Physical & Cognitive Exercise Are Similarly Effective DNA Protectors & Antioxidant Boosters in Elderly Men & Women

Brain builders and muscle builders are similarly effective DNA protectors in the elderly.

As a SuppVersity reader you won't be surprised to hear that Bernhard Franzke and his colleagues from the University of Vienna were able to confirm that resistance training can improve the resistance of human DNA to H2O2 damage in institutionalised elderly. What may be news to you, though, is that very similar effects can be achieved by cognitive training in form of coordinative or cognitive tasks that were performed only two times per week by the 105 institutionalised elderly women and men (aged 65–98 years) the scientists recruited from five different senior residences in the area of Vienna (Franzke. 2014).

DNA damage is obviously important, maintaining optimal lean mass levels is important, too

Tri- or Multi-Set Training for Body Recomp.?

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In the recent Austrian study, the subjects had been randomized to three groups. The previously described cognitive training group, which also served as a "control", as well as two resistance training groups.

"The RT groups (RT and RTS) performed two sessions of RT per week, supervised by a sport scientist, conducted on two non-consecutive days. Training attendance was recorded every session. The only equipment used was exercise bands and a chair. [...] The main part consisted of 10 exercises for the main muscle groups (legs, back, abdomen, chest, shoulder and arms). One training session started with 10 min of warm-up, continued with 30–40 min of strength training and ended with a 10-min cool-down. To keep the training stimulus high enough, the exercise program was adjusted to the participants’ individual needs, by either adapting the resistance of the elastic band (shorter or stronger band) or by modifying the exercise, by means of performing a more diffiult version. In the initial phase (4 weeks) one set of 15 repetitions was performed in order to learn the correct form of each exercise. From the fifth week on, the intensity and volume were progressively increased from two sets of light exercises to two sets of heavy resistance. If the participants could easily perform two sets of 15 repetitions they were told either to take more resistance or to perform a more difficult version of the exercise" (Franzke. 2014).

In contrast to the RT group, which did "nothing", but the previously described resistance training regimen, the subjects in the RTS group consumed a multi-ingredient supplement every morning, as well as directly after each training session. Said supplement consisted of 20.7g protein [56 energy (En) %, 19.7g whey protein, 3 g leucine, >10 g essential amino acids], 9.3 g carbohydrates (25 En%, 0.8 BE); 3.0 g fat (18 En%), 1.2 g roughage (2 En%), 800 IU (20 μg) of vitamin D, 250 mg calcium, vitamins C, E, B6 and B12, folic acid and magnesium (one portion FortiFit, Nutricia with a total energy content per drink of only 150 kcal).

Figure 1: Changes in parameters of DNA damage and antioxidant enzyme expression (Franzke. 2014).

In spite of the fact that the intake of the nutritional supplement was controlled at breakfast as well as after the training sessions, it did not provide significant additional benefits on top of the regular resistance training protocol.

We should keep in mind, though, that (a) non-significant benefits were visible for the formamidopyrimidine DNA glycosylase (FPG) and the expression of superoxide dismutase and that (b) the actual benefits of protein supplements would have become visible only if the scientists had accessed the changes in body composition, as well.

Maximal protein synthesis - How much protein do the elderly need? Find out in a previous SV article.

Bottom line: If you don't have a present for your grandpa or grandma, yet, I suggest you craft a voucher for 2 weekly resistance training and cognitive training sessions with yourself as a trainer and buy a tub of protein to round your present off...

All Christmas jokes aside, the study at hand simply confirms what the proverb "a rolling stone gathers no moss" implies. Exercise, no matter whether it's cognitive or physical exercise, protects aging men and women from pro-cancerous DNA damage and ensures that can maintain "a sound mind in a sane body" | Comment on Facebook!

References:

• Franzke, B. et al. "The impact of six months strength training, nutritional supplementation or cognitive training on DNA damage in institutionalised elderly." Mutagenesis (2015):147–153.

Stretch-Shortening Cycle Exercise Superior to Eccentric Exercises in the Elderly - Identical Size & Strength Gains, With a Functional Advantage for Stretch Shortening Ex.

A stretch-shortening cycle (SSC) is an active stretch (eccentric contraction) of a muscle followed by an immediate shortening (concentric contraction) of that same muscle - e.g. jump squats.

Sacropenia, i.e. the age-related loss of muscle mass is a huge problem in our society. A problem the consequences of which start to surface way before older men and women suffer from serious limitations in their mobility and their ability to master (no longer) ordinary everyday-life tasks.

The loss of muscle mass is after all associated with an ever-increasing risk of metabolic syndrome, i.e. obesity, diabetes, high blood lipids, etc. (Baumgartner. 2004; Kim. 2011) - in both, young and old individuals, as well.

In contrast to many pharma-funded which spends millions of dollar on "promising new drugs" (that's what they say) to solve the problem.

Learn more about building muscle at www.suppversity.com

Tri- or Multi-Set Training for Body Recomp.?

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Battle the Rope to Get Ripped & Strong

Study Indicates Cut the Volume Make the Gains!

Researchers like Márk Váczi and his colleagues from the University of Pécs have long recognized that the development "promising new drugs" holds much less promise that the optimization of exercise regimen that are targeted to prevent sacropenia. In their latest paper in Experimental Gerontology the researchers describe the results of an experiment that was conducted to compare the effects of exercise training using stretch-shortening (SSC) and eccentric contractions (ECC) on the mechanical function and size of the quadriceps muscle and hormonal adaptations in healthy old males (N=16; age: 60-70 year old).

Figure 1: The torque–time curves of a stretch-shortening cycle and an eccentric exercise training contraction highlight the main difference between SSC (short, ultra-intense) and ECC (long, medium intensity) knee extensions (Váczi. 2014)

In that, Vávzi et al used an experimental approach in which the total mechanical work was identical in the two training groups and hypothesized that mechanical, hormonal, and muscular adaptations would differ in response to SSC vs. ECC exercise (note: plyometric training harnesses the beneficial effects of SSC | learn more).

The exercise of choice was, as so often, the single-lateral knee extension. The subjects trained 2-3 times per week with 48h rest between two sessions (each between 9-11 am in the morning).

Benefit from SSC irrespective of your age after you've read the following SuppVersity Classic: "Building the Jack-of-All-Traits Legs Workout With Squats, Jump Squats and Body Weight Plyometrics? At Least for Physical Education Students that Seems to Work." | read more

"Subjects performed 4 sets of 8 to 14 repetitions of unilateral knee extensions with both legs, with 2 min of rest between sets. The exercising legs were alternated across sets. The training contractions in SSC and ECC groups were similar to the SSC and ECC test contractions. [...A] unique element of the training program was that the average mechanical work for a session was still similar in the two groups. This was achieved by manipulating the stretch-load in the SSC group. For example, if a subject in the ECC group improved mechanical work production due to adaptation to the training, the stretch-load was adjusted to match subject-pair's mechanical work in the SSC group." (Váczi. 2014)

If we take a look at the outcome of the work and volume matched training with stretch-shortening and eccentric leg extensions, we see the following differences and similarities, when comparing the two exercise regimen:

• 

  Figure 2: The hormonal response to the exercise regimen was more or less identical (Váczi. 2014)

  There was a significant group by period interaction for RTD30 [rate of torque development after 30ms] and RTD50 (p < 0.05), suggesting that the two groups responded differently to the training. 
• There was no group by period by time interaction in any of the hormonal variables, suggesting similar re sponses to the two training regimens. There was a significant time main effect in testosterone (p = 0.010), suggesting that the two exercise bouts (before and after 10 weeks training) uniformly increased testosterone 15% from pre to IP, and then decreased 10% from IP to 5 min post-exercise. 
• There was a time main effect for cortisol (p = 0.018), suggesting that the two exercise bouts uniformly increased cortisol 21% from pre to IP, and then further increased 6% to 5 min post-exercise. 
• There was a time main effect for testosterone/cortisol ratio (p = 0.002), suggesting that the two exercise bouts uniformly decreased the ratio 17% from pre to 5 min post-exercise. 

Now, in view of the fact that the overall strength (MCV) and size gains (CSA) were identical, as well. It would seem as if both types of exercise were equally beneficial.

Figure 3: Changes in maximum voluntary contraction (MVC), rate of torque development after 30ms and 50ms and cross sectional area of the quadriceps muscle (CSA) after 10 weeks of training (Váczi. 2014)

If we look at the most important functional deficits in aging muscle, however, it becomes obvious that the ostensibly negligible increase in the rate of torque development at the beginning of the exercise could determine whether an older individual falls and breaks a bone or whether he or she manages to "catch him-/herself" in time.

Bottom line: Overall the study at hand underlines there is more than just one way to skin the cat. In that, small allegedly practically non-significant differences like the increased rate of torque development in the study at hand can - from time to time - have important real-world relevance.

Figure 4: Strength & size gains in young men in response to 8 wk of SSC exercise training

And even if you are not 60 years and older, you can benefits. In 2005, Malisoux et al. evaluated the contractile properties of chemically skinned single muscle fibers from the leg muscle of eight young men before and after 8 wk of maximal effort stretch-shortening cycle (SSC) exercise training and found that their maximal leg extensor muscle force, vertical jump performance and peak force were improved 12%, 13% and 15-19% (depending on muscle fiber type), respectively; and the single-fiber crosssectional area increased 23% in type I, 22% in type IIa, and 30% in the most growth prone type IIa/IIx fibers. Needless to say that this makes SSC exercises "an effective training approach to improve fiber force, contraction velocity, and therefore power." (Malisoux. 2005) | Comment on Facebook!

References:

• Baumgartner, Richard N., et al. "Sarcopenic obesity predicts instrumental activities of daily living disability in the elderly." Obesity research 12.12 (2004): 1995-2004.
• Kim, Tae Nyun, et al. "Skeletal muscle mass to visceral fat area ratio is associated with metabolic syndrome and arterial stiffness: the Korean Sarcopenic Obesity Study (KSOS)." Diabetes research and clinical practice 93.2 (2011): 285-291.
• Malisoux, Laurent, et al. "Stretch-shortening cycle exercises: an effective training paradigm to enhance power output of human single muscle fibers." Journal of Applied Physiology 100.3 (2006): 771-779.

True or False: Older Men Have a Much Harder Time Building Strength, Building Muscle Borders the Impossible!

Are you training for nothing, if you are "too old" (whatever that may be)? Find out in today's SuppVersity Article!

"The older we get, the weaker we are." That's something most normal men accept as a given truth - according to the latest science, it does yet appear as if it was more of a self-fulfilling prophecy.

Researchers from the Department of Biology of Physical Activity and Neuromuscular research Center at the University of Jyväskylä in Finland have recently conducted a study to verify the common sense assumption that older men are having a much harder time to to maintain / increase their muscle strength than young ones.

To find out, whether this would also be true for those, who are willing to succumb to a high volume, medium load “hypertrophic” resistance training, the Häkkinen et al. recruited young (28 ± 5 yr, 179 ± 6 cm, 77 ± 12 kg, 21 ± 8 percent fat) and older (65 ± 4 yr, 177 ± 6 cm, 80 ± 10 kg, 23 ± 6 percent fat) men via an advertisement in a local newspaper.

Especially for older guys the anti-catabolic effects of HMB could be of interest!

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The experimental groups consisted of 23 young and 26 older men (training groups) and the non training control groups consisted of 10 young and 11 older men. The goal was to achieve maximum strength, muscle mass and muscle activation of the lower limbs in both groups.

Table 1:  Resistance training program of the young and older experimental groups (performed with resistance machines)

To this ends, both groups performed 10 weeks of whole-body resistance training twice per week with the emphasis on lower limb exercises. The training program consisted of high volume, medium intensity exercise with short inter-set rest intervals, as it is typically performed by bodybuilders (i.e. 2-5 sets of 8-14 repetitions, 1-2 min rest).

Lower limb exercises, i.e. leg press, knee extension and knee flexion, were performed before upper body exercises. At least 48 h rest was required between training sessions. Maximum dynamic and isometric neuromuscular performance, as well as lean leg and muscle mass were examined before and after the training period. The changes in body composition were assessed 3-4 d and neuromuscular measurements were performed 7 d after the last training session.

Before participating in the study at hand, the "subjects were physically active but unaccustomed to resistance training for the previous 6 months." Training and testing took place throughout the day (9am-7pm), but young and older subjects were pair-matched to avoid any time-of-day effects on neuromuscular performance measurements. All subjects were given nutritional advice in an attempt to maximize muscle hypertrophy, however, no direct nutritional intervention was performed in the present study.

It's a pity that the diet wasn't controlled for. In view of our main interest, i.e. the question "Are old guys at a disadvantage", on the other hand, it's actually quite interesting, because we usually assume that older guys would have to ingest extreme amounts of protein to keep up with their younger competitors. In the study at hand, they were only told to consume ~20 g of protein within 1 hour of training and in total ~1.5–1.8 g of protein per kg body mass per day, to optimize the muscle hypertrophy response. If you add the "30g of quality (=high EAA) protein with every meal rule that's pretty much the "SuppVersity Suggested" protein intake ;-)

The resistance training program consisted of . Briefly, leg exercises (bilateral leg press, knee extension, and knee flexion) were performad before upper body and torso exercises; bench press, pulldown, shoulder press, seated row, triceps pushdown, biceps curl, abdominal crunches and back raises.

"The subjects performed medium intensity, high volume training consisting of 2–3 sets and 12–14 reps (60–70% 1RM) per exercise (weeks 1–4), then 2–3 sets and 10–12 reps (70–80% 1RM) per exercise (weeks 5–7), and 3–4 sets per exercise and 8–10 reps (75–85% 1RM) per exercise (weeks 8–10). One min rest was given between sets during weeks 1–4, and then 2 min rest was given between sets during the remaining weeks 5–10. One set was performed to failure during each training session." (Häkinnen. 2014)

As you've probably recognized by now this is a more or less classic linear periodization; a very conservative periodization technique with a lot of back up that it works (learn more about periodization).

Figure 1: Pre- and post values for 1RM and isometric leg strength (Häkkinen. 2014)

If you look at the results, you'll see that this protocol led to significant increases in one repetition maximum (1RM) leg press performance in both training groups (young: 13 ± 7 %, P < 0.001; older: 14 ± 9 %, P < 0.001).

Interestingly, said performance improvements were accompanied by increased muscle activation, assessed by voluntary activation level (29 ± 51%, P < 0.05) and electromyography amplitude (35 ± 51 %, P < 0.01) in older men only. Unfortunately, only the young men showed significantly increased lower limb lean mass (2.4 ± 2.5 %, P < 0.01), which were furthermore significantly related to the strength increments (r = 0.524, P = 0.01, n = 23).

Figure 2: The rel. changes in total lean leg mass and vastus lateralis cross sectional area leave no doubt, you can gain muscle at the age of 65+ (Häkkinen. 2014)

Bottom line - true or false? The notion that you can't get stronger if you're past the 60-year mark is flawed. The common understanding that you'll have a significantly harder time to actually increase your total muscle mass and not "just" your strength, on the other hand, appears to be accurate. The signficant local increase in vastus lateralis CSA (Figure 2) does yet indicate that it's not impossible to grow even at the age of 65+ years (keep in mind, though, the subjects were previously more or less untrained!).

Nevertheless, in general, the study appears to suggest that young men are more likely to literally "grow stronger", while older men tend to draw on improvement in the mind-muscle connection, when it comes to lifting higher weights.

References:

• Häkinnen, et al. "Similar increases in strength after short-term resistance training due to different neuromuscular adaptations in young and older men." Journal of Strength and Conditioning Research (2014). Publish Ahead of Print.

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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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.

Sleepy Sunday: The Bone and Teeth Preserving Fat Loss Hormone Melatonin Should Not be Injected Twice a Day in Athletes Who Try to Gain Muscle Mass

She's doin' it right! If you want to optimize your natural melatonin production, a blindfold is the way to go.

Have you been out partying, yesterday? Saturday Night Fever ➲ Sunday Morning Hangover? If so, I hope you made sure you'd get enough sleep and have not increased your already exuberant sleep debt even more! Why? Well, I could give you a thousand reasons, but what about the "dynamic and escalating analog in cumulative daytime sleepiness and that asymptotic or steady-state sleepiness" (Dinges. 1997), the corresponding adverse effects on inflammatory cytokines (Vgontzas. 2004), the decrease in insulin tolerance and messed up (circadian) rhythmicity of cortisol (Spiegel. 1999), about which you've learned here at the SuppVersity that it is the actual reason cortisol can be "bad" for you (learn more).

I could continue this list endlessly, but...

... will rather use this opportunity to transition into the actual topic of this "sleepy Sunday" post: Melatonin and its (in parts surprising) effects as they have been observed in three recently published studies:

• High dose melatonin injections will blunt the training induced adaptive hypertrophy response in rodents -- With a human equivalent dose of 1.6mg/kg the amount of melatonin a group of researchers from the Graduate School of Inje University in Korea injected into their rodents legs may was unquestionably excessive (Hong. 2014), the fact that this lead to a reduction in the exercise induced growth stimulus (4-weeks, 5x per week 1h on the treadmill at 11 m/min), however, may still sound counter-intiuitive to those of you who still subscribe to the "the more antioxidants I get, the better" hypothesis.

  

  Figure 1: It's easy to see that the extremely high dose of melatonin (10mg/kg, twice a day) blunted the increae in skeletal muscle mass in response to 4 weeks of 5x/week 1h treadmill running (Hong. 2014)

  Personally, I feel like we have seen more than enough scientific evidence to understand that melatonin's negative effects on the exercise-induced adapatation processes is a result if its profound anti-oxidant effects and stands right in line with the recently confirmed negative effects of 540mg(day vitamin E and 1000mg/day vitamin C on cellular adaptation to endurance training in humans (Paulsen. 2014) - in that case albeit without negative consequences on the already non-significant changes in muscle mass that occurred in response to the combined HIT + HIIT intensity training in the Paulsen study (learn more).

Learn more about melatonin and sleep in the last "Sleep Quickie", here at the SuppVersity | read more

No effects on testosterone or other hormones! The provision of exogenous melatonin in sensible amounts of 1-10mg per day will not reduce your testosterone levels - even in the long(er) term (Luboshitzky. 2000).

What the restoration of a "deteriorated" melatonin rhythm will do, though, is increase the nocturnal GH peak (Petterborg. 1991). And if you simply throw a couple of milligram on top of your natural production, just like the 12 healthy volunteers (men and women) in a 1986 study did, nothing will happen... well, at least nothing that pertains to the levels or 24-h rhythm of LH, GH, T4, testosterone or cortisol (Wright. 1986).

• While blunting "good stress" is a bad thing, blunting bad stress will help you lose weight and stay lean -- This is at least what would explain the beneficial effects Beatriz de Luxan-Delgado and her colleagues from the Department of Morphology and Cellular Biology at the University of Oviedo in Spain observed in their most recent rodent experiment, in which they investigated the actions of daily melatonin administration on oxidative stress parameters and autophagic processes and found that the significant reduction in hepatic autophagy, as well as the reduced expression of the "fat storage protein ppar-gamma" (learn more) make melatonin "an interesting target molecule for the development of a potential therapeutic agent to curb body weight" (de Luxan-Delgado. 2014).
  

  

  Figure 2: Changes in selected relevant health parameters in humans and rodents in response to the administration of of 5mg/day and 0.5mg/kg/day melatonin (Kozirog. 2011; de Luxan-Delgado. 2014)

  Ok, I know another rodent study is not what you may have hoped for, but if you look at previous evidence from human studies you will be hard pressed to argue that the mechanisms the Spanish researchers observed in their rodent study were unrelated to the mprovements in blood pressure, lipid profile, and parameters of oxidative stress Kozirog et al. observed in patients with metabolic syndrome in response to the provision of 5 mg melatonin per day (2 hr before bedtime; see Figure 2, left based on Kozirog. 2011).
• Melatonin may help us win the battle against bone loss -- Contemporary statistical analyses show that even with existing osteoporotic therapies, bone-related disease, and mortality are on the rise, creating a huge financial burden for societies worldwide  No wonder that Sifat Maria and Paula A. Witt-Enderby get all psyched up about the potential use of melatonin for the prevention and treatment for osteopenia, osteoporosis, and periodontal disease and for use in bone-grafting procedures in their epinomous recent review (Maria. 2014).
  
  

  

  Figure 3: schematic demonstrating the relationship between melatonin secretion and bone resorption over a 24-hr cycle (Maria. 2014)

  Actually, it doesn't take much more than a brief glimpse at Figure 3 to realize why melatonin could be the solution to an increasingly severe problem.
  
  Figure 3 (taken directly from Maria. 2014) depicts a schematic demonstrating the relationship between melatonin secretion and bone resorption over a 24-hr cycle. As shown, both bone resorption (dotted line) and melatonin (solid line) display a diurnal rhythm with peaks occurring during the hours of darkness (filled in rectangles). Consequently, a suppression of nocturnal melatonin levels, either through light exposure at night (LAN) or through aging, increases bone resorption, i.e. the process by which osteoclasts break down bone and release the minerals, resulting in a transfer of calcium from bone fluid to the blood.
  
  Accordingly, only the restoration of the nocturnal melatonin peaks may - over time - protect against age- and lifestyle-induced bone loss by suppressing bone resorption. That this is more than just a hypothesis has been shown by Kotlarczyk et al. in 2012 with a relatively low dose of only 3mg of melatonin in perimenopausal women (Kotlarczyk. 2012). In younger individuals way below the 40+ and 60+ line in women and men, respectively (see Figure 4; Sack. 1986),  the younger folks will probably be able to achieve similar effects by paying more attention to their sleep hygiene.

Figure 4: At least in a 1986 study by Sack, women got into "melato-pause" earlier than men. While the melatonin production of the former dwindled in their late 40s, the men made it into the late 60s before their meltonin production broke away (Sack. 1986)

Bottom line: You don't have to stop partying on the weekend. If you make sure you get your 7-8h of restful sleep in a dark room / blindfolded and reduce the exposure to intense / blue light in the 2h before you head to bed, you can get all the antioxidant, obesity preventing, bone preserving benefits from your endogenous melatonin production while you are young without even having to think of blunting the exercise induced adaptive response.

Addendum for clarification (02/10/2014): If you want to support your natural melatonin production with 1-10mg/day that's perfectly fine for the "young" ones, as well - no chance this is going to hamper your gains.

If you belong to the group of over 40 and over 60-year old women and men (respectively), a small (1-10mg/day) dose of melatonin taken 1-2h before you head to bed may help you along without having to have any fear similar detrimental effects on skeletal muscle anabolism as they have been observed in the initially discussed study by Hong et al. (2014)

At least for those with low baseline levels, it does in fact appear to be more likely that the exact opposite will happen. Melatonin has after all been shown to prevent the apoptosis of muscle cells in cell and animal studies (Hibaoui. 2009; Kim. 2011) and is inversely related to the degree of sarcopenia (age-related muscle loss) in man (Lee. 2013)

References:

• Dinges, David F., et al. "Cumulative sleepiness, mood disturbance and psychomotor vigilance performance decrements during aweek of sleep restricted to 4-5 hours per night." Sleep: Journal of Sleep Research & Sleep Medicine (1997).
• Hibaoui, Youssef, Emmanuelle Roulet, and Urs T. Ruegg. "Melatonin prevents oxidative stress‐mediated mitochondrial permeability transition and death in skeletal muscle cells." Journal of pineal research 47.3 (2009): 238-252.
• Hong, Yunkyung, et al. "Melatonin treatment combined with treadmill exercise accelerates muscular adaptation through early inhibition of CHOP‐mediated autophagy in the gastrocnemius of rats with intra‐articular collagenase‐induced knee laxity." Journal of pineal research (2014).
• Kim, Chi Hyun, Kyung Hwan Kim, and Yeong‐Min Yoo. "Melatonin protects against apoptotic and autophagic cell death in C2C12 murine myoblast cells." Journal of pineal research 50.3 (2011): 241-249.
• Kozirog, Marzena, et al. "Melatonin treatment improves blood pressure, lipid profile, and parameters of oxidative stress in patients with metabolic syndrome." Journal of pineal research 50.3 (2011): 261-266. 
• Lee, Jee-Yon, Jung-Ha Kim, and Duk-Chul Lee. "Urine melatonin levels are inversely associated with sarcopenia in postmenopausal women." Menopause (New York, NY) (2013). 
• Luboshitzky, Rafael, et al. "Long-term melatonin administration does not alter pituitary-gonadal hormone secretion in normal men." Human reproduction 15.1 (2000): 60-65.
• Maria, Sifat, and Paula A. Witt‐Enderby. "Melatonin effects on bone: potential use for the prevention and treatment for osteopenia, osteoporosis, and periodontal disease and for use in bone‐grafting procedures." Journal of pineal research (2014).
• Paulsen, G. "Vitamin C and E supplementation hampers cellular adaptation to endurance training in humans: a double-blind randomized controlled trial." The Journal of Physiology (2014) Published online before print February 3, 2014, doi: 10.1113/jphysiol.2013.267419.
• Petterborg, L. J., et al. "Effect of melatonin replacement on serum hormone rhythms in a patient lacking endogenous melatonin." Brain research bulletin 27.2 (1991): 181-185.
• Sack, Robert L., et al. "Human melatonin production decreases with age." Journal of pineal research 3.4 (1986): 379-388.
• Spiegel, Karine, Rachel Leproult, and Eve Van Cauter. "Impact of sleep debt on metabolic and endocrine function." The Lancet 354.9188 (1999): 1435-1439.
• Vgontzas, A. N., et al. "Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines." Journal of Clinical Endocrinology & Metabolism 89.5 (2004): 2119-2126.
• Wright, J., et al. "The effects of exogenous melatonin on endocrine function in man." Clinical endocrinology 24.4 (1986): 375-382.

Low Testosterone, Low Life Expectancy: Plus: Chinese vs. US - Do the Same Reference Ranges Apply for Everyone?

This is what Photoshop and creativity can tell us about aging men.

It has been a while since we've taken a closer look at the effects of testosterone deficiency and its replacement aka TRT. Basically that's why I decided not to waste the interesting findings from a recently published study in the The Journal of Clinical Endocrinology and Metabolism (Yeap. 2013) in the Facebook News. In combination with the findings Xu et al. report in a paper on the difference in testosterone concentrations in young healthy US versus Chinese men the Yeap study does after all make a decent addition to the 269 of hitherto ~1500 archived SuppVersity articles that deal in one way or another with the famous androgen.

Virile men live longer! Ca. 30% longer, to be precise.

If you take a look at the link between serum testosterone, free testosterone and DHT and the all-cause mortality risk of the 16,451 community-dwelling older men from Perth in Western Australia it should be obvious that the third quartile of all these serum values, is where you want your androgen levels to be, if you intend to live to see your 90th birthday.

Figure 1: Relative reduction in all-cause mortality with total and free testosterone levels, as well as dihydrotestosterone levels in quartile 2,3 & 4 vs. quartile 1 (Yeap. 2013)

To quantify: You want to have your total testosterone levels in the 12.56 – 15.75 nmol/L (362ng/dl - 454ng/dL), your free testosterone levels in the 182.66 – 216.34 pmol/L (5.3-6.2 ng/dL) and your dihydrotestosterone (DHT) levels in the 1.34 – 1.83 nmol/L (DHT; 39-53ng/dL) range if you don't want to miss a couple of year's of your life.

Symptoms of low testosterone:

Somatic: Gynecomastia, de- creased body hair, hot flashes, decreased lean muscle mass, decreased strength, anemia, frailty, osteoporosis, easy fatigue, sleep disturbances, increased body fat or body mass index

Psychological: Depressed mood, irritability, emotional lability, impaired cognition and memory, decreased energy

Sexual: Diminished libido, erectile dysfunction, decreased nocturnal and morning erections, difficulty achieving orgasm, decreased performance (Traish. 2011).

And while your androgen levels shouldn't be significantly lower, you also don't want them in the fourth quartile, where the all-cause mortality risk begins to rise again. Unless you don't want to lose the ~30% all-cause mortality of being in the zone, you shouldn't let the rumors about a causal (not corollary) link between testosterone replacement therapy (TRT) and the incidence of prostate cancer upset you. Why, well because ...

"[...] to date, no study or review has definitively shown that androgen replacement therapy is an independent risk factor for development of prostate cancer." (Fisher. 2012) 

The thing you should ask yourself is thus whether you really want to give up on this 30% reduction in all-cause mortality, or the decrease in fatal cardiovascular events, Ramasay et al. list next to the reduction in body fat mass, and insulin resistance among the proven benefits of TRT in their 2012 review of the literature.

It's your decision and therefore you should make sure that it's you and not your doctor who takes this decision. If you decide to help your low testosterone levels along, it's your doctors job to help and assist you by ordering and interpreting regular hormone and, as Fisher et al. suggest, PSA tests.

Informed decisions, require information, lab values, and reference ranges!

Speaking about "interpreting" hormone panels. One of the problems you'll be facing is that nobody can actually tell you what your normal testosterone level should look like. Of course, every med-school graduate will believe that he knew exactly what's good for you, but when it's all said eand done, scientists (and doctors) tend to be a bit too egalitarian, when it comes to "normal ranges". So egalitarian, in fact that they simply assume that a lightweight Chinese pencil pusher must have the same testosterone levels as a 6.6 ft tall, 300lbs heavy Caucasian strongman.

Table 1: Normal ranges for total T.

How do we know what "normal" is? Actually we don't. I mean, if you look at the average American or Chinese men, neither his health, nor his physique, or intelligence are "optimal" and still they are the "norm" we use to gauge our testosterone levels. For young men, this is not that much of a problem, but accepting the reference ranges for old guys is - if you asked me - like surrendering to physical decline.

Figure 2: Total and bioavailable testosterone levels in US and Chinese young men (Xu. 2013)

It's thus quite refreshing that Xu et al. followed a different path and followed the heavily underused "Equal, but different!"-princple, when they decided to conuct what they claim is the first study to analyze and compare the total (TT), calculated free (FT), and bioavailable testosterone (Bio T) levels of healthy young men (18–29 years) from the Third National Health and Nutrition examination Survey (NHANES III) in the United States (US) to those of men living in a region of China with a similar living standard to the US, i.e., Hong Kong.

By this means, the researchers wanted to find out whether the potentially existing differences in androgen levels in Caucasian vs. Asian young men would warrant a revision / specification of the "normal" range for men from different ethnic backgrounds.

As you can see the results are not exactly easy to interpret (Figure 2) - is this a difference, or not?

If we take another look at the data in Figure 2 and compare the relative differences between the total testosterone levels of young US vs. Chinese men to those that made a significant difference, in the previously discussed study by Yeap et al. (see Figure 1), we will have to concede that the xisting differences can hardly be significant. They are after all a magnitude smaller than the quartiles in the Yeap study.

Free vs. total testosterone, measured vs. calculated: Direct measurement of free testosterone levels is different from using the total testosterone and SHBG levels (which were higher in US men, by the way; Xu. 2013) to calculate an estimated amount of free testosterone (cf. Vermeulen. 1999). Since it's cheap and usually pretty accurate this is yet what most labs will do. You should however be aware that the values are accurate, only, if your SHBG and albumin values are "normal" as well. If those are out of range, it's a good idea to get the free testosterone levels measured directly, to find out where you are standing.

That being said, there are at least three additional reason that speak against establishing specific testosterone cut-off values for different ethnic groups based on the Xu study:

1. The Xu study is not representative of "all" Chinese young men: The Xu study compares US citizens in the US to Chinese citizens in China. Who tells us that the values they obtained for young Hong Kongers are valid for 2nd generation Chinese immigrants to the US, as well? Environmental conditions, dietary factors, etc. all that could just as well be the reason for the measured differences as ethnicity-specific genetic differences.
2. The Xu study, or rather the NHANES data is not representative of a specific ethnicity: By analogy to (1), the Xu study, which uses data from NHANES III to gauge the average testosterone levels of male US citizens, relies on data from Asian, African American, Native American, Hispanic and Caucasian US citizens. How on earth would you establish ethnicity specific normal values based on that?
3. Using the Yeap study as a reference to determine "optimal levels" is unwarranted: With old men as study participants, the significance of the optimal total testosterone levels from the Yeap study (12.56 –15.75 mmol/L ≡ 362- 454ng/dL) is about as questionable as the assumption that older men are actually supposed to have significantly lower testosterone levels.

And even if you wouldn't agree that these objections are valid, there would be a simple, yet effective solution to end this discussion once and for all: Measure (or calculate) the free testosterone levels!

If you do that, i.e. compare free instead of total testosterone levels, you will find that the purported ethnic differences disappear. And this is true not solely for the comparison of the data from Chinese and US men Xu et al. analyzed, but also for the existing differences between Mexican-American, non-Hispanic black and non-Hispanic white men in the NHANES study by Rohrmann et al. (2007). Specific reference ranges for Asian, Caucasian, African American, Hispanics, ... are thus probably unwarranted (not sure about Aliens, though ;-).

The age related decline in testosterone is rapid: Accoring to Morley, et al. the average rate of decrement in testosterone concen-tration for men aged 60+ is 110 ng/dL every decade. A "normal" Caucasian man, who would still have a testosterone level of 500ng/dl when he's sixty (Rohrmann. 2013) would thus end up at 280ng/dl, which is right in the "highest risk of all-cause mortality" quartile (Q1) of the Yep study.

Bottom line: Despite the fact that our insights into the non-existent, or at least insignificant ethnic differences in free and total testosterone levels confirm the validity of the currently propagated "normal" ranges for young men, we are still left with the implications of the Yeap study and the questionable usefulness of "age adjusted" testosterone levels.

If we take into account that the age-induced androgen decline correlates with the aforementioned increases in all cause and cardiovascular mortality (Yeap. 2013), as well as lower levels of handgrip, hip flexors, hip extensors and abductors strength (Perry III. 2000) and an increase risk of development metabolic syndrome (48% higher risk; cf. Rodriguez. 2007), it would certainly appear that any "age-adjustment" that's based on observations in the average aging male is bogus...but I guess that's a topic for another SuppVersity article ;-)

References: 

• Ramasamy, R., Fisher, E. S., & Schlegel, P. N. (2012). Testosterone replacement and prostate cancer. Indian journal of urology: IJU: journal of the Urological Society of India, 28(2), 123.
• Yeap, B. B., Alfonso, H., Chubb, S. P., Handelsman, D. J., Hankey, G. J., Almeida, O. P., ... & Flicker, L. (2013). In Older Men an Optimal Plasma Testosterone Is Associated With Reduced All-Cause Mortality and Higher Dihydrotestosterone With Reduced Ischemic Heart Disease Mortality, While Estradiol Levels Do Not Predict Mortality. 
• Perry III, H. M., Miller, D. K., Patrick, P., & Morley, J. E. (2000). Testosterone and leptin in older African-American men: relationship to age, strength, function, and season. Metabolism, 49(8), 1085-1091. 
• Rodriguez, A., Muller, D. C., Metter, E. J., Maggio, M., Harman, S. M., Blackman, M. R., & Andres, R. (2007). Aging, androgens, and the metabolic syndrome in a longitudinal study of aging. Journal of Clinical Endocrinology & Metabolism, 92(9), 3568-3572.
• Rohrmann, S., Nelson, W. G., Rifai, N., Brown, T. R., Dobs, A., Kanarek, N., ... & Platz, E. A. (2007). Serum estrogen, but not testosterone, levels differ between black and white men in a nationally representative sample of Americans. Journal of Clinical Endocrinology & Metabolism, 92(7), 2519-2525.
• Traish, A. M., Miner, M. M., Morgentaler, A., & Zitzmann, M. (2011). Testosterone deficiency. The American journal of medicine, 124(7), 578-587. 
• Vermeulen, A., Verdonck, L., & Kaufman, J. M. (1999). A critical evaluation of simple methods for the estimation of free testosterone in serum. Journal of Clinical Endocrinology & Metabolism, 84(10), 3666-3672.
• Xu, L., Au Yeung, S. L., Kavikondala, S., Leung, G. M., & Schooling, C. M. (2014). Testosterone concentrations in young healthy us versus Chinese men. American Journal of Human Biology, 26(1), 99-102.