Sunday, September 21, 2014

Resistance training and other forms of exercise increase BDNF and brain volume

A study found that resistance training, i.e. weightlifting, increased levels of BDNF, or brain-derived neurotrophic factor. BDNF is a growth factor that causes neurogenesis and increased synaptic connections. Training augments resistance exercise induced elevation of circulating brain derived neurotrophic factor (BDNF). The change was transient, that is, resting BDNF levels did not change, but after several weeks of training, "the change in serum BDNF from rest to immediately post-exercise was 98% greater at post-intervention than at baseline."
Our study is the first to demonstrate that resistance exercise induces a robust, yet transient, elevation of circulating BDNF and that progressive resistance training augments this response; perhaps demonstrating one mechanism through which exercise influences brain health.
Another study which was much touted at the time of publication found that exercise increases brain volume, specifically that of the hippocampus. Exercise training increases size of hippocampus and improves memory.
The hippocampus shrinks in late adulthood, leading to impaired memory and increased risk for dementia. Hippocampal and medial temporal lobe volumes are larger in higher-fit adults, and physical activity training increases hippocampal perfusion, but the extent to which aerobic exercise training can modify hippocampal volume in late adulthood remains unknown. Here we show, in a randomized controlled trial with 120 older adults, that aerobic exercise training increases the size of the anterior hippocampus, leading to improvements in spatial memory. Exercise training increased hippocampal volume by 2%, effectively reversing age-related loss in volume by 1 to 2 y. We also demonstrate that increased hippocampal volume is associated with greater serum levels of BDNF, a mediator of neurogenesis in the dentate gyrus. Hippocampal volume declined in the control group, but higher preintervention fitness partially attenuated the decline, suggesting that fitness protects against volume loss. ...These theoretically important findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood, which is accompanied by improved memory function.
Note that both of these studies were trials and not associational.

So, exercise looks to be a potent way to retain brain volume with aging, or really at any age for that matter.

Saturday, September 20, 2014

Curcumin as antidepressant.

Curcumin, the supplement derived from the spice turmeric, has all kinds of interesting properties, such as being anti-cancer and extending lifespan. Both of these together make perfect sense, since cancer is largely a disease of old age; anything that stops cancer will extend life, and vice versa.

Another interesting property is that it may be an effective antidepressant. This isn't some wild, New Age stuff from people who just don't like drugs, but is real and is being tested. Curcumin for the treatment of major depression: A randomised, double-blind, placebo controlled study. This study has as one of its co-authors the estimable Michael Maes, one of the preeminent names in biological psychiatry. (He is also the man who has generated many useful insights into the genesis and treatment of chronic fatigue syndrome.) From the abstract:
Curcumin, the principal curcuminoid derived from the spice turmeric, influences several biological mechanisms associated with major depression, namely those associated with monoaminergic activity, immune-inflammatory and oxidative and nitrosative stress pathways, hypothalamus-pituitary-adrenal (HPA) axis activity and neuroprogression. We hypothesised that curcumin would be effective for the treatment of depressive symptoms in individuals with major depressive disorder.

In a randomised, double-blind, placebo-controlled study, 56 individuals with major depressive disorder were treated with curcumin (500 mg twice daily) or placebo for 8 weeks. The primary measure was the Inventory of Depressive Symptomatology self-rated version (IDS-SR30). Secondary outcomes included IDS-SR30 factor scores and the Spielberger State-Trait Anxiety Inventory (STAI).

From baseline to week 4, both curcumin and placebo were associated with improvements in IDS-SR30 total score and most secondary outcome measures. From weeks 4 to 8, curcumin was significantly more effective than placebo in improving several mood-related symptoms...

Partial support is provided for the antidepressant effects of curcumin in people with major depressive disorder, evidenced by benefits occurring 4 to 8 weeks after treatment.

Investigations with larger sample sizes, over extended treatment periods, and with varying curcumin dosages are required.
The dose strikes me as being not all that much. This article suggests that doses up to several grams a day are safe.

Curcumin may work in this way by increasing, or preventing the decrease of, levels of BDNF, brain-derived neurotrophic factor.

Tuesday, September 16, 2014

Three simple and effective ways to slow aging and increase lifespan

A recent study found that raising levels of the cell signaling molecule AMPK increased lifespan in fruit flies by 30%. (Cell Reports, PDF, press release.) AMPK did this by increasing activity of autophagy, which is the regulated process of cellular degradation, essentially removing junk molecules and organelles from the cells.

So by increasing AMPK and therefore autophagy, one has a good shot at retarding aging and increasing lifespan and health. There are a number of ways to do this, and they consist of all the usual suspects.

1. Intermittent fasting: "It is then the question of what the optimal strategy would be to improve healthy aging by enhancing autophagy without deleterious side effects. Intermittent fasting, for instance by alternating days of starvation with days of ad libidum feeding, can increase the life span of rodents as much as chronic caloric restriction without a concomitant major decrease in body mass—a measure that may avoid the negative effects of caloric restriction on bone density and consequent pathological fractures."

Calorie restriction, while effective at increasing longevity, results in decreased muscle and bone mass, besides the fact that permanently reducing calories by ~30% is very difficult, and results in low body temperatures and low libido. Intermittent fasting appears to offer all the benefits of calorie restriction with few of the drawbacks. A simple way to put intermittent fasting into effect is to eat only during an 8-hour feeding window daily, say 11 A.M. to 7 P.M. During the 16-hour fasting period, nothing is taken except perhaps coffee, tea, and water - these should be taken, as they make fasting much easier by decreasing hunger. The beauty of the 16-hour fasting period is that one is asleep for much of that time, and it involves extending a natural 12 hour fast by just a few hours.

2. Curcumin induces autophagy, as does resveratrol. Both are inexpensive OTC supplements that appear to have little downside. Autophagy knockout cells do not show increased stress resistance with curcumin or resveratrol, which shows that autophagy is the mechanism through which these compounds work.

3. Exercise induces autophagy, and in fact looks to be required to get the beneficial effects from exercise. How much exercise is a good question, but it seems that an intense exercise session of any kind should do it.

Tuesday, September 9, 2014

Drinking alcohol is healthy - or is it?

The evidence for alcohol and health

At Pacific Standard, a doctor, Stanton Peele, writes, The Truth We Won’t Admit: Drinking Is Healthy. He cites a number of studies that show greatly decreased mortality is associated with drinking alcohol. He even goes beyond what articles of this kind usually say, and that is that you can drink quite a lot and still get health benefits. Most such studies and articles come with the caveat that more than one or two drinks a day for a man, or just one for a woman, reduces health benefits, but Peele shows that even a man who has four drinks a day still has a lower mortality than a complete abstainer.

He also shows that another caveat is not relevant. This one is that the group of teetotalers will include both those who are too ill to drink as well as former alcoholics, and since they are likely to die younger, this skews the mortality statistics in favor of drinkers. But a study of only healthy people that controlled for things like smoking and BMI still found that drinkers had an advantage.

Peele also asserts that the legacy of the temperance movement and America's love-hate attitude to alcohol prevents doctors and health authorities from recommending drinking alcohol as a means to better health, and I think he may have a point.

Drinking is not the causative factor of longer life

There's only one problem: all the studies he cites are associational only. In other words, people who drink alcohol live longer, but it is far from being proven that alcohol is the cause of longer life. What is needed is a randomized controlled trial in which one group is counseled to drink, the other to abstain, and then see what happens. As far as I can tell, such a study has not been done.

Higher intelligence is robustly associated with better health

The biggest confounder in these studies is that intelligent people drink more alcohol, and IQ is robustly associated with longer life and better health. As the association between drinking and intelligence is often thought counter-intuitive by many people, I reproduce one of the graphs from Kanazawa:

So, the more intelligent people are, the longer they live, and the more they drink, but alcohol seems quite unlikely, in my view, to be the cause of longer life.

Where does that leave us?

I think that one thing we can say about alcohol is that it's not all bad, it doesn't harm health if drinking is moderate, at least as far as we can tell. But drinking for one's health probably won't work, and unfortunately IQ is hardly malleable at all, so nothing one can do there.

Bottom line: moderate drinking probably won't kill you, but it probably won't help much either. Cheers!

Friday, September 5, 2014

Undenatured whey for health, muscle, and cancer prevention

What is whey, and what's it good for?

Whey is the fraction of protein from milk that remains liquid when milk is curdled. The curdled portion mostly represents casein - which has its uses, but that's for another time. Hence whey has traditionally been a byproduct of cheese making, since only the curds are useful for that.

Whey is especially useful in bodybuilding and weightlifting, for a number of reasons. One is that it has a high content of branched-chain amino acids (BCAAs), and these are important as signals that tell muscle to grow. It's also high in essential amino acids (EAAs), which are the kind the body cannot make for itself. Whey is about 25% BCAAs, and about 50% EAAs. Along the same lines, whey is a "fast" protein, so a whey shake delivers an abundant amount of the right kind of amino acids quickly into the bloodstream, and this is a crucial determinant of the amount of muscle protein synthesis one gets from a workout. Even absent a workout, a dose of protein can help overcome sarcopenia (muscle wasting) in older people, which I wrote about here. I've got my mother, who is in her 90s, taking a whey shake daily.

Whey can help cure chronic illnesses

There's another aspect to whey, which is that properly made, it contains a number of biologically active peptides, that is, short-chain strings of amino acids. Among these are alpha-lactalbumin, beta-lactoglobulin, and immunoglobulins. The caveat here is "properly made", since ordinary processing destroys these peptides, breaking them down into their constituent amino acids.

These biologically active peptides can be useful in other contexts besides weightlifting. They promote higher glutathione levels and a better immune response. As such, whey may be useful in cancer prevention. There's even been a clinical trial on patients with metastatic breast cancer. There's some evidence that this type of whey can improve cognition. They also may increase endurance performance.

The best whey options

One catch here is that the specific kind of whey used in many of the studies linked above is called Immunocal, and it's quite expensive at over $130 for a pack of 30 10 gram packets. A serious weightlifter would burn through that in no time.

Another catch is that most whey of the kind sold in nutrition stores and the like is not undenatured. It's manufactured using whey left from cheese manufaturing and by acid processing, which means that no biologically active peptides remain. This kind will definitely still build muscle, but if you want all the health benefits of whey, you need to look elsewhere.

So the kind I like and use myself is a cold-processed, undenatured whey made by NutraBio. It's got the biologically active peptides, but at around the same price as garden-variety whey. Be sure to get the concentrate, or the isolate, but not the hydrolyzed version, as this will not have those peptides.

Tuesday, September 2, 2014

Can you increase your lean mass through diet alone?

What's the relation of dietary protein to lean mass?

How does dietary protein relate to lean mass - mainly muscle - in the absence of resistance training or any other form of exercise? Can you increase muscle just through a change in diet? Some researchers decided to find out: Increased Fat-Free Body Mass and No Adverse Effects on Blood Lipid Concentrations 4 Weeks after Additional Meat Consumption in Comparison with an Exclusion of Meat in the Diet of Young Healthy Women. In this study, the researchers divided a number of young women into two groups: one with additional meat in the diet, the other with no meat at all. The study lasted four weeks. In that time, the additional meat group gained .7 kg - about 1.5 lbs. - of lean mass, and the no meat group lost about the same in lean mass.

The meat group ate an additional 270 calories a day but gained no fat. They also ate about 2.25 grams of protein per kg bodyweight, which is a large amount, well into bodybuilders' territory. The no-meat group consumed about 1.15 g/kg protein daily. So all of the additional calories of the meat group were either burned or turned into muscle, or possibly other lean mass, such as bone.

The current opinion of exercise physiology is that about 1.8 grams of protein per kilogram of bodyweight maxes out the amount of muscle protein synthesis possible, anything above that being superfluous and burned off. The meat group in this study was well above that, but we don't know whether they didn't need that much, 1.8 g/kg being adequate, or whether they used all that excess protein.

Can even more protein be beneficial?

But is there any evidence that more protein than 1.8 g/kg can be beneficial? In fact there is, if one is trying to lose weight by restricting calories. In Evidence-based recommendations for natural bodybuilding contest preparation: nutrition and supplementation, the authors state that bodybuilders getting ready for competition by restricting calories really need to up the protein content of their diet to avoid losing muscle. It appears that well over 2 g/kg a day are necessary in this particular circumstance. In this case, the higher protein didn't put on muscle, but prevented bodybuilders who were trying to get shredded from losing muscle.

If you're dieting to lose weight, a much higher protein intake appears to be beneficial, since it will help preserve muscle, which you do not want to lose.

The gross inadequacy of U.S. government guidelines for protein

I found one aspect of the first-linked study on young women rather ominous, and that is that on an intake of 1.15 g/kg a day of protein, they lost lean mass. Yet at the same time the RDA, Recommended Dietary Allowance, for protein is only 0.8 grams per kilogram bodyweight, or about 56 grams a day for a 70 kg man. If young women lost lean mass on a diet that provided more protein than that, obviously something is wrong. What's wrong is the RDA for protein, which ought to be much higher. In The underappreciated role of muscle in health and disease, the author suggests that up to 1.8 g/kg bodyweight would be much healthier, as it's been shown that the RDA cannot maintain lean mass in older people. Or probably younger, as we've just seen.

Bottom line

If you already eat a diet relatively high in protein, featuring some animal protein at each meal, you may not be able to increase lean mass much by eating more protein. On the other hand, if you follow U.S. guidelines, you should stop that, increase your protein, gain some lean mass, and become healthier, whether you are a strength athlete or not.

Sunday, August 31, 2014

Glucosamine extends lifespan, mimics low-carb diet

Awhile back I posted on the fact that the OTC supplement glucosamine extends lifespan in both C. elegans and in mice. The mechanism resembles that of a low-carb diet. The study's main author, Michael Ristow, started taking glucosamine after this research.

Another study determined that there was an association in humans between glucosamine consumption and lower mortality rates.
Current (baseline) glucosamine and chondroitin use were associated with a decreased risk of total mortality compared to never use. The adjusted hazard ratio (HR) associated with current use of glucosamine (with or without chondroitin) was 0.82 (95% CI 0.75–0.90) and 0.86 (95% CI 0.78–0.96) for chondroitin (included in two-thirds of glucosamine supplements). Current use of glucosamine was associated with a significant decreased risk of death from cancer (HR 0.87 95% CI 0.76–0.98) and with a large risk reduction for death from respiratory diseases (HR 0.59 95% CI 0.41–0.83).
So about a 20% decrease in mortality rates with glucosamine, and around 40% decrease in death from respiratory diseases. This looks to be solid data, since many risk factors were adjusted for, such as BMI, smoking, etc., and there were more than 77,000 participants.

What I would like to know is whether glucosamine extends lifespan even in the presence of a low-carb diet, or whether it would be superfluous in that case.

This also tells us that a low-carb diet is a healthy one, and probably extends lifespan on its own.

Friday, August 29, 2014

What happens when you see the doctor

You've got some kind of physical or mental complaint and go to your doctor. What happens?

He'll very likely prescribe a drug, one that has side effects and in many cases could be worse than the illness. Sure, if you have an infection, you need an antibiotic. If you have a broken bone, you need painkillers (and more). Many conditions exist for which modern medicine literally saves lives.

What about if you have high blood pressure? This is a condition which lifestyle factors are important. But does any doctor prescribe diet? No, not a one, or at least as statistically close to zero as you could want. And even if they did, they don't know what to prescribe. In many cases, they're just as out of shape as their patients. No, you'll get a pill, which has serious side effects.

In doctors' defense, precious few of their patients will do anything to help themselves beyond popping a pill. So even were they so inclined, they don't discuss lifestyle factors - diet, exercise, sleep - or OTC supplements.

What if you're depressed? Medication can be of value, but these do have real and serious side effects, including possible long-term effects on the brain or perhaps a little suicidal ideation. However, they're a doctor's first resort. Exercise, magnesium, light therapy, n-acetylcysteine, even sleep deprivation therapy, all these can combat depression, and doctors are either ignorant of them or won't bother telling patients about them. Mostly the former, I think.

What if you have fatigue? This is possibly the number one symptom that patients tell doctors about. If the doctor discovers that his patient isn't sleeping well, he'll prescribe a sleeping pill, paying no attention to the coffee the patient drinks all afternoon that prevents him from sleeping. Again: diet, exercise, OTC supplements? No.

Feeling a little fuzzy in the head? Forget all the sugar you ingest and your lack of sleep. What you need is speed.

Wednesday, August 27, 2014

Overcoming anabolic resistance for the older man and the hardgainer

Not the author

What is anabolic resistance?

Anabolic resistance is the phenomenon in which muscle does not respond to stimulus with normal muscle protein synthesis, but rather a reduced response. The stimuli that would elicit such a response are resistance training, as the academics call it, and ingestion of protein. In young, healthy people, these stimuli cause increased muscle synthesis, and over the longer term this means bigger muscles, as they adapt to continued stimulus.

Sarcopenia and the "hard gainer"

In sarcopenia, that is muscle wasting, which is most often seen in older people, basal muscle anabolism and catabolism can be normal, but the muscle fails to respond properly to stimulus, namely resistance training and protein consumption.

In younger men, we find the phenomenon of the so-called "hard gainer", the guy who lifts and lifts and eats and eats, but can't seem to put on much muscle, or at least finds it much more difficult than others to do so.

The cause of anabolic resistance

Anabolic resistance has actually been studied a fair amount because it's a common condition in older people that leads to sarcopenia. Since sarcopenia often leads to disability, the inability to care for oneself (nursing homes) and ultimately death (from falls leading to hip fractures and the like), anabolic resistance is actually a major public health problem.

Researchers often focus on ways to fix it, but as to the cause, they are often reduced to saying that it's just "age". Sure, we know detailed cellular mechanisms of resistance, but why age causes these is another story.

However, I've come to the rescue, since I know what causes anabolic resistance. In a nutshell, inflammation, which increases greatly with age. Inflammation is also a cause of insulin resistance, also more common with age, and the two are related. It follows that with less inflammation and greater insulin sensitivity, anabolic resistance will diminish.

A large clue to how all this works is the fact that omega-3 fatty acids from fish oil are anabolic. For example, Omega-3 polyunsaturated fatty acids augment the muscle protein anabolic response to hyperinsulinaemia–hyperaminoacidaemia in healthy young and middle-aged men and women. In this study, fish oil caused a ~30% increase in muscle protein synthesis, and a ~50% increase in mTOR phosphorylation.

Even better results were seen in the elderly: Dietary omega-3 fatty acid supplementation increases the rate of muscle protein synthesis in older adults: a randomized controlled trial.

Fish oil can also help treat a condition that's similar to sarcopenia, cachexia: Eicosapentaenoic acid (EPA, an omega-3 fatty acid from fish oils) for the treatment of cancer cachexia.

How does fish oil decrease anabolic resistance?

Fish oil decreases anabolic resistance probably by two different means: it decreases inflammation, and restores normal fluidity in cell membranes, allowing receptors to work properly. Fish oil has clinically important anti-inflammatory effects.

How to overcome anabolic resistance

There are several ways that anabolic resistance may be overcome.

1. Fish oil: by decreasing inflammation and increasing insulin and other receptor sensitivity.
2. Increased protein consumption. In younger people, 20 grams of protein in one meal may be enough to promote maximum protein synthesis. Older people may need more. In one study, older men undergoing resistance training had better muscle protein synthesis when they ingested 40 grams of whey protein as opposed to 20.
3. Exercise itself reduces anabolic resistance.
4. "Faster" protein: the protein in meat, eggs, and the like digests slowly, and amino acids in the bloodstream therefore do not rise to as high a level as they do with a protein that digests faster, such as whey. The level of amino acids in the blood is a crucial determinant of anabolism. Therefore, taking a fast protein such as whey, whether with a workout or without it, will cause greater anabolism, other things being equal, such as quantity.
5. BCAAs and leucine: BCAAs, particularly leucine, crucially determine the amount of muscle protein synthesis. So ingesting protein high in BCAAs / leucine will cause greater anabolism. Whey has the highest fraction of BCAAs of any protein.
6. In older people, resistance training. It appears that sarcopenia may arise from a combination of inflammation ("inflammaging") or just disuse. Older people typically have good responses to resistance training, even into their 90s.

Don't let age be an excuse

There you have it. It is not "age" that causes anabolic resistance, but various metabolic derangements that accompany it. If you're older, or you're a hard gainer, you can use some of these methods I outlined to overcome anabolic resistance.

P.S.: I was asked what type of whey I like, and the answer is NutraBio, which is cold-processed and undenatured. Best one available, IMO.

Monday, August 25, 2014

N-acetylcysteine increases endurance performance

Production of free radicals is a determinant of performance and fatigue

One of the crucial determinants of fatigue is the production of radical oxygen species (ROS, also known as free radicals) and internal antioxidant status, the latter mainly consisting of total, reduced, and oxidized glutathione. Glutathione is a tripeptide consisting of three amino acids, and the rate-limiting amino acid - the bottleneck to production - is cysteine. So, if more cysteine is provided, more glutathione will be produced. N-acetylcysteine, the cheap over-the-counter supplement, provides cysteine, which cannot be taken in its native form due to high potential for oxidation.

When one performs any kind of intense or prolonged exercise, a large quantity of ROS is generated, and it's mainly glutathione that mops them up and keeps the body from entering a condition of oxidative stress. Glutathione can be thought of as an exercise buffer. But when it is depleted, the body is overwhelmed with ROS, and fatigue ensues.

N-acetylcysteine increases glutathione

The main function of n-acetylcysteine (NAC) is to increase glutathione levels. When ingested, it is rapidly taken up by cells, de-acetylated to cysteine, and then used in glutathione production. Since NAC does this, and since glutathione is a determinant of fatigue, it follows that NAC should increase exercise performance.

N-acetylcysteine significantly increases endurance and time to fatigue

Lo and behold, NAC does work this way: N-acetylcysteine enhances muscle cysteine and glutathione availability and attenuates fatigue during prolonged exercise in endurance-trained individuals. In this study, trained cyclists who received NAC increased their endurance performance, that is, time to fatigue, by a remarkable 26%. NB: the cyclists received a lot of NAC, in fact a constant IV infusion.

Another study that used a special type of whey as a cysteine donor found increased peak power and 30-second work capacity: Effect of supplementation with a cysteine donor on muscular performance.

And in a study on rats, those that had a glutathione deficiency had a 50% reduced endurance performance.

Fatigue of any kind is related to glutathione levels

In my book on chronic fatigue, I discuss at some length the relation between chronic fatigue and glutathione levels, which is critically important for those suffering from long-term fatigue from any cause. NAC can be of help in that condition as well. So we see that fatigue, whether from unknown cause, illness, bad nutrition, or prolonged exercise is related to glutathione. This is not the sole determinant of fatigue, but an important one.

Friday, August 22, 2014

Ketone body extends lifespan

Ketone bodies are the small molecules that are produced by the liver when the body is in a state of ketosis. These can be readily used by the body and, most notably, the nervous system, and one of their functions is to spare lean tissue during ketosis, since with the burning of ketones, the body does not have to break down muscle in order to make blood glucose.

The state of ketosis is readily entered when severely restricting carbohydrates in the diet for just a short while; for instance, if someone goes on the Atkins diet, or generally keeps carbs below 50 grams a day. (If one exercises a lot or is otherwise physically active, one can eat more carbs, say up to 100 grams, and remain in ketosis.)

It turns out that in the roundworm C. elegans, one of the ketone bodies, beta hydroxybutyrate, extends lifespan: D-beta-hydroxybutyrate extends lifespan in C. elegans.
βHB supplementation extended mean lifespan by approximately 20%. ... βHB did not extend lifespan in a genetic model of dietary restriction indicating that βHB is likely functioning through a similar mechanism. βHB addition also upregulated ΒHB dehydrogenase activity and increased oxygen consumption in the worms.
So, the ketone functioned similarly to dietary restriction, increased lifespan by 20%, and caused increased metabolism.

It looks like being in ketosis much of the time could be, gasp, good for you.

The probable future Nobel Laureate Cynthia Kenyon discovered that a mutation in insulin signalling in C. elegans caused radically increased lifespan. When she made that discovery, she herself went on a low-carbohydrate diet.

So, add all this to the evidence for the healthiness of a low-carb diet.

Thursday, August 21, 2014

Activate the stress response for health and long life

A pesticide extends lifespan in C. elegans

In a recent study, researchers screened for a number of chemicals that might extend lifespan in C. elegans, the tiny worm that is often used in aging research. They found one, a pesticide: Extension of Lifespan in C. elegans by Naphthoquinones That Act through Stress Hormesis Mechanisms
Hormesis occurs when a low level stress elicits adaptive beneficial responses that protect against subsequent exposure to severe stress. Recent findings suggest that mild oxidative and thermal stress can extend lifespan by hormetic mechanisms. Here we show that the botanical pesticide plumbagin, while toxic to C. elegans nematodes at high doses, extends lifespan at low doses. Because plumbagin is a naphthoquinone that can generate free radicals in vivo, we investigated whether it extends lifespan by activating an adaptive cellular stress response pathway. ... Our findings reveal the potential for low doses of naturally occurring naphthoquinones to extend lifespan by engaging a specific adaptive cellular stress response pathway.
It's important to note that low doses were used; at higher doses, the pesticide was still toxic. More isn't better in this case.

Stress response mechanisms are the key to health and long life

The stress response mechanism in this case, and many others, is known as hormesis, which is characterized by a U-shaped curve: beneficial effects starting at low doses, but the effects becoming harmful at higher doses. In other words, low doses of some substance that we normally think of as toxic can be actually beneficial. This has even been shown with such classic poisons as mercury (Hormesis associated with a low dose of methylmercury injected into mallard eggs).

Hormetic effects have been found in a wide range of substances and practices, but the key point is that they all activate cellular stress response mechanisms. One of the main mechanisms at work is Nrf2, which activates over 200 genes. These genes in turn are anti-inflammatory, antioxidant, and stimulate of mitochondrial biogenesis.

It's thought that the level of activation of Nrf2 plays perhaps the key role in differences in longevity between species.

Longevity promoting effects are due to activation of stress response

Many substances and actions have been found to activate the stress response. Calorie restriction and intermittent fasting, exercise, broccoli and curcumin, other fruits and vegetables, chocolate, and many other phytochemicals. Restricting glucose extends lifespan (in C. elegans) as well.

Furthermore, type 2 diabetes may come about due to a lack of hormesis. Since diabetes is a kind of archetype of aging and the ill health associated with obesity and modern life, it's not too far-fetched to say that the stress response due to hormesis is necessary for health and long life.

Daily doses of good stress for health

One must stress the body to remain in good health. Being a couch potato and eating to excess will send one's health on a downward spiral. In contrast, exercise, intermittent fasting, eating a variety of fruits and vegetables, an occasional glass of red wine, some supplements such as resveratrol and curcumin, restricting sugar and refined carbs in the diet, will all cause an increase in the cellular stress response and lead to better health and, hopefully, longer life.

Monday, August 18, 2014

Testosterone for muscle gain: it works

Steroids used for athletics have two functions: androgenic and anabolic. Androgenic signifies that it increases male sexual characteristics, and anabolic that it builds muscle. Steroids are essentially testosterone mimics with qualities that athletes want, such as longer half-life, more potent anabolic effects, and so on.

How does testosterone itself perform in that regard? Pretty well.

In a study of testosterone replacement therapy in hypogonadal men - that is, they had low T - they had an average 20% gain in muscle mass over 6 months. In other words, huge. Even better, they also had a loss of fat mass of 11%.

So, maybe testoserone's anabolic affects have an upper limit, that is, what about supraphysiologic doses in men who already have normal T? Yes, that works too: The Effects of Supraphysiologic Doses of Testosterone on Muscle Size and Strength in Normal Men. In this study, young men were given high doses of T, a 600 mg injection once weekly. They also did resistance training 3 days a week, and ate a diet with enough protein to support optimal muscle growth, 1.5 grams per kilogram body weight, or about 0.7 grams/lb.

Results: those in the T + exercise group gained 6 kg, or over 13 pounds, over 12 weeks, and it was all muscle. But to show the power of T: even those who did not lift weights gained 3.2 kg of muscle.

One lesson here is that if you're having difficulties in the gym with putting on muscle, a test for your T level would seem to be in order, whether you're young or old. Should your T levels be suboptimal, then comes the harder part: convincing your doctor to prescribe T for you. Granted, if you're youngish and in good health, some other strategies may work for increasing T, such as fat loss, ensuring adequate zinc in your system, and certain posture exercises, as shown here. Weightlifting itself, as well as a HIT exercise program, also improve T levels, so keep at it.

Saturday, August 16, 2014

Chocolate extends lifespan, improves cognitive performance, prevents diabetic complications

In rats it does, anyway. In the following study, the researchers used a special form of cocoa powder, Acticoa, which has been processed in such a way as to preserve a high content of flavanols. Acticoa is made in Switzerland and as far as I can see is not available in the U.S. Effects of long-term administration of a cocoa polyphenolic extract (Acticoa powder) on cognitive performances in aged rats.
Numerous studies have indicated that increased vulnerability to oxidative stress may be the main factor involved in functional declines during normal and pathological ageing, and that antioxidant agents, such as polyphenols, may improve or prevent these deficits. We examined whether 1-year administration of a cocoa polyphenolic extract (Acticoa powder), orally delivered at the dose of 24 mg/kg per d between 15 and 27 months of age, affects the onset of age-related cognitive deficits, urinary free dopamine levels and lifespan in old Wistar-Unilever rats. Acticoa powder improved cognitive performances in light extinction and water maze paradigms, increased lifespan and preserved high urinary free dopamine levels. These results suggest that Acticoa powder may be beneficial in retarding age-related brain impairments, including cognitive deficits in normal ageing and perhaps neurodegenerative diseases. Further studies are required to elucidate the mechanisms of cocoa polyphenols in neuroprotection and to explore their effects in man.
The rats fed cocoa lived 11% longer than controls, which I would say is a huge increase in lifespan from the mere addition of cocoa to their food.

The rats received 24 mg/kg of body weight. To convert to a human dose, multiply by 6/37 (see here), which comes to about 4 mg/kg. So, for a 75 kg (165 lb) man, the daily dose of cocoa would be about 300 mg. Keep in mind that this was a concentrated form of cocoa (Acticoa). According to their website, Acticoa has 5 or more times the amount of flavanols than regular cocoa powder, so adjust accordingly.

Another study found that the mere addition of epicatechin, one of the major flavonoids in cocoa, to the diets of diabetic mice, radically reduced the death rates from 50% in controls, to 8% in the epicatechin group. Dietary epicatechin promotes survival of obese diabetic mice and Drosophila melanogaster. What this tells me is that a hormetic response can protect against diabetes. There's good evidence that lack of hormesis contributes to diabetes: Resistance to type 2 diabetes mellitus: a matter of hormesis?

Despite the fact that even people who should know better refer to substances like epicatechin as antioxidants, in reality they are not. They work via hormesis, that is, by providing low doses of toxins to which the body mounts an anti-stress response. In the case of diabetes above, the flavonoids acted as hormetic agents and thus prevented diabetic mice from dying. That's my interpretation.

Also, cocoa has far more flavonoids, 2 to 4 times more, than tea or red wine. I have to remind myself to eat more chocolate.

Friday, August 15, 2014

Lithium and longer life

Lithium is an essential nutrient

Most people know lithium as the "drug" given to bipolar patients. In reality it is not a drug but a mineral, and in bipolar disorder it's given in high doses: the target dose is usually 900 to 1,800 mg a day.

However, lithium is a required nutrient. "The available experimental evidence now appears to be sufficient to accept lithium as essential; a provisional RDA for a 70 kg adult of 1000 μg/day is suggested." (1000 μg = 1 mg.) This is, as can be seen, much lower than the dose given in bipolar.

Furthermore, low levels of lithium in drinking water have been associated with violence, suicide, and homicide. See, for example, Lithium in Tap Water and Suicide Mortality in Japan.

Lithium increases lifespan in humans and animals

A study looked at epidemiological evidence of an effect of lithium on human lifespan, and found it. Low-dose lithium uptake promotes longevity in humans and metazoans. Mortality rates were inversely associated with lithium concentrations in tap water; furthermore, the lower mortality rate remained after adjusting for suicide, showing that lithium provides some other health benefit not strictly related to mental health.

Since this association does not show causality, the same authors used low-level lithium, at about the same concentration found in the tap water, and tested it on the worm C. elegans. It extended their lifespan, showing causality.

Lithium promotes autophagy

Lithium seems to extend lifespan by promoting autophagy, the cellular degradation process crucial to lifespan extension. It does this by an mTOR-independent mechanism, meaning that it does not depend on fasting. Through autophagy, lithium has been found to delay progression of amyotrophic lateral sclerosis.

How much lithium do you need?

As stated above, about 1 mg a day is a suggested RDA for lithium. Dose for bipolar patients are hundreds or thousands times higher, but there's considerable risk of toxicity at those doses, while there appears to be little for low doses. A common formulation, lithium orotate, provides 5 mg lithium.

Wednesday, August 13, 2014

Could intermittent fasting save you from a heart attack?

The rise and fall of coronary heart disease

Myocardial infarction - heart attack - is an important cause of death and disability. While we know that the immediate cause is due to arterial blockage, the longer term causes are less decided. The idea that it may be caused by high cholesterol due to high fat diets can safely be consigned to the garbage bin of history.

Furthermore, the rise and decline of coronary heart disease cannot be fully explained. My own guess would be that a combination of smoking, trans fat consumption from hydrogenated oils (like Crisco and margarine), and perhaps sugar consumption played a role.

Autophagy declines with aging

Autophagy is the process of controlled degradation of cellular components which is crucial to normal function, and it declines with aging. Whether the decline is causative of aging is an open question, but lifespan extension through calorie restriction or fasting requires autophagy, so there's obviously a close relationship between autophagy and aging. "[A]utophagy may act as a central regulatory mechanism of animal aging."

Autophagy and myocardial infarction

A recent study took a look at the expression of autophagy genes in peripheral leukocytes of patients with myocardial infarction. This simply means that the researchers looked at white blood cells obtained with a simple blood test. Patients who had suffered a heart attack were much more likely to have decreased expression of autophagy genes. This of course doesn't prove anything about causation. It could be simply a marker of increased aging, with which decreased autophagy is associated. We know that older people are much more likely to have heart attacks. Could this be due to decreased autophagy?

Intermittent fasting strongly increases autophagy

Autophagy increases in response to amino acid starvation. The body has very limited storage ability for dietary protein, which is composed of amino acids. What this means in practical terms is that, once protein in the diet has been digested, and the human or animal is no longer in the "fed" state, but is now fasting, muscle is broken down to provide the necessary amino acids in the bloodstream. Autophagy is the mechanism that does this. Normally, autophagy increases after a simple overnight fast. Longer periods of fasting strongly increase autophagy. "[A] growing body of literature suggests that fasting periods and intermittent fasting regimens can trigger similar biological pathways as caloric restriction (i.e., increased autophagy and mitochondrial respiratory efficiency), which can result in a host of beneficial biological effects including increased circulation and cardiovascular disease protection, and modulation of reactive oxygen species and inflammatory cytokines (Lee and Longo, 2011), periods have also been shown to have antimutagenic, antibacterial, and anticarcinogenic effects (Lee and Longo, 2011)." (Fasting or caloric restriction for Healthy Aging.)

Fasting may protect the heart

So, we know that both myocardial infarction and aging are associated with decreased autophagy, and that fasting retards aging and increases autophagy.

In animal studies, intermittent fasting protects the heart from ischemic injury, which is the type of injury heart attacks cause. (Beneficial effects of intermittent fasting and caloric restriction on the cardiovascular and cerebrovascular systems.) This shows a plausible mechanism by which autophagy protects against injury to the heart.

There's little downside to regular periods of intermittent fasting, and a using an 8-hour feeding window followed by 16 hours of fasting is easily done and will increase autophagy, due to deprivation of amino acids. Will it protect against a heart attack? It just might.

Monday, August 11, 2014

Intermittent fasting for fat loss or anti-aging?

Lots of people, even including those wanting to build muscle, are doing intermittent fasting (IF) these days. The goal for these people is to lose body fat and, hopefully, retain muscle or build muscle at the same time.

Others practice IF as an anti-aging method. This has solid science behind it, and it may even be more beneficial for anti-aging purposes than calorie restriction, heretofore the most effective strategy for inhibiting or reversing aging.

Branched-Chain Amino Acids

Many of those in the first camp (lose body fat, retain muscle) use branched-chain amino acids (BCAAs), or leucine (one of the BCAAs) or perhaps whey (which is rich in BCAAs) during their fast. BCAAs are powerful signals that tell cells to ramp up muscle protein anabolism and to decrease muscle protein catabolism. So the use of BCAAs while fasting is the practice that will give one the best shot at retaining or even building muscle, even while doing regular, periodic IF.

However, one thing that BCAAs, whey, or leucine do is to stop autophagy, the cellular self-cleaning process. This process is radically enhanced by fasting, and it is responsible for the beneficial effects of calorie restriction and fasting. No autophagy, no anti-aging benefit from fasting. One of the ways (not the only one) that BCAAs increase muscle protein synthesis is through increased insulin levels. Insulin suppresses autophagy.

So, if you practice IF for the purpose of anti-aging, you must not take any BCAAs, nor, if you are in the habit of taking small amounts of food during a fast, must you ingest any protein or carbohydrates, which raise insulin and stop autophagy, which is the central component of the anti-aging effect of IF.

Avoiding Intermittent Fasting Sabotage

However, fat, or in any case small amounts of it, do not raise insulin and do not signal the metabolic machinery to stop autophagy. Therefore you won't sabotage an anti-aging fast with small amounts of fat. The best thing to do here, if needed, is to drink coffee or tea with cream; the fat in the cream will help satisfy the appetite, and the caffeine in coffee or tea will diminish appetite.

That's why you should be clear on what your intermittent fasting purpose is. If it is for fat loss, by all means use BCAAs to decrease muscle breakdown. If your purpose is anti-aging, you should avoid BCAAs.

(I changed the post header on the advice of Mike at Danger and Play. Thanks, Mike.)

Sunday, August 10, 2014

Correlation between low sperm quality and soda consumption

Sugar-sweetened beverage intake in relation to semen quality and reproductive hormone levels in young men. The authors found that
SSB intake was inversely related to progressive sperm motility. Men in the highest quartile of SSB intake (≥1.3 serving/day) had 9.8 (95% CI: 1.9,17.8) percentage units lower progressive sperm motility than men in the lowest quartile of intake (<0.2 serving/day) (P, trend = 0.03). This association was stronger among lean men (P, trend = 0.005) but absent among overweight or obese men (P, trend = 0.98). SSB intake was unrelated to other semen quality parameters or reproductive hormones levels.

If you're dealing with male infertility, the lesson here is don't drink sugar-sweetened beverages. In any case, it's not a good idea to drink them no matter what.

The results could be, in my view, due to increased oxidative stress from dietary sugar. Ox. stress comes with diabetes and is at least one of the causes of its complications. "Oxidative stress can be reduced by controlling hyperglycemia and calorie intake." Link. Diabetics have lower sperm counts and semen volume. So, to avoid this fate, keeping blood sugar and insulin levels normal by refraining from SSBs would be a good idea.

Friday, August 8, 2014

N-acetylcysteine treats fatigue and ADHD in lupus, reduces DNA damage, and is dirt cheap compared to normal medication

Systemic lupus erythematosus

Probably not too many of you have systemic lupus erythematosus, but it is a serious and debilitating autoimmune disease, characterized by the production of anti-nuclear antibodies. It turns out that, in a trial of n-acetylcysteine in patients with lupus, they got significantly better. N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: A randomized, double-blind, placebo-controlled trial.
Systemic lupus erythematosus (SLE) patients exhibit T cell dysfunction, which can be regulated through mitochondrial transmembrane potential (Δψm) and mammalian target of rapamycin (mTOR) by glutathione (GSH). This randomized, double-blind, placebo-controlled study was undertaken to examine the safety, tolerance, and efficacy of the GSH precursor N-acetylcysteine (NAC). ...

This pilot study suggests that NAC safely improves lupus disease activity by blocking mTOR in T lymphocytes.
So far, so great. NAC proved to be safe, although one third of those taking 4.8 g/d developed reversible nausea. But it gets better.

N-acetylcysteine is over-the-counter and much cheaper than conventional lupus meds

From the discussion section:
The therapeutic importance of NAC for SLE is reflected by the achievement of clinical improvement within 3 months, as assessed by 2 validated disease activity scores; diminishing fatigue (21), which is considered the most disabling symptom in a majority of SLE patients (22); the absence of significant side effects; and the affordability of this medication. A monthly supply of 600-mg NAC capsules (120–240 capsules) costs $15–30 on the retail market. This sharply contrasts with the estimated average annual direct medical costs of ∼$22,580 per patient in 2009 (33). Thus, the cost of NAC at $180–360/year would be negligible compared to the overall expense to society caused by the disease and the expected benefit in reducing the need for vastly more expensive medications burdened with potentially serious side effects.
This explains why you won't be hearing much about NAC for lupus treatment: cost of $180 to $360 a year, as compared with over $22,000 a year for regular lupus meds. Drug companies have no reason for promoting such a cost-saving, profit-eating, effective supplement.

N-acetylcysteine works by increasing glutathione levels, and it reduces DNA damage

Another interesting item in this study is that NAC increased glutathione - which is its main mechanism of action - and by doing so inhibited mTOR (mammalian target of rapamycin), the chief driver of growth and hence aging. This suggests that n-acetylcysteine may have some potential as an anti-aging supplement. Whether anyone has looked into that, I don't know. (Here is a report that NAC reduced levels of DNA damage and "may have anti-immunosenescent potential in T cells in in vitro clonal and ex vivo polyclonal culture models." In other words, it prolongs the reproductive potential on cells in the immune system.)

N-acetylcysteine treats neuropsychiatric symptoms

Finally, another report by the same authors on lupus states that ADHD and other neuropsychiatric symptoms are prominent in lupus, and that NAC treats it: Attention Deficit and Hyperactivity Disorder Scores Are Elevated and Respond to N-Acetylcysteine Treatment in Patients With Systemic Lupus Erythematosus.
To investigate whether attention deficit hyperactivity disorder (ADHD) may serve as a marker of neuropsychiatric disease and as a target for N-acetylcysteine (NAC) treatment in patients with systemic lupus erythematosus (SLE).

In patients with SLE, elevated ASRS scores reveal previously unrecognized and clinically significant symptoms of ADHD that respond to NAC treatment.

N-acetylcysteine may treat fatigue and ADHD from other causes

If NAC treats fatigue and ADHD caused by lupus, it stands to reason that it may do so when caused by other pathologies. To the extent that these other pathologies correlate with a depletion of cellular glutathione, then NAC should be able to ameliorate them. In fact, we do see this in depression and bipolar (neuropsychiatric disorders), and I discuss NAC and how it can ameliorate fatigue in my book.

Thursday, August 7, 2014

Does overtraining exist, or is it an excuse for weak people?

Strangely enough, I've seen lots of denials that overtraining exists, that it's not a real phenomenon, on sites devoted to weightlifting and bodybuilding. The attitude seems to be that, since there's no such thing as overtraining, you're a wimp or lazy if you don't want to, or can't, hit the gym four, five, or more days a week. The guys that say this also seem to be young. Much of this comes from users of anabolic steroids, one of the main effects of which is to allow better exercise recovery and hence more exercise without overtraining. Of course most of these users don't admit to using steroids; they're "fake naturals", they don't reveal the secret of their remarkable staying power in the gym, but denigrate those who don't have their powers of recovery.

Overtraining doesn't exist for users of anabolic steroids

Androgenic anabolic steroids, such as testosterone and trenbolone cause increased rates of muscle protein synthesis, and as a consequence allow for better exercise recovery. Through increased insulin sensitivity, they also allow lifters to eat more without getting fat. If a lifter on steroids feels overtrained, he can up his dose and proceed back to the gym.

Overtraining does exist if you don't use steroids

On the contrary, coaches and elite athletes in just about every sport know very well that overtraining exists, because they need to guard against it if they're going to win competitions. Take a look at a PubMed search for "overtraining": 727 items returned. Overtraining is real.

How can you tell if you're overtraining?

An article at Men's Fitness lists 12 signs of overtraining, and they include fatigue, depression, insomnia, reduced immune function (you get sick a lot), and constant muscle soreness.

For the average gym rat, among whom I include myself, you feel reluctant to head to the gym, and if you do get there, lifting seems much more difficult. You will be unable to match your usual weights, sets, or reps.

Muscle soreness is common, and by that I don't mean the usual delayed onset muscle soreness (DOMS) that invariably follows a good gym session, usually in a day or two. In overtraining, one feels heavy and just sort of achy all over.

Mood takes a hit also. One feels a lack of ambition, and a kind of anhedonia.

Overtraining hits women harder and more frequently than it does men

Interestingly, female athletes seem even more likely to suffer from overtraining, since they are more likely not to eat enough, and especially of the right foods. They are less likely to eat enough meat, which is a potent source of iron, and they need more iron than men. Meat is of course a great source of protein, which athletes need to repair their tissues - whether they're a strength athlete or not - and if women don't eat enough meat, they'll suffer from that as well.

Chronic fatigue and overtraining are similar

Those who have had chronic fatigue understand what it feels like to be overtrained, as they are similar in many ways. One of the most prominent symptoms of chronic fatigue, in fact used to diagnose it, is exercise intolerance. The person who has chronic fatigue takes far longer to recover from an exercise bout that a healthy person - assuming he can do it in the first place. When I had chronic fatigue, I usually managed to take a daily walk. But too fast a pace, or walking an extra 15 minutes, could set back my energy levels for days. So one way to look at overtraining is as a form of chronic fatigue. It is. (For more on this, see my book, Smash Chronic Fatigue.)

How you can treat overtraining

So what do you do about it? The first thing is, of course, lots of rest. If you're genuinely overtrained, don't go back into the gym (or run, or whatever other intense exercise training you do) until you feel completely well. For weightlifters, you need to have the ability to perform at your maximum weight and/or number of reps and sets for each exercise. If you can't (unless you're just having an off day), you need more rest.

Use nutrition to prevent and treat overtraining

But nutrition can play a large role in recovery from overtraining. Consider the following: Contrasting plasma free amino acid patterns in elite athletes: association with fatigue and infection (pdf). The authors looked at three groups of athletes: Group A were track and field athletes with no signs of overtraining; Group B were judo athletes who reported heavy fatigue at night but who recovered with a night's sleep; and Group C, track and field athletes with chronic fatigue from overtraining who were unable to train at their normal levels. The study analyzed free amino acids in their blood, and found contrasting patterns.

Most germane to the analysis is that the persistently fatigued, often ill, and overtrained group had low plasma glutamine levels. The researchers advised some of them - leaving others that they did not advise as controls - to increase their protein intake, "to consume additional protein (an average or larger helping of lean meat, fish, cheese, or soya), at least once on most days a week, and to supplement protein intake with skimmed milk powder in cereals and drinks." This was additional protein of "a minimum of 20-30 g protein a day".

Most of the overtrained, fatigued athletes then recovered quickly, within three weeks, and their amino acid patterns returned to normal.

How much protein do you need to recover from overtraining?

So, to recover from and prevent overtraining, make sure that you get enough protein in your diet. The authors suggest that elite athletes in maintenance training need at least 1.6 g protein per kg bodyweight daily. That amounts to about .75 grams per pound of bodyweight.

So for example:

Bodyweight 200 pounds, you need about 150 grams of good quality protein daily.
Bodyweight 150 pounds, you need about 112 grams a day.

That's a fair amount, and you may not get that without supplementation. Whey protein is the best way to supplement, as it's high in leucine and cysteine, two of the most critical amino acids for athletes.

The best whey is cold-processed and undenatured, like NutraBio's.

I normally take one 25 gram whey shake a day. If you eat enough high quality protein at your regular meals, this may be more than enough to get you up to the optimum protein intake per day. If for some reason you can't get enough protein at your regular meals, you may need a couple shakes a day. Higher protein intakes are perfectly healthy.

If you practice intermittent fasting, a whey shake is a good way to mark the end of your fast, ensuring that you get your protein intake up to speed and get that muscle protein synthesis moving.