Mittwoch, 17. Juli 2013

Things that do not work, studies that fail, where do we stand on n3 supplementation?

If you have not kept up with the literature, I suggest you read my two blog posts for an introduction.

Cliffnotes on Vegetarianism and Diet in general: The Big Picture
Oy vey! Fish oil fails AGAIN

I do now favor moderate ALA intakes over EPA/DHA (or fish) for the primary prevention of disease - but it's close. An appropriate combination of the two may also be acceptable.
Actual CVD outcomes are similar, both types of fatty acids are backed by rather weak evidence. The term thin gruel comes to mind. ALA has the "biogerontologic" and ecologic argument on its side. The former, is explained by Michael if you follow the link.

Recently, Hu, Mozaffarian & colleagues again published a very interesting meta-analysis re. CVD, which I take as supporting my view.
DESIGN: We searched multiple electronic databases through January 2012 for studies that reported the association between ALA (assessed as dietary intake or as a biomarker in blood or adipose tissue) and CVD risk in prospective and retrospective studies. We pooled the multivariate-adjusted RRs comparing the top with the bottom tertile of ALA using random-effects meta-analysis, which allowed for between-study heterogeneity.
RESULTS: Twenty-seven original studies were identified, including 251,049 individuals and 15,327 CVD events. The overall pooled RR was 0.86 (95% CI: 0.77, 0.97; I² = 71.3%). The association was significant in 13 comparisons that used dietary ALA as the exposure (pooled RR: 0.90; 95% CI: 0.81, 0.99; I² = 49.0%), with similar but nonsignificant trends in 17 comparisons in which ALA biomarkers were used as the exposure (pooled RR: 0.80; 95% CI: 0.63, 1.03; I² = 79.8%). An evaluation of mean participant age, study design (prospective compared with retrospective), exposure assessment (self-reported diet compared with biomarker), and outcome [fatal coronary heart disease (CHD), nonfatal CHD, total CHD, or stroke] showed that none were statistically significant sources of heterogeneity.
CONCLUSIONS: In observational studies, higher ALA exposure is associated with a moderately lower risk of CVD. The results were generally consistent for dietary and biomarker studies but were not statistically significant for biomarker studies. However, the high unexplained heterogeneity highlights the need for additional well-designed observational studies and large randomized clinical trials to evaluate the effects of ALA on CVD.
Restricted to dietary studies only, the pooled RR was 0.90 (95% CI: 0.81, 0.99; 11,277 events)…
Visual inspection of a funnel plot (see Supplemental Figure 1 under “Supplemental data” in the online issue) and Begg's test did not indicate significant publication bias (P = 0.13). A sensitivity analysis testing the influence of individual study on the results suggested that one study (35) had the largest influence; after this study was excluded (35), the pooled RR was slightly attenuated (0.91; 95% CI: 0.83, 0.99) compared with that from the main analysis.
Given concern that retrospective case-control studies may be limited by recall bias for dietary ALA…we conducted a sensitivity analysis excluding retrospective case-control studies (n = 5)…The pooled RR was modestly attenuated to 0.91 (95% CI: 0.84, 1.00; 14,617 events); however, the I2 value was also reduced from 71.3% to 45.1%
In the pooled dietary analysis, each 1-g/d increment of ALA intake was associated with a 10% lower risk of CHD death (RR: 0.90; 95% CI: 0.83, 0.99;
 Issues & future directions
dietary estimates of ALA consumption do not correlate strongly with biomarker concentrations (average correlation of 0.35 for adipose tissue and 0.24 for blood concentrations)…
endogenous conversion of ALA to EPA is limited (<10%) and generally much lower in men than in women (47, 48)…
Our findings highlight the need for an appropriately designed, randomized, placebo-controlled clinical trial to evaluate the effects of dietary ALA on incidence of CVD…
Lyon Diet Heart Study (57), 605 post-MI patients were randomly assigned to a Mediterranean diet, including margarine supplemented with ALA (1.1 g/d)…A trial in India of an Indo-Mediterranean ALA-rich diet among 1000 patients with established CHD found similar results over a 1-y follow-up (58), but the interventions were not blinded and the validity of results from this group of investigators has been questioned (59).
A larger double-blind, placebo-controlled trial among 4837 post-MI patients tested the effects on cardiovascular events of 400 mg EPA+DHA/d and/or 2 g ALA/d this study was underpowered to detect an effect on CHD death, with only 17% power to detect a 25% reduction

Unfortunately, no time to go into details.

1. Am J Clin Nutr. 2012 Dec;96(6):1262-73. doi: 10.3945/ajcn.112.044040. Epub 2012 Oct 17.
α-Linolenic acid and risk of cardiovascular disease: a systematic review and meta-analysis.
Pan A, Chen M, Chowdhury R, Wu JH, Sun Q, Campos H, Mozaffarian D, Hu FB.

Freitag, 5. Juli 2013

Hypothesis testing: maple syrup urine disease, mTOR, autophagy and premature aging

As the title says, I am speculating here.

Maple syrup disease is a rare disorder (> 1:100 000) affecting branched-chain amino acid (BCAA) catabolism. The parent molecules and their keto-acids accumulate leading, among other issues, to leucinosis, neurologic symptoms and death unless treated with a low BCAA diet. Blood levels of these amino acids remain elevated despite treatment as far as I know and this could suppress autophagy via mTOR, I speculate.

Interestingly:
The BCAAs, especially leucine, are recognized as potent metabolic regulators of protein synthesis. This effect is mediated through mammalian target of rapamycin (mTOR)-dependent and mTOR-independent pathways (Kimball and Jefferson 2006). In the context of high BCAA levels experienced in MSUD, the effect on protein turnover has not been extensively studied.
http://link.springer.com/article/10.1007/s10545-011-9333-5/fulltext.html


Feel free to steal my idea, but do credit me and let me co-author.

If your urine smells funny, you can help science. Well, almost.