40g Casein Build Lean Muscle Overnight: 27% Elevated MPS Even W/Out Training (30% W/ Ex) - And That in 70-Y+ Olds!

40g Casein Build Lean Muscle Overnight: 27% Elevated MPS Even W/Out Training (30% W/ Ex) - And That in 70-Y+ Olds!

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Pre-bed protein (meal or shake) is always a good idea, no matter if you're young or old, if you work out in the PM or not - you don't want to miss the increased overnight protein synthesis.

Gaining muscle over night? No news! You will probably remember the two previous articles on "pre-bed protein ingestion", i.e. "12-Week Study: 25g Bed-Time Protein Almost Doubles Size & Increases Strength Gains" (read it) and "3.2kg of Lean Mass Over Night W/ 40g of Slow Digesting Protein 30min Before Bed!? Over One Year, a Positive Nitrogen Balance and +20% FSR Could Make It Happen!" (read it), but still! With this being the first study to show that even (on average) 71-year-olds can "build muscle overnight" with nothing but 40g of casein being ingested ~30 minutes before they went to bed, it is probably the most impressive of the previously referenced studies.

High-protein diets are much safer than the mainstream say, but there are things to consider...

Practical Protein Oxidation 101

5x More Than the FDA Allows!

More Protein ≠ More Satiety

Protein Oxidation = Health Threat

Protein Timing DOES Matter!

More Protein = More Liver Fat?

There is, allegedly, no long-term data (=actual gains) such as the increase in lean mass after 6-12 weeks, but with this study, which was actually designed to test the hypothesis that...

"[...] that physical activity can augment the impact of presleep protein ingestion on overnight muscle protein synthesis [in] 23 older men (71 6 1 y) who ingested 40 g casein protein intrinsically labeled with L-[1-13C]-phenylalanine and L-[1-13C]-leucine before going to sleep with (PRO+EX8; n = 11) or without (PRO; n = 12) a bout of physical activity being performed earlier in the evening" (Holwerda. 2016),

the study results (that were, by the way, only marginally in line with the scientists hypothesis from the previously cited introduction) exceed my personal expectations, significantly.

Figure 1: Overnight myofibrillar protein FSRs after PRO+EX (n = 11) or PRO (n = 12) presleep treatment in older men as calculated with L-[ring-2H5]-phenylalanine (A) or L-[1-13C]-leucine (B) as tracer. Values are means 6 SEMs. Data were analyzed with an unpaired Student s t test. *Different from PRO, P , 0.01. FSR, fractional synthetic rate; PRO, 40 g protein in rested state; PRO+EX, 40 g protein after resistance-type exercise (Holwerda. 2016)

Before we start discussing the results, though, let's take a look at what the authors of the study actually did: After their subjects had ingested the 40g of labelled casein (I cannot tell if that was micellar casein, but I can tell you that the scientists got it on the free market and that it was produced by Dr. Oetker, Germans and countrymen of the Dutch scientists will know the company), the authors measured the subjects' overnight protein digestion and absorption kinetics and myofibrillar protein synthesis rates by combining primed, continuous infusions of L-[ring-2H5]-phenylalanine, L-[1-13C]-leucine, and L-[ring-2H2]-tyrosine with the ingestion of intrinsically labeled casein protein.

Suggested Read for everyone w/ parents and grandparents: Creatine Will Protect Grandpa's Muscle Even if He Doesn't Train!? More Reasons "E-veryone" Could Take Creatine | more

What did the workouts look like? As you may have gathered by now only the PRO+EX group worked out before going to sleep at the lab. Here's what they did (keep in mind: the average age was 70 years!): "The physical activity protocol consisted of 60 min of moderate-intensity, lower-body, resistance-type exercise. After 15 min of self-paced cycling at 100 W with a cadence of 60–80 rpm, subjects performed 6 sets of 10 repetitions on the horizontal leg press machine (Technogym BV) and 6 sets of 10 repetitions on the leg extension machine (Technogym BV). The first 2 sets of both exercises were performed at 55% and 65% 1RM, respectively, and sets 3–6 were performed at 75% 1RM. Subjects were allowed to rest for 2 min between all sets" (Holwerda. 2016).

As the results in Figures 1-2 clearly indicate, the relatively high amount of protein ingested before sleep was

• normally digested and absorbed, with 54% ± 2% of the protein-derived amino acids appearing in the circulation throughout overnight sleep, and
• significantly boosted the overnight myofibrillar protein synthesis rates

In that, the increase in MPS was +31% (0.058% ± 0.002%/h compared with 0.044% ± 0.003%/h; P < 0.01; based on L-[ring-2H5]-phenylalanine) with exercise and at least +27% (0.074% ± 0.004%/h compared with 0.058% ± 0.003%/h; P < 0.01; based on L-[1-13C]-leucine) without exercise.

Figure 2: Eventually, it's the net balance that counts and this is where training provided a non-significant, but potentially still relevant difference (see Figure 3 for tracer incorporation) in the elderly subjects of the study at hand (Holwerda. 2016).

Accordingly, more dietary protein-derived amino acids were eventually incorporated into de novo myofibrillar protein (~new muscle mass) during overnight sleep in the PRO+EX than in PRO treatment (0.042 ± 0.002 compared with 0.033 ± 0.002 mole percent excess; P < 0.05).

This difference between the actual amount of the traced amino acids that ended up in the muscle, was not just statistically significant (see Figure 3, in bottom line). The 10% vs. 20% difference between the PRO and the PRO-EX group is also of potential practical relevance as it increased from - over weeks the muscle gains in the PRO-EX group can thus be expected to be significantly larger. Damas et al. (2016) have, after all, been able to show only recently that the (logical) correlation between acute increases in protein synthesis and lean muscle gains that has previously been doubted does exist - if you account for muscle damage (which is reduced after 1-3 weeks of training).

Figure 3: The incorporation of traced aminos shows that the advantage of working out before sleep may matter.

Bottom line: While working out pre-bed may be best, Holwerda et al. have proven that granny & grandpa will unquestionably benefit from consuming 40g of slow-digesting casein protein (probably micellar casein) 30 minutes before going to bed - "post-workout", or not.

With additional exercise, the net protein accrual, i.e. the actually relevant difference between the amount of amino acids that is eventually incorporated into the muscle and not broken down will be 20% higher (Figure 3), though - a stat. sign. and potentially relevant difference, neither your grand parents, nor you should miss. So what? Train - hit the weights at 2-5 (max!) times a week and inspire the rest of your family to do the same | Comment on Facebook!

References:

• Damas, Felipe, et al. "Resistance training‐induced changes in integrated myofibrillar protein synthesis are related to hypertrophy only after attenuation of muscle damage." The Journal of physiology (2016). Read the SuppVersity article about this study.
• Holwerda. "Physical Activity Performed in the Evening Increases the Overnight Muscle Protein Synthetic Response to Presleep Protein Ingestion in Older Men." First published June 8, 2016, doi: 10.3945/​jn.116.230086 J. Nutr. jn230086.

Protein Supps + Synthesis After 'Cardio': Milk (Natural 2:8 Whey:Casein) Protein is Best! Plus: 40g May Be Ideal Dose

Protein Supps + Synthesis After 'Cardio': Milk (Natural 2:8 Whey:Casein) Protein is Best! Plus: 40g May Be Ideal Dose

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Even though the study at hand has been conducted in an endurance training scenario, there's no reason to believe that the superiority of milk protein, the natural mix of whey and casein would be a "cardio-specific" thing. In fact, evidence to the contrary has been discussed previously, here and here.

Whey, casein, soy or the rarely used alternative, milk protein, what's best to kickstart the protein synthetic machinery even after endurance workouts? The absorption kinetics of the different proteins, the effects of which a group of scientists from Japan recently re-assessed would suggest that the answer is clear: whey protein, it's the fastest of the four proteins, contains the highest amount of BCAAs (esp. the mTOR- and MPS promoter leucine) content and has been repeatedly shown to rapidly cause significant hyperamonoacidemia (=extremely elevated amino acid levels in the blood | Boirie. 1997; Dangin. 2001; Norton. 2009).

In spite of the fact that whey is also the most insulinogenic of these proteins, it is yet also the one that has been shown to "maximize" amino acid oxidation, thereby contributing to a reduction in nitrogen retention (Boirie. 1997; Dangin. 2001). On the other hand, ingestion of CA causes slower but prolonged aminoacidemia and it has the best leucine net balance during the postprandial period (Boirie. 1997; Dangin. 2001), I've discussed in previous articles, such as "Protein Wheysting".

This is not an anti-high-protein article. It is one arguing in favor of "treating your protein right"

Practical Protein Oxidation 101

5x More Than the FDA Allows!

More Protein ≠ More Satiety

Protein Oxidation = Health Threat

Protein Timing DOES Matter!

More Protein = More Liver Fat?

This is where micellar casein (not sodium or calcium caseinate which are fast-, but slower-than-whey-absorbing "damaged" forms of casein, though) comes in. While casein does not produce the same rapid increase in serum amino acid levels it has been shown to cause moderate but prolonged muscle protein synthesis - the exact opposite of whey protein.

Figure 1: Fractional myofibrillar protein synthesis (A), plasma leucine (B) and plasma insulin (C) levels in young men after ingesting 0.3g/kg whey, casein or a protein-free control drink (Reitelseder. 2011)

The data from Reitelseder et al. (2011) illustrates the link between the time course of the myofibrilliar protein synthesis and a protein's digestion speed, the rate of appearance of leucine (Figure 1, B) in the blood and the protein's insulinogenic (Figure 2, C) effects quite nicely. It is thus only logical to assume and has in fact been shown that the co-ingestion of whey and casein, either mixed or as milk protein is superior to soy protein (SP) [22,23], but also to whey alone, even if the latter is "enhanced" with extra BCAAs and glutamine (learn more!)

Figure 2: As a SuppVersity reader you will rememeber that a previous study showed that whey + casein is profoundly more anabolic than whey that is combined with extra BCAAs and glutamine (Kerksick. 2006)

As the Japanese authors of the study at hand point out, these benefits are likely due to casein's ability to "contributes amino acids that have a prolonged protein-synthetic effect across the leg" - or, put more simply: whey pumps up the AA levels fast, so fast that your body gets wasteful; casein, on the other hand, provides them at a rate that's much more suitable for direct incorporation into the muscle.

Whey (open triangles) increases leucine +protein oxidation vs. casein (closed circles) in man (Boirie. 1997).

Thinking about the perfect mix: Wouldn't it make more sense to have more whey right after a workout and reduce the amount of casein? If that's what you are thinking right now, I have to warn you: As previously pointed out, there's a point of diminishing returns, when excess amino acids as you would increase them by increasing the amount of whey are oxidized and end up as "waste", namely ammonia (and after recycling urate) in your system. The increased leucine oxidation with whey (open triangles) vs. casein (filled circles), as it was observed by Boirie et al. 19 years ago in healthy subjects even though the subjects consumed 43g of casein and only 30g of whey to standardize the leucine content, attests to that. Needless to say, testing a 50:50 or even 60:40 ratio would be something for follow-up studies.

Table 1: Amino acids in milk (MP), caseinate (CA), whey (WP) and soy (SP) protein (Kanda. 2016).

What exactly the ideal ratio of whey to casein protein may be will still have to be determined (probably it'll depend on when you take your protein shake), but the 2:8 ratio, meaning 20% whey protein and 80% casein that was used in the study at hand is "nature's standard formula" and thus what your average milk protein will have. A protein, by the way, of which Kanda et al. wanted to confirm in their latest experiment that it "causes a prolonged increase in muscle protein synthesis compared to WP [whey protein]or CA [casein] alone" (Kanda. 2016).

In contrast to "the average" study, the Kanda et al. did so in the presence of an endurance, not a strength or no training stimulus at all and used both, the milk-derived proteins caseinate (CA | faster absorbing, non-micellar form of casein), whey (WP) & milk protein (MP) to soy (SP). You can review the individual amino acid composition of all four in Table 1 on the right and will notice that "technically speaking", i.e. judged based on its BCAA content, soy is the "worst muscle builder", whey the "best".

Time for the convenient, but annoying truth(s)!

Truth #1: It's a rodent study! That's convenient for the scientists, because using rodents is cheap and easy, but annoying for us, because rodents are a good model for humans, but only that - a model - and by no means the best one. Since we cannot switch the subjects, though, we have to live with the fact that the subjects in the study at hand were Sprague-Dawley rats with a bodyweight of approximately 150 g (at least there were many | n = 237) who were subjected to a swimming exercise protocol during which they swam for a whopping 2h.

You should care about postworkout protein synthesis! While previous studies had suggested that the FSR / MPS response to training and supplementation would not, a more recent study I discussed in detail, last week, clearly demonstrates that FSR / MPS does matter. Read it!

Now, where there's shadow, there's also light: The good thing about rodent studies (bad for the rats, though) is, after all, that, much in contrast to humans, rats can be sacrificed after an experiment like that and will thus allow researches to assess the effects of exercise and supplementation with the aforementioned proteins much more accurately than a single or even multiple muscle biopsies.

Table 2: Macronutrient profile of test proteins; milk (MP), caseinate (CA), whey (WP) and soy protein (SP | Kanda. 2016)

That does not fully compensate for truth #2, though, which is that the scientists made the mistake of using caseinate (Fonterra Co-operative Group, Ltd., Auckland, New Zealand), instead of the more expensive and slower/-est digesting (due to its micelle structure, which gels during the digestion process) molecularly intact micellar casein, of which one could expect that it may have postponed the peak in fractional protein synthesis (FSR) that occurred after 120 minutes with the caseinate even more (Figure 3, left).

Figure 3: Time course of the fractional protein synthesis after endurance exercise with all four proteins (left) and corresponding AUC values (~net protein influx, right | Kanda. 2016).

The previous hypothesis is obviously merely speculative and eventually irrelevant. I mean, micellar casein, or not, it is very unlikely that the overall AUC, i.e. the incremental area under the FSR curve and thus the net influx of protein into the muscle, would have been increased to a level that would top that of milk protein (black bar in Figure 3, right), which had a measurable, but not statistically significantly more pronounced effect on the protein influx than any other of the four proteins.

Bottom line: Yes, it's rodents, but eventually the study at hand simply extends previous studies (A, B) in humans, where the combination of whey + casein likewise outperformed the competition...

FSR during dose escalation study; the human equivalent dose (HED) of 3.09g/kg, the 100% dose, in rats is ~0.5g/kg in man and thus ca. 30-50g milk protein, depending on your body weight. (Kanda. 2015)

And when we are talking about "extending the existent research", it may be worth mentioning that the researchers also provide new evidence in regards to the "ceiling" or "muscle full"-effect that occurs when ingesting more protein won't yield any extra increases in protein synthesis. In the study at hand, this effect was reached at a human equivalent dosage of ca. 0.5g per kg body weight (that's the 100% dose in Figure 4) or ~ 40g which is - initially surprisingly - more than the often touted 20-30g (depending on the human study you cite). In view of the 20:80 mix of whey and casein, the lower leucine content and slower absorption of the latter, it is yet actually logical to need more milk protein vs. whey to "reach the ceiling" | Comment!

References:

• Boirie, Yves, et al. "Slow and fast dietary proteins differently modulate postprandial protein accretion." Proceedings of the National Academy of Sciences 94.26 (1997): 14930-14935.
• Dangin, Martial, et al. "The digestion rate of protein is an independent regulating factor of postprandial protein retention." American Journal of Physiology-Endocrinology And Metabolism 280.2 (2001): E340-E348.
• Kanda, Atsushi, et al. "Effects Of Whey, Casein, Or Milk Protein Ingestion On Muscle Protein Synthesis After Endurance Exercise." MEDICINE AND SCIENCE IN SPORTS AND EXERCISE. Vol. 46. No. 5. 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA: LIPPINCOTT WILLIAMS & WILKINS, 2014.
• Kerksick, Chad M., et al. "The effects of protein and amino acid supplementation on performance and training adaptations during ten weeks of resistance training." The Journal of Strength & Conditioning Research 20.3 (2006): 643-653.
• Norton, Layne E., et al. "The leucine content of a complete meal directs peak activation but not duration of skeletal muscle protein synthesis and mammalian target of rapamycin signaling in rats." The Journal of nutrition 139.6 (2009): 1103-1109.
• Reitelseder, Søren, et al. "Whey and casein labeled with L-[1-13C] leucine and muscle protein synthesis: effect of resistance exercise and protein ingestion." American Journal of Physiology-Endocrinology and Metabolism 300.1 (2011): E231-E242.

Health & Weight Loss Start in the Gut: Probiotics Trigger Fat Loss Without Dieting | Casein Improves Lipid Metabolism

Health & Weight Loss Start in the Gut: Probiotics Trigger Fat Loss Without Dieting | Casein Improves Lipid Metabolism

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Gut health is "all the rage", lately. So even if it's true that this may be one of the most culpably neglected areas of research in the past century, we should still be careful not to hype the effect of the gut on your physique and health too much.

Well, probiotics and the human microbiome (the one in the gut and elsewhere) are all the rage, these days. Against that background, it's not really surprising that a probiotic supplement and thus a human microbiome modulator made it into the SuppVersity news (again). What may be surprising, though, is the fact that casein didn't just do the same, but that its appearance here in the news is not due to its muscle building prowess. Rather than that, casein made the cut, because a recent study by Francois Mariotti, et al. shows that - even in comparison to whey protein - casein attenuates the potentially unhealthy postprandial triglyceride response to a mixed high-fat meal in healthy, overweight men.

You can learn more about the gut & your health at the SuppVersity

Fiber for Female Fat Loss

Sweeteners & Your Gut

Foods, Not Ma- cros for the Gut

Lactulose For Gut & Health

Probiotics Don't Cut Body Fat

Is Gluten Intolerance Real?

• Cheesy! Casein keeps your trigs in check - Due to the interaction between elevated postprandial triglyceride levels, insulin resistance and cardiovascular disease, the results of the previously mentioned study by Mariotti et al. (2015) may be of interest not just for all of us. After all, the proposed mechanism of which the authors, scientists from the AgroParisTech speculate that it is a direct result of the same

  "solubility of casein and its precipitation that forms a gel in the stomach [which have long been] known to influence its rate of absorption and postprandial protein metabolism in the context of regular, low-energy meals" (Mariotti. 2015),

  as the marked effect on the chylomicron kinetics and decrease in postprandial TGs, a risk factor for cardiovascular disease, the French scientists observed in the study at hand.
  

  

  Figure 1: Area under the curve for triglycerides (did respond), amino acids (didn't respond) and glucose (didn't respond) in 10 overweight subjects after consuming isocaloric high-energy meals with 15% of the energy from protein in form of casein (CAS), whey protein (WHE) or alpha-lactalbumin enriched whey (LAC | Mariotti. 2015)

  As you can see in Figure 1, the proteins which made up exactly 15% of the total energy content of the high-fat meal that was fed to 10 healthy overweight men with an elevated waist circumference (>94 cm) did not affect the subjects' postprandial plasma glucose, amino acids, insulin, or nonesterified fatty acid levels (which would, by the way, suggest that ingesting whey or an alpha-lactalbumin enriched whey protein with a meal ruins its amino acid absorption advantage). The study outcome that did differ, though were the postprandial triglycerides (TGs) levels, where the provision of casein lead to a highly significant 22% (+/- 10%) reduction in the 6-h area under the curve.

And I thought casein was bad for the heart? Well, there are in fact concerns that certain forms of casein - more specifically, beta-casein A1 - could be associated with ishaemic heart disease (McLachlan. 2001; Laugesen. 2003). Experimental evidence from humans that would confirm what epidemiologists suggests is yet lacking and the corresponding research happens to be pimped by New Zealand who have the lowest number of A1 cows in their herds | learn more.

• As the authors point out, similar trends were shown for plasma chylomicrons [apolipoprotein (apo)B-48; P < 0.05], yet not for the postprandial oxidative stress (plasma hydroperoxides and malondialdehyde), endothelial dysfunction (salbutamol-induced changes in pulse contour analysis), or low-grade inflammation. This is also why it is as of yet only a logical, but hitherto unsupported hypothesis that consuming casein (micellar casein, not regular sodium or calcium caseinates) would also reduce one's cardiovascular disease risk. Eventually, it does yet appear to be the more reasonable adjunct to a full meal anyway - the purpose of the latter is after all to keep you satiated for a long time; and that's where casein is unquestionably a better choice than whey.
• Probiotics - 0.5% body fat reduction, and a 2.68 cm² reduction in subcutaneous fat area are not much, but they occurred in the absence of diet and exercise - If the trend continued and the 120 nondiabetic and overweight subjects Jung et al. divided into two groups: There was the probiotic group with 60 individuals who consumed 2 g of powder of two probiotic strains, L. curvatus HY7601 and L. plantarum KY1032, each at 2.5 × 109 cfu, twice a day. And there was the and a placebo group, likewise 60 individuals, who consumed the same amount of powder that did not contain any probiotics.
  

  

  Figure 2: Changes in body composition according to waist measurement and CT scans - All values are relative changes in waist and fat area measure from week 0 to week 12 (Jung. 2015).

  Both groups were advised to take their supplements immediately after breakfast and dinner, but only the probiotic group saw relevant improvements in body fat at slow) pace - albeit a pace at which it would take them "only" 5 years to finally make it into healthy body fat zones.

Probiotics under urgently needed scrutiny: Many Probiotics Contain Antibiotic Resistant Bacteria. Plus: Number of Live Bacteria is up to 95% Below Label Claims | Learn more.

Prebiotic supplements are not created equal! You may remember my recent article on (a) antibiotic resistances in supplemental probiotics and (b) the lack of viable bacteria in the different supplements the researchers analyzed. It should be obvious that these results mean that even though the study at hand appears to suggest that everyone should take probiotics, further research is needed before we can say which of the many pills on the market this should be... ah, and by the way. It is still not clear whether the same bacteria that are benefical for the obese are anywhere close to beneficial for lean athletic individuals. Rather than general recommendations, I expect the future of probiotic supple-ments to be individual (based on diet and metabolic data).

• Ok, that's painfully slow, but given the fact that the food intake of both groups didn't differ significantly, it is still noteworthy that the 2 g of probiotic powder which contained contained 0.1 g of L. curvatus HY7601, 0.1 g of L. plantarum KY1032, 1.24 g of crystalline cellulose, 0.5 g of lactose, and 0.06 g of blueberry-flavouring agent made the subjects lose significant amounts of body fat, while their peers who received 2 g of a placebo powder that contained 1.34 g of crystalline cellulose, 0.6 g of lactose, and 0.06 g of blueberry-flavouring agent kept gaining.
  

  

  Figure 3: The provision of the probiotic supplement did also trigger significant improvements in the above markers of cardiovascular disease risk - if it's not the small fat loss, it would thus be the potential CVD risk reduction that makes the use of probiotic supplements attractive especially for overweight individuals (Jung. 2015).

  In conjunction with the likewise statistically significant beneficial effects on health markers like LDL oxidation and LDL particle size which indicate significant improvements in cardiovascular disease risk, this is still the first non-sponsored study (the study was financed by Korean Ministry of Science) that shows that supplementing with commercially available probiotics in man may actually produce health-relevant beneficial effects.

Probiotics aren't for the overweight and obese, only. A recently discussed study, for example, showed that a patented multi-strain probiotic will reduce the fat gain on a 4-week "bulk" by more than 50% - and that's in twenty young men who consumed an extra 1,000kcal per day | more.

You are kidding me, right? No, I am not. I know that neither casein nor probiotics appear to be game-changers, but eventually you will have to understand that the one trick, supplement or modification of your lifestyle cannot correct the 10,000 mistakes you have or even are still making. Losing fat and getting healthy is about taking one baby step at a time; and the studies by Mariotti et al. and Jung et al. describe two promising ways of taking another of these steps.

In that it would be great if we knew for sure how both of them work on a mechanistic (molecular) level. As of now, the only thing that appears to be certain, though, is that they act at the level of the gut. One by affecting the digestive process, the other by modifying the make-up of the intestinal microbiome of which more and more studies appear to suggest that it may not be triggering, but at least perpetuating the ill health effects of obesity | Comment!

References:

• Jung, Saem, et al. "Supplementation with two probiotic strains, Lactobacillus curvatus HY7601 and Lactobacillus plantarum KY1032, reduced body adiposity and Lp-PLA 2 activity in overweight subjects." Journal of Functional Foods 19 (2015): 744-752.
• Laugesen, Murray, and R. B. Elliott. "Ischaemic heart disease, Type 1 diabetes, and cow milk A1 β-casein." (2003).
• Mariotti, François, et al. "Casein Compared with Whey Proteins Affects the Organization of Dietary Fat during Digestion and Attenuates the Postprandial Triglyceride Response to a Mixed High-Fat Meal in Healthy, Overweight Men." The Journal of nutrition (2015): jn216812.
• McLachlan, C. N. S. "β-Casein A 1, ischaemic heart disease mortality, and other illnesses." Medical Hypotheses 56.2 (2001): 262-272.