dead horse for ages now. It is still nice to see it concisely explained why it doesn't work (or why there is an incredible volume of experiment evidence refuting it).

Thanks for sharing your thoughts on MitoQ. I'm semi hopeful for some substance like that -- not expecting it will massively extend life -- but as a way to make ordinary people realize something (very moderate in this case perhaps) can actually be done.

Since it's being discussed, this is Vladimir Skulachev's take on MitoQ compared to his mitochondrial antioxidant, SkQ1:

http://joshmitteldorf.scienceblog.com/2014/01/14/mitoq-targeted-coq10/#comments

It's the first reply in the comment section.

As far as I can see Reason and others are saying:

(1) There is no rigorous experimental evidence that MitQ or any other targeted antioxidant does anything.

(2) There have been rigorous experiments done looking for an effect, these experiments turned up decent evidence for antioxidants (including targeted ones) of having NO EFFECT whatsoever.

Come on guys, it is one thing to hope that an untested treatment may do something in the future. It is quiet something else to hope/say that something that has been as comprehensively proved to do NOTHING as MitQ targeted antioxidants will do something. You are sticking your heads in the sand.

MitoQ recently got some attention due to this: http://www.ncbi.nlm.nih.gov/pubmed/24665093

"The improvements in endothelial function with MitoQ supplementation were associated with normalization of age-related increases in total and mitochondria-derived arterial superoxide production and oxidative stress (nitrotyrosine abundance), as well as increases in markers of vascular mitochondrial health, including antioxidant status. MitoQ also reversed the age-related increase in endothelial susceptibility to acute mitochondrial damage (rotenone-induced impairment in EDD)."

If that result COULD be replicated in humans in would be amazing.

Whenever you are talking about SENS, aging is a multifaceted thing where you have to repair 7 different categories of things to have any significant effect, and finding anything that fixes one of the problems is a cause for celebration.

Whenever you are talking about "supplements", that all goes out the window, and you suddenly throw away as worthless anything that doesn't completely cure all categories of aging simultaneously. That's a rather disturbing double standard.

Now, some issues I have with this theory that antioxidants are bad...

Humans, and their ancestors, evolved in an environment full of antioxidants. Everything we know about evolution suggests than in such an environment humans would at the very least evolve defenses against antioxidants, and in many cases would actually put those harmful antioxidants to productive use.

The food that healthy people eat naturally contains antioxidants.

Antioxidants that people take frequently have other beneficial effects beside their antioxidant effect.

There is a huge anti-vitamin movement exactly like the anti-vaccine movement, which has forced its dogma onto the establishment. That causes people who want to be respected to be biased against supplements.

"The food that healthy people eat naturally contains antioxidants."

Correct, eaten in moderation that food is excellent for humans.

"Antioxidants that people take frequently have other beneficial effects beside their antioxidant effect."

Wrong, there is no proof for pills with antioxidants. In fact, that is the subject of the current post.

"Whenever you are talking about SENS, aging is a multifaceted thing where you have to repair 7 different categories of things to have any significant effect, and finding anything that fixes one of the problems is a cause for celebration.

Whenever you are talking about "supplements", that all goes out the window, and you suddenly throw away as worthless anything that doesn't completely cure all categories of aging simultaneously. That's a rather disturbing double standard."

I completely agree with Carl here. I like this blog but honestly I find Reason's stance on supplements too radical. Is supplementing with vitamin D wrong for instance if there is a clear need for it? I would love to hear Reason's reply to this question.

"Correct, eaten in moderation that food is excellent for humans."

The more distant ancestors of humans ate massive amounts of fruits getting more than a gram of vitamin C, which caused those with a mutation impeding vitamin c synthesis to easily propagate as it was easily available in the environment. Along with vitamin C those large doses of fruit probably packed large doses of phytonutrients, including other antioxidants.

More recent ancestors eating plenty of berries, nuts, and fruits also got plenty of antioxidants.

Besides many supplements work not necessarily through antioxidant mechanisms, and herbal extracts contain the beneficial substances of certain plants without calories and at lower costs. There's plenty of studies, thousands upon thousands of studies with positive improvements in varied parameters related to many supplements.

Whle individual CR partial mimetics may not extend lifespan in all animal models, their combination if complementary and thorough enough could reproduce CR gene expression in its totality.

My view of supplements:

1) There is no reasonable expectation that any amount of time and money devoted to the development of supplements in the present model will meaningfully extend human life spans. E.g. add decades to healthy life for old and young.

2) No existing supplement can provably produce a benefit for healthy people that is even a small fraction of the benefits provided by exercise and calorie restriction, which are themselves probably little more than 5 years of life expectancy (though more impressive benefits to health span).

3) And yet the funds spent on supplement development, evaluation, marketing, and so on dwarf that spent on aging research in general. We live in a world in which there are so many new, promising, and as yet poorly developed medical technologies built on our increasing ability to control and manipulate cells and tissues - SENS-like work, essentially. This work could, if pursued aggressively, add decades of healthy life for young and old, and thus it is sheer madness that people fixate on supplements.

4) There are many medical conditions in which aggressive supplementation of something is a treatment worth undertaking. That is largely irrelevant to considerations of aging and life extension.

5) If a supplement is dirt cheap and has rock-solid evidence for not causing any harm, and a range of mixed evidence for causing benefits, then why not take it? Very little falls into this camp, however: possibly a multivitamin, vitamin D, fish oil, and a few others. The effects will be small compared to exercise and calorie restriction, if they are even there for you, and you should expend a correspondingly small amount of effort on this.

The very best things to emerge from the grey area between supplements and drugs, like plastiquinones, are not going to match calorie restriction. None of these things, even in their ultimate, best possible forms, can possibly deliver the same degree of extended life and health as serious attempts at repair biotechnologies - again, SENS-like work.

So we shouldn't waste time and energy on supplement dvelopment. It isn't where wondrous new advances are going to happen, it isn't the path to meaningfully longer lives. Thinking otherwise is just self-delusion. We should take all that energy and put it into something that might actually achieve meaningful results.

I presume this website to be frequented by educated people with scientific interest and pointed interest in anti-aging. So I am a bit taken back in this discussion that there is no mention of hormesis, Nrf2 activation of internal antioxidant enzymes, etc.

It was recent shown that cultured calorie-restricted cells increased expression of stress-response genes and enhanced tolerance to oxidants. Cells cultured in serum from CR individuals showed a 30% increase in resistance to H2O2 damage. Consistently, SOD2 and GPX1 mRNA, two key endogenous antioxidant enzymes, were increased by 2 and 2.5 folds respectively in cells cultured with CR sera. [ http://www.ncbi.nlm.nih.gov/pubmed/23912304 ]

Deleterious effects of supplemental antioxidants like C and E are over-stated, they are basically ineffective at preventing disease and prolonging life but are useful in states of true deficiency. Mega-dose antioxidants could be ineffective because they negate the mild pro-oxidant effect Nrf2 activators that produce internal antioxidant enzymes.

I must also point out that it appears some knowledgeable aging researchers intentionally used mega-dose antioxidants in experiments to produce a known negative effect. It is widely known that polyphenols if overdosed will go from being antioxidants to pro-oxidants, releasing copper instead of binding copper. Such a shameful experiment was recently published. Aging (Albany NY). 2014 Feb;6(2):149-57. Multiple dietary supplements do not affect metabolic and cardio-vascular health. http://www.ncbi.nlm.nih.gov/pubmed/24659610

Reason keeps touting high-tech answer to aging that are simply not affordable. Gene therapy in regard to repair of inherited diseases only represents 2% of disease. Most diseases are environmentally controlled via epigenetics, meaning they are modifiable by diet and small molecules found in dietary supplements.

Metabolic waste largely is represented by lipofuscin which accumulates due to calcification and rusting of lysosomes within living cells that enzymatically reduce cellular debris. Reduce calcification and rusting and the lysosomes will spring to life and lipofuscin can be eradicated, i.e. aging reversed.

Stem cell treatments have been conjured up for a couple of decades with little success and tainted by scientific fraud. The body makes its own stem cells. The problem is, these stem cells cannot survive the free radical storms. Early experiments show the provision of resveratrol prior to stem cell injection produces stem cell survival and daughter cells produce progeny. Dr. Stuart Richer of the VA Medical Center is Chicago has captured direct images of internal stem cell regeneration via the use of small polyphenolic molecules in retinal disease.

The dismissal of mitochondrial reinvigorators is inexplicable as only recently David Sinclair PhD showed that rejuvenation of mitochondria via restoration of communication between mitochondria and cell nucleus using a niacin-like (nicotinamide riboside) NAD precursor was able to rapidly convert aging markers in animal muscle tissue, equivalent to making 60-year old tissue 20-years old in just one week! Don't say it can't be done. It was just recently demonstrated.

@Bill Sardi: I find your dismissal of the effectiveness of stem cell therapies to be a strange viewpoint. There is more going on there in just the last few years to produce meaningful therapies than the entire supplement industry has managed to produce in the last four decades.

I don't see much support for your views on calcification and lysosomal dysfunction. Lipofuscin expressly consists of things that the lysosome cannot break down, and it is the presence of lipofuscin that harms lysosomal function. Calcification is a parallel concern, but not, I think, a cause.

As to the the rest, you're mixing your metaphors. I commented on the Sinclair lab research last year; it has little in common with work on mitochondrially targeted antioxidants and much more to do with manipulation of the heat shock response. Completely different mechanisms are involved.

https://www.fightaging.org/archives/2013/12/increasing-nad-to-reduce-hif-1-reverses-age-related-inflammation-and-insulin-resistance-in-muscle-tissue.php

I think if you find something in supplements that works for you that's great and it's a good idea to be mindful of your health at all ages.

We should be aware though that even if there were some supplement that slowed our aging by a significant degree we will still need therapies that will repair and reverse the damage in our bodies after it occurs. Some of these things are close to being available like stem cell therapies and immuno-therapy for various Amyloid based diseases.

Even still there exists gaps in the panel of therapies that will reverse you biological aging and restore youthful function. If you want to increase the likelihood of medicine that treats underlying causes of age related diseases in the near future (like the two mentioned) you should donate a modest and non-burdensome amount to the SENS research foundation and move on with your life.

If the supplements guys would say, spend 1000 dollars a year on joining the 300 rather than blowing it on supplements that have been experimentally proven again and again to do nothing, we'd all be a lot closer to living a lot longer.

"1) There is no reasonable expectation that any amount of time and money devoted to the development of supplements in the present model will meaningfully extend human life spans. E.g. add decades to healthy life for old and young."

This depends on how much genetic change is necessary to reach multicentury lifespan. There are primates that live about a decade, we humans are close relative and with not that many modifications multiplied lifespan 10 fold. If you asked a SENS proponent what is needed to extend a primate's lifespan they'd show you the SENS LIST and suggest thorough implementation to extend lifespan. Yet we see that nature merely by tweaking mostly gene expression a little managed to get about a 1000% lifespan increase between primate species.

AFAIK, the negligible senescence do not implement sens strategies such as WILT, it is also unknown the status of mitochondrial to nucleus gene transfer, afaik, maybe they do have all remaining mitogenes transferred to the nucleus, but it may ver well be the case that this is neither done. So UNLESS it is shown that as longevity increases more and more SENS strategies are implemented, the SENS approach may be overengineering and mere tweaks to the genome mostly to gene expression should suffice for exponential lifespan increase.

Supplements and drugs can tweak gene expression, sometimes to substantial degrees. If the relevant longevity related gene expression is changed to resemble that of a more long lived animal, it could very well result in mimicking the changes nature itself would do if the species was evolving towards greater longevity, and as a result could result in greater longevity.

"2) No existing supplement can provably produce a benefit for healthy people that is even a small fraction of the benefits provided by exercise and calorie restriction, which are themselves probably little more than 5 years of life expectancy (though more impressive benefits to health span)."

While not a supplement a handful of nuts provides about 3 years of lifespan increase. Exercise if done at optimal yet moderate levels can supposedly provide up to 6 years. Nut and exercise are additive in their benefits such that together they can add up to 9 years to lifespan.

I would venture to guess that Calorie restriction too should add at least 9 years lifespan.

"The very best things to emerge from the grey area between supplements and drugs, like plastiquinones, are not going to match calorie restriction. None of these things, even in their ultimate, best possible forms, can possibly deliver the same degree of extended life and health as serious attempts at repair biotechnologies - again, SENS-like work."

It is said that there are closely related species where one ages and one does not(think it was some type of fish, iirc). If that is true, it suggests the genetic changes necessary might not be that large. The question is did nature IMPLEMENT MOST OR ALL OF SENS to achieve negligible senescence or did it do mostly small changes to the genome primarily to gene expression(as it is said protein structure tends to be conserved and most changes in evolution are regulatory related)? If it is the latter, it is very likely that there exist small molecules that either alone or in combination can induce gene expression changes in the direction of greater longevity.

"blowing it on supplements that have been experimentally proven again and again to do nothing, we'd all be a lot closer to living a lot longer."

Well the rodents that were supplemented with glycine which mimicked methionine restriction which mimicked calorie restriction, seemed to have lived 30% longer.

Pomegranate extract, think in combination with some drug, was shown to be able to reverse arterial plaque build-up to a significant degree.

That's just two examples. There are thousands of studies showing diverse and varied benefits for many supplements.

Regarding the comments of Reason and Bill Sardi -

According to one of today's press releases -

"New clues to cognitive decline" http://www.medicalnewstoday.com/releases/276588.php

- NAD precursors appear to rescue neural stem cells by providing them additional energy sources that decline with age.

It would be interesting to know if they work in other tissues - possibly protecting other stem cell pools.

That's all well and good but you're still going to need things that remove and degrade damage that has already occurred in your adult body. Supplements aren't going to negate oxidized cholesterol, remove crosslinks or remove amyloids out of your brain et al. No matter what happens you are definitely going to need these things developed.

"That's all well and good but you're still going to need things that remove and degrade damage that has already occurred in your adult body. Supplements aren't going to negate oxidized cholesterol, remove crosslinks or remove amyloids out of your brain et al. No matter what happens you are definitely going to need these things developed. "

It is possible. But there were promises of drugs that could target crosslinks. Dietary changes have been said to reverse atherosclerosis, pomegranate extract was also said to reduce the thickening of blood vessels. While the study was not repeated successfully, there was also another drug that supposedly caused the brain to clear amyloid out.

IT remains to be seen what happens in the negligible senescent organisms. If it's merely mostly gene expression changes, than it may be that if ramped up the body's repair and maintenance mechanisms can deal with any changes that increase mortality, and those not dealt with do not present an issuue at least for multiple centuries.

Again you are going to need the things described in the SENS panel, no matter what happens.

"Again you are going to need the things described in the SENS panel, no matter what happens."

WILT doubt it. Nature has managed to reduce cancer risk in animals with ever greater number of cells and long lifespan. We can simply see the direction of genetic change as cell number increases and extrapolate from there.

Regards mitochondria genes to nucleus, we will soon have the bowhead whale genome, if these animals do not have any additional mitogenes moved to the nucleus, it will likely indicate that such is unecessary engineering as these animals are suggested to live up to 200+ years(impressive as there are single cells, neurons, that would last that long). It is possible there exist a mitochondria quality control mechanism that if ramped up can maintain quality of the population.

Senescent cells. We have to see, as lifestyle interventions can restore telomere length, and there are those searching for small molecules(supplements, drugs) that could restore telomere length. This should rescue senescent back to a more functional state.

Intracellular and extracellular junk, well we would have to see what happens in negligible senescence organisms again. It is likely that ramping up the machinery of the body will cause what cannot be processed to be exported outside the body and cleared in such a way.

crosslinks again we need to see what happens with the negligible senescence. But it is possible an intervention here may be necessary, but this would be if it is seen that negligibly senescent organism rather than upregulate existing mechanism implement novel mechanisms.

cell loss and atrophy. This is something I believe will be necessary, especially in the brain as most of the brain does not experience cell replacement in case of injury or disease. That said, it is likely that if the body could be kept in apt state with gene expression more similar to a longer lived animal, this intervention might not be necessary until well past the century mark, maybe even past the second century mark. We do know that a human lasted for 122 years without any intervention, and if it's true that death was from choking, could've lasted longer.

You've just described the Gerontological approach to treating aging and if that's the way you feel then this blog probably isn't for you. This blog is primarily about promoting restoring the body to a time before it suffered damage using regenerative medicine rather than attempting to co-opt mechanisms from other species or using supplements in an attempt to slow damage. If you're interested in resembling Jeanne Calment at an advanced age instead of appearing like yourself in your twenties then, by all means, eschew any SENS style therapies developed in the near future.

[quote]his blog is primarily about promoting restoring the body to a time before it suffered damage using regenerative medicine rather than attempting to co-opt mechanisms from other species or using supplements in an attempt to slow damage.[/quote]
You're assuming damage cannot be reversed by ramping up repair and maintenance processes. Lifestyle approaches have reverted thickening of the blood vessels. At least intracellular amyloid has been cleared by resveratrol. The brain has a mechanism to pump out wastes, for example beta amyloid is pumped out by this glymphatic system. Upregulation of mitochondria quality control, has been shown to reduce the number of mutant or aberrant mitochondria, and restore to a population richer in more functional mitogenome.

BTW other animals share most of the same metabolic machinery, co-opt mechanisms from other species? There are primates that live about a decade we live about a century, that's probably small tweaks to gene expression mostly. Once we see another mammal with even greater lifespan, we should be able to get a hint of the direction of change performed to get that lifespan. It's remains to be seen, but I doubt special mechanisms are at play, probably mostly differing regulation of gene expression.

That said again, the example is not only to co-opt their mechanisms*(as said probably our mechanisms too just upregulated), but to also show that if it is found that with similar metabolic machinery they can remain ageless, share most of our dna, and not implement many aspects of sens(most certainly not WILT)... then that clearly tells us that SENS may be overengineering.

[quote] If you're interested in resembling Jeanne Calment at an advanced age instead of appearing like yourself in your twenties then, by all means, eschew any SENS style therapies developed in the near future. [/quote]
Problem is, telomerase restoration of skin cells telomeres is said to've restored tissue to a youthful appearance. It probably does similar to other tissues, it will at least get rid of the toxic emitting senescent cells.

Calment again was under no intervention. Supplements and drugs are interventions. Ideally genetic engineering would be used to provide more robust changes and abolish the need for external agents.

Forgot to add this to my last reply as an example take the bonobo, lifespan 40yrs, genetic similarity to humans 98.7 percent. Yet humans live over twice as long. Again this is double the lifespan, what aspects of SENS were implemented to accomplish this doubling of lifespan?(as our common ancestor was likely more similar to bonobos in lifespan)

We can see off the bat that AFAIK neither WILT nor additional mitogene to nucleus transfer were necessary to accomplish this doubling of lifespan. It seems that a small change to the genome was all that was necessary(note that not all the genetic difference is due to longevity only a small part of the genetic difference is likely necessary for longevity increase).

IMHO if small genetic changes can move from a decade to half a century(primates) to a century, then I've reason to believe that similarly small changes should allow us to reach 2 centuries and probably more. IF analysis of negligible senescent organisms turn out to share most of the same maintenance and repair mechanisms merely upregulated, or maybe chemical changes to reduce damage production and allow existing mechanisms to be more effective, then we will see that the hypothesis is likely true we'd only need small changes. On the other hand if we see most of sens implemented with novel proteins, then we will at least have the solution to aspects of sens as we can simply transfer the genes coding for these proteins to us.

If you feel like you don't need any SENS-like therapy as it is described that is your prerogative.

"If you feel like you don't need any SENS-like therapy as it is described that is your prerogative. "

As I said I do believe that some interventions are necessary such as the fact that cell loss is a real issue, especially in the brain, which does need to be addressed. Other issues such as WILT, I would prefer alternatives such as seeing the type of changes implemented by nature in longer lived yet larger animals, and doing similar or more extensive work in the area. Mitochondria quality, it may be that ramped up the mitochondria quality control mechanisms can keep mito population quality in check without need for additional transference of genes from mitochondria to nucleus.

Other types of problems, such as junk, would like to see what nature did, but if it's true what they say that protein structure tends to be conserved in evolution and most change is too regulatory elements, then whatever is being done in longer lived mammals may be relevant for us, as it may simply require difference in gene expression to implement interventions in this area.