17 Feb 2024

From saturated fat to arterial plaque: cholesterol and beyond

Cardiovascular diseases (CVDs) are still the leading cause of death globally (OWID), but vary markedly by demographics and in relation to various lifestyle factors. In particular, in the second half of the 20th century, the seminal Seven Countries Study illuminated associations with diet, especially saturated fatty acids (SFAs), which at 50-year follow-up remain strongly associated with coronary heart disease mortality (n=16 cohorts, r=0.92) 1. Many other studies have further probed this relationship, and while some heterogeneity emerged, so have general themes. For instance, some prospective cohort studies and meta-analyses thereof fail to find independent associations with SFA intake 2; however, studies performing substitution analyses report that replacing sources of SFAs with unsaturated fatty acids (UFAs) (not animal-sourced MUFAs 3,4) or complex carbohydrates (not simple carbs 5–7) lowers CVD risk and mortality (e.g. US 3–5,7–9, Europe 6,10,11 and pooled 12,13). Importantly, in the US population it was also revealed that SFAs are typically replaced by refined grains and added sugars, which are also associated with CVD, potentially explaining prior null findings 5. A number of randomised controlled trials (RCTs) have also been conducted, and in the latest Cochrane meta-analysis lowering SFAs significantly lowered CVD events, mainly being driven by replacement with various PUFAs (n=8, RR=0.79, 95% CI 0.62–1.0) and carbs (n=5, RR=0.84, 95% CI 0.67–1.06), but not mortality (albeit with 75% less death vs. event data) 14. Further supporting this, a diverse literature of shorter RCTs show replacement of SFAs can favourably modulate various biomarkers of risk and pathophysiology; e.g. lipids/lipoproteins 15–17, immune-inflammation 18,19, glucose-insulin homeostasis 20, liver fat 21, endothelial integrity and platelet activity 22,23.

17 Jul 2022

Redox and the gut microbiome

Host redox biology shapes the gut microbiome and vice versa; relationships which may be important in oxidative stress-associated disease and ageing. Here’s an overview…

Gut oxygen

Reduction-oxidation (redox) processes play fundamental roles in biology, while shifting redox environments have shaped the evolution of life on this planet. The primordial earth was virtually anoxic when life appeared ~3.8 billion years ago, with the advent of photosystem II (i.e. early photosynthesis) and geochemical changes eventually increasing atmospheric oxygen (O2) (i.e. Great Oxidation Event). This exposed life to a double-edged sword: a toxic oxidant and an energetically favourable respiratory acceptor. Consequently, while some committed anaerobes became confined to anoxic zones, others went aerobic, creating the present dichotomy 1,2. Moreover, aerobic metabolism facilitated the evolution of complex multicellular metazoa 3,4, and novel biogeographical redox environments therein. In particular, the human gut is populated by trillions of microbes, predominantly anaerobes, which have co-diversified with us acquiring traits such as O2 intolerance 5.

16 Apr 2022

Ascorbate supports folate?

Folate (vitamin B9) is an essential carrier of 1-carbon (1C) units for DNA synthesis and methylation. More specifically, this involves reduced tetrahydrofolate (THF; H4PteGlu) derivatives which are highly sensitive to oxidation; initially to dihydrofolate (DHF; H2PteGlu), before eventually being destroyed by irreversible scission of the C9–N10 bond. It has long been known that the antioxidant ascorbic acid (vitamin C) can reduce DHF (to THF) and protect folate from degradation 1. Further, in humans, dietary ascorbate and THF synergistically correlated RBC folate 2, and ascorbate supplementation boosted the blood response to both natural 5-methyl-THF (over 8 hours) 3 and synthetic folic acid (after 45 days) 4, supporting physiological relevance.

4 Oct 2021

Solid vs. liquid fat—a biophysical perspective

As reviewed previously, dietary fats have differential effects on the body in relation to various mechanisms. This post explores why from a more fundamental perspective.

The body is largely an aqueous environment, compartmentalised by amphipathic lipid barriers/membranes containing specific hydrophobic fatty acids; and similarly, lipids are transported in amphipathic lipoproteins and metabolised by water-soluble enzymes (e.g. lipases). However, dietary fats have diverse structures and physiochemical properties. Foremost, unsaturated fatty acids (UFAs) are liquid at body temperature (37°C), while saturated fatty acids (SFAs) have higher melting points, which increase with chain length, resulting in short–medium chain fatty acids (e.g. C3–11:0) being liquid and longer chains solid; with a parallel relationship to water insolubility (Wiki). Could these basic characteristics underlie some of their differential effects?

10 Apr 2021

Differential effects of fats on gut–host health

Dietary fats are ubiquitous and essential, while their quantity and quality modulate health. Recently, effects on the gut microbiome are being revealed. This post explores their differential effects on the gut–host dialog and underlying mechanisms relevant to many diseases.

Dietary fats appear to differentially affect human physiology; and perhaps most notoriously in the case of cardiovascular disease (CVD), the leading cause of death globally. For instance, in large observational studies, substitution analyses suggest opposing effects of saturated vs. monounsaturated and polyunsaturated fatty acids (i.e. SFAs vs. MUFAs and PUFAs, respectively) on CVD 1–3; a relationship tested and supported by meta-analyses of randomised controlled trials (RCTs) 4, and referenced in many dietary guidelines. Further, in 3–4 week RCTs on healthy adults, adjusting the habitual palmitate/oleate ratio (i.e. the most abundant SFA/MUFA) affects blood/tissue lipids, alongside energy metabolism, immune activity and brain function 5–11. And even single meals with different fats can have markedly different effects on postprandial cardiometabolic biomarkers 12.

8 Dec 2020

Oxidative ageing: from proximate to ultimate causes

Oxidative stress seems really important in age-related decline and disease—but what causes it? Here I’ve tried to express a broadening perspective, by exploring its core, context and ultimate causes; and largely anchored in human studies where possible.

We all die—what matters is how. While human life expectancy has increased, non-communicable diseases are now the major cause of disability and death globally (WHO and OWID). These are mostly age-related diseases (e.g. CVD, cancer, COPD, dementia, etc.), which develop slowly over time, and coexist as multimorbidity (e.g. most people >65 in US/UK 1,2); resulting in functional decline/frailty and socioeconomic burden (i.e. productivity, sick care). This situation is growing globally, as populations are ageing, and diseases occur earlier—so we may live longer but sicker 1. Moreover, this invisible epidemic underlies susceptibility to (communicable) infectious diseases, such as COVID-19 3, elevating chronic disease to acute threat.

27 Jul 2020

Synthetic vs. organic B12 metabolism—is cyanocobalamin inferior?

Cyanocobalamin is a common synthetic form of vitamin B12 used in supplements and fortified foods—how does it compare to natural forms?

Vitamin B12 (cobalamin, Cbl) has the most complex structure of all vitamins, which consists of a central cobalt atom bound to a corrin ring, a displaceable lower (a) ligand (5,6-dimethylbenzimidazole, DMBI) and a variable upper (b) ligand (e.g. cyano-, methyl-, 5’-deoxyadenosyl-, etc.) 1 (see).

Cbl was originally isolated as cyanocobalamin (CNCbl), which was later recognised as an artefact arising from extraction methods 2. Further advances led to identification of natural forms in microbes, animals and humans 2–5, where methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl) serve as vital coenzymes for methionine synthase (MS) and methylmalonyl-CoA mutase (MCM), respectively.

1 Jun 2020

Redox regulation of immunity

This data summary table collects studies showing how redox and Nrf2 regulate immunity and infections. I may finish a full post on this at some point.

29 May 2020

Supplement concerns—an appeal to nature

I’ve become increasingly concerned about the efficacy and safety of some typical nutritional supplements—here’s why.

Initially, my concern is a logical appeal to nature. Food contains a complex matrix of chemicals in the balance and structure of life, to which our physiology (e.g. digestion, metabolism and microbiome) is adapted. By comparison, supplements supply concentrated food ingredients, to an extreme of isolated chemicals in unnatural forms and mega doses. My concern is fed by some studies reporting on potentially negative effects and long-term health outcomes (see table); common themes are the use of synthetic/isolated nutrients and high doses (note their use also in ME/CFS studies 1–5). Could these deviations from nature impair bioactivity or induce imbalances which limit efficacy and introduce risk? Some specific examples are discussed below.

15 May 2020

Reversal of CVD with diet and lifestyle

Among the ocean of research, I’m very interested in natural interventions which have reversed common diseases, since they help reveal basic ecology. Here’s a mini-review based around my initial reading of such CVD trials.

Cardiovascular disease (CVD) is the leading cause of mortality worldwide, accounting for 31% of all deaths (WHO). The most common forms are coronary artery and cerebrovascular diseases (affecting heart and brain, respectively) driven by atherosclerosis (i.e. plaque build-up) 1,2. Further, CVD and intracranial atherosclerosis are also linked to dementia 3,4, another leading cause of death (e.g. Dementia Hub).