The Role of Cow's Milk Consumption in Breast Cancer Initiation and Progression.

PURPOSE OF REVIEW: This review evaluates cow milk's impact on breast carcinogenesis by linking recent epidemiological evidence and new insights into the molecular signaling of milk and its constituents in breast cancer (BCa) pathogenesis. RECENT FINDINGS: Recent prospective cohort studies support the association between cow's milk consumption and the risk of estrogen receptor-α-positive (ER+) BCa. Milk is a complex biological fluid that increases systemic insulin-like growth factor 1 (IGF-1), insulin and estrogen signaling, and interacting hormonal promoters of BCa. Further potential oncogenic components of commercial milk include exosomal microRNAs (miR-148a-3p, miR-21-5p), bovine meat and milk factors, aflatoxin M1, bisphenol A, pesticides, and micro- and nanoplastics. Individuals with BRCA1 loss-of-function mutations and FTO and IGF1 gain-of-function polymorphisms enhancing IGF-1/mTORC1 signaling may be at increased risk for milk-induced ER+ BCa. Recent prospective epidemiological and pathobiochemical studies identify commercial milk consumption as a critical risk factor of ER+ BCa. Large meta-analyses gathering individuals of different ethnic origins with milk derived from dairy cows of varying genetic backgrounds and diverse feeding procedures as well as missing data on thermal processing of milk (pasteurization versus ultra-heat treatment) make multi-national meta-analyses unsuitable for BCa risk estimations in susceptible populations. Future studies are required that consider all vulnerable periods of breast carcinogenesis to cow's milk exposure, beginning during the perinatal period and puberty, since these are the most critical periods of mammary gland morphogenesis. Notwithstanding the need for better studies including detailed information on milk processing and vulnerable periods of human breast carcinogenesis, the available evidence suggests that dietary guidelines on milk consumption may have to be reconsidered.

Debunking the vegan myth: The case for a plant-forward omnivorous whole-foods diet.

Vegan diets are widely promoted as protective against cardiovascular disease (CVD); however, removing all animal foods from a human's diet usually causes unfavorable health consequences. Our hominin ancestors began consuming meat, fish, seafood, and eggs >2 million years ago. Consequently, humans are genetically adapted to procure nutrients from both plant and animal sources. In contrast, veganism is without evolutionary precedent in Homo sapiens species. Strict adherence to a vegan diet causes predictable deficiencies in nutrients including vitamins B12, B2, D, niacin, iron, iodine, zinc, high-quality proteins, omega-3, and calcium. Prolonged strict veganism increases risk for bone fractures, sarcopenia, anemia, and depression. A more logical diet is a plant-forward omnivorous eating pattern that emphasizes generous consumption of natural, unprocessed foods predominantly from plants. To balance this diet, modest amounts of wholesome animal foods, such wild-caught fish/seafood, pasture-raised meat and eggs, and fermented unsweetened dairy should be consumed regularly.

Estimated macronutrient and fatty acid intakes from an East African Paleolithic diet.

Our genome adapts slowly to changing conditions of existence. Many diseases of civilisation result from mismatches between our Paleolithic genome and the rapidly changing environment, including our diet. The objective of the present study was to reconstruct multiple Paleolithic diets to estimate the ranges of nutrient intakes upon which humanity evolved. A database of, predominantly East African, plant and animal foods (meat/fish) was used to model multiple Paleolithic diets, using two pathophysiological constraints (i.e. protein < 35 energy % (en%) and linoleic acid (LA) >1.0 en%), at known hunter-gatherer plant/animal food intake ratios (range 70/30-30/70 en%/en%). We investigated selective and non-selective savannah, savannah/aquatic and aquatic hunter-gatherer/scavenger foraging strategies. We found (range of medians in en%) intakes of moderate-to-high protein (25-29), moderate-to-high fat (30-39) and moderate carbohydrates (39-40). The fatty acid composition was SFA (11.4-12.0), MUFA (5.6-18.5) and PUFA (8.6-15.2). The latter was high in α-linolenic acid (ALA) (3.7-4.7 en%), low in LA (2.3-3.6 en%), and high in long-chain PUFA (LCP; 4.75-25.8 g/d), LCP n-3 (2.26-17.0 g/d), LCP n-6 (2.54-8.84 g/d), ALA/LA ratio (1.12-1.64 g/g) and LCP n-3/LCP n-6 ratio (0.84-1.92 g/g). Consistent with the wide range of employed variables, nutrient intakes showed wide ranges. We conclude that compared with Western diets, Paleolithic diets contained consistently higher protein and LCP, and lower LA. These are likely to contribute to the known beneficial effects of Paleolithic-like diets, e.g. through increased satiety/satiation. Disparities between Paleolithic, contemporary and recommended intakes might be important factors underlying the aetiology of common Western diseases. Data on Paleolithic diets and lifestyle, rather than the investigation of single nutrients, might be useful for the rational design of clinical trials.

Organic fitness: physical activity consistent with our hunter-gatherer heritage.

Many of the pervasive health concerns in modern society are the result of diet and lifestyle choices that are at odds with the evolutionary milieu for which we remain genetically adapted. This systematic displacement from a very physically active lifestyle in a natural outdoor environment to a sedentary indoor lifestyle may be at the root of many chronic diseases that are endemic in our culture. A proposed solution is to simulate indigenous human activity patterns in a way that is possible and practical for individuals to achieve. Suggestions for exercise mode, duration, intensity, and frequency are outlined, with a focus on realigning our daily physical activities with the archetype that is encoded within our genome. In a sedentary individual, this type of daily physical activity should help confer the robust vigorous health that enabled our ancestors to survive and thrive as hunter-gatherers in the wild.

Evolution, body composition, insulin receptor competition, and insulin resistance.

OBJECTIVE: Better understanding of the relationships between body composition and insulin resistance. RESULTS: Average human adiposity and sarcopenia have attained unprecedented levels and the resultantly abnormal body composition distorts insulin receptor balance. Compared to evolutionary norms we now have too many adipocyte insulin receptors (in adipose tissue and liver) and too few myocyte insulin receptors. The body's insulin receptors can be conceptualized as competing for insulin molecules released from the pancreas. When an insulin molecule docks on an adipocyte receptor, substantially fewer glucose molecules are cleared from the blood than when an insulin molecule docks on a myocyte insulin receptor. Populational insulin receptor imbalance would seem to parallel the secular rise in insulin resistance and offers an attractive pathophysiological explanation for the accompanying type 2 diabetes epidemic. CONCLUSION: An evolutionary perspective regarding body composition, insulin receptor imbalance, and the consequent impact on carbohydrate metabolism should enhance public acceptance of recommendations to increase physical activity.

Postulating the major environmental condition resulting in the expression of essential hypertension and its associated cardiovascular diseases: Dietary imprudence in daily selection of foods in respect of their potassium and sodium content resulting in oxidative stress-induced dysfunction of the vascular endothelium, vascular smooth muscle, and perivascular tissues.

We hypothesize that the major environmental determinant of the expression of essential hypertension in America and other Westernized countries is dietary imprudence in respect of the consumption of daily combinations of foods containing suboptimal amounts of potassium and blood pressure-lowering phytochemicals, and supraphysiological amounts of sodium. We offer as premise that Americans on average consume suboptimal amounts of potassium and blood pressure-lowering phytochemicals, and physiologically excessive amounts of sodium, and that such dietary imprudence leads to essential hypertension through oxidative stress-induced vascular endothelial and smooth muscle dysfunction. Such dysfunctions restrict nitric oxide bioavailability, impairing endothelial cell-mediated relaxation of the underlying vascular smooth muscle, initiating and maintaining inappropriately increased peripheral and renal vascular resistance. The biochemical steps from oxidative stress to vascular endothelial dysfunction and its pernicious cardiovascular consequences are well established and generally accepted. The unique aspect of our hypothesis resides in the contention that Americans' habitual consumption of foods resulting in suboptimal dietary intake of potassium and supraphysiological intake of sodium result in oxidative stress, the degree of which, we suggest, will correlate with the degree of deviation of potassium and sodium intake from optimal. Because suboptimal intakes of potassium reflect suboptimal intakes of fruits and vegetables, associated contributors to oxidative stress include suboptimal intakes of magnesium, nitrate, polyphenols, carotenoids, and other phytochemical antioxidants for which fruits and vegetables contain abundant amounts. Currently Americans consume potassium-to-sodium in molar ratios of less than or close to 1.0 and the Institute of Medicine (IOM) recommends a molar ratio of 1.2. Ancestral diets to which we are physiologically adapted range from molar ratios of 5.0 to 10.0 or higher. Accordingly, we suggest that the average American is usually afflicted with oxidative stress-induced vascular endothelial dysfunction, and therefore the standards for normal blood pressure and pre-hypertension often reflect a degree of clinically significant hypertension. In this article, we provide support for those contentions, and indicate the findings that the hypothesis predicts.

Coronary artery disease prognosis and C-reactive protein levels improve in proportion to percent lowering of low-density lipoprotein.

This editorial outlines the data supporting aggressive lipid goals and options for treating low-density lipoprotein (LDL) cholesterol to a range of approximately 30 to 70 mg/dl. The physiologically normal cholesterol range is approximately 30 to 70 mg/dl for native hunter-gatherers, healthy human neonates, free-living primates, and virtually all wild mammals. Randomized statin trials in patients with recent acute coronary syndromes and stable coronary artery disease have demonstrated that cardiovascular events are reduced and cardiovascular survival optimized when LDL cholesterol is reduced to <70 mg/dl. Secondary prevention trials have shown a decrease in all-cause mortality in proportion to the magnitude of LDL cholesterol reduction. An original analysis of available data shows that the ability of a lipid-lowering therapy to reduce the C-reactive protein level is closely correlated with its efficacy in LDL cholesterol reduction. Randomized trial data have shown no relation between either percentage LDL cholesterol decrease or final LDL cholesterol level achieved and the risk for myopathy or hepatic transaminase elevations associated with statins. Therefore, intensive LDL cholesterol reduction to levels of 30 to 70 mg/dl should be pursued in subjects with or at high risk for coronary artery disease.

Nutritional strategies for skeletal and cardiovascular health: hard bones, soft arteries, rather than vice versa.

The focus of this paper is to explore better strategies for optimising bone strength and reducing risk of fracture, while at the same time decreasing risk of cardiovascular disease. The majority of Americans do not consume the current recommended dietary allowance for calcium, and the lifetime risk of osteoporosis is about 50%. However, traditional mononutrient calcium supplements may not be ideal. We comprehensively and systematically reviewed the scientific literature in order to determine the optimal dietary strategies and nutritional supplements for long-term skeletal health and cardiovascular health. To summarise, the following steps may be helpful for building strong bones while maintaining soft and supple arteries: (1) calcium is best obtained from dietary sources rather than supplements; (2) ensure that adequate animal protein intake is coupled with calcium intake of 1000 mg/day; (3) maintain vitamin D levels in the normal range; (4) increase intake of fruits and vegetables to alkalinise the system and promote bone health; (5) concomitantly increase potassium consumption while reducing sodium intake; (6) consider increasing the intake of foods rich in vitamins K1 and K2; (7) consider including bones in the diet; they are a rich source of calcium-hydroxyapatite and many other nutrients needed for building bone.

Milk miRNAs: simple nutrients or systemic functional regulators?

Milk is rich in miRNAs that appear to play important roles in the postnatal development of all mammals. Currently, two competing hypotheses exist: the functional hypothesis, which proposes that milk miRNAs are transferred to the offspring and exert physiological regulatory functions, and the nutritional hypothesis, which suggests that these molecules do not reach the systemic circulation of the milk recipient, but merely provide nutrition without conferring active regulatory signals to the offspring. The functional hypothesis is based on indirect evidence and requires further investigation. The nutritional hypothesis is primarily based on three mouse models, which are inherently problematic: 1) miRNA-375 KO mice, 2) miRNA-200c/141 KO mice, and 3) transgenic mice presenting high levels of miRNA-30b in milk. This article presents circumstantial evidence that these mouse models may all be inappropriate to study the physiological traffic of milk miRNAs to the newborn mammal, and calls for new studies using more relevant mouse models or human milk to address the fate and role of milk miRNAs in the offspring and the adult consumer of cow's milk.

Origins and evolution of the Western diet: health implications for the 21st century.

There is growing awareness that the profound changes in the environment (eg, in diet and other lifestyle conditions) that began with the introduction of agriculture and animal husbandry approximately 10000 y ago occurred too recently on an evolutionary time scale for the human genome to adjust. In conjunction with this discordance between our ancient, genetically determined biology and the nutritional, cultural, and activity patterns of contemporary Western populations, many of the so-called diseases of civilization have emerged. In particular, food staples and food-processing procedures introduced during the Neolithic and Industrial Periods have fundamentally altered 7 crucial nutritional characteristics of ancestral hominin diets: 1) glycemic load, 2) fatty acid composition, 3) macronutrient composition, 4) micronutrient density, 5) acid-base balance, 6) sodium-potassium ratio, and 7) fiber content. The evolutionary collision of our ancient genome with the nutritional qualities of recently introduced foods may underlie many of the chronic diseases of Western civilization.

Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal.

The normal low-density lipoprotein (LDL) cholesterol range is 50 to 70 mg/dl for native hunter-gatherers, healthy human neonates, free-living primates, and other wild mammals (all of whom do not develop atherosclerosis). Randomized trial data suggest atherosclerosis progression and coronary heart disease events are minimized when LDL is lowered to <70 mg/dl. No major safety concerns have surfaced in studies that lowered LDL to this range of 50 to 70 mg/dl. The current guidelines setting the target LDL at 100 to 115 mg/dl may lead to substantial undertreatment in high-risk individuals.

Implications for the role of diet in acne.

Within the dermatology community, a general consensus has emerged that diet is unrelated to the etiology of acne. Except for 2 poorly designed studies, now more than 30 years old, there are few objective data to support this notion. In contrast, a large body of evidence now exists showing how diet may directly or indirectly influence the following 5 proximate causes of acne: (1) increased proliferation of basal keratinocytes within the pilosebaceous duct, (2) incomplete separation of ductal corneocytes from one another via impairment of apoptosis and subsequent obstruction of the pilosebaceous duct, (3) androgen-mediated increases in sebum production, (4) colonization of the comedo by Propionibacterium acnes, and (5) inflammation both within and adjacent to the comedo. This article will provide a review of the currently available literature on the association between diet and acne vulgaris as well as a discussion of the physiologic principles that may underlie this association.

Cardiovascular disease resulting from a diet and lifestyle at odds with our Paleolithic genome: how to become a 21st-century hunter-gatherer.

Our genetic make-up, shaped through millions of years of evolution, determines our nutritional and activity needs. Although the human genome has remained primarily unchanged since the agricultural revolution 10,000 years ago, our diet and lifestyle have become progressively more divergent from those of our ancient ancestors. Accumulating evidence suggests that this mismatch between our modern diet and lifestyle and our Paleolithic genome is playing a substantial role in the ongoing epidemics of obesity, hypertension, diabetes, and atherosclerotic cardiovascular disease. Until 500 generations ago, all humans consumed only wild and unprocessed food foraged and hunted from their environment. These circumstances provided a diet high in lean protein, polyunsaturated fats (especially omega-3 [omega-3] fatty acids), monounsaturated fats, fiber, vitamins, minerals, antioxidants, and other beneficial phytochemicals. Historical and anthropological studies show hunter-gatherers generally to be healthy, fit, and largely free of the degenerative cardiovascular diseases common in modern societies. This review outlines the essence of our hunter-gatherer genetic legacy and suggests practical steps to re-align our modern milieu with our ancient genome in an effort to improve cardiovascular health.

Acne vulgaris: a disease of Western civilization.

BACKGROUND: In westernized societies, acne vulgaris is a nearly universal skin disease afflicting 79% to 95% of the adolescent population. In men and women older than 25 years, 40% to 54% have some degree of facial acne, and clinical facial acne persists into middle age in 12% of women and 3% of men. Epidemiological evidence suggests that acne incidence rates are considerably lower in nonwesternized societies. Herein we report the prevalence of acne in 2 nonwesternized populations: the Kitavan Islanders of Papua New Guinea and the Aché hunter-gatherers of Paraguay. Additionally, we analyze how elements in nonwesternized environments may influence the development of acne. OBSERVATIONS: Of 1200 Kitavan subjects examined (including 300 aged 15-25 years), no case of acne (grade 1 with multiple comedones or grades 2-4) was observed. Of 115 Aché subjects examined (including 15 aged 15-25 years) over 843 days, no case of active acne (grades 1-4) was observed. CONCLUSIONS: The astonishing difference in acne incidence rates between nonwesternized and fully modernized societies cannot be solely attributed to genetic differences among populations but likely results from differing environmental factors. Identification of these factors may be useful in the treatment of acne in Western populations.

Metabolic effects of milk protein intake strongly depend on pre-existing metabolic and exercise status.

Milk protein intake has recently been suggested to improve metabolic health. This Perspective provides evidence that metabolic effects of milk protein intake have to be regarded in the context of the individual's pre-existing metabolic and exercise status. Milk proteins provide abundant branched-chain amino acids (BCAAs) and glutamine. Plasma BCAAs and glutamine are increased in obesity and insulin resistance, but decrease after gastric bypass surgery resulting in weight loss and improved insulin sensitivity. Milk protein consumption results in postprandial hyperinsulinemia in obese subjects, increases body weight of overweight adolescents and may thus deteriorate pre-existing metabolic disturbances of obese, insulin resistant individuals.

The impact of cow's milk-mediated mTORC1-signaling in the initiation and progression of prostate cancer.

Prostate cancer (PCa) is dependent on androgen receptor signaling and aberrations of the PI3K-Akt-mTORC1 pathway mediating excessive and sustained growth signaling. The nutrient-sensitive kinase mTORC1 is upregulated in nearly 100% of advanced human PCas. Oncogenic mTORC1 signaling activates key subsets of mRNAs that cooperate in distinct steps of PCa initiation and progression. Epidemiological evidence points to increased dairy protein consumption as a major dietary risk factor for the development of PCa. mTORC1 is a master regulator of protein synthesis, lipid synthesis and autophagy pathways that couple nutrient sensing to cell growth and cancer. This review provides evidence that PCa initiation and progression are promoted by cow´s milk, but not human milk, stimulation of mTORC1 signaling. Mammalian milk is presented as an endocrine signaling system, which activates mTORC1, promotes cell growth and proliferation and suppresses autophagy. Naturally, milk-mediated mTORC1 signaling is restricted only to the postnatal growth phase of mammals. However, persistent consumption of cow´s milk proteins in humans provide highly insulinotropic branched-chain amino acids (BCAAs) provided by milk´s fast hydrolysable whey proteins, which elevate postprandial plasma insulin levels, and increase hepatic IGF-1 plasma concentrations by casein-derived amino acids. BCAAs, insulin and IGF-1 are pivotal activating signals of mTORC1. Increased cow´s milk protein-mediated mTORC1 signaling along with constant exposure to commercial cow´s milk estrogens derived from pregnant cows may explain the observed association between high dairy consumption and increased risk of PCa in Westernized societies. As well-balanced mTORC1-signaling plays an important role in appropriate prostate morphogenesis and differentiation, exaggerated mTORC1-signaling by high cow´s milk consumption predominantly during critical growth phases of prostate development and differentiation may exert long-term adverse effects on prostate health. Attenuation of mTORC1 signaling by contemporary Paleolithic diets and restriction of dairy protein intake, especially during mTORC1-dependent phases of prostate development and differentiation, may offer protection from the most common dairy-promoted cancer in men of Western societies.

Exercise like a hunter-gatherer: a prescription for organic physical fitness.

A large proportion of the health woes beleaguering modern cultures are because of daily physical activity patterns that are profoundly different from those for which we are genetically adapted. The ancestral natural environment in which our current genome was forged via natural selection called for a large amount of daily energy expenditure on a variety of physical movements. Our genes that were selected for in this arduous and demanding natural milieu enabled our ancestors to survive and thrive, leading to a very vigorous lifestyle. This abrupt (by evolutionary time frames) change from a very physically demanding lifestyle in natural outdoor settings to an inactive indoor lifestyle is at the origin of many of the widespread chronic diseases that are endemic in our modern society. The logical answer is to replicate the native human activity pattern to the extent that this is achievable and practical. Recommendations for exercise mode, duration, intensity, and frequency are outlined with a focus on simulating the routine physical activities of our ancient hunter-gatherer ancestors whose genome we still largely share today. In a typical inactive person, this type of daily physical activity will optimize gene expression and help to confer the robust health that was enjoyed by hunter-gatherers in the wild.