There are many vitamins and minerals with antioxidant actions that are essential nutrients, meaning that your body cannot synthesize enough of the nutrient by itself and therefore a certain quantity of said nutrient must come from your diet. The consequences of deficiencies of these essential micronutrients are dire. As an example of this, vitamin C deficiency results in scurvy, a condition characterized by anemia, general weakness, gum disease, and skin hemorrhages.

So, oxidative stress is bad, and antioxidants are good for you, right? Everyone knows that…

… not so fast.

In recent years, our understanding of antioxidants has advanced remarkably, and nowadays we are so fortunate that deficiencies in micronutrients are very rare in many parts of the world, including North America. So, deficiencies aren’t so pertinent to us. More tellingly, some activities that routinely lead to health benefits increase oxidative stress acutely.  For example, scientists have known for several decades that exercise promotes longevity and protects against the development of diseases like type 2 diabetes, but we’ve also known for 40 years that exercise increases mitochondrial metabolism and oxidative stress. (Listen to this episode of humanOS Radio for more on optimizing mitochondrial energy production.) This raises the question of whether oxidative stress is a mechanism by which exercise exerts health benefits, bringing us to the subject of today’s podcast.

 

Guest

In this episode of humanOS Radio, I interview Michael Ristow, Professor of biochemistry and physiology of aging, exercise, obesity, and type 2 diabetes in the Department of Health Sciences and Technology at ETH Zürich.

More than a decade ago, Professor Ristow’s research team had shown that reducing the amount of glucose available to roundworms prolongs the worms’ lifespans by activating their mitochondria and increasing oxidative stress in these organelles. (The worms were Caenorhabditis elegans, organisms with characteristics that make them exceptionally useful to studying longevity.) This vaccination-like response in which an organism’s mitochondrial function and hence resilience increase in response to an acute stressor that raises oxidative stress is sometimes called “mitohormesis”. This in some ways contradicts the widely-espoused Free Radical Theory of Aging that posits that oxidative stress is the main effector of senescence. Anyway, studies of mice by Professor Ristow and others had also provided preliminary evidence that mice that had been genetically modified in ways that reduce antioxidant signaling had improved blood sugar regulation – a key determinant of diabetes risk.

 

Mice that had been genetically modified in ways that REDUCE antioxidant signaling had improved blood sugar regulation – a key determinant of diabetes risk. Click To Tweet

 

Juxtapose the results of the above studies and you might speculate about whether reducing oxidative stress during exercise offsets its beneficial effects on blood sugar control. Professor Ristow sought to carefully answer this question, the product of which a seminal study in the field of exercise science.

 

Antioxidant supplements and exercise

In this study, Professor Ristow and his colleagues supervised a group of people while they underwent a four-week exercise program in which they did 20 minutes of cycling or running and 45 minutes of circuit training five times a week. Half of the participants took 1 g vitamin C and 400 IU vitamin E each day throughout the program. Before and after the intervention, Professor Ristow’s team assessed participants’ sensitivity to insulin, the only hormone that directly lowers blood sugar.

The results were remarkable: Whereas exercise increased insulin sensitivity in the control group, antioxidant supplementation negated the beneficial effects of exercise on insulin sensitivity. Not only that, antioxidant supplementation offset the exercise-induced increase in people’s own in-built (endogenous) antioxidant defense capacities – only the control group experienced this benefit.

This research built on previous work by Mari-Carmen Gomez-Babrera and her colleagues, who found that supplementing with 1 g vitamin C blunted how much people’s endurance performance increased during an eight-week exercise program, probably by reducing the formation of new mitochondria.

The key concept here is that excessive or mistimed intakes of some antioxidant supplements may not just be benign, it may actually be detrimental.

These early studies paved the way for the flurry of important research that has followed. We discuss this at length in the show, addressing topics such as:

• The critical distinctions between primary and secondary antioxidants.
• Effects of antioxidant vitamins on other health outcomes.
• Whether you can boost your adaptations to exercise by increasing exercise-induced oxidative stress.
• The potential promise of compounds (“exercise mimetics”) that recapitulate some of the signaling cascades by which exercise exerts beneficial effects.
• The potential promise of compounds (“calorie-restriction mimetics”) that recapitulate some of the signaling cascades by which calorie restriction exerts beneficial effects.
• Which micronutrients you may want to supplement with.
• Professor Ristow’s thoughts on the recent resurgence of interest in ketogenic diets.

 

This is a very important subject for our health. For this reason, we’ve included extensive notes on many relevant compounds below.  

 

Compounds that directly support mitochondrial mass and function

At several points in today’s episode, we discuss compounds that directly support the formation of new mitochondria and/or mitochondrial function. These include Pyrroloquinoline quinone (PQQ), Mitoquinone mesylate (MitoQ), ergothioneine, methylene blue, and nicotinamide riboside. 

You may remember from my conversation with Cal Tech Professor, Bruce Hay, that the reactive oxygen species generated by mitochondria can cause mutations to mitochondrial DNA (which is different to nuclear DNA). So, are reactive oxygen species healthy or unhealthy? It’s likely that the location of these signals is key. When the reactive oxygen species are in a cell’s cytosol, they often alter the activity of proteins (transcription factors) that modify the activity of many genes, resulting in beneficial effects downstream. But when oxidative stress is proximal to mitochondrial DNA, mitochondrial DNA damage can occur. This suggests that the following strategy may be advantageous:

1. Permit oxidative stress in the cytosol.
2. Decease mitochondrial DNA damage by reducing oxidative stress within the mitochondria (or by prevention mitochondrial DNA damage resulting from those signals).

Here are some compounds that are being evaluated to achieve these ends:

Pyrroloquinoline quinone (PQQ)

PQQ is not so much an antioxidant as it is a redox agent, meaning that it can act both as an oxidant and as an antioxidant. After acting as an antioxidant, a “master” antioxidant named glutathione can help recycle PQQ back into an active form. The advantage of this recycling is that PQQ can undergo thousands of cycles of antioxidant activity!

PQQ’s antioxidant activity is primarily directed at proteins near cells surfaces, and PQQ is involved in cellular growth and differentiation and has anticancer, antidiabetic, and brain health-promoting effects in some organisms. We know little about the effects of PQQ in humans, but it may help quench excessive inflammation and protect the brain against aging. It is plausible that PQQ enhances mitochondrial function in humans too.

Most relevant to this podcast, PQQ increases the activity of a signaling cascade involving PGC-1alpha. In Professor Ristow’s study, antioxidant supplements blunted PGC-1alpha responses to exercise. You needn’t worry about nuances of this pathway, but you should know that it is key to certain adaptations to exercise and stimulates the production of new mitochondria.

 

Mitoquinone mesylate (MitoQ)

MitoQ is very similar to coenzyme Q10 (technically, it’s an “analog”). Like PQQ, coenzyme Q10 is a “pseudovitamin” (it is needed for life, but dietary deficiency doesn’t lead to disease) that is important to mitochondrial energy production. The difference is that MitoQ is bound to a negatively charged, lipid-loving ion, the result of which is an affinity for the site of the most oxidative stress within the mitochondrial matrix.

Mitochondrial dysfunction in neurons contributes strongly to neurodegenerative diseases such as Alzheimer’s. MitoQ has been shown to thwart oxidative stress and protect against the formation of toxic levels of a sticky plaque known as β-amyloid in mouse neurons. As a result, MitoQ protects against hallmark characteristics of Alzheimer’s in mice. More recently, a study of isolated dopamine-producing neurons found that MitoQ alleviated damage incurred by excessive oxidative stress by activating PGC-1alpha. Loss of such neurons in a part of the brain named the substantia nigra is a central driver of Parkinson’s disease.

Finally, adding MitoQ to the drinking water of mice fed high-fat, high-sugar diets may support liver function and protect against obesity by reducing calorie intake and increasing energy expenditure. Please understand, however, that not all studies (see this one, for example) have found any advantageous effects of MitoQ, and we know little about its actions in humans yet. To date, the studies of humans have not shown many beneficial effects of MitoQ supplementation. This study, for example, found that MitoQ had no effects on how people responded to an exercise training program. MitoQ is also very expensive! MitoQ seems promising, but time will tell if it’s worth the investment.

 

Methylene blue

Whereas our knowledge of applications of compounds like MitoQ is nascent, methylene blue was first synthesized in 1876 and is used in medicine for various purposes, from treating malaria to taming septic shock. It’s also used as a dye, and your tongue goes a really cool color when you take it. Findings from recent studies suggest that methylene blue is remarkably effective in protecting other animals from a variety of brain pathologies, from Alzheimer’s to Parkinson’s to traumatic brain injury, and methylene blue is a strong candidate for people seeking ways to offset declining brain function with advancing age.

Such neuroprotection seems to reflect several effects of methylene blue on mitochondria. Specifically, methylene blue redirects electrons within the electron transport chain. This is a series of complexes that shuttles positively-charged hydrogen ions out of the mitochondrial matrix. The result is a charge gradient that is then used to transport the hydrogen ions back into the matrix through an enzyme named ATP synthase, generating ATP (the “energy currency” of your cells) like water flowing through a turbine. Don’t sweat the specifics, but methylene blue increases the activity of complex IV in this chain, and the result is increased mitochondrial activity but reduced oxidative stress. I’ll add that effects of methylene blue are not confined to the brain either. And the good news is that methylene blue has been used in humans for some time, so we know a lot about its safety profile.

 

Ergothioneine

Few organisms make this amino acid. Among these are certain bacteria found in our guts, such as actinobacteria and cyanobacteria, as well as certain mushrooms. Importantly, ergothioneine is concentrated in mitochondria, so it can protect mitochondrial DNA from the oxidative damage that occurs when mitochondria generate an oxidant named superoxide. Again, when mitochondrial DNA is damaged and mutates, the mitochondria produce proteins that are less effective at making energy. Finally, since there is an association between the composition of a person’s gut microbiota and how long they live, could ergothioneine made in the gut and transported to cells influence longevity? This is speculative but interesting.

 

Nicotinamide riboside (NAD+)

NAD+ dysregulation tends to coincide with mitochondrial dysfunction and metabolic health impairments. NAD+ is an enzyme cofactor. Cofactors assist in enzyme activity, performing certain, necessary, reactions that enzymes cannot perform alone. But NAD+ is also a signaling molecule, acting substrate for enzymes such as SIRTUINs (SIRTs), a family of seven enzymes (aptly named SIRT 1 to 7) in us mammals. SIRT1, 2, 6, and 7 are located in cells’ nuclei, SIRT 1 and 2 are also found in the cytoplasm, and SIRT 3, 4, and 5 are mitochondrial. Collectively, SIRTs have pivotal roles in numerous cellular processes, from inflammation to resilience to stressors such as calorie restriction.

These functions implicate NAD+ in aging, so it should be no surprise that people are intrigued by ways to amplify NAD+ levels in their quest for the elixir of life. Scientists have explored multiple dietary means of boosting NAD+, several of which support NAD+ synthesis by providing its precursors. NAD+ precursors include compounds as quotidian as niacin, but there’s nothing very sexy about vitamin B3. Media have latched on to nicotinamide riboside (a precursor vitamin found in milk) as a potential anti-aging elixir in recent times. The irony is that we’ve known about nicotinamide riboside for several decades!

Ingestion of nicotinamide riboside dose-dependently increases blood NAD+ in humans, and supplementing nicotinamide riboside and pterostilbene (a polyphenol found in blueberries) appears to be safe. This is a good start. In mice, nicotinamide riboside activates SIRT1 and SIRT3, supporting mitochondrial function and blunting the adverse metabolic consequences of a high-fat, high-sugar diet (1, 2). Better yet, nicotinamide riboside reportedly acts on mitochondria in aged mice to increase muscle stem cell numbers, improve muscle strength, and prolong lifespan. And nicotinamide riboside may act centrally too, for it bolstered PGC-1alpha expression in the brain, offsetting β-amyloid production and cognitive decline in a mouse model of Alzheimer’s.

Nicotinamide has several characteristics that make it an especially attractive NAD+ stimulator, such as its whole-body effects and actions on both nuclear and mitochondrial SIRTs (SIRT1 and 3, respectively), but we still know very little about its effects on humans!

 

Calorie restriction mimetics

A class of compounds that we discuss in today’s show is those that mimic calorie restriction, generally by inhibiting the breakdown of sugar (glycolysis). Restricting calories tends to boost endogenous antioxidant defenses, reduce activity of signaling pathways broadly implicated in senescence (like IGF-1 and mTOR), and stimulate cascades involved in mitochondrial function and longevity (such as AMPK and FoxO). The result is lifespan and healthspan extension in many organisms, including some non-human primates.

The problem is that long-term calorie restriction sucks – it’s just not sustainable for most people. So, what about dietary compounds that simulate calorie restriction?

Calorie restriction mimetics can act at different levels within the process of energy metabolism. Those that act as early in this process as possible (the digestive system) are arguably the most attractive candidates, for they’re likely to have the most wide-ranging effects. These include ways to inhibit digestion and hence increase excretion of calories. A relatively new class of antidiabetic drugs (SGLT2 inhibitors) accomplishes this by reducing the amount of sugar absorbed in the kidneys, thereby increasing sugar excretion in urine. Other calorie restriction mimetics act further along the chain of energy metabolism, targeting things like the SIRTs. For this reason, some of the compounds discussed above are calorie restriction mimetics too. In this episode we also touch on several calorie restriction mimetics that may inhibit glycolysis, including chitin, chitosan, and glucosamine.

 

Blocking the renin-angiotensin system to boost mitochondrial function and slow aging?

Finally, we briefly touch on a novel approach to improving mitochondrial function and staying youthful: blocking the renin-angiotensin system. When you think about this system, the first thing that probably comes to mind is a series of enzymes and peptides produced by the adrenals and kidneys that influences fluid balance and blood pressure. It was therefore fascinated to learn that this system also modulates many of the molecular targets discussed above, including mTOR and SIRTs.

Not only that, but one of the hormones in this system (angiotensin II) may have other effects. Angiotensin II boosts blood pressure by stimulating vasoconstriction and raising production of two hormones (aldosterone and vasopressin) that increase fluid retention. Interestingly, angiotensin II acts in several ways to amplify oxidative stress within some mitochondria, thereby contributing to the dysfunction of these organelles. As a result, medications that block angiotensin activity may emerge as anti-aging drugs. These include angiotensin converting enzyme (ACE) inhibitors and drugs that target angiotensin II type 1 receptors.

But are drugs the only way to intervene? It seems not. A recent review reported that more than 70 families of plants have ACE inhibitory activity. Furthermore, at least 16 plant families may block angiotensin II type 1 receptors. Exciting times!

 

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Contributions

Dan prepared for and conducted the interview and wrote the ergothioneine section of this blog post, Greg wrote the other sections of this blog post, and Professor Ristow did the hard work!

 

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TRANSCRIPT

Micheal Ristow:	00:06	Specific antioxidants like vitamin E or A or beta carotene are actually increasing cancer rates and shortening life span, so most people are still not aware of that, and they’re still taking it.
Kendall Kendrick:	00:18	Human OS. Learn, master, achieve.
Dan Pardi:	00:29	Okay. Professor Mike Ristow. Welcome to Human OS Radio. I’ve been aware of your work since your seminal findings looking at the effects of antioxidants on the effects of exercise, and I’d like to get into that more in a moment. Generally, your work is looking at the cellular bioenergetics and how cells produce energy, in particular, a very in-depth look at mitochondria, so I very much look forward to a discussion on that today.
Dan Pardi:	00:48	To start off, perhaps we can go back to that seminal work looking at the effects of antioxidants on exercise. Tell me what the prevailing thesis was at the time about how antioxidants were good for exercise and for the body.
Micheal Ristow:	01:02	Back then I was mainly working on diabetes and getting more and more into mitochondria, these little organelles that produce energy in the cell. What we observed is that activating mitochondria would improve [inaudible 00:01:17] and, essentially, have an anti-diabetic activity. Now, what I always was confused during those years was that activating mitochondria produces more oxidized stress or reactive oxygen species than down-regulating mitochondria. So the conundrum was how can an increase in oxidative stress ameliorate a metabolic disease like diabetes but also other diseases? The idea that arose back then is maybe reactive oxygen species do something that is not entirely harmful but rather health-promoting. We weren’t the only people observing that there were other lapses that also had early experimental evidence for that, but everyone was kind of hesitant to really nail it down and to make the claim there is a function for reactive oxygen species.
Dan Pardi:	02:06	Can you tell more details about the subjects that were used in the protocol?
Micheal Ristow:	02:10	Okay so the current state back then was periodicals of that and antioxidants, mainly vitamin E or vitamin C that inactivates free radicals would improve health. And that has been around for decades. It started in the late 1950s and increasingly got prevalent in the 70s and 80s, and so forth, and everyone always knows. So what we did, based on the possibility that these periodicals have some health-promoting functions, we did a clinical study based on lab work which we did before, but this clinical study consisted of 40, mid-20 year-old men, and we randomly subdivided them into two groups. One group would receive a cocktail of antioxidants on a daily basis, and the other would receive the so-called placebo, which is identical-looking pills that contain not anything useful, so no antioxidants at all. And these 40 people, then, underwent a exercise regiment over four weeks, on a daily basis, except for Sundays, and we took samples before they started this and afterwards.
Micheal Ristow:	03:16	The idea was to test whether the health-promoting effects of exercise would be influenced by antioxidants and the placebo control group essentially was the were we would anticipate not having any effect by these pills. The outcome, in brief, was that exercise is healthy, so it promotes all types of parameters that are known to be associated with longevity, and so forth. [inaudible 00:03:39] went down, and cholesterol, and so forth. However, the group that would on antioxidants, we did not see any effect of exercise, or at least the effects were strongly reduced. The unexpected conclusion was antioxidants interfered with the health-promoting effects of exercise, and the confusion mechanistically being the free radicals that are produced during exercise are really the cause for exercise being healthy.
Dan Pardi:	04:07	Yeah. This became a global news story, because it so counter to what people had expected at the time, and that thesis had been prior to that, antioxidants would reduce the damage which would actually would help people have a greater training effect. But this seemed to be the opposite. What were some of the molecular mediators of the effects of exercise that were then inhibited in the presence of antioxidants?
Micheal Ristow:	04:28	Since this was a human study, there are quite a few limitations to really study that in depth, but what we observed during that study, that there’s certain, previously established transcription factors and proactivators, lines called PGC-1Alpha, that is activated by exercise levels, known for a long time. It was also know that free radicals may activate that and what we could show is that in the presence of antioxidants, this factor was not activated, or activated to a reduced extent. That is one explanation, mechanistically, but really, the real mechanistic basis, we noticed it in other model organisms. We’d like to work with small worms that are easier to study, and so forth. There are so-called molecular switches that respond to free radicals, and get activated, and then they downstream activate further mechanisms, especially defense mechanisms, not only against oxidant stress, but against other stressors, against DNA damage, and so forth.
Dan Pardi:	05:24	So when we exercise, we are increasing the flux of energy that’s going through the mitochondria. That produces more reactive oxygen species and to those reactive oxygen species are actually good, because they trigger a series of molecular mechanisms that not only help to improve physical functioning, that exercise response, but also have secondary health benefits that are a direct result of the stress that is induced from the exercise.
Micheal Ristow:	05:45	That’s absolutely accurate. Yes.
Dan Pardi:	05:47	Tell me a little bit about the timing of the antioxidants relative to when the exercise occurred. Was that consistent?
Micheal Ristow:	05:53	That was pretty consistent, but there are follow-up studies in different regiment, timings and so forth. If you want to summarize that, essentially, there is a number of studies that observe pretty much the exact same effect that we observed. And then there’s other studies that did not consistently see that antioxidants would impair the training effects, but there is not a single study showing that antioxidants would help at all. I think it’s pretty irrelevant when the antioxidant … you take it before or after, and cause … that probably does not make a difference. It may have some positive effect, and I’m sure we have not done that, but there’s some literature that during a long-distance race, like a marathon, potentially antioxidants before could have an effect. The evidence is not great, but I don’t want to leave that confusion out, so you may want to know that.
Micheal Ristow:	06:45	For people who want to increase fitness or muscle mass or endurance, there are multiple studies out there, and they pretty consistently say either it has no effect or if there’s an effect, it’s a lot of [inaudible 00:06:57].
Dan Pardi:	06:57	The key questions for me were about timing. Would it matter if you took the antioxidants before or … hours, and if so, how many hours? What about the effects of different types of people that were doing the protocol? Are they young and healthy, or old and possibly have some metabolic derangement?  And then, also, what is the magnitude or actually training? Is it heavy weight training? Or is it endurance? Do you get to the point where you’re producing so many free radicals through really long, extensive exercise, then the antioxidants could have a benefit? But how would you know to mediate that? Hard to project, I’d say.
Micheal Ristow:	07:26	There is different studies out in the literature that have addressed some sense of your questions, but I especially agree with elderly people exercising … there is very little literature on that. And I could very well imagine that they may be different observations from what we see in young people, but that’s pure speculation. So, I can’t exclude that, but again, evidence is [inaudible 00:07:49].
Dan Pardi:	07:48	Had any work been done since then that looked to augment the training effect by increasing the amount of reactive oxygen species? I know that arachidonic acid had been looked at in some circles.
Micheal Ristow:	07:58	Yes. That’s an excellent question, and the answer is implicitly, yes; explicitly, no. Let me explain that: there are quite a few compounds that have been tested in regards to increasing exercise performance and they have different names, including exercise magnetics, so they mimic training. They don’t train, but they just go and make your body think you were training, so capacity increases, and so forth.
Micheal Ristow:	08:26	Either of these compounds which are effective for different extents, but there’s few around, include a so-called polyphenols. Polyphenols are compounds found in many plants, and especially lots of fruits and berries, and these compounds, to a limited extent, but successfully have such an effect. Now, we know from other studies, some more basic science-oriented studies, on the exact same compounds, that they indeed increase reactive oxygen species in cells [inaudible 00:08:54] organisms. So, if you put these seemingly independent evidences together, that would imply there are compounds that are known to increase oxidant stress, that are independently known to increase exercise performance. So, my [inaudible 00:09:08], that would mean, compounds work to a limited extent increase oxidant stress could also be used as mediators [inaudible 00:09:16] as performance.
Dan Pardi:	09:17	That seems to be a confusing thing in the literature, so what polyphenols and other plants substances are called antioxidants, but they’re really antioxidants producing compounds, because they’re actually stressful. They’re xenohormetics, and yet they’re all called antioxidants, and that, I think does a disservice to clarity.
Micheal Ristow:	09:33	Seems you got very thoroughly prepared for this meeting! Yes. It’s not, because almost no one knows that, but what you are saying is exactly right. There’s a huge confusion about what I call primary antioxidants and this includes Vitamin E and Vitamin C, and so-called secondary antioxidants. These are compounds like polyphenols which are not directly inactivating reactive oxygen species, but rather they induce a stress response in the cell or in the human body that prepares us to be in a better a defense state against oxidative stress. In the long run, this will lead to lower levels of oxidative stress during normal life, but also exercise based on the fact that we exposed ourself to compounds that increase oxidative stress for a short period of time, repeatedly, by ingesting them on a daily basis, or twice a week, or whatever.
Dan Pardi:	10:26	On the subject of some of the mediators of positive benefits on production of endogenous antioxidants, superoxides dismutates 1 and 2, and glutathione peroxidase, and mediators of insulin sensitivity, like PPAR-gamma and PPAR-gamma co-activators. Talking about exercise memetics, PQQ seems to mediate its effects through activation of PGC-1Alpa, like taking compounds like polyphenols across a lifespan would be good for somebody to have across their whole life, or is it something that becomes increasingly beneficial once somebody reaches a certain age?
Micheal Ristow:	10:56	Personally, I’ve not been working on DT2, but I’m aware of this and related compounds like G10, and they directly interact with the exact place where free radicals formed in the cell also during exercise. And the exact mechanism of action is not established, but it’s quite possible that interfering with mitochondria electron transfer by compounds like [inaudible 00:11:19], so [inaudible 00:11:20] production of reactive oxygen species, so it’s quite possible that this is, again, the same effect as with polyphenols, and things we talked about before.
Dan Pardi:	11:29	I’ve heard you mention the benefits of glucosamine on longevity. What is glucosamine typically used for? And what is your opinion about it’s ethicacy there? And then what are excited about glucosamine for, relative to longevity and cellular health?
Micheal Ristow:	11:44	Glucosamine is a normal intermediate of a breakdown glucose in the human body. It’s naturally produced but only very little amounts. It’s very similar to sugar, but it does not provide energy and does not cause more [inaudible 00:12:00]. It’s been in use by humans for many decades to restore joint health. The idea is that glucosamine could increase cartilage massa and cartilage growth, so if you feel like your knees are not working properly during running, taking glucosamine for a long period of time was the standard application to improve that. Now, there have been quite a few large control studies on whether glucosamine is really effective there, as previously [inaudible 00:12:28], placebo controlled, so there was really an objective [inaudible 00:12:32]. The outcome is not really clear and I personally think the evidence is shaky, however, what has been established by millions of people taking glucosamine, is it totally harmless. There is no side effects and people for years and, at least, they don’t suffer any damage.
Micheal Ristow:	12:53	It certainly may impact their willingness to exercise, which is a side effect, but certainly important, and see there are data over 80,000 people at … which live in Washington State. They have been observed, and whether glucosamine would decrease their risk of dying. So, it’s a large population; you can quantify the likelihood to die. What turned out to be the case is that those people who took glucosamine had about 20% reduced risk of dying as compared with those people who did not take it. Which is huge. So, [inaudible 00:13:26] healthy eating [inaudible 00:13:28] effects more than 15%. This is an observational study which is not a proof, really, that glucosamine is the cause, but in addition to our data and worms and mice, where glucosamine very consistently extends lifespan, it’s a very good support for this supplement being potentially very useful.
Dan Pardi:	13:48	What are the mechanisms by which glucosamine is exerting its effects?
Micheal Ristow:	13:51	What glucosamine is doing … it interferes with the breakdown of glucose. We know glucose is a component of all sugars, and a sugar is something that provides energy to the cell in a manner that is independent of the mitochondria. Mitochondria are the place where a lot of energy is converted, however, providing a lot of sugar as a nutrient essentially shuts off the mitochondria, because they are not replenishing them. By contrast, exercise, for example, depends on the mitochondria, at least exercise that lasts longer than two-three minutes. What exercise is doing is forcing the mitochondria into activity. What sugar is doing is shutting down mitochondria.
Micheal Ristow:	14:31	Having said that, what glucosamine is doing is interfering with this mitochondria independent energy provisions, so what the organism has to do with it’s own glucosamine … it is forced to activate its mitochondria like it is when it exercises. The idea is to mimic a carbohydrate-reduced diet by providing glucosamine. Whoever takes glucosamine is not capable of forming/metabolizing carbohydrates and sugar anymore, and tries … switches to mitochondria metabolism, which is more focused on fatty acids. That’s the idea. Again, what it comes down to is mitochondria producing small amounts of free radicals … that’s what we see in animals ,,, is the cause for increased longevity.
Dan Pardi:	15:16	Most people take glucosamine for joint health. The effects on joint health is suspect, but one thing that has been clearly shown is that it’s safe. Most interestingly, though, are the geroprotecting effects that associate with its usage. In other words, people who take glucosamine have comparatively 20% reduction in premature mortality. And a way that it might be working is by inhibiting glycolysis, forcing more energy production to occur through the mitochondria instead of glucose metabolizing pathways when you are metabolizing carbohydrates. And by doing this, glucosamine has an exercise memetic effect, causing more free radicals to be produced, and initiating the downstream benefits of that homeotic stimuli.
Dan Pardi:	15:54	What about other glycolysis and [inaudible 00:15:56], like xylitol, or chitin? Would you be inhibiting glycolysis too much if you’re taking all of these glycolysis inhibitors?
Micheal Ristow:	16:02	I think the compounds you just mentioned, the chitin and others, have been less well-studied. The other compound that has been studied in detail is deoxyglucose, which has been used in cancer therapy since the 1970s, but deoxyglucose is very difficult to dose, and it becomes toxic when you overdose it, so that is not a choice. Chitin and other things that are on the market systematically, to my knowledge, they have not been studied. I cannot exclude them. They may be helpful, but the evidence, at least to what I know, is very limited. However, I think It might be worth studying them a bit more in detail.
Dan Pardi:	16:36	We just published a blog last week on eating bugs, and how there’s over 2000 different cultures around the world that eat bugs, and many different species of them. And chiton, for the listener, is part of the exoskeleton, and it was probably just a regular part of the human diet, even though the evidence, like you said, is fairly scarce.
Dan Pardi:	16:53	It’s a new idea of westerner worlds to think about bugs as a healthy source of food.
Micheal Ristow:	16:57	I’ll put that on my list …
Dan Pardi:	17:00	Great! About glucosamine, similar to the questions about antioxidants, the timing about antioxidants relative to exercise, what about the timing of glucosamine? Do you have any visibility into how much we need to be taking per day to get that effect that was seen in the Washington study? And does timing matter? So, would you want to have glucosamine, let’s say, before a meal, so that it’s inhibited glycolysis?
Micheal Ristow:	17:19	That’s difficult to answer. With the animal experiments, we would just provide it through the food, so whenever they would eat, they would automatically eat a certain portion of their daily allowance of glucosamine. Certainly, that doesn’t work for humans, however, there are no systematic studies in humans on longevity or lifespan. With glucosamine, the upstate Washington study I just cited was observational, so we don’t even know when people took it. What really needs to be done is a controlled intervention trial, where people are systematically given either placebo or glucosamine, and if you define dose, and you define time of the day, and then wait for ten or fifteen years and see what the incidence of diseases is, what the mortality is. This, of course, is very expense and time consuming, plus it is not so interesting for the industry, since it’s difficult to patent. And the financial impact is limited from an industrial viewpoint.
Micheal Ristow:	18:16	When talking to people who might fund [inaudible 00:18:19] and institutions, but it’s a [inaudible 00:18:21]. But which only applies to glucosamine, metformin in the US, and the [inaudible 00:18:26] study that has been [inaudible 00:18:27] approved by the FDA faces its own problems, so nobody really wants to finance that. We should emphasize something here: it’s not about the living longer. It’s about extending period of life where you’re healthy without really effecting the total lifespan.
Micheal Ristow:	18:43	More like the quality of life improves, and that is good for the individual, but importantly, healthcare costs drastically decrease, if one of these interventions would work systematically in humans. The societal impact would be huge by reducing our costs by up to 80%. There’s colleagues who have calculated that. Eighty … Eight zero percent. While the individual’s point of life would … there’s almost no intervention in society that is good for the individual, as is good for the entire society. I think health insurers and also the government should be very aware of this, and also think about this to fund studies like this, and then also support people participating in such types of studies.
Dan Pardi:	19:26	I am interesting to see if we can extend maximum human life span. That’s going to take technology that is beyond our capability now, but for now, as David Katz says, “Have more life in your years.” The societal cost is massive, but the cost of the individual is huge, you just get to live a better life for longer. And we all want that.
Dan Pardi:	19:46	Let’s switch gears, talking a little bit more about the relative quality of the different mitochondrial targeted antioxidants, and how to best determine how they’re good, because we have different types. We’ve talked a little bit about PPQ. There’s now been more interesting, something called MitoQ. Coenzyme Q10 has been used for quite a long time. It’s fairly popular. There’s methylene blue. And so, when you’re assessing the impact of a potential mitochondrial effecting agent, what are the things you look for? Think would be a good way to intervene? Without disrupting or interrupting the processes that we also want to have happen, by stimulating the mitochondrial biogenesis?
Micheal Ristow:	20:19	I’m naturally aware of all these compounds. Some of them have been the studied in detail in regards to their exact mechanism. Others … we don’t actually know how they function, and quite a few of these compounds target a subunit within the mitochondria that is known to produce small amounts of a free radicals when partly inhibited, and that’s the so-called complex one of the electron transfer chain that essentially is a very important part of the mitochondria. Is very sensitive to [inaudible 00:20:49] compounds.
Micheal Ristow:	20:50	And many compounds have been shown to act exactly there. Also compounds where you would not ever imagine this is happening … one very interesting observation, for example, is that the most famous group of a cholesterol lowering drugs, the so-called statins, they very effectively have an inhibiting effect on this part of the mitochondria. So does metformin. So do many other compounds. And quite a few of those compounds that are on the market to specifically target the mitochondria, may either work through this mechanism, or mechanisms closely related to that. I’m not saying there is an established common denominator, but I’m pretty sure it will emerge within the next five to ten years, to always come down to a very similar proof of [inaudible 00:21:35].
Dan Pardi:	21:36	Yeah. Interesting.
Dan Pardi:	21:37	And, have you had a chance to look into methylene blue much?
Micheal Ristow:	21:41	No, I haven’t, but not because I don’t find it interesting. It’s more like it was not too much related to our initial focus on energy metabolism, but I think it’s a promising compound. I’m aware of ongoing studies elsewhere that may look very promising. Of course, I can’t really talk about that, but from what’s published, it is certainly interesting.
Dan Pardi:	22:02	We’ve talked about exercise memetics. Are there any calorie restriction memetics that you feel are promising? So, things like nicotinamide riboside or oxaloacetate? What is your opinion about those calorie restriction memetics?
Micheal Ristow:	22:13	Anything dealing with the nicotinamide in a de-metabolism certainly is a very valid target. This is related to a group of proteins called citrines, and citrines are well established to have a huge impact on the aging processes, and also currents of diseases into [inaudible 00:22:32]. Now, the real compound is NAD+, which is an essential cofactor for these storage units. And any plus, unfortunately, is very unstable, so you can’t store it at home, and if you swallow it, it’ll never reach the cell because it will decay. What different labs and different companies have done is look for precursors or intermediates that in the end get converted into energy plus in the cell, and get active there.
Micheal Ristow:	22:57	And there is a number of potential compounds, solitaire nicotinic acid works, [inaudible 00:23:03], both of which out there for at least five decades. The newer ones [inaudible 00:23:08] riboside, and others essentially do a similar thing. And there’s lots of debate: which are more efficient and more directed line to the cell? A comparative study precisely addressing that is lacking, but to sum things up, whatever deals with NAD metabolism, I totally approve. And for some of these compounds would be great to have a few more larger that address that in a proper scientific way with control, but again, this same with restraints as previously mentioned for glucosamine and metformin, also apply here. It’s not a criticism, it’s just scientifically speaking, this is not.
Micheal Ristow:	23:41	So, other compounds that interfere with not only a nutrient metabolism, with many calorie restriction, are out there. Some of them have been studied in mice, but there are also found in humans. If we want to do that systematically, there’s a compound called acarbose, which is a drug that is swallowed and that prevents enzymes and all that, to release the sugar from carbohydrates. The consequences, you can eat a pizza or tons of pasta, but the sugar contained within will not ever reach your blood or the inside of your body, but will rather be excreted through the guts.
Micheal Ristow:	24:17	This is very efficient in avoiding caloric overload. The problem being that the [inaudible 00:24:22] carbohydrates and they produce lots of gas from that. You can imagine that the side effects are socially not too compatible. That’s a problem. A new drug that may be promising, but has not been studied in this regard is increasing the excretion of glucose through the urine. It’s already being used to treat Type II Diabetes and the positive side effect looses energy by losing glucose, instead of metabolizing. It lowers blood sugar and it causes loss of energy through urine. And since it’s pretty brand new drug, it well need to be seen whether this is functional as a calorie restriction memetic, but I would think it could be promising. And so, we will see about that.
Dan Pardi:	25:05	And that’s a drug [crosstalk 00:25:06]?
Micheal Ristow:	25:05	That’s a drug.
Micheal Ristow:	25:06	And then, of course, there’s shifting your eating regimen. I personally think that caloride rates are overrated by the official [inaudible 00:25:15] recommendations. Nowadays, it’s still around 50% [inaudible 00:25:20] caloride rate. I don’t mind caloride rates, as long as they contain lots of fiber, and as long as you eat [inaudible 00:25:26] takes a long time to eat, otherwise, but unfortunately, most caloride rates are not in that state, but rather in sugar rate or processed pasta or whatever state, and that definitely is a problem. There’s lot evidence on that.
Micheal Ristow:	25:40	Replacing carbohydrates by high fiber or low carbohydrate components always is a good idea, as long as you don’t replace it with meat or something, because meat has added disadvantages that would totally destroy the effect of reducing the caloride rates.
Micheal Ristow:	25:55	And then, there’s lots of not so well studied components that may interfere with nutrient metabolism within the body, but I think relevant ones we’ve been discussed already.
Dan Pardi:	26:06	So, are most of the mechanisms that we’re discussing here either through calorie restriction, carb production, or exercise, do they have a common place where they meet? It sounds like many of them still acting, really, on the same energetic pathways, but doing so in slightly different ways, or really the same way, once you kind of get farther enough down the biochemical chain.
Micheal Ristow:	26:24	I think quite a few of these interventions essentially target voluntarily or involuntarily the mitochondria-
Dan Pardi:	26:31	Yeah.
Micheal Ristow:	26:31	-where we started off. And the majority of those with the mitochondria produces raw signals that cause the effect. Not all, but quite a few. Then a rather independent set of interventions is in the range of energy plus [inaudible 00:26:47] certainly relays compounds, though they all seem to act with mitochondria, but there is quite a few effects that are independent of the mitochondrial pathways. And then there’s effects where we still don’t really know how they act, but certainly they do. And that includes quite a few chains and ways to activate chains without us really knowing all that’s happening. That’s a big matter of debate.=, and of course, there’s quite a bit of research going on in this area.
Dan Pardi:	27:13	Two more compounds to discuss: ergothioneine and then angiotensin [inaudible 00:27:17]. Do you think that those are providing anything novel relative to what we’re speaking about, or is it, again, just another way to get at what we’ve discussed?
Micheal Ristow:	27:24	I’m not sure, but I have to say that my knowledge on these specific compounds is limited, and I’d rather refrain from judgmental comments on them. There’s so many potentially promising compounds out there, for me as a scientist it’s always, like, show me the evidence, show me in [inaudible 00:27:39] tiny worms that they profit from getting these compounds. And then ideally some human study that quantifies evidence on that. And, again, it’s not blaming companies not doing that. I know it’s difficult and expensive, but really, before we can judge whether it’s worth trying or not, I think that is required.
Micheal Ristow:	27:57	As long as we can be sure there’s no harm done by whatever compound it is, it won’t be totally okay that people just try it out and see whether it works without having proof or not. When it becomes difficult, Like with certain antioxidants, and opposed to that, I’ve acknowledged for 15 years now that specific antioxidants, like vitamin E or A or beta carotene, actually increases cancer rates and shortening lifespan. Most people are still not aware of that, they’re still taking it. And, again, it’s not like they’re harmless and not having any effect. The problem is they have a detectable increase in mortality rates, cancer rates, and that’s a problem that should be conveyed.
Dan Pardi:	28:34	Do you think that the natural amounts that we find in food, if we’re eating natural amounts, then we’re fine? Or should we be careful to actually even consume food that contain high amounts?
Micheal Ristow:	28:44	Not at all. Don’t get me wrong here. When we talk about is this active supplementation with normal to large doses of specific antioxidants, I can’t trust whatever you could imagine never contains the amounts of antioxidants that come even close to what is contained in supplements. What we should remember is foods are not healthy because they contain antioxidants, and especially vegetables and certain foods are not healthy because of that, this happens independent of that. I’m pretty sure if there was a way to produce an apple or carrot or a broccoli not containing antioxidants, it would be as healthy or maybe even slightly healthier. But again, the reason why fruits and vegetables are totally advised, and totally health promoting are not mediated by antioxidants, they’re mediated by other things in there, including polyphenols, as talked about earlier, and people should not at all stay away from them.
Micheal Ristow:	29:38	What they should stay away from is supplements that contain certain antioxidants. I’m not opposed to an [inaudible 00:29:44] of supplements, as you may have realized. There’s also certain vitamins that are health promoting, like vitamin A, E, Beta carotene, and certainly do not belong in there.
Dan Pardi:	29:53	So, if you’re looking for a multivitamin, it might be better to just look for one that has more of a multi-mineral-
Micheal Ristow:	29:59	It is very difficult to be undernourished with vitamins and micronutrients in Western society. There are certain supplements I totally endorse. For example, vitamin D, especially, in Winter, when there’s little sunlight. Also for especially women, aged beyond 40 to prevent osteoporosis, that’s all good. Also for children. And then there’s other things like folic acid for women whom may become pregnant. They should take it before they become pregnant. Once they know, it’s too late anyway. So, totally okay, Selenium, big debate in North America. I would stay away from that. In Europe … very different situation. There is too little selenium in the soil, so in Europe, I would promote taking it.
Micheal Ristow:	30:40	You really have to go for the details. Zinc, same thing. Zinc is known to protect from flu and things, studies supporting that … would I take zinc on a regular basis for that reason? No! Same for magnesium. Lots of cramps? Get a regiment of magnesium. If you have cramps, take it. Supplement it on a regular basis? [inaudible 00:30:57]
Micheal Ristow:	30:57	I personally think there’s no reason to have a general supplement on a daily basis, except for certain subgroups, like vitamin D, which in most studies really has been proven to be a good thing.
Dan Pardi:	31:11	There is the idea that, if something’s good for you, then more is better, but going back to the idea of getting most of your nutrients from whole foods is a very smart idea, and yet at the same time there do seem to be some things that make sense to supplement with as we’re discussing. One of the things that was not mentioned so far: are there other minerals that you feel are interesting? Like lithium for lifespan?
Micheal Ristow:	31:31	We’ve been working with lithium in the past [inaudible 00:31:33], and also others, including Gordon Lithgow at the Buck Institute.
Dan Pardi:	31:38	Yeah.
Micheal Ristow:	31:39	[inaudible 00:31:39] and we both independently observed that lithium in our worms extends lifespan. What we did then, in a collaboration with a Japanese group was , the Japanese colleagues had published a study where they correlated suicide rate with lithium concentration in normal tap water. What they observed is that they more lithium people have through tap water, the less likely they are to commit suicide. Now, lithium, since the 1920s, has been used to treat psychiatric disease, and the idea of my Japanese colleagues was that providing a little lithium through drinking water, inadvertently make you happier and prevent suicide.
Micheal Ristow:	32:17	Very interesting. We thought, oh great! They not only have suicide rates but they probably also have mortality rates and average lifespan, so what they analyzed on the same data set was the link between lithium concentration in drinking water and average lifespan. Indeed the more lithium in drinking water there’s the more likely you are to reach a certain age.
Micheal Ristow:	32:38	Now, again, this is not people supplementing this, as far as lithium contained in drinking water, and since then, I occasionally get emails from people asking about this mineral water from some Italian mountain that has a high lithium concentration. Do you think that I’ll live longer if I drink it? I can’t tell you, but there’s a certain chance to do that.
Micheal Ristow:	32:56	There was another full on study from a large population in Texas. Seeing the exact same thing as seen in japan. This is interesting because genetically. People in Texas are quite heterogenous and definitely distinct from Japan. It seems to apply to different populations but we are far from saying, “Okay, there should be a low dose lithium supplementation to promote longevity.”
Micheal Ristow:	33:18	Is this a possibility? Maybe. Is the evidence for that sufficient? I wouldn’t think so. The problem with lithium is it can be easily overdosed, and people who were treated with lithium for psychiatric diseases are always on the verge of overdosing. The side effects are kind of dangerous. The drinking water lithium is 10,000 times lower, but still I would definitely not recommend to anyone on a personal basis to try to obtain lithium, and then try it out. Chances are you would overdose it, significantly.
Dan Pardi:	33:45	So, there appears to be consistent evidence that some amount of lithium does seem to be a good thing for longevity, but you can over do it, so we don’t know where that sweet spot is yet, and how, exactly to dose it. But if you have a higher amount in your water, that seems to be a good thing. But it’s still a very low amount relative to a dosing schedule for somebody that would take it for psychiatric issues.
Micheal Ristow:	34:04	Exactly. So, don’t go for the pills. That is way too much. And if you find drinking water or mineral water that contains a certain amount of lithium, that’s certainly safe, and that’s totally unproblematic, and maybe even healthy.
Dan Pardi:	34:15	I interviewed Copes a while back, and he and then worked directly on C elegans, looking at the mechanism of action for beta hydroxybutyrate extending lifespan. Basically, there’s two different mechanisms by which it seems to do so, but activation of focile at four and also enter in FG pathways, so again, that seems to be mediated by the production of reactive oxygen species through the metabolism of beta hydroxybutyrate through the mitochondria. So again, we’re seeing a lot of things coalescing. Have you had a chance to look into [inaudible 00:34:40] diet yourself, and what are your thoughts on it?
Micheal Ristow:	34:41	We have personally not actively studied that, but I’m in contact with different labs, including [inaudible 00:34:46] Reading, and I find that work very fascinating, since absolutely matching my perspective on reactive oxygen species and our [inaudible 00:34:54] direction. And, actually, [inaudible 00:34:56] and some of our studies also show up, so it’s in very important nutritional intervention which has been underrated for many decades and finally it’s getting the attention it should have had along time ago.
Micheal Ristow:	35:07	And I fully endorse their results and I’m very curious where this is going and whether it will change as a societal approach to nutrition.
Micheal Ristow:	35:15	I’m pretty sure for the subsets, this will apply as in scientifically, it’s not fully resolved, but the data that is available is certainly very promising.
Dan Pardi:	35:23	So, lastly, what are some of the things that your lab currently investigating? What are some of the questions that you are looking into at the moment?
Micheal Ristow:	35:28	What we started doing a really long time ago is to identify genes and by that also methods to modulate these genes are being compounds and nutrition that are regulating longevity in very different organisms. So we compare to lower organisms, like flies or worms, with mice, and also with human cells. Then out of this huge data set, a lot of small list of candidates. One that we are doing is working individually on genes in this list.
Micheal Ristow:	35:58	Then on the next level we work on prescription factors similar to NRF2 that regulate these genes all together or is the major portion of that, all of which is now published. And there is these two very interesting candidates. And we also have number of natural compounds contained in the daily food and certain vegetables, and so forth, that very specifically worked through these transcription factors. And once this is established, now, we can anticipate that there will be more factors coming, to really target that. On top of these established one, like foxil, and NRF2.
Micheal Ristow:	36:31	And thirdly, we work on other projects that are rather free-floating related to questions that are still not properly being addressed. For example, why do protein aggregates cause Alzheimer and other diseases. How can this be modulated [inaudible 00:36:47] and things like that.
Micheal Ristow:	36:48	But these are rather, not by relevance, but by number of people working on side projects. So the main focus is generally pathos, and more bodily transcription factors, like modulate these pathways. And nutritional and other interventions by natural compounds, and how to modulate them.
Dan Pardi:	37:03	I really appreciate your approach of looking at natural compounds, because at the end of ever paper on that subject, it’s always maddening to see the last sentence or two say, “And hopefully, we can come up with some synthetic drug candidate targets.” I understand the pressures in order to do that. As we have discussed, research takes lot of money to get there and if nobody can benefit at the end of it, who’s going to do that work? But at the same time, we find compounds that increasingly target some of these pathways, like bar gamma and [inaudible 00:37:27] activators with increasing strength, and that might create a situation where we are creating a condition that might have more harm than good.
Dan Pardi:	37:34	And so, we have all of the wonderful compounds through foods, and if we have a better understanding of how they work, we can increase our appreciation that, yes, we should eat a high vegetable diet over the lifespan, which is something we already know.
Micheal Ristow:	37:43	Yep. I totally endorse that, plus we as a society, and also in politics should possibly reconsider their approach of treating society as a [inaudible 00:37:53]. I think the Eastern concept of [inaudible 00:37:56] investing into the prevention of diseases is way better than the Western approach, in … we wait until disease shows up, and then we want to treat it. So, people who have a healthy lifestyle and eat healthy and exercise … they already do that, but on the individual level.
Micheal Ristow:	38:10	What about health insurances and public services endorsing that? And even having incentives of promoting that, including, but only restricted to compounds we’ve been talking about, which would be in the cent range per day, so absolutely no investing for the government. But the societal outcome, and also the reduction after the costs would be huge and everyone would profit from that.
Dan Pardi:	38:30	I think that’s a great way to end, and I appreciate all the work that you’ve done! To come along and see things differently, and be finally connected what the actual research is saying. I respect and appreciate that. Thank you for all your contributions! Thank you for time today! It’s been great having you on the show!
Micheal Ristow:	38:43	Thank you!
Kendall Kendrick:	38:46	Thanks for listening and come visit us soon at HumanOS.me!