Links: Go to episode page (with study links) Receive Sigma's email newsletter Subscribe to PREMIUM - get study notes to this episode About This Episode: In 1959 a landmark clinical trial, often referred to as the LA Veterans Study, began with the aim to investigate the effects of replacing dietary saturated fats with polyunsaturated fats, on the progression of atherosclerosis and cardiovascular outcomes. This was an eight-year clinical trial in 846 domiciled male veterans in the US. The diets between the control and experimental groups differed by saturated fat and polyunsaturated fat (particularly linoleic acid) content, but were similar in calories and total dietary fat. The findings of the study suggested that replacing saturated fat with polyunsaturated fat was beneficial for reducing heart disease risk. However, the study also reported an unexpected increase in non-cardiac mortality in the intervention group, which raised concerns. In this episode, we discuss why the LA Veterans Study was such a seminal trial and what we can learn from it.

Links: Go to episode page (with resources) Subscribe to Premium Learn more about Sigma Nutrition About This Episode: The Lyon Diet Heart Study (LDHS) is often cited as one of the pivotal studies that helped establish the Mediterranean diet as a recognized and recommended dietary pattern for cardiovascular health. A clinical trial conducted in Lyon, France, the LDHS showed significant reduction in cardiac death could be achieved in secondary prevention patients using a dietary intervention. Conducted between 1992 to 1996, the study involved 605 participants who had previously experienced a heart attack (myocardial infarction). LDHS showed an incredible 75% lower risk of cardiac death in these patients. This remarkable reduction was unexpected and led to considerable attention from the medical and scientific communities. LDHS is interesting to dig into for several reasons. First, it’s clever methodology was able to account for some challenges of doing nutrition research. Second, the dietary intervention, whilst named as a “Mediterranean diet”, should perhaps be considered differently. In this episode, Alan and Danny dig into all the details, highlighting some important lessons we can take from LDHS.

Links: Go to episode page (with study links) Subscribe to Premium Past episodes referenced: Episodes 493, 481 & 317 Further reading: How Diet Influences Heart Disease Risk About This Episode: The Sydney Diet-Heart Study was a clinical trial conducted in the 1960s and 1970s that aimed to examine the hypothesis that reducing saturated fat intake in the diet would lead to a reduced risk of heart disease. However, it really only gained attention after a more recent re-analysis by Ramsden et al., which in recent years has been used as supporting evidence for the idea that increased polyunsaturated fat (PUFA), and specifically linoleic acid, in addition to reduced saturated fat intake, can increase heart disease risk. This was based on the findings that substituting linoleic acid in place of saturated fat increased all-cause, CVD and CHD mortality. This is of course counter to prevailing consensus and guidelines in this area, which routinely show reduced risk on replacing SFA with PUFA. Could this trial undermine the common conclusions that replacing saturated fat with polyunsaturated fat decreases heart disease risk? In this episode Alan and Danny discuss some of the crucial aspects to understand about this study and what it means for what conclusions can be made about the impact of PUFA broadly, and linoleic acid specifically, on our health.

Note: This is a Premium-exclusive episode, so in order to listen to the full episode you’ll need to subscribe to Sigma Nutrition Premium. About This Episode Nutritional epidemiology has faced strong criticism over time. While some of the methodological limitations are fair, often there are criticisms that are misguided and inaccurate. In this episode, Danny touches on a few examples of the misunderstandings of the field and how such claims can be addressed in a more accurate manner. Links: Subscribe to Premium Go to episode page See recommended resources Receive weekly emails from Sigma

Links: Go to episode page (with study links) Subscribe to PREMIUM Receive emails from Sigma Nutrition Sigma's Recommended Resources About This Episode: The field of research exploring sex differences in exercise response has yielded intriguing findings, shedding light on the complex interplay between biology, physiology, and training adaptations. One of the fundamental areas of investigation pertains to sex disparities in strength, power, and hypertrophy. Historically, it’s been well-established that males, on average, exhibit greater absolute strength and muscle mass compared to females. This discrepancy often traces its roots back to inherent physiological distinctions. However, when it comes to responses to strength and hypertrophy training, the narrative becomes more nuanced. Research indicates that, when individuals of both sexes follow matched resistance training protocols, the relative improvements in strength and hypertrophy are quite similar. So, do women need to be trained differently than men? The answer, it appears, is not as much as one might assume. The principles of progressive overload, specificity, and other training fundamentals remain constant. While individualization is key, the idea of drastically distinct training guidelines based on sex lacks compelling empirical support. The guest in this episode, Dr. David Nolan, is a researcher in the area of sex differences in exercise response, and has looked at the influences of menstrual cycle and hormonal contraceptive use in female athletes on their performance. In this episode, we discuss the research to date, and what this means practically for athletes and coaches.

Links: Subscribe to PREMIUM to get study notes to this episode Go to episode page to see background detail & links See our recommended resources for further learning Previous episodes referenced: SNP17: Is Personalized Nutrition Superior to General Nutrition Advice? 414: Will Machine Learning Overtake Traditional Nutrition Research Methods? 469: Chrononutrition – New Findings & Updated Views About This Episode: To mark the 500th episode of the podcast, Danny and Alan take a look at some of the current outstanding questions in nutrition science, what areas have largely been resolved, and how their own thinking has evolved and changed over time. This brings them into areas such as personalized nutrition, ultra-processed foods, time-restricted eating, salt & health, and the difference between being “evidence-based” and “reference-based”. We Discuss: Outstanding questions in nutrition science Personalized nutrition Ultra-prosessed foods (UPFs) Diet-Microbiome-Health Omega-3 Fatty Acids Largely resolved questions Sodium & CVD risk TRE/TRF Macronutrient breakdown & weight loss Evolution in our thinking Epistemology at the forefront “Reference-based” to evidence-based Reading research: understanding “highest quality evidence”

Links: Subscribe to PREMIUM Go to episode page (with further reading links) Receive our weekly emails About This Episode: Sensory cues, comprising taste, smell, texture, and appearance, serve as the initial drivers that influence our food preferences and liking for particular items. These sensory cues can be both inherent, such as the natural sweetness of fruit, and learned, as in the association between a particular aroma and a favorite dish. One crucial aspect of this research is delving into how sensory properties of food, like texture and taste, contribute to our choices and consumption patterns. Food texture, for example, plays a key role in determining how quickly we consume a meal, with softer textures often being associated with faster eating rates. Sensory intensity and palatability are also central themes in this research. Moreover, research into dietary fat reveals intriguing phenomena like “fat blindness,” where the ability to discriminate different levels of fat diminishes as taste intensity increases. Understanding these relationships can help shed light on factors contributing to overeating and potential avenues for behavior modification. To give us a better insight into this field of research, Professor in Sensory Science and Eating Behavior at Wageningen University, Prof. Ciarán Forde, is on the podcast to discuss these ideas.

Links: Subscribe to PREMIUM Go to episode page Learn more about the podcast Sigma's recommended resources About This Episode: PREDIMED (Prevención con Dieta Mediterránea) is a landmark clinical trial conducted in Spain. The study made a huge splash due to the rarity in nutrition of having large RCTs with hard endpoints. In addition, it had results of a large magnitude; showing a 30% reduction in cardiovascular events. But the study did face criticisms and controversies over methodological issues, including randomization procedures at certain centers, ultimately leading to a retraction of the original paper and a re-analysis. Participants in the PREDIMED trial were randomly assigned to one of three groups: A Mediterranean diet supplemented with extra-virgin olive oil. A Mediterranean diet supplemented with mixed nuts (walnuts, almonds, and hazelnuts). A control group following a low-fat diet. Despite the issues it still ends up being an incredibly useful source of data. In this episode we discuss the findings from PREDIMED, some of the potential limitations, and where it sits among the wider Mediterranean Diet literature. Note: This is a Premium-exclusive episode, so in order to listen to the full episode you’ll need to subscribe to Sigma Nutrition Premium.

Links: Subscribe to PREMIUM Go to episode page (with linked studies) Receive the weekly Sigma email newsletter Recommended resources About this Episode: The PROPEL (Promoting Successful Weight Loss in Primary Care in Louisiana) trial was a cluster-randomized weight loss trial, specifically tailored to address the pressing health concerns of an underserved population in Louisiana, where obesity rates have reached alarming levels. The core of the intervention comprises a pragmatic, high-intensity lifestyle-based obesity treatment program, thoughtfully designed to be integrated within primary care settings. Over a 24-month duration, this multi-component weight loss program is delivered by skilled health coaches who are embedded in primary care clinics, with the aim of instigating substantial and sustainable weight loss outcomes. In this study, 803 participants were enrolled, of whom 67% identified as Black and 84% as female, thereby ensuring a diverse representation. The research design randomized 18 clinics, allocating them equally into two groups: usual care and an Intensive Lifestyle Intervention (ILI). The usual care group continued to receive their customary primary care, serving as the benchmark against which the ILI’s efficacy will be measured. In this episode we have the opportunity to delve deeper into the intricacies of the PROPEL trial and gain insights from one of its lead researchers, Dr. John Apolzan of the Pennington Biomedical Research Center.

Links: Go to episode page Subscribe to PREMIUM Recommended resources Receive Sigma's free email newsletter Learn more about the podcast About This Episode: Food frequency questionnaires (FFQs) have been widely employed in nutrition research to assess dietary intake patterns among study participants. However, debates surrounding the reliability of FFQs have persisted both inside and outside the academic community. These debates primarily revolve around issues related to measurement error, recall bias, and the appropriateness of FFQs for diverse populations. One prominent concern is the potential for measurement error in FFQs. These questionnaires rely on self-reported data from participants, which can introduce inaccuracies due to memory limitations and social desirability bias. Participants may not accurately recall their food consumption frequencies and portion sizes, leading to imprecise estimates of nutrient intake. Recall bias is another critical issue in the reliability debate. Participants may selectively remember or misreport the consumption of certain foods or nutrients, leading to an overestimation or underestimation of actual dietary intake. Two concepts are crucial to understand: validity and reproducibility. FFQs are validated by cross-referencing the FFQ data with other dietary assessment tools (or other methods). It’s also important to consider if an FFQ gives reproducible results when used on multiple occasions. When we ask “are FFQs reliable?”, we must first understand the conceptual exposure of interest: average intake over time. Second, we must consider what nutrients we are looking at. And third, in what population. In this episode, Danny & Alan discuss the reliability of FFQs and how to have a deeper, more accurate understanding of their use. They take a look at valid critcisms of FFQs, as well as some of the more ill-informed criticisms.

Links: Subscribe to Premium Sigma recommended resources Learn more about the podcast About this episode: In 1985 a paper titled “Sick Individuals and Sick Populations” was published in the International Journal of Epidemiology. The paper, authored by eminent epidemiologist Geoffrey Rose, can be considered as seminal and important because it brilliantly raised the concept of the “prevention paradox” and challenged traditional approaches to public health and preventive medicine. The paper’s insights have had a lasting impact on how we understand and approach population health interventions. And it raised many contentious public health issues, which are still debated and relevant today. The ideas have very important implications for how we can tackle diet-related diseases in meaningful ways. In this episode, Danny and Alan discuss the central themes of the paper, why they are so crucial to understand, and what this means for our understanding of diet and chronic disease prevention.

Links: Go to episode page Subscribe to PREMIUM Get our free weekly emails Learn more about Sigma Nutrition Radio About This Episode: The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC) stands as a seminal and pioneering research endeavor within the domain of epidemiology and cancer prevention. Conducted in Finland, the study aimed to examine the potential protective effects of alpha-tocopherol (vitamin E) and beta-carotene supplementation against the occurrence of various cancer types, particularly lung cancer, among male smokers. Initiated in the early 1980s, the study’s comprehensive design, rigorous methodology, and its focus on a specific high-risk population have contributed significantly to the understanding of the interplay between dietary antioxidants and cancer risk. The ATBC study was founded on a growing body of evidence suggesting the potential role of antioxidants in mitigating the deleterious effects of oxidative stress and free radical damage, which are recognized as contributors to carcinogenesis. The selection of male smokers as the study cohort was strategically significant, given the heightened susceptibility of this group to lung cancer and other malignancies due to the synergistic action of smoking and oxidative stress. The study’s rigorous double-blind, placebo-controlled design ensured a high degree of scientific rigor, minimizing biases and confounding factors that might influence the outcomes. One of the primary reasons for the study’s seminal status is its contribution to the understanding of the complex relationship between antioxidants and cancer risk. While the study did not find a significant reduction in lung cancer incidence among the intervention group receiving alpha-tocopherol and beta-carotene supplements, its findings spurred critical discussions within the scientific community. The neutral or inconclusive results underscored the intricate nature of carcinogenesis and highlighted the limitations of simplistic cause-and-effect interpretations in the context of cancer prevention. Moreover, the ATBC study contributed to a shift in research paradigms, prompting scientists to explore broader dietary and lifestyle factors that influence cancer risk beyond single-nutrient interventions. In this episode we discuss the three most important publications from the study, with a specific look at what crucial lessons they teach us about the nuances, challenges, and unique aspects of nutrition as a scientific field.

Links: Episode page with extra resources Subscribe to PREMIUM Receive our free weekly emails Learn more about Sigma Nutrition Radio About this Episode: The field of circadian biology has long been associated with regulating diurnal physiological processes, notably the sleep-wake cycle. However, recent advances have unveiled a broader role for circadian clocks across various tissues, including skeletal muscle. Within this context, the investigation of circadian clocks within the skeletal muscle milieu has emerged as a frontier of scientific inquiry. These intrinsic timekeeping mechanisms exhibit multifaceted regulatory capacities beyond mere temporal synchronization. This episode delves into the implications of “circadian clocks” operating within skeletal muscle tissue, with the esteemed Prof. Karyn Esser as this week’s guest. Her pioneering work has been instrumental in understanding the interplay between circadian rhythmicity and muscular physiology.

Links: Go to episode page (with study links & resources) Subscribe to PREMIUM Receive our weekly newsletter More episodes on cholesterol & heart disease About This Episode: The Multiple Risk Factor Intervention Trial (MRFIT) was a groundbreaking clinical trial conducted in the 1970s and 1980s. Its main objective was to investigate the relationship between various risk factors and the incidence of heart disease. The study aimed to determine whether modifying risk factors, such as high blood pressure, high cholesterol levels, and smoking, could lead to a reduction in cardiovascular events. The trial spanned several years, with participants being followed up for a period of approximately six years to assess the incidence of cardiovascular events and mortality. The primary outcome measures included coronary heart disease (CHD) mortality and overall mortality. The MRFIT trial yielded several important findings that have significantly influenced our understanding of cardiovascular health and prevention strategies. In this episode we take a look at why this is such seminal research, as well as the contribution of one of the greatest researchers ever in the field, Jeramiah Stamler.

Links: Go to episode page (with resources for this episode) Subscribe to PREMIUM Join the Sigma email newsletter Learn more about Sigma Nutrition Radio About this Episode: One of the most important and influential papers in nutrition science is one by Ancel Keys and his colleagues that was published in The Lancet in 1957. This seminal paper examined the relationship between dietary fat intake and serum cholesterol levels. The researchers investigated how different types of fats in the diet affected cholesterol levels in a series of their previous tightly-controlled dietary experiments.. Those studies involved feeding the participants various diets with different compositions of fats. The researchers analyzed the participants’ blood samples to measure changes in serum cholesterol levels in response to dietary changes. The most important aspect of this paper is the presentation of the ‘Keys Equation’; a predictive equation for the impacts of saturated, monounsaturated, and polyunsaturated fats, and dietary cholesterol, on blood cholesterol levels. Crucially, the Keys Equation identifies the importance of the ratio of polyunsaturated to saturated fats in the diet; known as the ‘P:S ratio’. It showed that the P:S ratio is the most important dietary factor impacting blood cholesterol levels. And specifically that saturated fats increase total and LDL cholesterol twice as much as polyunsaturated fats lower them. The findings of this study were significant in highlighting the potential impact of dietary fat subtypes on serum cholesterol levels and heart disease risk. It contributed to the growing body of evidence supporting the hypothesis that high serum cholesterol levels, particularly due to a diet rich in saturated fats, were associated with an increased risk of cardiovascular diseases. In this episode, as part of our new series taking an in-depth look at seminal nutrition studies, we go through this influential paper from Keys, Anderson and Grande.

This is a Premium-exclusive episode, so here you'll only hear a preview. In order to listen to the full episode you’ll need to subscribe to Sigma Nutrition Premium. About This Episode: It has been clearly demonstrated that elevated LDL-cholesterol (LDL-C), or perhaps more specifically pro-atherogenic lipoproteins, is causal in atherosclerosis development in humans. One crucial concept within this is that the risk relates not only to the magnitude of elevated LDL-C, but the duration of exposure. Thus, the role of LDL-C in driving atherosclerosis is referred to as a “cumulative, integrated exposure over the lifecourse”. But, what exactly does this mean? In this episode, Danny discusses the cumulative exposure model of LDL-C in atherosclerosis, the evidence supporting it, and the implications of this for the “debates” that get raised in relation to LDL-C (or apoB-containing lipoproteins) and heart disease. Links: Subscribe to PREMIUM See more episodes on heart disease and lipids Receive the free Sigma email newsletter

Links: Resources and info for this episode Subscribe to PREMIUM Receive Danny's weekly email newsletter About This Episode: Losing at least 5% of one’s initial body weight is associated with improvements in glycaemic control, blood pressure, triglyceride levels, and other positive outcomes. Due to these reasons, it is typically recommended that individuals classified as overweight or obese should engage in effective weight loss interventions. However, despite the potential for clinically significant weight loss through these interventions, weight regain is a common occurrence. This can be attributed to a combination of low adherence to weight control strategies and compensatory physiological mechanisms that influence weight regain. Consequently, this may result in a cycle of losing and regaining weight over the long term, which is commonly referred to as “weight cycling.” There are concerns regarding the potential harm to health and increased risk of chronic diseases associated with weight cycling. Some mechanisms have been proposed, such as the loss of lean mass during weight loss periods that is not regained when weight is regained. However, the evidence supporting the harmful effects of weight cycling on health is incomplete and many unanswered questions remain. In this episode, we will examine the evidence published to date and draw evidence-based conclusions regarding the impact of weight cycling on long-term health.

Links: Episode Resources Subscribe to PREMIUM Receive our weekly newsletter About This Episode: There has been interest in, and debate about, how protein intake impacts metabolic health, particularly in relation to insulin resistance and type 2 diabetes risk. Recently, there has been interest in higher protein intakes as an intervention in diabetes, owing to a variety of potential mechanisms. For example, the satiety value of protein, the promotion of insulin secretion by protein, and imapcts on incretin hormones. However, others have warned against high protein intakes. With some going as far as to claim high, or even moderate, protein intakes can lead to insulin resistance or negatively effect beta-cell function. In this episode, we look at the research typically cited in support of such claims, and dig into the details. We consider the overall evidence in this area to answer the question ‘do high protein diets cause insulin resistance or increase diabetes risk?’.

Links: Go to episode page Subscribe to PREMIUM Receive our free weekly emails About This Episode: The management of type 2 diabetes has long been a challenge, but a new study conducted by researcher Mark Lyngbaek and his colleagues has the potential to add important considerations to the approach to treatment. Titled the “DOSE-EX” randomized clinical trial, their study uncovers the impact of exercise and weight loss on beta-cell function, a key factor in diabetes progression. DOSE-EX is a four-armed randomized trial involving 82 individuals with newly diagnosed type 2 diabetes. The participants were divided into four groups: standard care, calorie restriction, calorie restriction with exercise three times per week, and calorie restriction with exercise six times per week. Over a span of 16 weeks, the researchers assessed the effects of these interventions on beta-cell function using various indicators. The study’s findings are incredibly interesting, demonstrating that exercise in combination with diet-induced weight loss leads to a substantial improvement in glucose-stimulated beta-cell function. Importantly, the results indicate the importance of considering both: a) the exercise dose, and b) the methodology of assessing beta-cell function, when evaluating intervention effectiveness. In this episode, Dr. Lyngbaek will elucidate the implications of these findings for the management of type 2 diabetes. We will explore the potential of exercise as a therapeutic tool, its optimal dosage, and the considerations for integrating it into individualized treatment plans. About The Guest: Dr. Mark Lyngbæk is a physician, currently in an introduction position at the Department of Rheumatology and Internal Medicine 2 at Holbæk Hospital, and also a PhD student at the Centre for Physical Activity Research at Rigshospitalet. His research has looked at exercise, beta-cell function and type 2 diabetes. He is supported by a research grant from the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation (grant number NNF17SA0031406). The Centre for Physical Activity Research is supported by TrygFonden (grants ID 101390, ID 20045, and ID 125132). Subscribe to PREMIUM

Links: Subscribe to PREMIUM Episode page Receive Sigma emails About this Episode: We've just released a lengthy 'ask me anything' episode, where Dr. Alan Flanagan addressed specific listener questions, over on the Sigma Nutition Premium feed. In this episode, you'll hear one detailed answer from that AMA, in which Alan discusses the concept of "causal risk factors". This is a term that is regularly mentioned on the podcast, and has a very specific and important meaning. This episode will give you an in-depth understanding and comfort with the term, which will enhance your future understanding and learning. If you wish to hear the other 10 questions Alan answered, you can subscribe to Sigma Nutrition Premium here.