Melatonin the Anabolic On-Switch!? Is Supplementation Necessary for Older and Beneficial for Younger Trainees?

Whatever sleeping position you and your partner prefer, you better make sure you do get some sleep. There'll still be time for life's other pleasures, don't worry  ;-)
If you are - as I would highly suggest - following the 6-12 SuppVersity Short News on Facebook, you will be aware of the accumulating evidence suggesting that a lower resistance to the inflammatory assault of exercise is at the heart of the age-induced decline in muscle gains.

We all know that especially those of us, who are still in good shape in their 60s and beyond are already having a hard time to keep the status quo, and only a handful of them appears to be able to make constant progress. But is this something you just have to accept or can the latest research help you overcome or at least lower the "anabolic" resistance? And if so, could young(er) individuals benefit from the same or similar interventions?

Age, inflammation, recovery and supercompensation

In a soon-to-be-published study from the University of Alabama at Birmingham an analysis of the vastus lateralis muscle gene expression and protein cell signaling of the IL-6 and TNF-α pathways in myoblasts from young (AGE28) and old (AGE64) donors, which have been pre-treated with TNF-α revealed that ...
"[i]ndices of activation for the pro-inflammatory transcription factors STAT3 and NFκB were highest in AGE76. Resistance loading reduced gene expression of IL-6 receptor, MuRF1, and atrogin-1, and increased TWEAK receptor expression. Donor myoblasts from AGE64 showed impaired differentiation and fusion in standard media, and greater NFκB activation in response to TNF-α treatment (compared to AGE28)".(Meritt. 2013; you know it already, if you are following
These findings show for the first time that the aging process alone is associated with a hightened susceptibility to muscle inflammation.

Graphical illustration of what you should have learned by now, if you read the previous installments of the Intermittent Thoughts; note: while I have used the arrows rather indiscriminately (they do not necessary mean "causes"), the stops at the end of other lines indicate an inhibition, eg. the line from exercise to myostatin indicates that exercise inhibits myostatin, which would inhibit increases in myonuclear domain sizes, if it was not "switched off" by exercise... (learn more)
In view of the importance of "controlled inflammation" in the context of muscle damage, repair and supercompensation (learn more in the Intermittent Thoughts on Muscle Building, spec. this episode), the goal should thus be to (a) lower the inflammatory load to a level that allows the aging body to cope with it and (b) improve your body's ability to cope with a certain (yet to be determined) amount of inflammation that's necessary for the hormetic response to exercise to take place.

As alluded to in the introduction to this article, the same 500mg+ of vitamin C + 400IU+ of mixed tocopherols per day that are - at best - useless for a young trainee could in fact make a smart and valuable addition to the supplement stack of an older physical culturist, who is more reliant on exogenous ROS scavengers than the young grasshopper, for whom the exercise-induced inflammation is part of the training: A training for his endogenous defense system and a potential prerequisite for the structural remodeling process of the muscle (check out the figure on the right and learn more).

Melatonin: Protection beyond ROS scavenging

At least for the well-educated SuppVersity student you are ;-) It should be obvious that the "classic" anti-oxidants like vitamin C and E are not the only venues molecules to control inflammation. In fact, the emerging science shows that alternatives to these "Kamikaze"-inhibitors (ROS scavengers) can, in this, as well as other contexts, deliver much better results.

As a SuppVersity reader you'll know that melatonin is also an Alzheimer protectant, can help you shed body fat, could be the goto-supplement for ultra-marathon runners, figures in the cardio-protective and controls the circadian rhythm, the disturbance of which is involved in "all things bad" ranging from metabolic syndrome over diabetes to cancer.
Think of DHEA, for example. The adrenal hormone, which happens to decrease from year to year once you've passed your late 20s can even help young men to cope with the muscle damage of 5 days of concomitant combined endurance, strength and HIIT training in young men (read the whole story).

Or - and now we are finally zoning in on the actual news - think of melatonin, which has been shown to boost your anti-oxidant defenses, reduce the oxidaton of the lipids in your cell walls and modulate the immune response to intensive training, when it is supplemented in relatively high amounts of 6mg (learn more; don't forget to check out the links in the infobox to the right, as well).

It will therefore only come as a minor surprise for a diligent SuppVersity reader like yourself that a recent rodent study that has just been accepted for publicaton in the Journal of Pineal Research comes to the conclusion that..
[...a]dequate levels of circulating melatonin are [...] necessary to improve energetic metabolism efficiency, reducing body weight and increasing insulin sensitivity [in aging animals]. (Mendes. 2013)
Ah, and just to make that clear, I am not willing to start the "mice are no little men"-debate, here, but will take it for granted that you keep in mind that results, I have plotted for you in figure 1 have to be verified in future human trials (personally, I am confident, they will).
Figure 1: Relative levels of visceral fat, triglycerides, change in distance covered from month 0-2, running speed, citrate synthase activity, muscle & liver glycogen and glucose AUC during tolerance test; all data expressed relative to sedentary (S-) unsupplemented (-C) control, SC (Mendes. 2013)
So what are we seeing here in figure 1? Well, first of all there is a surprisingly significant (compared to the SC group) decrease of total, but more importantly visceral fat weight in both, the sedentary (SM), as well as the trained (TM) rodents. The latter goes hand in hand with
  • Expression of the muscle anabolic enzymes PI3K, p-AKT, as well as AMPK and GLUT4 in muscles of the supplemented (SM & TM) and non-supplemented (SC & TC) rodents in arbitrary units (Mendes.2013)
    significant improvements of the amount of triglycerides (a if not the no1 risk factor for CHD) even in the absence of exercise (compare the SC vs. SM groups)
  • a mind boggling increase in the distance covered and the running speed of the animals in both the trained and the sedentary rodents "on" melatonin (in view of the fact that this increase remains statistically significant even when you compare it to the baseline levels, similar effects may even occur in young animals)
  • almost 3x respectively 4x elevations in citrate synthase activity, a maker of fatty acid oxidation in the sedentary and trained melatonin treated rodents
  • a 6x and 12x increase in muscle glycogen levels and an ameliorative effect on the exercise induced glycogen increase in the liver, both of which could not just explain the massive increase in exercise tolerance, but the previously observed beneficial effects on glucose tolerance, as well
  • a 30-40% reduction in the glucose AUC that corresponds with the increased glycogen storage mentioned in the previous bulletin point
and lastly and for many of the physical culturists in the posterior half of their lives maybe most importantly, highly significant increases in the activity of the pro-anabolic PI3K, MAPK and AKT that were not increased at the expense of the fat-burning, anti-cancer, anti-diabetes AMPK energy switch (see figure 2).

Bottom line: It is beyond doubt that the small amount of exercise corresponding to the four to five sessions at 0.3 – 0.5 km/h running on a 0% grade treadmill [questionable whether this is a typo on the speed, by the way] for 10 min/day in the study at hand alone are good for aging individuals. It's also almost certain that the addition of supplemental melatonin ameliorates these exercise-induced benefits and induce benefits on their own.

Don't forget t take appropriate time off, otherwise even 15g of melatonin are not going to help you overcome a growth plateau. Why? Well "Chronic Resistance Training Reduces the Anabolic Signaling in Response to Exercise - 12 Days of Detraining Restore It" (read more)
What is yet highly questionable still is the optimal dosage. The 1mg/kg body weight that were used in the study at hand would translate to roughly 0.16mg per kg for a human being and thus ~13mg for an adult (male) human being. Personally, I don't think this is exorbitantly high, but I know that real and pseudo-experts would be bashing me, if I even remotely suggested that you consume similar as much supplemental melatonin on a regular basis... what all of us would probably agree on is the fact that future human studies are necessary, and if you asked me not so much to avoid potential harm, but rather not to miss what Mendes et al. believe would be an outstanding chance to "improve the beneficial responses induced by regular exercise in aging individuals, promoting a better quality of life and a healthier aging process" (Mendes. 2013).

  • Mendes C, de Souza Lopes AM, Gaspar do Amaral F, Peliciari-Garcia RA, de Oliveira Turati A, Massao Hirabara S, Scialfa Falcão JH, Cipolla-Neto J. Adaptations Of The Aging Animal To Exercise: Role Of Daily Supplementation With Melatonin. Journal of Pineal Research. 2013 [accepted manuscript]
  • Merritt EK, Stec MJ, Thalacker-Mercer A, Windham ST, Cross JM, Shelley DP, Tuggle SC, Kosek DJ, Kim JS, Bamman MM. Heightened muscle inflammation susceptibility may impair regenerative capacity in aging humans. J Appl Physiol. 2013 May 16.
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