Science is able to correct itself (in contrast to the media)

Science is a human endeavor and as such prone to errors. Therefore the peer review process, which is the check of scientific methods and results by scientific peers prior to or after their publication, plays an important role in scientific knowledge generation. Most journals still apply the pre-publication review principle, meaning that a paper only gets published after careful checking and acceptance by one or more reviewers.

A 2014 meta-analysis on the effects of low carbohydrate diets on weight loss seems to provide an alarming example of the failure of the pre-publication peer review process. In this study led by Celeste Naude from the Stellenbosch University of Cape Town, South Africa, the authors concluded [1]: “There is probably little or no difference in weight loss and changes in cardiovascular risk factors up to two years of follow-up when overweight and obese adults, with or without type 2 diabetes, are randomised to low CHO diets and isoenergetic balanced weight loss diets.” This result apparently received large media coverage, particularly in South Africa, with headlines and comments claiming a “debunking” of low carbohydrate diets and even warnings against their usage. While this already shows the strong bias against the low carbohydrate approach in the media, a re-examination of the original data by Zoe Harcombe and Tim Noakes now reveals so many errors and mistakes in the meta-analysis that one has to seriously consider the possibility that the errors were made on purpose to achieve at least an even result between the low carbohydrate and “balanced” diets [2].

Composition of the „low carb“ and „balanced“ diets in the meta-analysis of Naude et al. [1]. How can one call the diet on the right side balanced?

First of all, Harcombe and Noakes rightfully point out that the “low carbohydrate” diets included in the meta-analysis are at best “lower carbohydrate” diets as shown in the figure where I have plotted the average macronutrient composition of the “low carb” and the “balanced” reference diets (I always wonder how anyone could seriously consider a diet with >50% energy balanced). Harcombe and Noakes further show that four of the 14 studies included in the meta-analysis should not have been included according to the inclusion criteria stated by Naude et al. Even worse, they reveal at least ten errors or inconsistencies in data extraction from the included studies of which nine biased the result in favor of the higher carb diets. By re-analyzing the data of the ten studies fulfilling the Naude et al. inclusion criteria without these errors, the standardized mean weight loss difference between the low carb and high carb diets was -0.272 (95% confidence interval [-0.506, -0.039]), which indicates a significantly greater weight loss on the low carb diets at 3-6 months.

For me, the probability that Naude et al. [1] happened to make these serious mistakes unintentionally is very small, since they almost exclusively contributed to a disadvantage of the low carb diets. According to Harcombe and Noakes, many of these authors were also known for publicly opposing lower or low carb diets. Thus, there were probably serious conflicts of interest involved in conduction the meta-analysis, producing another example of scientific “waste”. The bad thing is that such waste managed to survive the peer review process that should have detected it and cleaned it up. Even worse, the wrong result stimulated a totally overdrawn media response that could have misinformed laypersons about the possible benefits of low carb diets. The good thing is that Harcombe and Noakes discovered these errors. Of course, they were probably driven by their own interests and beliefs, but personal opinions and beliefs belong to any human scientist and are not bad per se as long as they are honestly acknowledged or tried to be avoided in the scientific methodology. Even if the media probably will not correct their former misinformation – at least science seems able to correct itself.

 References:

[1]         Naude CE, Schoonees A, Senekal M, Young T, Garner P, Volmink J. Low carbohydrate versus isoenergetic balanced diets for reducing weight and cardiovascular risk: A systematic review and meta-analysis. PLoS One 2014;9:e100652.

[2]         Harcombe Z, Noakes T. The universities of Stellenbosch/Cape Town low- carbohydrate diet review: Mistake or mischief? South African Med J 2016;106:1179–82.

It’s the sugar stupid!

Observations that caloric restriction, i.e. a reduction in total energy intake from what would usually be consumed (called ad libitum intake), retards tumor growth in experimental animals have been published as early as 1909 by C. Moreschi [1]. In recent years, calorie restriction has been more systematically investigated, usually as a 20-40% proportional reduction of energy intake from ad libitum feeding. It has been found that it not only retards tumor growth but could also sensitize tumor cells to pro-oxidative therapies such as ionizing radiation and chemotherapeutics. The big question is through which mechanism(s)? In contrast to restriction of specific nutrients, caloric restriction restricts several nutrients at the same time. Usually, carbohydrates constitute the major proportion of the usual diet, so that an absolute reduction of energy intake, when keeping this proportion constant, results in carbohydrates being restricted the most. Take a 2000kcal diet: If 50% energy are from carbs (250g), 20% from protein (100g) and 30% from fat (66.7g), a reduction to 1600 kcal (-20%) would be equivalent to a reduction of carbs by 50g, but protein by 20g and fat by only 13.3g (assuming 4kcal/g for carbs, 9kcal/g for fat, 4kcal/g for protein). As me and my colleagues have repeatedly pointed out, the main effects of calorie restriction are thus most probably due to the overall restriction of carbohydrates [2–4]. As the seminal work of Klein and Wolfe has shown [5], fat is the most neutral and carbohydrate the most disruptive macronutrient in humans with respect to their interference with the response to fasting, and hence calorie restriction in general. This is the rationale of using very low carbohydrate, high-fat ketogenic diets as fasting-mimicking diets for prevention or treatment of various diseases or general health promotion.

Now a new study nicely shows that it’s indeed the reduction of carbohydrates that is responsible for the effects of calorie restriction in a mouse model of non-Hodgkin lymphoma [6]. This cancer type is frequently found to have a genetic defect in the gene encoding the “induced myeloid leukemia cell differentiation protein” Mcl-1, resulting in its overexpression. Mcl-1 belongs to the family of Bcl-2 proteins which are inhibitors of apoptosis, the cell death mechanism that should ideally be activated if a normal cell turns towards the malignant direction. Their counterparts are the so-called BH3 proteins (e.g. Bim, Puma,Noxa, Bad, etc.) which are pro-apoptotic. Bcl-2 and the BH3-proteins are able to bind to and inhibit each other. For this reason, BH3 mimetics have been developed with the aim of binding members of the Bcl-2 family in the hope of inducing apoptosis in cells overexpressing Bcl-2 proteins such as Mcl-1. The problem, however, is that so far BH3-mimetics have shown only low affinity for Mcl-1, so that aggressive forms of lymphoma with a high expression of Mcl-1 are hardly susceptible to them (a brand new study in Nature, however, just reports encouraging findings of a Mcl-1 specific BH3 mimetic [7]).

In 2013, the working group of Jean-Ehrland Ricci in Nice, France, has already shown that 25% calorie restriction in mice is able to reduce Mcl-1 expression and sensitize lymphoma cells to BH3-mimetics [8]. In their new paper [6], the authors additionally introduced diets restricted by 25% in either carbohydrates or protein (by weight), but with the same energy content as the control diet. Their work shows that the carb-restricted diet, but not the protein-restricted diet, induced very similar effects as the calorie restricted diet they evaluated before. In particular, 25% carb restriction, but not protein restriction, led to a 50% reduction in Mcl-1 expression and sensitized experimental non-Hodkin lymphomas to cell death through treatment with a BH-3 mimetic. Noteworthy, carb restriction alone did not improve survival of the mice, but combined with the BH3-mimentic it doubled the maximal survival time from 40 to 79 days. This is another example of an experiment in which dietary manipulation alone was not sufficient to prolong survival, but supported the action of a targeted therapy.

What is striking is that the low-carb diet still yielded 54% energy from carbohydrates (compared to 70.9% in the control diet and 73.6% in the low-protein diet). In the real world, I would still consider such a diet as high carb. Thus, the non-Hodgkin lymphomas tested in these mice must have been extremely sensitive to the amount of carbohydrate in the diet. Nevertheless, this study provides further evidence that it’s the carbs (or the sugar once they are digested) that mostly interfere with cancer treatment, much more than protein and far way more than fat. Yes, there are examples in which protein restriction or restriction of certain amino acids resulted in tumor growth retardation, but I would predict that (besides a few exceptions) in these cases an alternative carb restriction would have performed even better. Another very recent study in rats [9] also indicated that even high amounts of the amino acid leucine would not promote tumor growth (despite leucine being a major stimulator of the cell growth-promoting mTOR pathway) but probably benefit the tumor host, e.g. by stimulating skeletal muscle anabolism. Exactly for the latter reason restricting protein is hardly an option for treating cancer patients. Therefore carb restriction – besides the fact that it’s the best strategy to accommodate for the altered metabolism of many tumor patients – should be the first consideration − period.

[1]         Moreschi C. Beziehungen zwischen Ernahrung und Tumorwachstum. Zeitschrift Für Immunitätsforsch 1909;2:651–75.

[2]         Klement RJ. Mimicking caloric restriction: what about macronutrient manipulation? A response to Meynet and Ricci. Trends Mol Med 2014;20:471–2.

[3]         Klement RJ, Fink MK. Dietary and pharmacological modification of the insulin/IGF-1 system: exploiting the full repertoire against cancer. Oncogenesis 2016;5:e193.

[4]         Fine EJ, Champ CE, Feinman RD, Márquez S, Klement RJ. An Evolutionary and Mechanistic Perspective on Dietary Carbohydrate Restriction in Cancer Prevention. J Evo Health 2016;1:15.

[5]         Klein S, Wolfe RR. Carbohydrate restriction regulates the adaptive response to fasting. Am J Physiol 1992;262:E631–6.

[6]         Rubio-Patiño C, Bossowski JP, Villa E, Mondragón L, Zunino B, Proics E, et al. Low carbohydrate diet prevents Mcl-1-mediated resistance to BH3-mimetics. Oncotarget 2016 [Epub ahead of print]

[7]         Kotschy A, Szlavik Z, Murray J, Davidson J, Maragno AL, Le Toumelin-Braizat G, et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature 2016;538:477–82.

[8]         Meynet O, Zunino B, Happo L, Pradelli LA, Chiche J, Jacquin MA, et al. Caloric restriction modulates Mcl-1 expression and sensitizes lymphomas to BH3 mimetic in mice. Blood 2013;122:2402–11.

[9]         Viana LR, Canevarolo R, Luiz ACP, Soares RF, Lubaczeuski C, de Mattos Zeri AC, et al. Leucine-rich diet alters the 1H-NMR based metabolomic profile without changing the Walker-256 tumour mass in rats. BMC Cancer 2016;16:764.

 

Ein paar Gedanken zum Fasten

Ich kann es nicht glauben, aber kaum ein Tag vorbei und schon wieder ein neuer Blog-Post! Der Grund ist eine einfache Frage, die mir eine Arbeitskollegin heute stellte. Ich hatte die letzten drei Tage meine jährliche „Fastenkur“ gemacht, in der ich nur Wasser und Tee zu mir nahm. Es geht mir dabei vor allem um zwei Dinge: (i) schnelles Erreichen einer Ketose und Aktivierung von Autophagie, der zellulären „Müllabfuhr“ [1]; (ii) Testen der Willensstärke (Fasten fällt mir als Genussesser extrem schwer). Drei Tage betrachte ich als Maximum, da ich nicht zu viel Muskelmasse verlieren will. Die klassischen Komponenten des Heilfastens wie Abführen, Gemüsesäfte, starke körperliche Schonung lasse ich weg, versuche aber die Tage bewusster, aufmerksamer und spiritueller als sonst zu verbringen. So  marschierte ich am 3. Tag bei einer 17 km  langen Wallfahrt vom fränkischen Dettelbach nach Wipfeld mit, was zwar aufgrund des Fastens körperlich fordernd, aber sehr meditativ war.

Besagte Frage meiner Kollegin lautete nun, ob ich nicht bei dieser Wanderung in „Unterzucker“ geraten wäre. Ich war zunächst so verdutzt dass ich kurz überlegen musste warum sie so etwas fragt. Mein Blutzucker vor und nach der Wallfahrt lag bei 58 mg/dl um 6:30 morgens und 64 mg/dl um 17:00. Dann viel mir ein, dass ich früher tatsächlich Probleme mit solch niedrigen Konzentrationen bekommen hätte, denke ich nur an die vielen Hungeräste, die ich noch vor 10-15 Jahren öfter bei langen Radfahrten zu spüren bekam. Heutzutage glaube ich, dass solch niedrige Blutzuckerspiegel physiologisch sind und während der Evolution des Menschen regelmäßig vorkamen. So versuchte ich der Kollegin zu erklären, dass bei guter Keto-Adaption so etwas wie Unterzucker nicht mehr vorkommt, da das Gehirn wunderbar auf Ketonkörper als Energiequelle umschalten kann. Sehr schön belegt haben das in den 1970er Jahren Ernst J. Drenick und Kollegen, die Probanden nach 2 Monaten Fasten mittels Insulin bis auf 9 mg/dl (!!) Blutzucker herunterbrachten, ohne irgendwelche Symptome von Hypoglykämie auszulösen [2]. Wieder mal ein Beispiel dass das was heutzutage als normal gilt, nicht normal sein muss, sondern die Folge unseres „neuen“ Lebensstils ist, in dem eine stabile physiologische Ketose nach dem Baby-Stadium nie mehr auftritt. Eigentlich sehr schade und wahrscheinlich dumm, eine solch nützliche Fähigkeit freiwillig abzugeben.

  1. Rojas-Morales P, Tapia E, Pedraza-Chaverri J. β-Hydroxybytate: A signaling metabolite in starvation response? Cell Signal. 2016;28: 917–923.
  2. Drenick EJ, Alvarez LC, Tamasi GC, Brickman AS. Resistance to Symptomatic Insulin Reactions after Fasting. J Clin Invest. 1972;51: 2757–2762.

Die Paleo Convention 2016

Zwar ist die Paleo-Convention in Berlin, das größte Paleo-Event Europas, jetzt auch schon wieder über einen Monat her. Da das aber nichts ist im Vergleich zu der Zeit seit meinem letzten Blog-Beitrag, dachte ich mir: eine gute Gelegenheit mal wieder einen solchen zu schreiben.

Es ist schon krass was Leon Benedens und Paul Seelhorst innerhalb von 1-2 Jahren da auf die Beine gestellt haben. Ich erinnere mich noch gut an das erste Zusammentreffen mit den beiden bei der fränkischen Schlachtschüssel vom Bio-Schwein in Geldersheim bei Schweinfurt, die im Rahmen der Mitgliederversammlung der Deutschen Gesellschaft für Paläoernährung (DGPE) nach deren 2. Symposium im November 2014 stattfand. Damals erzählten sie von ihrer Idee, eine große Convention nach dem Vorbild der amerikanischen Paleo FX in Berlin auszurichten und baten um Unterstützung seitens der DGPE. Eine Weile war ich sehr skeptisch bezüglich der Größe des Vorhabens, nicht zuletzt da ich wusste wie schwierig es ist, Sponsoren allein für eine eintägige Konferenz zu diesem Thema heranzubekommen.

Trotzdem wurde die Paleo Convention 2015 ein Megagroßes Event, wenn auch mit einigen offensichtlichen Fehlplanungen wie zum Beispiel dem akustisch sehr schlechten Vortragsgebäude mit einem Tontechniker, der mehr mit Rauchenund Trinken beschäftigt war, als sich um die Tonqualität und Technik zu kümmern. 2016 hatten die beiden Jungs Leon und Paul offensichtlich aus diesen Fehlern gelernt, denn mit dem Postbahnhof stand eine deutlich bessere Lokation bezüglich der Ausstellungs- und Vortragsflächen zur Verfügung. Einziger Kritikpunkt meinerseits ist das Konzept, teilweise drei Vorträge und einen Workshop gleichzeitig abzuhalten, was zumindest in mir ständig den Zwiespalt erzeugte, welchen Vortrag ich besuchen sollte. Dazu kam ein ständiger Druck, nichts zu verpassen, so dass ich mich öfter in sehr guten Gesprächen dabei ertappte, wie ich in Gedanken schon bei der Startzeit des nächsten Vortrags oder einem Ausstellungsstand, den ich noch besuchen wollte, war. Hier würde ich mir für das nächste Jahr weniger Masse bei der gleichen Klasse von Vorträgen und mehr „Freizeit“ ohne Programm wünschen. Ohne Wahl auch keine Qual.

Es liegt mir noch am Herzen zu erwähnen, dass während der Convention ein großes Gemeinschaftsgefühl aufkam, das man durchaus als „weltverbesserisch“ bezeichnen könnte. In der Tat glaube ich, dass die Paläobewegung wie keine andere das Potential hat, der Gesellschaft eine logische und nachhaltige Option für die Bewältigung gesundheitlicher und die Umwelt betreffender Probleme des „Anthropozäns“ zu bieten [1]. Auch die vielen kleinen Firmen und Handwerksbetriebe, die auf der Convention vertreten waren, sind ein exzellentes Beispiel dafür, welch hoher Wert auf Nachhaltigkeit und Qualität in diesen Kleinunternehmen gelegt wird, in krassem Kontrast zu großen Konzernen, die oftmals für jede beliebige Anforderung zu den günstigsten Bedingungen zu produzieren versuchen und entsprechend qualitativen Schrott anbieten (schön beschrieben in dem Kapitel The Antifragility and Ethics of (Large) Corporations aus dem Meisterwerk Antifragile von Nassim N. Taleb [2]). So habe ich mich guten Gewissens mit Wachteleieiern, Paleo Jerky und Wildgulasch für meinen Vorrat im Büro auf der Arbeit eingedeckt, bevor ich mit viel neuer „Steinzeit in den Knochen“ den Heimweg angetreten bin.

  1. Klement RJ, Gonder U, Orsó E, Paul S, Schilling F, Spitz J. Proceedings of the 2nd annual symposium of the German Society for Paleo Nutrition held in 2014. J Evo Health. 2014;1: 6.
  2. Taleb NN. Antifragile: Things that gain from disorder. 1st ed. New York: Random House LLC; 2014.

 

Calories, Carbs and Cancer

More than 125 years ago, Vienna medical student Ernst Freund noticed a strange phenomenon in some of his patients. Similar to diabetics, those with cancer had an “abnormal sugar content” in their blood that disappeared after surgical removal of the tumor. Some decades later, as a professor, he and others showed that compared to normal cells, cancer cells have a particularly sweet tooth in the sense that they would take up large amounts of glucose from culture medium which would stimulate their rapid growth. The most famous experiments were conducted by Otto Warburg and his colleagues in the 1920s at the Kaiser-Wilhelm Institute for Biology in Berlin. Warburg, a German biochemist and later Nobel laureate, had shown that tumor cells distinguish themselves from almost all normal cells through their preference to ferment glucose to lactate in a process known as glycolysis (1, 2). Continue reading