DHEA Revives Liver of Aged Rats and Improves Antioxidant Reserves and Akt Signaling in Young and Old Rats.

Image 1:  I don't think celebrities realize it, but there is more to anti-aging than an unlined face. New studies show that DHEA could after all help with all sorts of age related diseases (img. antiagingpossible.com)

It's been a while since DHEA was in the news. While I have posted a handfull of mostly beneficial findings related to dehydroepitestosterone (DHEA), the hype that sourrounded its purported anti-aging effect in the late 1990s has completely abated. In view of DHEA's implication  (or rather the lack of the latter) in age-related autoimmune disease, sexual disfunction, osteoporisis, deteroiations of lipid metabolism, type 2 diabetes and cardiovascular and liver disease (Basci. 2007- ignificance of  dehydroepiandrosterone  and  dehydroepiandrosterone  sulfate  in  different  diseases), it is questionable how people beyond the age of 40, when DHEA production declines by 2% per year(!) could not benefit from a carefully planned and monitored DHEA treatment. A group of scientists from Brazil obviously thought the same and decided to take a fresh look at what happens on a molecular level, when 3 (young rats) and 24 months (old rats) old male Wistar-rats are given 10mg/kg deyhdroepitestosterone [human equivalent: 1.62mg/kg; 80kg human: 130mg/day] subcutaneously per day for 5 weeks (Jacob 2011).

Figure 1: Relative changes in total, reduced and oxidized glutathione in young and old rats after 5 weeks on 10mg/kg DHEA (data adapted from Jacob 2011)

As you can see in figure 1, the treatment induced profound increases in total and reduced glutathione and age-dependendly increased (young) or decreased the absolute level of oxidized glutathione (GSSG). Despite the absolute increase in GSSG, usually a marker of oxidative stress, the more important GSH / GSSG ratio, i.e. the ratio of reduced to oxidized glutathion, a more comprehensive marker of the balance of pro- vs. anti-oxidant metabolic processes, improved even more in the twelve young rats, (+6% GSH/GSSG) than in their older companions (+1% GSH/GSSG).

Figure 2: p-Akt levels in young and old rats with and without DHEA supplementation (data adapted from Jacob 2011)

As a faithful student of the SuppVersity, the serine/threonine kinase Akt should not be a stranger to you, after all, mTOR and p706SK (the "muscle builders", you've read about in the context of BCAAs, leucine and exercise-induced protein synthesis), are among its intracellular substrates. In agreement with previous studies, chronic administration of DHEA increased p-Akt-expression in the study at hand (cf. figure 2). The scientists speculate "that the Akt activation in this organ [the liver] is a protective answer" and could, after all, be the underlying reason for the preservation / restauration of hepatic function in the old rats.

Image 2: Oral DHEA supplements are sold for a few bucks over-the-counter (at least in the USA). Yet,
esp. for people under the age of 35, it probably does not make sense to buy and use those. At least, for
as long as it takes for the results of the study at hand to be confirmed in humans. And the allegedly benign 7-Keto DHEA could wreak havoc on your natural corticosteroid metabolism.

So how much DHEA should I take? Given the fact that the name of this blog is SuppVersity, I should have apprehended DeDeRa's question on which form and how much DHEA I would suggest you take. My answer is quite simple: NONE! Why? Well, this is a rodent study done with injectable DHEA. Not only would it be imprudent to extrapolate any dosing suggestions for oral DHEA supplements in humans, without clinical tests, we cannot even be sure that the effects would be identical, even if we hit the right dosage. Thus, while I am convinced that DHEA is probably more benign than many other OTC "supplements", especially people under the age of 30-35 should think twice or better thrice before popping any DHEA supplement - this includes 7-keto, the cortisol-suppressant effects of which can wreak havoc on your natural corticosteroid balance, make you feel tired and sluggish and deprive your body of an important anti-inflammatory pathway.

Most importantly, however, the study does away with the longstanding prejudice that DHEA (at the given dosage) "represent[s] a toxic potential to [the] liver". The isolated finding that endogenous DHEA lead to increased oxidation in the liver (it still does, but the overall pro- vs. anti-oxidant balance still improves!), as well as insufficient funding by the pharmaceutical industry, who obviously is not interested in naturally occuring and thus non-patentable treatment methods, had been one of the primary reasons many scientists decided not to dig deeper into the ameliorative, preventive and restaurative effects of DHEA in the context of age-related diseases. Personally, I hope that the few new studies that have been published, lately, will encourage other researchers to have another look at a hormone with profound yet complex and complicated effects on numerable aspects of the mammalian metabolism.

Anserine + Carnosine Supplementation: A Capped Fountain of Cognitive Youth? Plus: Beta-Alanine + Creatine Could Be A Similarly Brainy Supplement Stack for Young & Old

Carnosine + anserine supps could help her keep up with her grand daughter - physically and mentally!

As a SuppVersity reader you know that  carnosine is the stuff you actually want to increase, when you are taking beta alanine supplements - you want the beta alanine to bind to L-histidine and from β-alanyl-L-histidine aka carnosine. If you are a student who reads and memorizes all article and not just a diligent reader, you will also remember that carnosine acts as a cellular "stress" buffer and that this buffer, as important as it may be during intermittent high intensity exercise, is actually even more important for your neuronal health, or put simply, your brain!

So, even if you haven't heard about anserine before, at least the idea that taking carnosine supplements, or maybe I should say, increasing brain carnosine levels could be a good thing for your cognitive abilities should sound vaguely familiar... and if it does not, this would be another reason to read this article ;-)

You can learn more about brain health at the SuppVersity

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Amphetamines in DS Craze & other Supps!

Coffee & Blue Light for Your Brain

You should not be concerned, though, if it doesn't sound familiar, when I tell you that Budzen et al. report in their paper in the Archives of Gerontology and Geriatrics that the provision of both, carnosine and its "bird analogue" anserine, which is the major "buffering" dipeptide in bird muscle, will have astonishingly significant beneficial effects on the cognitive functioning and physical capacity of elderly individuals.

No wonder, considering the fact that carnosine, anserine and related compounds are reported to play an important physiological role in the body.

Carnosine can be transported across the blood-brain-barrier. Beta alanine, too, but as Sale et al. (2013) point out, we don't know if it will "form carnosine or act as a neuromodulator / neuro- transmitter itself, once it's in the brain" (illustration + quote from Sale. 2013). If it does the latter it will, similar to taurine interact with the GABA receptor (Horikoshi. 1988)

• They have antioxidant properties, cytosolic buffering capabilities and maintain an acid-base balance in excitable tissues of animals and humans. 
• Carnosine is an antiglycating agent. That means it protects your cells from the sugary glue that plasters their exhaust pipes until they start malfunctioning (What? No, that's not an accurate analogy, but I guess, you get what it means ;-)
• They have metal ion-chelating properties and can thus prevent toxic damage from "bad" and not so "bad" metals. Eventually even things like zinc and copper, iron, and calcium, metals your body needs for proper function, will harm you, when they cannot be handled by the body appropriately - as amino acid chelates (you don't have to take them in this form, you just have to have the building blocks your body needs to produce them!)
• Carnosine has also been shown to extend the life of cells in cell culture conditions and to regulate the activity of calcium channels in skeletal muscles.

Due to their overall ability to blunt the negative effects of oxidative and carbonyl stress, both agents have long been touted as potential "pharmacological" (in the widest sense) agents.

Studies conducted on rats and mice show that carnosine has a neuroprotective potential against cerebral ischemia, and indirectly reduces the mortality of the animal (Stvolinsky. 2000; Dobrota. 2005; Rajanikant. 2007). Human studies in patients with chronic discirculatory encephalopathy stress, a specific form of what you could call "brainflammation" (=chronic inflammation of the brain) show that carnosine enhances the efficacy of basal therapy of these patients.

Aging ➯ carnosine ↓, physical & cognitive performance ↓ - probably not a coincidence!

Suggested Read: Hydrated or Dumb: Dehydration Affects Brain, Muscle and Other Vital Organs - Plus: 15+ Causes of Dehydration  | read more

Against that background the chronic decline in whole body carnosine levels with age is something scientists have been eyeballing with concerns for quite some time. Studies have shown that the exogenous provision of beta-alanine can bring the carnosine levels in the musculature back up. In view of the fact that "brain biopsies" are not exactly on the list of favorite experimental procedures the average human study participant wants to undergo, it is yet not 100% sure whether similarly significant increases in carnosine, as they have been observed by Favero et al. in skeletal muscle, will occur in the brain and cells of the peripheral nervous system, as well.

So, if we don't know if beta alanine converts, why don't we administer carnosine, directly? That's a good question, but also one that tells me that you are no true "muscle head". Otherwise the information that carnosine is immediately metabolized and won't even make it to your muscle or brain would already have been hardwired into your brain by the marketing machinery of the fitness industry.

If carnosine is metabolized so quickly, isn't the whole study protocol bullocks, then? Yeah...ah I mean, no. It isn't. In fact it's actually quite clever! By administering carnosine in form of a chicken extract ant thus alongside its natural co-factors, of which anserine is probably only one, the scientists made use of the results of a 2011 study by Peters et al. who were able to show that anserine inhibits the previously mentioned degradation of carnosine and could thus solve the "zero bioavailability problem" (Peters. 2011).

Now, I would be curious what other co-factors in the 2g of chicken-protein hydrolysate may have had an impact on the study outcome, as well. Unfortunately, the only thing we know about the supplement that was administered daily for 13 weeks, is that it was standardized for 1g of anserine and carnosine at a 2:1 ratio (i.e. 667mg of  anserine and 333mg of carnosine).

Figure 1: Beneficial effects of the chicken protein extract anserine + carnosine supplement (Budzeń. 2014)

Practically speaking, this means that the effects I have summarized graphically in Figure 1, were brought about by ca. 667mg anserine and ca. 333mg carnosine the fifty-six 65y+ agers consumed on top of a macronutrient-wise astonishingly "anabolic" diet (1.5g/kg body weight protein,  2.5g/kg carbohydrates and 1g/kg fat).

Let's see what else happened in response to this "minimal" intervention

If you take a look at the other differences between the active treatment group, who received 2.5g of the chicken extract that contained 1g of anserine + carnosine at a 2:1 ratio, and the placebo group, you will see that next to the changes, I illustrated in Figure 1,

• 

  If the influx of beta alanine into the brain was not controlled it could have toxic effects | learn more

  the dangerous diastolic blood pressure of the elderly subjects in the placebo arm kept kreeping up, while the one of the anserine + carnosine treated subjects did not budge,
• the resting heart rate of the placebo group measured at the before and after session increased, while it remained unchanged in the active arm of the study, and
• the body mass index of the subjects in the placebo arm of the study remained steady, while the subjects who received the anserine + carnosine supplements lost a significant, but certainly not earth-shattering 0.51kg/m².

It should yet be obvious that the the changes which are shown in Figure 1, namely significant improvements in the "foot up and go", the "back scratch" and the borg scale, a measure of perceived physical exertion during exercise / physical activity, as well as the improvements in the Mini Mental State Examination, a brief 30-point questionnaire test that is used to screen for cognitive impairment, and the Short Test of Mental Status, which is a classic test that's used with dementia patients, are the more important inter-group differences the researchers from the University School of Physical Education in Wroclaw listed in their hitherto only accepted paper for the Archives of Gerontology and Geriatrics.

With exercise and EGCG (green tea), beta alanine has already been shown to increase neuro- genesis - at least in mice: The corresponding paper by Jessica Ossyra from the University of Illinois has not been published yet, but tis wouldn't be the SuppVersity if I didn't tell you that a combination of the green tea extract ingredient EGCG, beta alanine and exercise has obviously recently been shown be a major promotor of neuro- genesis in mice (Ossyra. 2014).

Now, personally, I see no reason why the provision of beta alanine in an endurance training context (medium intensity is still the best brain builder | learn more), alone, i.e. even in the absence of EGCG, would not produce similar effects in human beings. I still have to curb your enthusiasm and add: "This assumption warrants experimental verification."

Bottom line: In conjunction with significant improvements in abstraction, construction and Copying, as well as memory recall the aforementioned changes and improvements in cognitive and physical performance were all supplementation specific and support the notion that the provision of carnosine, when it is administered at a 2:1 ratio with anserine is not in vain.

What you are now probably asking yourselves, though, is whether a similar if not even more pronounced effect couldn't have been achieved by a much cheaper dietary supplement: Beta alanine. The universal carnosine precursor that's no longer "all the rage", but still "the rage" in the fitness industry? Well, why don't we take a look at the archives? ... I don't see anything, sorry. As of now there is no peer-reviewed study we could be used as a comparison, but if you asked me, it seems unlikely that it sustained release beta alanine formulas increase the physical performance of elderly subjects (del Favero. 2012) without having at least minor beneficial effects on the brain -- and if you take a look at the box to the right, you will see: In rodents it does already work :-)

What? If the 3x800mg you would take for 6 weeks to maximize your muscle carnosine levels suffice? Well, I can't tell you that, but that's certainly a good point to start from. And you know what? If you add 1.5g of creatine to each of these servings, this would be a brain-saver stack for both yourself and your grandma. Why? Well, creatine has been shown to compensate for experimentally (following sleep deprivation) or naturally (due to aging) compromised cognitive function, as well (Rawson. 2011).

References:,

• Budzeń, S., et al. "Anserine and carnosine supplementation in the elderly: effects on cognitive functioning and physical capacity." Archives of Gerontology and Geriatrics (2014).
• del Favero, Serena, et al. "Beta-alanine (Carnosyn™) supplementation in elderly subjects (60–80 years): effects on muscle carnosine content and physical capacity." Amino acids 43.1 (2012): 49-56.
• Dobrota, Dusan, et al. "Carnosine protects the brain of rats and Mongolian gerbils against ischemic injury: after-stroke-effect." Neurochemical research 30.10 (2005): 1283-1288. 
• Guiotto, Andrea, et al. "Carnosine and carnosine-related antioxidants: a review." Current medicinal chemistry 12.20 (2005): 2293-2315. 
• Horikoshi, Tetsuro, et al. "Taurine and β-alanine act on both GABA and glycine receptors in Xenopus oocyte injected with mouse brain messenger RNA." Molecular Brain Research 4.2 (1988): 97-105.
• McMorris, Terry, et al. "Creatine supplementation and cognitive performance in elderly individuals." Aging, Neuropsychology, and Cognition 14.5 (2007): 517-528.
• Ossyra, Jessica, et al. "The influence of nutritional supplementation with epigallocatechin gallate and β-alanine in combination with physical exercise on adult hippocampal neurogenesis and contextual fear conditioning in young adult BALB/cJ mice (629.4)." The FASEB Journal 28.1 Supplement (2014): 629-4.
• Peters, Verena, et al. "Anserine inhibits carnosine degradation but in human serum carnosinase (CN1) is not correlated with histidine dipeptide concentration." Clinica Chimica Acta 412.3 (2011): 263-267.
• Rajanikant, G. K., et al. "Carnosine is neuroprotective against permanent focal cerebral ischemia in mice." Stroke 38.11 (2007): 3023-3031.
• Rawson, Eric S., and Andrew C. Venezia. "Use of creatine in the elderly and evidence for effects on cognitive function in young and old." Amino Acids 40.5 (2011): 1349-1362. 
• Sale, Craig, et al. "Carnosine: from exercise performance to health." Amino acids 44.6 (2013): 1477-1491.
• Stvolinsky, Sergey, et al. "Carnosine protects rats under global ischemia." Brain research bulletin 53.4 (2000): 445-448.