Milk and mortality: The impact of over-activated mTORC1 signalling and unnoticed bovine microRNA uptake
Michaëlsson et al.1 reported that a high intake of milk is associated with higher mortality in two large Swedish cohorts of men and women. They proposed that milk-derived D-galactose may accelerate aging.1 Although their data strongly support life shortening effects of milk consumption the authors ignored milk´s physiological function as a signalling system facilitating postnatal growth.2 Milk´s growth promoting activities will be presented as key mechanisms accelerating age-related diseases that increase mortality. McCay and Crowell3 provided evidence that slowing growth favours longevity. The key modulator of ageing and age-related diseases is the nutrient-sensitive kinase mTORC1 (mechanistic target of rapamycin complex 1).4
Milk´s growth-promoting function is restricted to the postnatal period of lactation. Therefore milk activates the central cellular growth regulator, mTORC1.2 mTORC1 activity is stimulated by essential branched-chain amino acids, glutamine and palmitic acid, major components of milk, which represent milk´s hardware promoting mTORC1-dependent growth. Importantly, commercial cow´s milk delivers abundant virus-like exosome particles (50-100 nm), that transfer bovine microRNAs to the milk consumer.5 Milk microRNAs reach the systemic circulation of the human milk consumer, are taken up by human blood cells and subsequently modify gene expression.6 Bovine milk microRNAs and human microRNAs exhibit substantial sequence homology and apparently represent milk´s software regulating gene translation of the milk recipient. Baier et al.6 estimated that the 245 microRNAs of cow´s milk affect the expression of more than 11,000 human genes.6 A major milk microRNA type is microRNA-217 which suppresses translation of important tumour suppressor proteins such as PTEN and thereby increases mTORC1 signalling and cell cycle progression.8 MicroRNA-21 acts as an oncogene, is overexpressed by cancer cells, and stimulates adipocyte differentiation.9 10 Thus, milk consumption enhances mTORC1 and microRNA-21 signalling, which synergistically accelerate cell proliferation, anabolism as well as adipogenesis. Increased mTORC1 signalling is regarded as the driving force of obesity, diabetes, cancer, and accelerated aging.4 11
Milk consumption in children and adolescents increases body weight.12 13 Mice fed with cow´s milk in comparison to milk-free controls exhibited increased liver and adipose tissue mTORC1-S6K1 activity and developed obesity.14 Milk intake of children has been associated with early onset of menarche,15 a risk factor for the development of type 2 diabetes.16 mTORC1 activates the kinase S6K1, which down-regulates insulin receptor substrate-1, inducing insulin resistance.17 In fact, insulin resistance has been observed in children consuming daily 53 g milk protein in comparison to 53 g meat protein.18
Remarkably, populations with a high (>30%) prevalence of lactose malabsorption (LM) whose milk intake is low have a lower risk of ischaemic heart disease than populations with a LM prevalence under 30% and high milk consumption.19 Epidemiological data support the association between milk consumption and death of coronary heart disease.20 In another large Swedish cohort study, people with lactose intolerance, characterised by low milk and dairy consumption had decreased risks of lung, breast, and ovarian cancers.21
Increased milk intake has been associated with prostate cancer-specific mortality among U.S. male physicians.22 Activated mTORC1 signalling plays a pivotal role in the initiation and progression of prostate cancer.23 24 Notably, milk added to prostate cancer cells in culture increased cancer cell proliferation by 30%.25 Rats with anthracene-induced mammary tumours fed commercial milk doubled tumour mass and numbers in comparison to milk-free controls.26
The age-related neurodegenerative diseases Alzheimer and Parkinson exhibit increased mTORC1-mediated phosphorylation of tau proteins resulting in tau protein dyshomeostasis.27 28 A significant association between milk consumption and Parkinson´s disease has been observed in the Greece EPIC cohort.29 An extensive Chinese meta-analysis confirmed a dose-response relationship with a 17% increased risk of Parkinson´s disease for every 200 g/day increment in milk intake.30 Thus, persistently over-activated mTORC1, milk´s crucial biological function, accelerates aging and the onset of age-related diseases of civilization.31 32 Notably, only the “civilized” countries provide the technical requirements allowing fresh milk consumption.
In contrast, pharmacological inhibition of mTORC1 in animal models prolonged life span and improved cognitive functions in mice models of Alzheimer´s disease.33 34 The anti-diabetic drug metformin, which controls diabetes and decreases the risk of cancer35 has recently been found to prolong life span.36 Importantly, metformin operates as a multifunctional inhibitor of mTORC137 that counteracts milk-mediated activation of mTORC1.
Milk signalling physiologically operates only during the lactation period of mammals with the exception of Neolithic humans. From the perspective of evolutionary biology, milk consumption represents a novel human behaviour that could exert adverse long-term health effects.12 Half a century ago, the antagonistic pleiotropy theory solved the mystery of aging by postulating genes beneficial early in life at the cost of aging.38 Early in life, the mTORC1 pathway drives a developmental program, which persists later in life as an aimless quasi-program of aging and age-related diseases.38 Since the 1950´s, daily milk consumption containing bioactive microRNAs has been introduced into the Western food chain by the implementation of pasteurization and refrigeration technology. From that time on, diseases of civilization increased dramatically. Thus, neither galactose nor lactose intake but daily, lifelong overstimulation of mTORC1 and the intake of bioactive bovine milk microRNAs provide a more reasonable explanation for accelerated aging and increased mortality. Compared to human milk, cow´s milk apparently induces a much higher magnitude of mTORC1 activation as calves duplicate birth weight four times faster than human infants.
Importantly, Michaëlsson et al.1 only observed a higher mortality rate in association with milk but not with the consumption of fermented milk products. Masai, Samburu and Bantu predominantly consume fermented milk19 that may contain reduced amounts of bioactive milk microRNAs. Thus, future studies have to differentiate health outcomes between cooled fresh milk and milk products that still carry bioactive microRNAs versus processed milk/dairy products that do not transfer the gene regulatory software of the bovine mammary gland to the human milk recipient.
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Competing interests: I have read and understood the BMJ policy on declaration of interests and declare the following interests: none.
Competing interests: No competing interests