Tuesday, January 10, 2012

"High Dose" of Leucine Ameliorates Age-Related Increase in Body Fat, But Fails to Preserve Lean Tissue Mass

Image 1: While these images are from a study on premature aging in mice, they go to show that the little critters are by no means better of than human, when their time is near. First they get fat, then they lose all their muscle and then they pass away (img from de Boer. 2002)
It is literally on everyone's lips these days - leucine! The amino acid that is hailed to be "as anabolic as a weak anabolic steroid". I guess, those of you who have read my latest treatise on testosterone and the effects of natural vs. artificial means of enhancing the latter, will be aware that this statement is about as incorrect as the claim that "l-arginine will increase your pumps" ;-) It is however well-established that the ingestion of non-negligible (>1g) amounts of the branched-chain α-amino acid l-leucine triggers a number of metabolic switches, which will subsequently increase the rate of protein synthesis and decrease the rate of protein breakdown. And although studies in athletes and young individuals appear to confirm our current theoretical model, the real world results of leucine supplementation in elderly subjects are contradictory, to say the least (Balage. 2010).

Too little, too short or simply too inefficient?

Apart from the absence of the necessary complementary amino acids, which is in fact a design flaw in many of the trials, both the amount of supplemental leucine, as well as the total duration of the dietary intervention could possibly explain why "[c]hronic free leucine supplementation alone did not improve lean body or muscle mass during resistance training or in elderly" (Balage. 2010). Against this background Daiana Vianna and her colleagues from the Universities of Sao Paulo and Texas conducted a trial in which they fed 6-month old adult (and thusly not yet old!) mice diets to which either a standardized amino acid mixture or a huge bolus of leucine (cf. figure 1) for 40 weeks (Vianna. 2011):
Figure 1: Basal diet composition (left), additional amino acids (middle), vitamin and mineral mix (right) of the diet the mice in the control and leucine groups of the study were fed (data adapted from Vianna. 2011)
With 4% of the diet consisting of either a complex, yet leucine-free amino acid mixture or leucine, only, this practice mirrors the intake of ~6g of leucine for a human being and would probably only be considered "high" by overcautious scientists, who will probably make an argument that the ingestion of "large" amounts of leucine and the subsequent (over-)expression of the mTOR-pathway could potentially increase a subjects risk to develop cancer or metabolic derangements related to an artificially created imbalance between mTOR and AMPK (cf. "The AMPK vs. mTOR Metabolic Seesaw").

The intake of "large" amounts of leucine is totally benign

From the scientists' perspective, the first important (yet not actually surprising) result of the Vianna study was thusly that (I quote) "despite the relatively high dose of leucine in the diet", the mice in the leucine group did not exhibit a "significantly higher mortality rate". However, as the data in figure 1 shows, the expected and highly desirable effects on the retention of lean muscle mass in the aging mice were similarly non-significant (cf. figure 2):
Figure 2: Relative change  (expressed relative to adult mice) in lean body mass during aging in old mice on control and old mice on high leucine diet (data calculated based on Vianna. 2011)
The supplemental leucine ameliorated neither the loss of lean mass, nor the reduction of total body protein or gastrocnemius protein content to a statistically significant degree. It is thusly all the more surprising that the mice in the high-leucine group gained significantly less body fat than their peers who were fed a non-essential amino acid mixture consisting of Alanine, Aspartate, L-Cystine, Glutamate, Glycine, Proline and Serine. In view of the fact that both groups consumed identical amounts of chow, this would be another  infringement of the "first law of thermodynamics", if, ... well, if mammals were "closed systems", but since they obviously are not, we better take a look if another of the usual subjects, improvements in glucose metabolism, for example, could be the root course of the reduced fat gain, which was - and this would hint at insulin / glucose as an underlying mechanism - particularly pronounced in the visceral fat depots of the lab animals.
Figure 3: Relative change (expressed relative to adult mice) in leptin, triglycerides, blood glucose, insulin, and HOMA-IR during aging in old mice on control and old mice on high leucine diet (data calculated based on Vianna. 2011)
If we discard the reduced increase in leptin levels (that is a simple consequence of the reduced body fat levels), it is however obvious that neither glucose nor insulin show significant inter-group differences. The same is true for the triglyceride levels and the HOMA-IR index value (indicator of insulin resistance) - within the statistical margin the changes are identical in both groups.

Leucine is no magic bullet

Overall the results of this long term, high dose (allegedly rodent) study are thusly similarly disappointing as previous human trials, after all the desired ameliorative effect on age-related declines in muscle mass did not occur and the ameliorative effect on body fat accumulation may be statistically significant, but does not detract from the fact that the animals in the leucine group...
[...] still presented a marked accumulation of body fat compared with young adult animals (78% and 57% more body fat in the control and leucine groups, respectively, compared with the adult group). Thus, the attenuation of fat gain observed with leucine supplementation was not sufficient to promote an equivalent decrease in the cardiovascular risk indicators studied.
So that the main take home messages of this study probably are that
  1. in situations like aging, where the protein synthetic machinery is already stuttering, neither "high dose" (whether a human equivalent of ~6g is actually "high" may be debatable, though and the fact that this were no "bolus ingestions", but the 6g of leucine were distributed across one day certainly didn't help either) nor long-term leucine supplementation alone  is able to reduce the age induced decline in muscle mass, and
  2. either leucine or the "absence" (in view of the fact the diet contained enough casein that there would be "all" of the N-EAAs present in the diet, we should probably say "lower amounts") of any of the other non-essential amino acids (N-EAAs) the control group received must have a non-negligable effect on the age-induced increase in body fat levels, we do not yet fully understand
And while I can neither tell you the reasons for the fat loss in the leucine group, nor whether we would see similar results in human studies, I can tell you that a mixture of HMB+Arginine+Lysine works wonders, where leucine fails... but if you have been a faithful student this should be no news to you... what? Yeah, the Suppversity news from August, 9, 2011 "Strengthless Gains: HMB+Arginine+Lysine Build Muscle", the one which showed increases instead of decreases in lean muscle mass after one year of supplementation with the leucine metabolite HMB, arginine and lysine and increases in strength, if the subjects had adequate vitamin D levels. So, if it would require further evidence that muscle building / maintenance is no "one-man-show" and that leucine is only one out of a whole host of superstars (if you see arginine and lysine, you should think of growth hormone and IGF-1, for example) on stage, this study would be it.