The Vampire Approach to Longevity - Young Blood Revives Muscle, Brain & More | Plus: 6+ Less 'Horrific' Alternatives

Download the podcast this article relates to at superhumanradio.net

You will probably remember from the SuppVersity Facebook news (@SuppVersity | March 15, 2018) that scientists believe that they've found the molecule that's responsible for the rejuvenating effects of "young blood". In their study, which expanded on rodent data indicating that the injection of "young blood", i.e. blood from young mice, into the circulation of old(er) mice has multi-dimensional rejuvenating effects, the researchers grew human muscle cells (C2C12 myoblasts) in a petri dish and stimulated them w/ media conditioned with 5% plasma from healthy male participants that were either younger (n = 6, 18–35) or older (n = 6, >57 years).

What Kalampouka et al. (2018) observed was that the muscle cells reacted differently to a stimulus in form of a scratch (intended to simulate muscular injury and recovery) depending on whether the cultured in media conditioned plasma from younger (18-35 years) or older individuals (>57 years).

This is quite the long article, so you better get your coffee ready ;-)

For Caffeine, Timing Matters! 45 Min or More?

Caffeine Helps When Taken Intra-Workout, too

Coffee can Help You Get into Ketosis

Post-Workout Coffee Helps With DOMS

Coffee Brewing 101 (Optimal Health)

Quantifying the Benefits of Caffeine on Ex.

Traditionally, experiments like that have been done to establish the effect of individual signaling proteins and/or other endocrine factors on certain biological processes. In the study at hand, the goal was yet not so much to isolate, extract, analyze, recreate, patent and cell one of the growth factors/inhibitors. Rather than that, Kalamouka et al. the put a deliberate focus on the "environmental change" of which they believe that it was the true underpinning of the effects of ageing on muscle function.

While this is an 'innovative' conception that contrasts the (still prevalent) assumption that aging was a process that's completely innate to the tissue, it is by no means new. Eventually, the scientists simply replicated a specific aspect of the rejuvenating magic of what scientists call "parabiosis". The compound word its inventors derived from the Greek words "para" (beside) and "bios" (life) is used to denote states of shared blood supply as they would naturally occur in regular twins or animals that share the same placenta in the womb or conjoined twins, as well as in the laboratory, when scientists knit rats together in a way that allows the blood from one rat to pass through the body of the other (see Figure 1). As Megan Scudellari highlights in her 2015 article

"[...] parabiosis presents a rare opportunity to test what circulating factors in the blood of one animal do when they enter another animal" (Scudellari 2015). 

If we are honest, though, this technology is by no means revolutionary new. In fact, it has been known and used back in the early 21st century already and significant breakthroughs in endocrinology, tumor biology and immunology (Bunster 1933; Coleman 1973; Walker 1973, etc.) depended on it. Against that background, it is quite surprising that for reasons that "are not entirely clear, the technique fell out of favor after the 1970s" (Scudellari 2015) and reappeared on the radar of contemporary researchers only recently. As I pointed out in yesterday's episode of Super Human Radio with Carl Lanore, it is possible that the concept of (ab-)using plasma transfusions (PT) or conjoining animals is perceived to be rather the topic of a science-fiction, dystopian or horror novel than scientific practice.

PRP may be done locally and with a concentrated form of your own (not a younger person's) blood plasma, but the purported mechanism is identical.

Plasma transfusion vs. stem cells - What's the difference? The answer to this question is probably best explained with an example you are more familiar with: Platelet Rich Plasma (PRP) and stem cell treatments as they have been offered in orthepedic practices all around the world for years, now. Both are (local) rejuvenation techniques which are meant to help your ligaments repair and regenerate faster. Even the underlying mechanisms are similar. What? Yeah. The mesenchymal stem cells (MSCs) that are extracted from someone's own fat tissue have the ability to differentiate into multiple lineage pathways, but what kind of cell they'll become depends on the cellular environment and chemical signaling.

The latter, i.e. the signaling part, is fulfilled by cytokines and (growth factors/signaling) proteins in the platelets. It is the specific cocktail of signaling molecules that stimulates stem cells and activates the cellular repair process in the surrounding tissue.

"Ok, I get it, PRP helps with tissue repair and is used for skin rejuvenation, hair growth etc. but that's PRP not the plasma of a 20-year-old fellow human being, wtf!?"

If the above reflects your thoughts accurately, you're obviously right. The plasma transfusions (PT) let alone para-symbiotic treatments (I hope nobody ever tries that on human beings) are not identical with either PRP or stem cell therapy, but the underlying processes are identical. You get what supplement vendors would label "the full spectrum of rejuvenating signaling molecules" albeit (and that's not as marketable) not from your own blood, but rather from the blood of human specimen with fewer years of wear and tear on their scalp/hairline, their facial skin, their tendons, and and all the other body parts/organs (see illustration) where PRP is currently being used for "medical" purposes in beauty clinics - ah, and as gross as it may seem to be injected with someone else's plasma logic alone (and the papers discussed in this article) suggest that - disregarding potential side effects that are beyond the scope of this article - you're better off with the growth factor + signaling molecule mix from a younger + healthier individual than you'd be with the reinjection of a more concentrated version of the cocktail you already have in your blood.

A more likely explanation for the transient disinterest in this line of research is the success scientists have had with the isolationist approach to drug development. If you have identified an individual substance as a drug candidate for the treatment of a given disease that's obviously of much greater interest for the pharmaceutical industry that's sponsoring your research than the creepy and impractical concept of collecting human plasma from young donors to rejuvenate clients via [comparably] complex and expensive plasma transfusions (PT).

Where the isolationist approach to drug development fails, plasma transfusions may succeed

Since what I've previously labeled as "the isiolationist approach to drug development" has been hitting walls for years now, scientists have started turning back to the good old Frankenstein + Dracula methods to find a cure for life-threatening diseases such as cancer and Alzheimer's and the fountain of youth. As part of modern cancer-, (anti-)aging and auto-immune research parabiotic experiments have thus gotten more scientific and, due to their nature and promising initial results, public attention. Within the past decade, only, pertinent studies observed...

Figure 1: Schematic depicting the parabiotic pairings in Villeda 2014; a treatment that's obviously far more invasive than a blood transfusion.

• the regeneration of the myelin sheath that's defective in MS patients in mice (Ruck 2012), 
• the successful treatment of murine auto-immune cholangitis (inflamed bile ducts | Yang 2016),
• the reversal of age-related cognitive impairments in mice (Villeda 2014),
• the vascular and neurogenic rejuvenation of the aging mouse brain (Katsimpardi 2014),
• kidney-specific anti-aging effects of young blood in mice (Huang 2017), and ...
• substantial insights into the aging immune system in heterochronic (see Figure 1, right) rodent-models (Davies 2015).

Be warned, though, in some, but not all of the studies, the things the scientists did to their hairy subjects were far worse than what you'll see in your average vampire flick or even the "medical treatments" in the TV show "The 100" where the inhabitants of an old bunker depend on the blood of the young, radiation adapted protagonists and their peers.

Figure 2: Katsimpardi et al. (2014) saw a significant restoration of the blood vessel volume (left) and cerebral blood flow (right) in the SVZ region of the old (O) mice, when they were in parabiosis with young (Y) mice (i.e. young+old mice that share one circulatory system); since baseline data from the young mice is missing, it is not possible to answer the question from the podcast, i.e. whether the young mice in a heterochronic parabiotic pair will age faster.

Both, Katsimpardi et al (2014 | Figure 2) and Yang et al., for example, didn't just inject the sick mice with the blood of healthy peers, just as it was common practice in the early days of this research, they literally knit the mice together (see Figure 1) so that they would share a common circulatory system.

You don't want to be together with someone else? Don't worry.

Calm down, scientists believe and have actually shown that similar benefits as they occur when you actually join the two organisms may be achieved by the transfusion of blood plasma or specific bloodborne factors from young humans to older ones. In that, it is only logical that rejuvenation of the human brain and body being one of the applications that receive the most attention (Musiek 2014), the previously hinted at profane benefits of PRP therapies such as a younger skin, regrowing scalp hair etc. are yet probably as marketable "side effects" of the treatment ;-)

Ambrosia LLC has been running a pilot study. Data acquisition has ended only in Jan 2018, though. So don't expect published data before the end of 2018 (very optimistic estimate).

Will the Thiels and Trumps of this world live forever, while the rest of us perish? Shortly after the publication of the previously cited study by Katsimpardi et al., people began to voice concern about ethical issues. In her "in-depth" article in "Nature", Jocelyn Kaiser writes that - over all the excitement over the latest research results - people tend to overlook that "there's a big caveat" - a financial caveat worth $8,000-$10,000 per treatment. The latter is what the company, Ambrosia, currently to charges participants for a one-time treatment with 1l or 2l of "young blood", respectively... needless to say that logic (and the fact that all this originated from parabiosis studies, in which the blood is constantly rejuvenated) dictate that you would have to repeat this procedure in pretty short intervals. Even the generous assumption that you'd have to undergo the two-day treatment (I know vampires are faster ;-) only every-other-week puts a $208,000-$260,000 price-tag on a treatment that is as of yet "experimentally".

With the promise of having found the fountain of youth "Ambrosia" has convinced 600 clients to participate in a "study". Since data the collection for the study has ended only recently, we don't know much about these people, but their medium age supposedly gravitates towards 60 years and their sex is almost exclusively male. Some alleged early results that transpired - probably via investors or other players on the finance market - say that the scientists who are running the start-up observed a significant decreases (ca. -20%) of the levels of carcino-embryonic antigens and amyloids - both supposedly causally involved in the growth of cancer and progression of Alzheimer’s disease, respectively. Even if this figure is accurate, though, it cannot tell us whether the plasma transfusions (PT) will actually allow the wealthy clients of Ambrosia to "buy" a significant number of extra-years on earth... or, as the Stanford neuroscientist Tony Wyss-Coray says in an interview: "There's just no clinical evidence [that the treatment will be beneficial] and you're basically abusing people's trust and the public excitement around this".

I guess that's also why it wasn't very difficult for the scientists who founded the start-up "Ambrosia" to find 800 participants for what they label as a pilot trial. Unfortunately, the results of the trial [clinicaltrials.gov (NCT02803554)] are not yet available, which is understandable because Ambrosia LLC has been collecting data until recently (i.e. January 15, 2018). That data analysis, peer-review, and publication will take some time should be obvious and is not a sign of scientific malpractice (rather the opposite). Eventually, we will thus simply have to wait patiently ... I guess at least until early next year for more information.

Despite any pilot studies: No long-term study = no real-world results

Whatever the results of the pilot study may be, there's one thing you should be aware of: the description of trial NCT02803554  suggests that the scientists assessed the 1-months response to a single treatment with 1.5l of "young plasma". Why's that interesting? Well, while it may be true that a single treatment will trigger measurable improvements within 1 month, it is not realistic to assume that those will last "forever". In other words, it is highly unlikely that you can buy 10, 5 or even as little as 1 healthy extra-year on earth for just 8,000-$10,000, which is the current costs of a single blood plasma transfusion (costs according to the Ambrosia website | effective March 2018).

Figure 3: Protein factors and other molecules that circulate in the blood of a young mouse exert rejuvenating effects on the brain of an old mouse after intravenous delivery (Wyss-Coray 2016). It is those protein factors, not the transfusion of "young blood" that is used to identify them, most researchers are ultimately interested in.

Don't get me wrong, I don't want to imply that the costs of a medical procedure determine its efficacy (the US healthcare system provides sad evidence that money cannot buy health - especially not if it's wasted on useless and expensive, but profitable new drugs and an inefficient health-infrastructure | see Figure 3), but let's face it: The origin of the whole concept of "rejuvenation by transfusion", the previously described parabiosis trials, clearly suggests that a continuous exchange of your "old" with a donor's "young" blood will be necessary to provide long-lasting practically significant effects - if you can get away with intervals, e.g. monthly injections, will thus be one of the most important questions researchers and "young blood vendors" will have to answer.

Figure 5: If science teachers us anything, longevity or I should say maximizing your genetic potential for longevity is all about managing. Managing your body comp, your (healthy) diet, your physical acivity, your sleep, your stress levels and your intake and (ab-)use of alcohol and cigarettes. But hey, don't stress about it that's bad for your health! ;-)

Until these (hopefully then placebo-controlled) long-term trials become available (if they are even done) it will probably take decades and the "vampire approach to longevity" is neither the only nor the most promising technique in the coffins of longevity researchers. Chances are that, by the time those trials are available, other hopefully less expensive anti-aging treatments may be available... and if not, there's still the tried and proven, yet unpopular "healthy lifestyle" of which we may not know exactly what its optimal incarnation is (and it may well be that this varies from one person to the other) but which seems to include:

• staying normal-weight (better maintaining a healthy body composition)
• lots of exercise- and non-exercise physical activity, 
• a whole-foods based low (simple-)sugar diet with a balanced fat intake, 
• conscious monitoring of both sleep quantity and quality, 
• effective stress management 
• refraining from cigarettes completely and limiting your alcohol intake to ≤ 1 glass of wine/d

I know it's disappointing to hear that, but as "boring" as it sounds these are the things that will not just increase your chance to make the most of your genetically determined aging potential, but - even more importantly - to allow you to get there being in good physical and cognitive condition.

Figure 6: A proposed hierarchical model for the effects of calorie restriction on health and longevity (based on animal studies | Most 2017)

Things to keep in mind when reviewing the "starve yourself to a longer life"-literature: While there's no doubt that caloric restriction has an effect on longevity, this effect is (a) probably smaller in humans than in roundworms or rodents, that it has (b) always been observed in animals (on humans) on ad-libitum + crappy diets (Heilbronn 2003), that (c) the former only one out of many potentially life-saving (in the literal sense) lifestyle factor that have not been taken into account in the pertinent research, and that (d) it rarely takes into account that significant reductions in energy intake will (and that's proven) comes with side-effects such as reduced fertility (Greer 2009).

In this context, it is also worth mentioning that it is as of yet unknown whether and to which extent chronic reductions in energy intake, as they have (a) been observed in people with exceptional longevity whose diets are often below what you'd expect them to eat based on their body weight and activity levels (Rajpathak 2011) and (b) been confirmed in animal models ranging from roundworms to rodents, actually work in human beings - and, more importantly, to which extent they are able to prolong your life (% or total number of years) without compromising our quality of life is completely unknown as of yet (Heilbronn 2003, Most 2017).

Figure 7: Differential effects of long-term caloric restriction in rodents, non-human primates and (expected effects) in non-obese humans.; (1) total energy expenditure relative to lean mass (Heilbronn 2003).

In spite of the fact that the basic effects of "starving" will be the same in humans (see Figure 7), we cannot expect that "starving yourself" is going to prolong the human lifespan by the same impressive ~42-50% Greer et al. (2009) calculated based on dietary deprivation studies in roundworms or the still desirable ~30% reported by Bartke et al. (2001) for regular mice. Both are - almost certainly - out of reach.  As far as a specific number is concerned, though, I will follow the example of the researchers on whose work I base my assumption and refrain from doubtful guessing... the same goes for the benefits of intermittent energy restriction/fasting, by the way: yes, it looks as if it should provide similar benefits, but there's too little data to recommend any of its various incarnations (16/24 hours, every-other-day, 2/5 days, 2/4 weeks fasting, etc.) as scientifically proven anti-aging tools - as one component of a healthy lifestyle, on the other hand, all the different regimen have been shown to have tangible benefits.

Figure 8: Dave Carpenter nailed it with this cartoon about how most of us feel about leading a 'healthy lifestyle' when he drew this one (Cartoonstock)

So what? Stick to what's definitely working: Commit to a 'healthy lifestyle'. I've already pointed out at the end of the main part of this article that the term 'healthy lifestyle', which is used inflationary and in the absence of a globally accepted standard, has five components you will find in all of its various incarnations: (1) normal body comp., (2) physical activity, (3) diet, (4) sleep, (5) stress management, and (6) the conscious and limited use of drinks and tobacco. Unfortunately, adhering to one, let alone all of the corresponding dos and don'ts is - in the most literary sense - "inhuman". We are great fat storers (1), we are lazy, and programmed to conserve energy (2), feast on energy-dense foods to maximize our energy intake (3), living in a 24/7 work and entertainment world (4), don't understand how stress management works (5), and enjoy (+often depend on) the immediate gratification alcohol, cigarettes & co can provide.

Part of the problem certainly is that we feel overwhelmed when we hear the long list of things we have to or must not do to qualify as someone who's leading a 'healthy lifestyle'. Plus: We are so used to feeling the way we feel that we don't even recognize that we're suffering from brain fog and would, just as the participants in Small et al.'s 2006 study (35-69 year-old average Joes), see significant improvements in our cognitive function and brain metabolism from as little as 14 days of committing to a lifestyle program that combined mental and physical exercise, stress reduction, and a healthy diet.

Figure 9: Meta-analyses show that you can reduce your all-cause mortality risk by whopping 66% if you adhere to more than 5 of the lifestyle factors (obesity, alcohol consumption, smoking, diet, and physical activity | Loef & Wallach 2012)

If you can say "I got all the five previously listed aspects of a healthy lifestyle dialed in" while being honest to your yourself, props to you. You are doing much better than 97% of the American population, of which a 2005 study by Reeves et al. (data used was from 2000) shows that they miss out on one or more aspects and thus fail to collect the 66% reduction in all-cause mortality risk, two German scientists calculated in what is one of the few large-scale meta-analyses of data that's not limited to specific mortality outcomes (Loef & Walach 2012 | see Figure 7 for details).

There are nevertheless two caveats people tend to ignore. Firstly, we're talking about a 66% reduction compared to the worst of the worst, those who are doing practically everything wrong. And, secondly, your genes are almost 2x more important (Khera 2016) for your life-expectancy than your diet, the amount of exercise, the hours you spend on meditation etc. So, it's hopeless? By no means: As I said on SHR (download the podcast if you haven't done so, yet) what you do for your health before you'll be 6 feet underground determines whether you can fully exploit your genetic healthy-aging potential |  Comment on Facebook!

References:

• Blau, Helen M., Benjamin D. Cosgrove, and Andrew TV Ho. "The central role of muscle stem cells in regenerative failure with aging." Nature medicine 21.8 (2015): 854.
• Bunster, Eduardo, and Roland K. Meyer. "An improved method of parabiosis." The Anatomical Record 57.4 (1933): 339-343.
• Coleman, Douglas L. "Effects of parabiosis of obese with diabetes and normal mice." Diabetologia 9.4 (1973): 294-298.
• Davies, John, et al. "Heterochronic parabiosis: allowing the dissection of the aged immune system (LYM2P. 723)." (2015): 62-4.
• Greer, Eric L., and Anne Brunet. "Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans." Aging cell 8.2 (2009): 113-127.
• Huang, Qi, et al. "A young blood environment decreases aging of senile mice kidneys." The Journals of Gerontology: Series A (2017).
• Kaiser, Jocelyn. "Antiaging trial using young blood stirs concerns." (2016): 527-528.
• Kalampouka, Ifigeneia, Angel van Bekhoven, and Bradley T. Elliott. "Differing Effects of Younger and Older Human Plasma on C2C12 Myocytes in Vitro." Frontiers in physiology 9 (2018): 152.
• Katsimpardi, Lida, et al. "Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors." Science 344.6184 (2014): 630-634.
• Khera, Amit V., et al. "Genetic risk, adherence to a healthy lifestyle, and coronary disease." New England Journal of Medicine 375.24 (2016): 2349-2358.
• Liu, Kiang, et al. "Healthy Lifestyle Through Young Adulthood and the Presence of Low Cardiovascular Disease Risk Profile in Middle AgeClinical Perspective: The Coronary Artery Risk Development in (Young) Adults (CARDIA) Study." Circulation 125.8 (2012): 996-1004.
• Loef, Martin, and Harald Walach. "The combined effects of healthy lifestyle behaviors on all cause mortality: a systematic review and meta-analysis." Preventive medicine 55.3 (2012): 163-170.
• Most, Jasper, et al. "Calorie restriction in humans: an update." Ageing research reviews 39 (2017): 36-45.
• Musiek, Erik. "Young Blood Rejuvenates the Aging Brain." Science Translational Medicine 6.238 (2014): 238ec95-238ec95.
• Rajpathak, Swapnil N., et al. "Lifestyle factors of people with exceptional longevity." Journal of the American Geriatrics Society 59.8 (2011): 1509-1512.
• Reeves, Mathew J., and Ann P. Rafferty. "Healthy lifestyle characteristics among adults in the United States, 2000." Archives of Internal Medicine 165.8 (2005): 854-857.
• Ruckh, Julia M., et al. "Rejuvenation of regeneration in the aging central nervous system." Cell stem cell 10.1 (2012): 96-103.
• Scudellari, Megan. "Blood to blood." Nature 517.7535 (2015): 426.
• Small, Gary W., et al. "Effects of a 14-day healthy longevity lifestyle program on cognition and brain function." The American journal of geriatric psychiatry 14.6 (2006): 538-545.
• Villeda, Saul A., et al. "Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice." Nature medicine 20.6 (2014): 659.
• Walker, Donald G. "Osteopetrosis cured by temporary parabiosis." Science 180.4088 (1973): 875-875.
• Wyss-Coray, Tony. "Ageing, neurodegeneration and brain rejuvenation." Nature 539.7628 (2016): 180.

Science Round-Up Seconds - GABA & Exercise: Both Can Improve and Mess With Your Sleep. Plus: Natural GABA Alternatives and Sleep As An Overtraining-Gauge

Don't forget that and prioritize proper sleep hygiene over pills and powders.

Let me make get this straight, yesterday's episode (please note that at the minute I post this article, the download is not yet working, should go up within the next hour, though) of the Science Round-Up on Super Human Radio was not only ultra-long (120min+), it was also largely speculative. If you already listened to the show, you will know that Carl and I took up on a discussion Dan Rollins triggered on his, Carl's and my Facebook page(s). Contrary to what you would expects Dan felt that gamma-Aminobutyric acid aka GABA would not help him calm down and let him sleep. For him GABA turned out to have stimulative rather than sedative effects.

I am not going to repeat all the potential explanations I went through in the first ~40min of the show here. Instead, I'd suggest you simply download the podcast and listen to the various hypothesis which range from (a) the general issue of whether or not GABA even crosses the blood-brain-barrier, over (b) the possibility that the GH spike, the sedative (low blood glucose) and the agitating effect (catecholamine + cortisol release with very low blood glucose) could all be brought about by a GABA induced increase in insulin production and a corresponding reduction in blood glucose levels to (c) potential confounding factors such as caffeine consumption (Roca. 1988; Desaulles. 1991; Mukhopadhyay. 1995), interactions with beta alanine, taurine or glycine (Tiedje. 2010; El Idrissi. 2013; Kletke. 2013), (d) genetic differences as with the tingling for beta alanine (Macphee. 2013) or (e) the influence of exercise on the density of GABA receptors in the brain (Dishman. 1990).

Enough of the speculations: What are proven alternatives

Against the background that we still don't really know why Dan and others don't seem to benefit from GABA supplementation the way Carl and Alisa do, we do know that there are other natural alternatives:

• Valerian [dosage: 400-900mg] - inhibits breakdown of GABA in the brain; assuming that GABA makes it across the blood-brain-barrier, valerian would thus work synergistically with oral GABA 

• 

  Due to its anti-PPAR-gamma effect ginseng also made it into the list of "agents that may help you to stay lean" I posted earlier this year. Want to know about the other "20 Anti-Obesity Agents Have the Potential to Inhibit Fat Gain Right at the Cellular Level"? Here you go!

  Ginseng [1-2g crude root extract or 200-600mg of extract] - ginsenoids compete with GABA on both the GABA-A & GABA-B receptor and are thus thought to exert their calming (only in low! doses) effects on the CNS via direct GABA-ergic effects; sedative effects have been observed for Panax ginseng (Korean or Asian ginseng), Panax quinquefolius (American ginseng), and Panax vietnamensis (Vietnamese ginseng); if you feel agitated, reduce the dosage
• Kava kava [180-210mg of kava lactones] - the active agents in Kava kava belong to a group of resinous compounds known as kava lactones or kava pyrones, they bind to the benzodiazepine binding site of the GABA receptor, which could reduce the risk of unwanted excitatory effects
• Passion flower (Passiflora incarnata) [4-8g as a tea] - has been used as a sleeping aid for centuries; chrysin, a mild anti-estrogen appears to be the active ingredient (GABA-A binding; cf. Zhai. 2008); warning: must not be consumed by pregnant women (!) PI can initiate uterine contractions

• 

  I know you don't want to hear that, but(!) don't forget that it could also be your BCAA product that keeps you you from falling asleep and makes you wake up several times during the night by blocking the uptake of tryptophan and thus depleting your brain of the raw material for serotonin (read more).

  Hops (Humulus lupus) [0.5g of dried herb] - has binding affinities to both the melatonin and serotonine receptor (Abourashed. 2004) and can increase GABA in the brain (Franco. 2012); warning: must not be consumed by women with a (family) history of breast cancer (!) hobs has mild, but distinct pro-estrogenic activity (Hajirahimkhan. 2013)
• L-tryptophan [1g] / 5-HTP [100mg] - both will increase serotonin and could thus be stacked with agents that act on GABA; incidentally, there is paucity of research on the efficacy of either of the two as sleep aid
• Melatonin [1-10mg] - as both Carl and I pointed out on the show, melatonin is not an acute sedative, but a signal that it's time to "shut down", don't expect it to actively "send you into sleep", like a sleeping pill

Aside from these agents, Carl and I talked about accupuncture and low energy emission therapy (LEET), as well. While the mechanisms of the former are still not fully understood (e.g. Kwok. 2013), the amplitude modulated high frequency fields the LEET mouthpiece emits right into your brain have been shown to modify the release of GABA and the concentration of benzodiazepine receptors in the rat brain. In addition, low level electromagnetic fields can directly induce the release of melatonin in mammals (Reiter. 1993).

If you are sprinting because of the increase in EPOC, you are a fool.

Read more about exercise and energy expenditure tomorrow! With the info on energy expenditure also crammed into this article it would have been too packed. Therefore you will have to live with a 24h deleay until you learn about the energetic costs of bench pressing, the laughable EPOC effects of HIIT and the evidence that exercise does not just make you hungry. If you feel that's not tolerable, you can already learn about the pathetic EPOC effects of HIIT and exercise & hunger in previous articles.

I already hinted at the physiological (side?) effects of chronic endurance training on the expression of the GABA receptors in rodent brains early in the show (and this article). It should thus not surprise you that exercise can have major impacts on the onset, quality and duration of your sleep - both positive and negative ones, obviously [based on data from Youngstedt (1997; published online 2003)]:

• 

  "90 Min Sleep Restriction Changes in Insulin Resistance Last For One Week"

  Timing of your workouts: While working out 4-8h before bed will have you fall asleep easily, you may experience problems if you have to ignore the onset of tiredness, because you have been exercising more than 8h before you go to bed or to close to hitting the hay. Incidentally, working out 4-8h before bed another advantage: It will help you to sleep through.
• Working out outdoors: The light exposure, the fresh air all that makes working out outdoors so healthy for you (as long as you are not living in Beijing ;-) will energize you and could keep you from falling asleep.
• Duration of your workout: There is a U-shaped dose-response curve for the negative effects of working out on your REM sleep. As Carl rightly pointed out during the show the negative effects of short exercise durations (<1h) is probably in as much a question of intensity / exhaustion (you train intense, when you train short) as the cumulative effects of "exercising" for more than 2h straight (which is by the way more than twice as detrimental for your sleep quality than the <1h exercise)
  
  Aside from its effect on the workout duration will also affect your overall sleep needs with both exercises in the 1-2h and exercises in the >2h range having a major impact on the amount of time you got to spend in bed to recover.
• Exercise intensity*: With a high propensity of low intensity exercise to help you sleep through, a walk on a treadmill in the evening is not going to compromise a good nights sleep, the HIIT workout that would improve your postprandial triglyceride response on the next day (I used this SuppVersity Facebook News as a discussion starter in the live-show), on the other hand may have you wake up several times during the night (*note: I used the studies on the post-exercise heat load in Youngstedt et al. as a proxy for intensity).

If you wanted to distill some practical advice on how you can / should exercise to avoid that your workouts will interfere with your sleep, you should (a) leave at least 4h between any intense workout and hitting the hay (HIIT, weight lifting, etc.) and (b) make use of the beneficial effects of moderate duration (20-40min) light intensity workouts (walking on an incline treadmill, cycling etc.) on sleep onset and quality.

Did you know that...

there are other agents that can "spike" GH temporarily?

• intravenous (iv) insulin 0.2 IU/kg - 50x increase
• intramuscular (im) glucagon 1 mg - 21x incr.
• iv. arginine 20 g/m² as an infusion over 30 minutes - 11x incr.

All observed in a human study involving 18 perfectly healthy young men(Rahim. 1996).

In view of the effect GABA has on the release of insulin from the pancreas, it is not unlikely that my previously voiced hypothesis that the "relaxation" and the "agitation" are responses to low and very low glucose levels would also explain the increase in GH as a response to the hypoglycemic effects of insulin.

What can you take away from the first part of this installment of the Science Round-Up Seconds?

• GABA does not work for everyone
• esp. in higher doses GABA can have excitatory, instead of calming effects
• the exact reasons that this happens is not clear; temporary hypogylcemia is albeit not the least likely candidate
• the hypoglycemia would also explain the GH release which is yet very unlikely to have beneficial effects on muscle growth (GH & gains don't correlate) or fat loss
• among the GABA alternatives, those with a specificity for the benzo docking site on the GABA receptor could work for people for whom GABA itself is excitatory
• working out too late / too intense can compromise sleep
• being "tired but wired" indicates sympathetic overtraining (too much intensity)
• constant fatigue + an increased sleep demand, but light and ineffective sleep is more indicative  parasympathetic overtraining (too much volume)

References:

• Abourashed EA, Koetter U, Brattström A. In vitro binding experiments with a Valerian, hops and their fixed combination extract (Ze91019) to selected central nervous system receptors. Phytomedicine. 2004 Nov;11(7-8):633-8.
• Desaulles E, Boux O, Feltz P. Caffeine-induced Ca2+ release inhibits GABAA responsiveness in rat identified native primary afferents. Eur J Pharmacol. 1991 Oct 2;203(1):137-40. 
• Dishman RK, Dunn AL, Youngstedt SD, Davis JM, Burgess ML, Wilson SP, Wilson MA. Increased open field locomotion and decreased striatal GABAA binding after activity wheel running. Physiol Behav. 1996 Sep;60(3):699-705.
• El Idrissi A, Shen CH, L'amoreaux WJ. Neuroprotective role of taurine during aging. Amino Acids. 2013 Oct;45(4):735-50. doi: 10.1007/s00726-013-1544-7. Epub 2013 Aug 21.
• Kletke O, Gisselmann G, May A, Hatt H, A Sergeeva O. Partial agonism of taurine at gamma-containing native and recombinant GABAA receptors. PLoS One. 2013 Apr 30;8(4):e61733.
• Kwok T, Leung PC, Wing YK, Ip I, Wong B, Ho DW, Wong WM, Ho F. The effectiveness of acupuncture on the sleep quality of elderly with dementia: a within-subjects trial. Clin Interv Aging. 2013;8:923-9.
• Macphee S, Weaver IN, Weaver DF. An Evaluation of Interindividual Responses to the Orally Administered Neurotransmitter β -Alanine. J Amino Acids. 2013;2013:429847.
• Mukhopadhyay S, Poddar MK. Caffeine-induced locomotor activity: possible involvement of GABAergic-dopaminergic-adenosinergic interaction. Neurochem Res. 1995 Jan;20(1):39-44.
• Rahim A, Toogood AA, Shalet SM. The assessment of growth hormone status in normal young adult males using a variety of provocative agents. Clin Endocrinol (Oxf). 1996 Nov;45(5):557-62.
• Reiter RJ. Electromagnetic fields and melatonin production. Biomed Pharmacother. 1993;47(10):439-44.
• Roca DJ, Schiller GD, Farb DH. Chronic caffeine or theophylline exposure reduces gamma-aminobutyric acid/benzodiazepine receptor site interactions. Mol Pharmacol. 1988 May;33(5):481-5.
• Tiedje KE, Stevens K, Barnes S, Weaver DF. Beta-alanine as a small molecule neurotransmitter. Neurochem Int. 2010 Oct;57(3):177-88.
• Youngstedt SD, O'Connor PJ, Dishman RK. The effects of acute exercise on sleep: a quantitative synthesis. Sleep. 1997 Mar;20(3):203-14.
• Zhai K, Hu L, Chen J, Fu CY, Chen Q. Chrysin induces hyperalgesia via the GABAA receptor in mice. Planta Med. 2008 Aug;74(10):1229-34.

Science Round Up Seconds: Are Statins Good for Your Brain? Have the Scientists Just Forgotten About the Risks?

Brainy question of the day: Will statins revive or criple your brain?

Those of you who made it in time for yesterday's live-show, will already know that I have "postponed" publishing the (by then) commented list of dietary supplements to improve and maintain insulin sensitivity to Sunday.

It was my original plan to publish this list along with three suggested supplement stacks on Sunday and sticking to it has the advantage of a "true" ending to the "Maintain and Improve Your Insulin Sensitivity" series (read previous posts) - there is already enough chaos among the 1351 published SuppVersity posts ;-).

Furthermore, it will unquestionable be good for your brain, if I do not flood it with an informational overload by trying to cram all the information about the insulin sensitizers, as well ;-)

Download!

Don't forget to download the podcast: If you have not already done so, I suggest you download and listen to the show. With Carl's questions and comments the radio show does also deliver some extra information that is not part of this summary.

I have to admit that I must have over-read the original article a listener who goes by the name "Rad Fox" referenced in an email he send to onair@superhumanradio.com (feel free to bother us with questions for future episodes). In this email "Rad" referenced an article which turned out to be one of these notorious copy + paste pieces of a press release. The latter came from John Hopkins Medicine and discussed the results of an as of now unpublished paper about the incidence of dementia in patients on statin therapy.

This is not the first review that connects statin use to brain health!

Despite their bad reputation within the health and fitness community, the use of statin drugs has in fact been shown in numerous studies to keep your brain on top of the game. Another very recent meta-analysis of data from studies with 2851 cases and 57020 participants, for example, says that statin use is associatied with a statistically significant -48% reduction in dementia risk (Song. 2013). Similarly, Steenland et al. write in a paper that's been published roughly a month ago:

"Research volunteers with normal cognition at baseline evaluated an average 4.1 times over 3.4 years (1,244 statin users, 2,363 nonusers) and with mild cognitive impairment (MCI) at baseline evaluated an average 3.9 times over 2.8 years (763 users, 917 nonusers)." (Steenland. 2013)

Irrespective of the high number of empirical studies that seem to support the efficacy of statins as "anti-dementia" drug, I did not even have to bother with PubMed or any other medical database to find trials that suggest that the use of statin drugs will have the exact opposite effects. I just had to scroll down to the end of the article, where I found a news report on an study that claims that Pravachol, obviously likewise a statin drug, would be "linked to memory impairment" (read the news story).

Beneficial or detrimental? Which results can you trust?

Your body does in fact produce i's own anti-dementia "drug": Melatonin. With the natural decline of the metlatonion production with age, it is thus only logical that you develop dementia, only in your older age - learn how to protect yourself with melatonin

I know it can be enervating at time, but it's one of the central characteristics of science that it's results are usually ambiguous and far from achieving the status of "undebatable truths". If you've been around the SuppVersity for some time now, you should by now have overcome this naive understanding of the nature of science by now, anyways.

"The promising results obtained in vivo and in epidemiological studies are generally not in accordance with those of placebo-controlled randomized clinical trials." (Silva. 2013)

You should also be aware that the best way to reconcile these discrepancies between epidemiological and experimental evidence is to identify the underlying mechanism behind the effects statins exert on the build-up of neuronal plaque. As soon as we know exactly what's happening we may well be able to decide whether the protective effects we see are "real" or just an "epidemiological Fata Morgana".

The most important question we have to answer is: "HOW?"

Unless we have a rationale explanation for the protective effects statins may have on the brain of (elderly!) individuals, we can file the claim "statins protect elderly brains against cognitive decline" in the "still to be investigated" folder and let it rest there until we have a verifiable theory (= sum of hypothesis) to explain how the use of a drug that was originally designed to block the endogenous production of cholesterol could have such an effect on the brain.

Dietary vs. endogenously produced cholesterol: I know that most of you will be aware that statins reduce your bodies own (=endogenous) production of cholesterol. Most of you will probably also know that it is this endogenously produced cholesterol that is - if any form of cholesterol - to be held responsible for coronary heart disease and (purportedly) the formation of plaque in the brain.

If you are not a narrow-minded text-book physician, you will have to acknowledge that eggs promote an anti-artherogenic cholesterol profile and will thus probably have anti-Alzheimer's and anti-dementia effects (learn more)

For the average human being, his dietary cholesterol intake will have no or only minor influence on the serum levels of cholesterol and cholesterol rich foods such as eggs, have actualle been found to exerd positive effects on the cognitive function of elderly individiuals (Aparicio. 2013); and despite the fact that the results did lose their significance, when they were stratified for total energy intake and education level, the Aparicio study should remind us that the role cholesterol rich foods do not necessarily increase your dementia risk, even if cholesterol was mechanistically involved in the etiology of dementia - even if studies in rodents and rabbits who were fed with synthetic high cholesterol diets suggest otherwise (learn more about the problems with synthetic diets).

And what about saturated fat? In a study from Japan (the Hisayama Study; cf. Ozawa. 2013), the consumption of a diet with a normal amount of saturated fat in it and not the allegedly healthier "almost zero SFA" pattern were associated with reductions in all cause (-34%), Alzheimer's (-35%) and vascular dementia (-55%) - a direct negative effect of saturated fats is thus unlikely. A negative impact of certain foods that happen to have a high amount of saturated foods in them, on the other hand, cannot be excluded.

The most straightforward explanation for the beneficial effects scientists observed in numerous epidemiological studies would obviously be a direct one: "Statins take away a substrate that's necessary for the amyloid plaque to form." This hypothesis would also be supported by significant correlations between elevated serum cholesterol levels and plaque build-up in the brain, as they were observed by (among others) by Matzusaki et al. in who used the same cohort Ozawa et al. analyzed in their study on the influence of certain dietary patterns on the risk of developing dementia (see red box above). In the corresponding paper Matzusaki et al. report:

Table 1: Official "normal" levels for total, LDL & HDL cholesterol, as well as triglycerides (based on AHA recommendations)

• 23x higher risk for total cholesterol > 5.8mmol/L
• 13x higher risk for LDL > 4.02 mmol/L
• 70% higher risk for HDL < 1.04 mmol/L (p > .5)
• 3.5x higher risk for triglycerides >1.56mmol/L
  that's compared to Q1 <0.51mmol/L
• 7x higher risk for LDL / HDL > 3.48 mmol/L
• 3.1x higher risk for “non-HDL” > 4.61 mmol/L

What makes Matzusaki et al.'s observation particularly interesting is the fact that they are based on 147 autopsies that were performed between 1998 and 2003. Autopsies? Yes, I know that sounds gross and irrelevant, but it has the advantage of

• being able to measure the amount of plaque directly,
• having physical and quantitative data, and
• not being limited to diagnosed cases of dementia.

In other words: Your data is not going to be skewed by analyzing only those who are already sick enough to be treated, when you are able to look at the brains of a representative sample of the population after they died.

Dead or alive, there is more than one hypothesis

Remember: We are inclined to forget that the only difference between "effects" and "side effects" is our assessment of the latter. The beneficial effects statins have on the expression of AGE receptors, for example would be  "side effects" for a classic statin which is obviously supposed to lower cholesterol and nothing else. In the context of dementia prevention, this side effect it is the intended effect and the cholesterol lowering effects of statins are the "side effects".

In view of the myriad of already discovered and hitherto undiscovered "side effects" of statins it is however just as likely that the reduced dementia risk is a result of  ...

• a reduction in advanced glycation end product receptors in the brain and thus a protection against the negative effects AGEs exert on the brain (Liu. 2012; Deane. 2012).
  On a side note: If you want to counter the production of endogenous AGEs you can do so with taurine (Nandhini. 2004). This would obviously render the use of a statin to reduce the receptor density obsolete.
• a blockade of the “maturation” from plague precursors to amyloid beta plaque (Hosaka. 2013)

... or a combination of all these effects with the direct and indirect role cholesterol plays in the formation of plaque in the brain (Fantini. 2013; Hung. 2013).

Whether we will ever really know that it is that appears to protect statin users from dementia is thus obviously still anybody's guess. What is not "anybody's guess" is whether it makes sense to take a statin solely to protect yourself from developing dementia. That would - in my humble opinion - rather be a sign of existing cognitive decline than a protection against its development ;-)

Bottom line: Despite the fact that I have never been a statin advocate it is difficult to argue with the current epidemiological evidence: People who take statins have a lower incidence of dementi *fullstop* Whether this is even related to cholesterol is however as questionable as Carl's suggestion that it's an overall reduction in inflammation as it has been observed by Reis et al. (2012) in the context of Malaria infections, where statins appear to be able to sooth the "brainflammation" that's behind the beneficial effects of statin drugs.

Those who take statins can benefit from eating pomegranate | learn more

What is more or less undebatable, though, is that "there is insufficient evidence to recommend statins for the treatment of dementia" (McGuinness. 2013). I will leave you with this conclusion from the latest Cochrane review and a discreet reference to the influence of APO-E phenotypes on both baseline cholesterol levels and the development of Alzheimer's disease. Who knows? If we controlled for the APO-E4 allele, we may well find that carriers of the AA (=2x positive) form of the APO-E4 gene, of which a recent study from the University of Toronto suggests that having this homozygous APO-E4 gene poses a 56.0x higher risk (no typo!) of developing dementia (all forms), benefit from taking a statin while others don't? I will obviously keep you posted on all future developments.

References: 

• Aparicio Vizuete A, Robles F, Rodríguez-Rodríguez E, López-Sobaler AM, Ortega RM. Association between food and nutrient intakes and cognitive capacity in a group of institutionalized elderly people. Eur J Nutr. 2010 Aug;49(5):293-300.
• Barberger-Gateau P, Letenneur L, Deschamps V, Pérès K, Dartigues JF, Renaud S. Fish, meat, and risk of dementia: cohort study. BMJ. 2002 Oct 26;325(7370):932-3.
• Deane R, Singh I, Sagare AP, Bell RD, Ross NT, LaRue B, Love R, Perry S, Paquette N, Deane RJ, Thiyagarajan M, Zarcone T, Fritz G, Friedman AE, Miller BL, Zlokovic BV. A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease. J Clin Invest. 2012 Apr 2;122(4):1377-92. 
• Fantini J, Yahi N, Garmy N. Cholesterol accelerates the binding of Alzheimer's β-amyloid peptide to ganglioside GM1 through a universal hydrogen-bond-dependent sterol tuning of glycolipid conformation. Front Physiol. 2013;4:120. doi: 10.3389/fphys.2013.00120.
• Liu R, Wu CX, Zhou D, Yang F, Tian S, Zhang L, Zhang TT, Du GH. Pinocembrin protects against β-amyloid-induced toxicity in neurons through inhibiting receptor for advanced glycation end products (RAGE)-independent signaling pathways and regulating mitochondrion-mediated apoptosis. BMC Med. 2012 Sep 18;10:105. 
• Hosaka A, Araki W, Oda A, Tomidokoro Y, Tamaoka A. Statins reduce amyloid β-peptide production by modulating amyloid precursor protein maturation and phosphorylation through a cholesterol-independent mechanism in cultured neurons. Neurochem Res. 2013 Mar;38(3):589-600.
• Hung YH, Bush AI, La Fontaine S. Links between copper and cholesterol in Alzheimer's disease. Front Physiol. 2013;4:111. 
• Matsuzaki T, Sasaki K, Hata J, Hirakawa Y, Fujimi K, Ninomiya T, Suzuki SO, Kanba S, Kiyohara Y, Iwaki T. Association of Alzheimer disease pathology with abnormal lipid metabolism: the Hisayama Study. Neurology. 2011 Sep 13;77(11):1068-75.
• Nandhini AT, Thirunavukkarasu V, Anuradha CV. Stimulation of glucose utilization and inhibition of protein glycation and AGE products by taurine. Acta Physiol Scand. 2004 Jul;181(3):297-303. 
• Ozawa M, Ninomiya T, Ohara T, Doi Y, Uchida K, Shirota T, Yonemoto K, Kitazono T, Kiyohara Y. Dietary patterns and risk of dementia in an elderly Japanese population: the Hisayama Study. Am J Clin Nutr. 2013 May;97(5):1076-82.
• Reis PA, Estato V, da Silva TI, d'Avila JC, Siqueira LD, Assis EF, Bozza PT, Bozza FA, Tibiriça EV, Zimmerman GA, Castro-Faria-Neto HC. Statins decrease neuroinflammation and prevent cognitive impairment after cerebral malaria. PLoS Pathog. 2012 Dec;8(12):e1003099.
• Silva T, Teixeira J, Remião F, Borges F. Alzheimer's disease, cholesterol, and statins: the junctions of important metabolic pathways. Angew Chem Int Ed Engl. 2013 Jan 21;52(4):1110-21.
• Song Y, Nie H, Xu Y, Zhang L, Wu Y. Association of statin use with risk of dementia: A meta-analysis of prospective cohort studies. Geriatr Gerontol Int. 2013 Mar 6.
• Steenland K, Zhao L, Goldstein FC, Levey AI. Statins and cognitive decline in older adults with normal cognition or mild cognitive impairment. J Am Geriatr Soc. 2013 Sep;61(9):1449-55.

SuppVersity Science Round-Up Seconds: All About DHEA. Plus: In Practice - Supplementation Benefits & Dosages?

A lack of libido appears - if at all - treatable w/ DHEA only in peri-menopausal women (Maggi. 2013; Pucchino. 2013); there are however a lot of other things DHEA can do for you.

The power of electricity made it possible. Yesterday's show went really smoothly, but despite the fact that I really tried hard to cover all the most interesting topics, there was simply too much for a 1h show. That being said, I still suggest you first download and listen to the podcast before you go ahead and read the Seconds with further basic information about dehydroepiandrosterone aka DHEA, its specific effects, its clinically investigated areas of application, a handful of surprising studies, its (non-excessive) conversion to estrogen, other things you may consider interesting and - as promised - a short-list of "candidates for DHEA supplementation" that may help you to find out whether you can benefit or not.

On a related note: Downloading the podcast is also well worth it, because you get Chris Masterjohn's interview on vitamin D as a "free goodie". Well worth it, I promise (download the podcast).

Let's not waste time, but get straight to the point

As you have heard DHEA is the most abundant steroid hormone in your body, it is produced in the mainly in the adrenal gland (~31mg in men and 18mg in women). In women specifically, DHEA is also the main precursor to androgens (testosterone, DHT & metabolites). For both men and women DHEA and DHEA-S the most abundant, sulfur-bound stable transport form of DHEA. It acts as a neurosteroid the age-induced decline of which has long been implicated as one, if not the main hormonal underpinnings of the cognitive decline we experience as we age.

Figure 1: Age-induced decline in DHEA, effects of oral contraceptice use, hormonal cascade that leads to the formation of DHEA (enzymes to the side) and overview of reasons for DHEA decline.

Looking at the data in Figure 1 (upper left hand) this would actually appear logical. After all DHEA is on a steady decline that starts as early as in our late twenties. As with "paleo logic", the "naked ape hypothesis" and the vitamin D craze (listen to the previously mentioned interview with Dr. Masterjohn and you'll know what I am talking about, here), not everything that appears to be perfectly logic is also correct. So, it should not come as a suprise that corresponding studies involving healthy individuals aged 60 years and over who were treated with (near) physiological doses of DHEA (50-100 mg/day) have yielded very few positive results (Hildreth. 2013).

Fitness is rewarded: Did you know that men who exercise regularly have 2x higher DHEA-S levels than sedentary slobs? they also have 41% lower body fat %-ages (Tissandier. 2001) - coincidence? Probably not! Being fat lowers DHEA and low DHEA increases fat gain (Pritchard. 1998). The beneficial effects of DHEA on body comp, on the other hand, are mediated by the modulation of the effects of cortisol (listen to the show) and direct lipolytic effects on subcutaneous (women) and visceral (men) fat (Hernández-Morante. 2008; more evidence).

Specifically with respect to the cognitive effects, or rather their absence in corresponding trials, it may yet well be that our problem is administration specific and/or of pharmacokinetic nature and thus a mere result of the fact that you cannot replace the endogenously produced DHEA in the central nervous system (which is next to the gonads #2 of the non-adrenal tissues that is capable of synthesizing DHEA from pregnenolone; Dong. 2012). The short-lived pronociceptive (=pain reducing) effects (<150min) of oral DHEA supplementation at 10mg/kg in rodents would furthermore suggest that we are not so much suffering from low systemic levels as we are from our bodies inability to regulate DHEA levels on demand (Gąsińska. 2012).

Apropos regulating DHEA levels "on demand"

Actually DHEA is supposed to increase in response to stress. When stress is becoming "normal", however, the stress-induced DHEA release becomes blunted (Lennartsson. 2013). This process is actually characteristic of the early stages of "adrenal fatique" - I deliberately use the term in quotation marks, because there is no "fatigue" involved here, it's a "simple" deregulation of the up and down that should be characteristic of our stress natural and health response; see "Science Round-Up Seconds: All About Cortisol, Fat Loss, Body Composition and the Efficacy & Safety of 7-Keto & Co" | read more.

And while it may make some sense to supplement with DHEA in the early stages of "adrenal fatigue" (high cortisol, minimally decreased DHEA) its "anti-cortisol" effects are going to do more harm than good, once the initially high cortisol levels are breaking away, and dropping from high to rock bottom. In these latter stages of adrenal fatigue DHEA only treatments could actually make you believe that life sucks even more than it does already.

Figure 2: Elevetated DHEA levels in the AM and PM and a low DHEA / cortisol ratio in the AM (8h) are characteristic of patients with major depression (Assies. 2004)

Life sucks? Yeah, right that reminds me of something else I could not squeeze into the life show: Did you know that the level of DHEA in the cerebrospinal fluid of suicide attempters is elevated (Chatzittofis. 2013)? No, well what about its association with regular depression, then (see Figure 2)?

"DHEA-S was significantly elevated, in conjunction with normal cortisol levels. Based on DHEA-S at 22:00 h only, 77% of the subjects were correctly classified in a discriminant analysis as depressed or control. When simultaneously entered in a multiple regression analysis, DHEA-S (morning and evening) and cortisol (evening only) predicted symptom severity in depressed patients. These preliminary results suggest that DHEA-S may be a more sensitive indicator of depression and symptom severity than cortisol in medicated but still clinically depressed patients." (Assies. 2004)

Surprised? You shouldn't be. At least as a regular here at the SuppVersity you should by now be aware that more of a good thing is not necessarily better.

Too much of a good thing is probably also the reason for most side effects

I actually went into pretty much detail on the connection between dosing schemes and ranges, on the one hand, and potential side effects, on the other hand during the live show, already. I will therefore stick to a reminder here: The more DHEA you take, and the higher the individual dosages, the greater the hard-to-predict conversion to androgens and estrogens.

Figure 3: These hormone levels (expressed relative to placebo control at baseline) do not look exactly as if they would be able to induce a -31% reduction in body fat within one month. Plus: They do by no means look like the results of 1,600mg of DHEA per day - that would be ~53x more than your body produces on a daily basis (data adapted from Nestler. 1988)

Against that background it is all the more surprising to read that Johne E. Nestler et al. claim to have supplied their subjects with 1,600mg DHEA per day (no typo I had a mistake in my show notes and said 1,800mg during the live show - sorry for that, but the general notion is the same - that's a totally crazy! dosage).

"The men then took orally, in a double blind fashion, capsules containing either placebo or 400mg(138.7mmol) DHEA four times daily [total daily DHEA dose, 1600mg or 28days]." (Nestler. 1988)

The data in the study at hand is even less credible, if we look at the results of a more recent study which showed age- dependent increases of 100-300% in testosterone, when young(er), middle aged and older men took 50mg of DHEA the night before they undertook a HIIT regimen (learn more)... but hey, maybe the guys trained once during the 30 day study period and hat a 3000% T-boost

Without changes in activity levels or dietary intake this insane (don't to this at home or anywhere else ;o) DHEA protocol lead to a 31% reduction in body fat within one month. If you listened to the show, already, you will know that I am pretty skeptical, though,

1. whether these results are accurate or simply the result of faulty measurements
2. if more than 10% of the ingested DHEA actually was absorbed

I mean let's face it: With statistical significant increases only for DHEA (280%) and androstenedione (+100%) but in the absence of significant increases in testosterone, estrogen (neither E2, nor E1), decreases in SHBG or blood sugar and insulin resistance this result is simply incredible (in the most literal sense of the word)... ah, you do remember: Don't give it a try! Right?

High estrogen is not a regular side effect

No, no and no. Look at the data from the Nestler study. 1,600mg per day and NO (=ZERO) change in estrogen. This is however not the norm - the norm is a proportional increase in estrogen and testosterone which tends to leave healthy men with a higher testosterone to estrogen ratio than before. Examples? Here you go:

Figure 4: Effects of 50mg DHEA for 36 months in 70yr old men (left) and 100mg of DHEA for 6 months in men and women (Müller. 2006; Morales. 1998)

As you can see the results may be very different: Increases in estrogen and testosterone in the Müller study with 50mg for 36 months in 100 nonhospitalized, nondiseased, independently living men, aged 70 yr and over with low scores on strength test, on the one hand; and no effects in the male participants of the study by Morales et al. (1998), on the other hand.

The Morales study should by the way remind us of one of the most important functions of DHEA in women - it's the main precursor to male sex hormones (here testosterone Figure 4, right-top and DHT Figure 4, right-bottom); as discussed further down, DHEA can thus in fact be used as a "HRT"-like treatment in women, but not in men.

So who can benefit?

Actually the previously mentioned sex difference segues nicely into my here's who benefits list, Carl and I did not really have the time to cover, yesterday... so let's see:

• 

  DHEA increases Testosterone & Blunts Muscle Damage (read more)

  people with low (age-corrected) DHEA levels - in this case DHEA is like any other hormone replacement therapy and should be monitored by a medical professional of whom you should make sure that he controls for confounding factors that would point towards confounding and causal factors
• people in their late 40s or later - as discussed in the show, the changes in hormonal levels, body comp and quality of life questionnaires may not be significant, but if you compare them to the control groups there is usually a benefical trend (gaining muscle and losing fat is better than the other way around, even if its only in the 500g range; cf. Müller. 2006; also discussed in the live show); still in view of the fact that you really don't know what you will get - get tested (must: DHEA-S, testosterone, DHT, estrogen (E2); optional: SHBG, free testosterone, E1, insulin, cholesterol panel, PSA (addition as per Daria's suggestion) - the latter two may in fact improve, by the way) after 1-2 months and every 6 months thereafter

• 

  DHEA blunts fat deposition more effectively than testosterone; for both the effects are mediated via PPAR-gamma (read more)

  men and women with low androgens - though (esp. for men) "real HRT" is probably the better way to go, you can try what I outlined for 40+ agers to bump up your androgens, as well
• women in early menopause - benefits have been observed for both the Kupperman score (index to quantify menopause symptoms) and vasomotor symptoms of menopause (Stomati. 2000).
  
  Some authors even consider it an adequate hormone replacement alternative for women (both studies used "only" 50mg/day!):
  

  

  Suggested read: "Carnitine as Repartitioning Agent? IGF-1, p-AKT & mTOR Up, Catabolic Proteins Down + 7% Improvement in Lean- to Total Mass Ratio" | read more

  "Administration of DHEA significantly affects several endocrine parameters in early and late postmenopausal women independently from body mass index. Our data support the hypothesis that DHEA treatment acts similarly to estrogen-progestin replacement therapy on the GHRH-GH-IGF-1 axis. This suggests that DHEA is more than a more than a simple "diet supplement" or "antiaging product"; rather it should be considered an effective hormonal replacement treatment." (Genazzani. 2001)

  another pro-argument is certainly the increase bone mineral density, which is and will probably always remain one of the major issues in menopause.
• Other things worth mentioning: Actually I have a couple of pages of additional notes, but I guess these are the most interesting points → DHEA increases intramuscular DHT, which is associated with increased insulin sensitivity (Sato. 2011) → DHEA improves both GLUT-4 and Akt (could also increase protein synthesis) in diabetic rodents (Sato. 2009) → DHEA improves the levels of the master anti-oxidant GSH in aging (or sick) livers (Jacob. 2011) → DHEA slows the development of type II diabetes (Byrne. 2001; rodent model) → Salivary cortisol and DHEA-S concentrations reflect the activity of the HPA axis (Ghiciuc. 2011) → DHEA opposes the immune suppressive effects of cortisol (Chen. 2004) → DHEA has thermogenic effects (Lardy. 1995) → DHEA is on the WADA list of prohibited substances, but doping researchers say its effect / side effect profile is not worth it anyway (Hahner. 2010) → DHEA has anti-breast cancer effect in rodent model of developing mammary cancer (via conversion to androgens; Labrie. 2001)
  men and women with hyperthyroidism - the increased thyroid activity "burns" through all adrenal hormones, so that backup (of both DHEA and cortisol) can become necessary (Agbaht. 2013)
• patients on glucocorticoids (e.g. for inflammatory or immune diseases) - cortisol and synthetic glucocorticoids suppress DHEA production - it's thus logical that backfilling the missing hormones can help
• people on severe chronic stress - the military, for example has conducted a handful of interesting studies; two of the most recent studies were conducted by Taylor et al. (2012) and Taylor (2013) - the researchers report neuroprotective and anabolic effects with 50mg/day (classroom phase) and 75mg/day (training in the field), respectively
• people using non-aromatizing steroids - DHEA can provide a precursor for a baseline estrogen level even on suppressive non-aromatizing drugs (listen to the show for more details)
• patients suffering from lupus erythematosus ["syndrome like" = very unspecific autoimmune disease usually with sever joint pain and arthritis, ca. 5 mio people world-wide suffer; every year 100,000 new cases in the US / constantly increasing (Buvat. 2003); honestly I suspect this leaves more cortisol to get the inflammation under control, but hey what do I know; usually women, often African American or latino] proven benefit from 200mg/day
• women with diminished ovarian reserve - while the latest review says the evidence was not there, I consider the results of a study by Gleicher (2009), alone, worth giving it a try: The researchers observed a restoration of the rate of miscarriages to normal levels in the 73 cases they evaluated – that’s a reduction of -51% risk of having a miscarriage and direct effect on the occurrence of genetic disorders like "Trisomy 21" [= down syndrome] in women with diminished ovarian reserve (Gleicher. 2010) - still: don't even think about messing with your hormones, when you are healthy and wand to become pregnant!

The worst candidate for benefits are the intended costumers of the recently released DHEA-derivates from various producers - young men in the prime of their life. Chances they will benefit are slim, but not impossible. Whether one of the DHEA based alternatives deliver is yet questionable.

---

Suggested read for those who cannot get enough of DHEA stories: "Less Than 15mg of DHEA Exert Identical Beneficial Effects on Insulin Sensitivity as 1h of Cardio 5x Per Week. Both Effects Mediated Via Increases in Intra-Muscular DHT" | read more, expect similar, but not 1:1 identical results in humans

Bottom line: I guess I would have to go on for at least 10,000 additional words (now we are at ~2,300 words, by the way ;-) to give you at least a 25% "complete" image of all you could know about DHEA, but that's not really the intention of this summary. I would be happy if you felt that listening to the podcast and reading the "Seconds" improved your understanding and you remember that 2x25mg/day are probably the best way to boost DHEA-S, while 1x50 - 2x50mg per day is more of a "hormonal" booster including a higher risk for a hardly controllable conversion to downstream metabolites.

Whether the latter will or won't have beneficial effects will vary from person to person and makes testing all the more important. If you remember that and the fact that the fairy tales on the bulletin boards all over the Internet don't provide an adequate picture of what works, what sucks and what you side effects will or won't occur (listen to the podcast for additional details), I'd say you know plenty about DHEA... and if you disagree, just check out what I previously wrote about DHEA, here.

References:

• Agbaht K, Gullu S. Adrenocortical reserves in hyperthyroidism. Endocrine. 2013 Mar 27.
• Assies J, Visser I, Nicolson NA, Eggelte TA, Wekking EM, Huyser J, Lieverse R, Schene AH. Elevated salivary dehydroepiandrosterone-sulfate but normal cortisol levels in medicated depressed patients: preliminary findings. Psychiatry Res. 2004 Sep 30;128(2):117-22.
• Buvat J. Androgen therapy with dehydroepiandrosterone. World J Urol. 2003 Nov;21(5):346-55. Epub 2003 Oct 10. Review.
• Byrne JJ, Bradlow HL. DHEA-PC slows the progression of type 2 diabetes (non-insulin-dependent diabetes mellitus) in the ZDF/Gmi-fa/fa rat. Diabetes Technol Ther. 2001 Summer;3(2):211-9.
• Chatzittofis A, Nordström P, Hellström C, Arver S, Asberg M, Jokinen J. CSF 5-HIAA, cortisol and DHEAS levels in suicide attempters. Eur Neuropsychopharmacol. 2013 Feb 28. 
• Chen CC, Parker CR Jr. Adrenal androgens and the immune system. Semin Reprod Med. 2004 Nov;22(4):369-77.
• Dong Y, Zheng P. Dehydroepiandrosterone sulphate: action and mechanism in the brain. J Neuroendocrinol. 2012 Jan;24(1):215-24. 
• Gąsińska E, Bujalska-Zadrożny M, Sar M, Makulska-Nowak H. Influence of acute and subchronic oral administration of dehydroepiandrosterone (DHEA) on nociceptive threshold in rats. Pharmacol Rep. 2012 Jul;64(4):965-9. 
• Genazzani AD, Stomati M, Strucchi C, Puccetti S, Luisi S, Genazzani AR. Oral dehydroepiandrosterone supplementation modulates spontaneous and growth hormone-releasing hormone-induced growth hormone and insulin-like growth factor-1 secretion in early and late postmenopausal women. Fertil Steril. 2001 Aug;76(2):241-8. 
• Ghiciuc CM, Cozma-Dima CL, Pasquali V, Renzi P, Simeoni S, Lupusoru CE, Patacchioli FR. Awakening responses and diurnal fluctuations of salivary cortisol, DHEA-S and α-amylase in healthy male subjects. Neuro Endocrinol Lett. 2011;32(4):475-80.
• Gleicher N, Ryan E, Weghofer A, Blanco-Mejia S, Barad DH. Miscarriage rates after dehydroepiandrosterone (DHEA) supplementation in women with diminished ovarian reserve: a case control study. Reprod Biol Endocrinol. 2009 Oct 7;7:108.
• Gleicher N, Weghofer A, Barad DH. Dehydroepiandrosterone (DHEA) reduces embryo aneuploidy: direct evidence from preimplantation genetic screening (PGS). Reprod Biol Endocrinol. 2010 Nov 10;8:140. 
• Hahner S, Allolio B. Dehydroepiandrosterone to enhance physical performance: myth and reality. Endocrinol Metab Clin North Am. 2010 Mar;39(1):127-39, x.
• Hildreth KL, Gozansky WS, Jankowski CM, Grigsby J, Wolfe P, Kohrt WM. Association of serum dehydroepiandrosterone sulfate and cognition in older adults: sex steroid, inflammatory, and metabolic mechanisms. Neuropsychology. 2013 May;27(3):356-63. 
• Jacob MH, Janner Dda R, Araújo AS, Jahn MP, Kucharski LC, Moraes TB, Dutra Filho CS, Ribeiro MF, Belló-Klein A. Dehydroepiandrosterone improves hepatic antioxidant reserve and stimulates Akt signaling in young and old rats. J Steroid Biochem Mol Biol. 2011 Nov; 127(3-5):331-6. 
• Labrie F, Luu-The V, Labrie C, Simard J. DHEA and its transformation into androgens and estrogens in peripheral target tissues: intracrinology. Front Neuroendocrinol. 2001 Jul;22(3):185-212. Review.
• Lardy H, Kneer N, Bellei M, Bobyleva V. Induction of thermogenic enzymes by DHEA and its metabolites. Ann N Y Acad Sci. 1995 Dec 29;774:171-9.
• Lennartsson AK, Theorell T, Kushnir MM, Bergquist J, Jonsdottir IH. Perceived stress at work is associated with attenuated DHEA-S response during acute psychosocial stress. Psychoneuroendocrinology. 2013 Sep;38(9):1650-7.
• Maggi M, Buvat J, Corona G, Guay A, Torres LO. Hormonal causes of male sexual dysfunctions and their management (hyperprolactinemia, thyroid disorders, GH disorders, and DHEA). J Sex Med. 2013 Mar;10(3):661-77.
• Morales AJ, Haubrich RH, Hwang JY, Asakura H, Yen SS. The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and women. Clin Endocrinol (Oxf). 1998 Oct;49(4):421-32.
• Muller M, van den Beld AW, van der Schouw YT, Grobbee DE, Lamberts SW. Effects of dehydroepiandrosterone and atamestane supplementation on frailty in elderly men. J Clin Endocrinol Metab. 2006 Oct;91(10):3988-91.
• Nestler JE, Barlascini CO, Clore JN, Blackard WG. Dehydroepiandrosterone reduces serum low density lipoprotein levels and body fat but does not alter insulin sensitivity in normal men. J Clin Endocrinol Metab. 1988 Jan;66(1):57-61.
• Pluchino N, Carmignani A, Cubeddu A, Santoro A, Cela V, Alcalà TE. Androgen therapy in women: for whom and when. Arch Gynecol Obstet. 2013 Aug 3.
• Pritchard J, Després JP, Gagnon J, Tchernof A, Nadeau A, Tremblay A, Bouchard C. Plasma adrenal, gonadal, and conjugated steroids before and after long-term overfeeding in identical twins. J Clin Endocrinol Metab. 1998 Sep;83(9):3277-84.
• Sato K, Iemitsu M, Aizawa K, Ajisaka R. DHEA improves impaired activation of Akt and PKC zeta/lambda-GLUT4 pathway in skeletal muscle and improves hyperglycaemia in streptozotocin-induced diabetes rats. Acta Physiol (Oxf). 2009 Nov;197(3):217-25. 
• Sato K, Iemitsu M, Aizawa K, Mesaki N, Fujita S. Increased muscular dehydroepiandrosterone levels are associated with improved hyperglycemia in obese rats. Am J Physiol Endocrinol Metab. 2011 Aug;301(2):E274-80.
• Stomati M, Monteleone P, Casarosa E, Quirici B, Puccetti S, Bernardi F, Genazzani AD, Rovati L, Luisi M, Genazzani AR. Six-month oral dehydroepiandrosterone supplementation in early and late postmenopause. Gynecol Endocrinol. 2000 Oct;14(5):342-63. 
• Taylor MK, Padilla GA, Stanfill KE, Markham AE, Khosravi JY, Ward MD, Koehler MM. Effects of dehydroepiandrosterone supplementation during stressful military training: a randomized, controlled, double-blind field study. Stress. 2012 Jan;15(1):85-96. 
• Taylor MK. Dehydroepiandrosterone and dehydroepiandrosterone sulfate: anabolic, neuroprotective, and neuroexcitatory properties in military men. Mil Med. 2013 Jan;178(1):100-6.
• Tissandier O, Péres G, Fiet J, Piette F. Testosterone, dehydroepiandrosterone, insulin-like growth factor 1, and insulin in sedentary and physically trained aged men. Eur J Appl Physiol. 2001 Jul;85(1-2):177-84.