By Dr Josh Lamaro
This series was initially to be only a two part thing, however the recent twitter storm regarding Catalyst’s Low-Carb-High-Fat program, which aired over the weekend, provided further inspiration to write about belief-based opinions permeating the larger audience and causing confusion. (Here is a run down on the show.) On the pro-LCHF side was Tim Noakes, Steve Phinney, and of course a 2014-obligatory-cameo by chef Pete Evans, who is apparently now qualified to give expert opinions on nutrition. The against side was represented by Dietician Rosemary Stanton, and Deakin University nutritionist Associate Professor Tim Crowe. The main arguments presented by the “against” party were that LCHF diets result in constipation, halitosis, and a lack of vitamins and nutrients from vegetables (and whole grains). This is taking the assumption that a LCHF diet completely ignores vegetables altogether, which it doesn’t.
Of course anything challenging the present day dogma results in Australian Dieticians getting their knickers in a knot, and twitter seems to be an institution for this, but rarely does one see a convincing rebuttal encompassing all the current literature surrounding LCHF…On the other hand, we have a chef representing LCHF “paleo 1.0” resulting in the entire twitter audience now referring to anything attached to the word paleo as “pseudoscience” – great.
Interestingly, in related news, one Australian newspaper also ran a story over the weekend on an anti-aging pill in the works based on David Sinclair’s research on SIRT1 and restoration of NAD levels. Also see here for a description of his research. The crux of the research is that as mammals age, levels of NAD drop by 50%; with less of the compound, the communication between the cell and its mitochondrial energy source also falters, and the cell becomes vulnerable to common aging assaults — inflammation, muscle wasting and slower metabolism. By tricking the cell into thinking it’s young again, with adequate amounts of NAD, aging can theoretically be reversed. So what is NAD, and what has this got to do with LCHF diets?
NAD+ is a coenzyme found in all living cells whose primary function is to serve as an electron transfer agent in redox reactions (how our bodies transfer energy.) Thus, it is found in cells in two forms: NAD+, (or, if phosphorylated, NADP+), the oxidizing agent that accepts electrons and is reduced to NADH [or NADPH], which can then be used as an electron donor. The NAD+:NADH ratio (the balance between the oxidized and reduced forms of NAD) is a key component of the redox state of a cell and a biomarker that reflects cellular health as well as metabolic activity. NAD+ is a required cofactor for histone deacetylation, which is an important part of DNA repair. In this capacity, NAD+ serves as substrate for the deacetylating enzymes, including the sirtuin enzymes transcribed by SIRT1. This is the target of the research by Sinclair. NADH is the inhibitor of this reaction.
Cytochrome 1 of the mitochondria uses NAD+ and NADH to create a small pulse of superoxide to signal cellular energy states under normal conditions, to correctly signal mitochondrial change patterns. Depletion of NAD+, or Raised NADH leads to increased ROS/Free Radical formation (positive charge) at the mitochondrial membrane. This directly destroys the normal redox signaling in mitochondria. When the charge on the inner mitochondrial membrane drops, and is allowed to stay low chronically it begins to create the molecular signal of aging and disease – the Hydroxyl Free Radical. We call this oxidative stress, which destroys cell membranes everywhere resulting in apoptosis. When apoptosis occurs, the body must use a stem cell to create a new part. As stem cells disappear, aging ensues. NAD+ high = good. NADH high = bad. Got it?
Oxidative stress causes calcium go from the endoplasmic reticulum to the mitochondria, where it inhibits complex 1. This is a bigger effect in our modern world because non native EMF also causes massive calcium efflux from all cell lines. As a result of this release of calcium, more NADH and less NAD+ is made at cytochrome 1.
The cell is making boatloads of NADH which leads to boatloads of ROS. The ROS made sits right next to mitochondrial DNA stores in cells. That ROS destroys the mitochondrial DNA that make your cytochrome proteins.
Carbohydrate metabolism also increases NADH levels at cytochrome one of the mitochondria. Nora Volkow and Peter Achermann’s research shows that non native EMF also up-regulates glucose metabolism. This means non native EMF increases NADH at cytochrome one naturally too. In a modern environment laden with non-native EMF frequencies, one would expect massive increases in carbohydrate metabolism in all tissues, resulting in huge levels of ROS formation.
When the two primary aspects of NAD+ utilization—as redox monitor and enzyme substrate—are seen together, it’s obvious that oxidative stress, which depletes NAD+, not only compromises cellular energy production, but sirtuin activation. Since NAD+ is the substrate for the sirtuin enzymes, if NAD+ availability is compromised then their activity will be inhibited. So how does one maintain or maximise NAD+??
Well, to maintain adequate NAD+ (in addition to assembling it de novo from tryptophan), cells salvage and recycle compounds containing nicotinamide.
The three natural compounds containing the nicotinamide ring and used in these salvage metabolic pathways are nicotinic acid (Na), nicotinamide (Nam) and nicotinamide riboside (NR). Despite the presence of these several salvage options, humans still require a constant supply from the diet or supplements because NAD+ is constantly consumed at the same time. In the diet, the mixture of nicotinic acid and nicotinamide are called vitamin B3 or niacin. Thus Niacin is a precursor to maintaining adequate levels of NAD+. This has also been researched by Sinclair.
In addition to providing precursors to NAD+, Niacin can prevent apoptosis (programmed cell death) in cells exposed to agents that induce oxidative stress. There is a growing body of literature suggesting that niacin favorably alters the number of circulating LDL particles of various sizes. It was initially reported in 1955 that niacin lowered cholesterol levels in normal subjects as well as in patients with hypercholesterolemia. There have been many subsequent studies that have supported niacin as a broad-spectrum lipid-regulating medication. Niacin reduces total cholesterol, triglycerides, VLDL-C, LDL-C and lipoprotein (a) (Lp[a]) levels, in addition to increasing HDL-C levels.
Many biological processes act through receptors and molecular binding sites. The niacin effect on lipids is a receptor mediated processes too. Niacin binds to a receptor that has evolved to bind to a naturally occurring ligand, beta hydroxybutyrate. This Ketone Body is naturally manufactured by the liver in times of starvation or carbohydrate restriction, ie ketosis: aka LCHF. Well well. Low carbohydrate diets naturally produce ketone bodies. They certainly elevate protective HDL cholesterol levels too. So it is a marker of good things happening in the metabolism. Might this be due to a positive effect on NAD+? Might this then also infer that LCHF diets directly affect longevity?
(Now may be the time for Dietitians and internet wellness frauds to consider withdrawing any pre-conceived rebuttals based on diet-heart hypothesis or cholesterol hypothesis dogma: Heart Foundation i am looking at you here, too.)
Let’s quickly look at some cholesterol panel (LDL) patterns:
Pattern ‘A’ is good (all nice large buoyant fluffy particles). Large LDL fit ‘perfectly’ into LDL receptors on cholesterol-requiring tissues like our sex organs (which produce testosterone and estrogen from cholesterol) and the all-important adrenal glands, which regulate our blood pressure, tension in the endothelium/smooth vasculature, and minute-to-minute brain functions by issuing cortisol, another cholesterol-based derivative that is mandatory for life.
Pattern ‘A’ is desirable and highly associated with regressive patterns for calcification in the vasculature, whether the plaque build up (scar-tissue) is in the renal (kidney) arteries, carotid (neck) arteries, peripheral (legs), coronary (heart), or inner lining of the entire arterial tree (hypertension). Hypertension? This is just extensive calcium deposition occurring at the smooth muscle, endothelium and vessel wall fibroblast level in the vascular tree. Calcium efflux at it again.
Pattern ‘B’ is clearly BAD. Pattern ‘B’ consists of small dense LDL particles which quickly and rapidly become oxidized LDL (OxLDL) which do NOT fit into traditional LDL Receptors. They instead are attracted to many non-LDL receptor surfaces and tissues. They cause heart disease.
What promotes these small dense LDL or pattern ‘B’?
Silent and overt celiac disease (gluten intolerances: wheat barley rye) and other food allergies (A1-casein, egg whites, nightshades, nuts, etc) ie inflammation.
Excessive dietary carbs (grains, potatoes, peas, corn and fruit). Candy/sweets. Artificial sweetners. Lack of omega-3 fats. (DHA makes lumens more hydrophillic. In fact anything that reduces proteins makes them more hydrophillic and this scales to the size and shape of lipoproteins to alter their thermodynamic properties.) Excessive omega-6 refined fats.
Lack of saturated fatty acids.
Lack of antioxidants.
Lack of hormones (thyroid, estrogen, testosterone, adiponectin, vitamin D, melatonin, etc). ie Pregnenolone steal syndrome associated with oxidative stress.
The medical literature is rife with studies demonstrating that the conversion of small dense LDL to buoyant LDL is associated with regression of coronary artery disease. In the HATS trial where 90% of cardiac death and events were COMPLETELY AVERTED after 3 yrs of niacin ultra-high-dose of 3-4 grams daily (and low low dose of weak-statin 10-40mg/d), conversion to Pattern A occurred in an astounding 70% of the treatment arm. Even niacin alone produces similar outcomes of 60-70% relative risk reduction, compared with statins 17-25%. In other words, niacin alone or in combo is 300-400% better than statins relatively speaking.
What mimics niacin? What binds ‘niacin’-receptors? Beta-Hydroxy Butyrate (Ketone bodies) generated from a ketotic diet, eg high protein or high fat and very low carbohydrate.
Conversion of sdLDL to large buoyant LDL is ultimately promoted by:
High-protein, Low Carb Diets (Clifton P, Krauss RM, et al. Am J Clin Nutr. 2008 May;87(5):1571S-1575S.)
Carb restriction (Volek JS et al. J Nutr. 2009 Sep;139(9):1667-76.)
Ketotic Diets (Clifton P et al. Obes Rev. 2006 Feb;7(1):49-58.)
Niacin (ultra high dose) (HATS trial, NEJM 2001)
Here are the leading causes of death in Australia by sex (age group has been cut off):
Coronary Artery Disease is numero uno for both men and women. For all persons, Cerebrovascular disease (stroke) and Dementia/Alzheimers disease follow (although i would argue alzheimers is more a symptom of a wider pathology pertaining to a system-wide drop in energy production – NAD+ alert…) Prostate and breast cancers also make an appearance, which are also fundamentally an issue with redox states in mitochondria too. The key change is NAD+ levels in the nucleus. Without adequate NAD+ in the nucleus, SIRT 1 and SIRT6 cannot function. Sirtuin 1 and Sirtuin 6 is directly tied to excessive nuclear aging. This again is the basis of Sinclair’s work.
When nuclear levels of NAD+ are low chronically, a sequence of events occurs in the cell nucleus that ultimately results in a lack of adequate expression of mitochondrial DNA genes that are required for the construction of Complex I, III, and IV in mitochondrial electron transport. In this scenario, the nuclear-encoded proteins required for mitochondrial electron transport chain are still expressed normally, but the proteins whose genes are encoded only by mitochondrial DNA are not expressed. This is the critical point in cancer generation that occurs long before you have brain cancer diagnosed.
When this happens, normal mitochondrial electron transport cannot occur to generate ATP. This leads these altered cells to develop a metabolic picture which is “typical” in cancer, which is called the Warburg effect. Mina Bissell is credited with rediscovering this type of metabolism in breast cancer research. With a Warburg-type metabolism, cells become dependent on cytoplasmic generation of ATP via aerobic glycolysis. This is a very different and very inefficient way of transferring energy around a cell, but it is fast. Rapidly growing cells need energy delivered quickly. This is why this pathway is chosen. What prevents this picture from emerging? What reverses it? Ketogenic diets once again, as investigated by Dom D’Agostino.
Looks like we have mounting evidence that carbohydrate restriction in favour of high fat ketogenic diets positively impacts all mitochondrial disease, including oncogenesis and cancer growth and proliferation, diabetes type 1 and 2, as well as many neurodegenerative disorders such as parkinson’s and alzheimers disease. (also outlined here, summarised by Mercola here, and by Jack Kruse here, as well as this page) whilst simultaneously reducing heart disease risk factors and dyslipidemia….Problem, Dieticians?