Risk of Fat Mass- and Obesity-Associated Gene-Dependent Obesogenic Programming by Formula Feeding Compared to Breastfeeding.

It is the purpose of this review to compare differences in postnatal epigenetic programming at the level of DNA and RNA methylation and later obesity risk between infants receiving artificial formula feeding (FF) in contrast to natural breastfeeding (BF). FF bears the risk of aberrant epigenetic programming at the level of DNA methylation and enhances the expression of the RNA demethylase fat mass- and obesity-associated gene (FTO), pointing to further deviations in the RNA methylome. Based on a literature search through Web of Science, Google Scholar, and PubMed databases concerning the dietary and epigenetic factors influencing FTO gene and FTO protein expression and FTO activity, FTO's impact on postnatal adipogenic programming was investigated. Accumulated translational evidence underscores that total protein intake as well as tryptophan, kynurenine, branched-chain amino acids, milk exosomal miRNAs, NADP, and NADPH are crucial regulators modifying FTO gene expression and FTO activity. Increased FTO-mTORC1-S6K1 signaling may epigenetically suppress the WNT/ß-catenin pathway, enhancing adipocyte precursor cell proliferation and adipogenesis. Formula-induced FTO-dependent alterations of the N6-methyladenosine (m6A) RNA methylome may represent novel unfavorable molecular events in the postnatal development of adipogenesis and obesity, necessitating further investigations. BF provides physiological epigenetic DNA and RNA regulation, a compelling reason to rely on BF.

Acne Transcriptomics: Fundamentals of Acne Pathogenesis and Isotretinoin Treatment.

This review on acne transcriptomics allows for deeper insights into the pathogenesis of acne and isotretinoin's mode of action. Puberty-induced insulin-like growth factor 1 (IGF-1), insulin and androgen signaling activate the kinase AKT and mechanistic target of rapamycin complex 1 (mTORC1). A Western diet (hyperglycemic carbohydrates and milk/dairy products) also co-stimulates AKT/mTORC1 signaling. The AKT-mediated phosphorylation of nuclear FoxO1 and FoxO3 results in their extrusion into the cytoplasm, a critical switch which enhances the transactivation of lipogenic and proinflammatory transcription factors, including androgen receptor (AR), sterol regulatory element-binding transcription factor 1 (SREBF1), peroxisome proliferator-activated receptor γ (PPARγ) and signal transducer and activator of transcription 3 (STAT3), but reduces the FoxO1-dependent expression of GATA binding protein 6 (GATA6), the key transcription factor for infundibular keratinocyte homeostasis. The AKT-mediated phosphorylation of the p53-binding protein MDM2 promotes the degradation of p53. In contrast, isotretinoin enhances the expression of p53, FoxO1 and FoxO3 in the sebaceous glands of acne patients. The overexpression of these proapoptotic transcription factors explains isotretinoin's desirable sebum-suppressive effect via the induction of sebocyte apoptosis and the depletion of BLIMP1(+) sebocyte progenitor cells; it also explains its adverse effects, including teratogenicity (neural crest cell apoptosis), a reduced ovarian reserve (granulosa cell apoptosis), the risk of depression (the apoptosis of hypothalamic neurons), VLDL hyperlipidemia, intracranial hypertension and dry skin.

Potential Pathogenic Impact of Cow's Milk Consumption and Bovine Milk-Derived Exosomal MicroRNAs in Diffuse Large B-Cell Lymphoma.

Epidemiological evidence supports an association between cow's milk consumption and the risk of diffuse large B-cell lymphoma (DLBCL), the most common non-Hodgkin lymphoma worldwide. This narrative review intends to elucidate the potential impact of milk-related agents, predominantly milk-derived exosomes (MDEs) and their microRNAs (miRs) in lymphomagenesis. Upregulation of PI3K-AKT-mTORC1 signaling is a common feature of DLBCL. Increased expression of B cell lymphoma 6 (BCL6) and suppression of B lymphocyte-induced maturation protein 1 (BLIMP1)/PR domain-containing protein 1 (PRDM1) are crucial pathological deviations in DLBCL. Translational evidence indicates that during the breastfeeding period, human MDE miRs support B cell proliferation via epigenetic upregulation of BCL6 (via miR-148a-3p-mediated suppression of DNA methyltransferase 1 (DNMT1) and miR-155-5p/miR-29b-5p-mediated suppression of activation-induced cytidine deaminase (AICDA) and suppression of BLIMP1 (via MDE let-7-5p/miR-125b-5p-targeting of PRDM1). After weaning with the physiological termination of MDE miR signaling, the infant's BCL6 expression and B cell proliferation declines, whereas BLIMP1-mediated B cell maturation for adequate own antibody production rises. Because human and bovine MDE miRs share identical nucleotide sequences, the consumption of pasteurized cow's milk in adults with the continued transfer of bioactive bovine MDE miRs may de-differentiate B cells back to the neonatal "proliferation-dominated" B cell phenotype maintaining an increased BLC6/BLIMP1 ratio. Persistent milk-induced epigenetic dysregulation of BCL6 and BLIMP1 expression may thus represent a novel driving mechanism in B cell lymphomagenesis. Bovine MDEs and their miR cargo have to be considered potential pathogens that should be removed from the human food chain.

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.

Milk Exosomal microRNAs: Postnatal Promoters of ß Cell Proliferation but Potential Inducers of ß Cell De-Differentiation in Adult Life.

Pancreatic ß cell expansion and functional maturation during the birth-to-weaning period is driven by epigenetic programs primarily triggered by growth factors, hormones, and nutrients provided by human milk. As shown recently, exosomes derived from various origins interact with ß cells. This review elucidates the potential role of milk-derived exosomes (MEX) and their microRNAs (miRs) on pancreatic ß cell programming during the postnatal period of lactation as well as during continuous cow milk exposure of adult humans to bovine MEX. Mechanistic evidence suggests that MEX miRs stimulate mTORC1/c-MYC-dependent postnatal ß cell proliferation and glycolysis, but attenuate ß cell differentiation, mitochondrial function, and insulin synthesis and secretion. MEX miR content is negatively affected by maternal obesity, gestational diabetes, psychological stress, caesarean delivery, and is completely absent in infant formula. Weaning-related disappearance of MEX miRs may be the critical event switching ß cells from proliferation to TGF-ß/AMPK-mediated cell differentiation, whereas continued exposure of adult humans to bovine MEX miRs via intake of pasteurized cow milk may reverse ß cell differentiation, promoting ß cell de-differentiation. Whereas MEX miR signaling supports postnatal ß cell proliferation (diabetes prevention), persistent bovine MEX exposure after the lactation period may de-differentiate ß cells back to the postnatal phenotype (diabetes induction).

Exosome-Derived MicroRNAs of Human Milk and Their Effects on Infant Health and Development.

Multiple biologically active components of human milk support infant growth, health and development. Milk provides a wide spectrum of mammary epithelial cell-derived extracellular vesicles (MEVs) for the infant. Although the whole spectrum of MEVs appears to be of functional importance for the growing infant, the majority of recent studies report on the MEV subfraction of milk exosomes (MEX) and their miRNA cargo, which are in the focus of this review. MEX and the dominant miRNA-148a play a key role in intestinal maturation, barrier function and suppression of nuclear factor-κB (NF-κB) signaling and may thus be helpful for the prevention and treatment of necrotizing enterocolitis. MEX and their miRNAs reach the systemic circulation and may impact epigenetic programming of various organs including the liver, thymus, brain, pancreatic islets, beige, brown and white adipose tissue as well as bones. Translational evidence indicates that MEX and their miRNAs control the expression of global cellular regulators such as DNA methyltransferase 1-which is important for the up-regulation of developmental genes including insulin, insulin-like growth factor-1, α-synuclein and forkhead box P3-and receptor-interacting protein 140, which is important for the regulation of multiple nuclear receptors. MEX-derived miRNA-148a and miRNA-30b may stimulate the expression of uncoupling protein 1, the key inducer of thermogenesis converting white into beige/brown adipose tissue. MEX have to be considered as signalosomes derived from the maternal lactation genome emitted to promote growth, maturation, immunological and metabolic programming of the offspring. Deeper insights into milk's molecular biology allow the conclusion that infants are both "breast-fed" and "breast-programmed". In this regard, MEX miRNA-deficient artificial formula is not an adequate substitute for breastfeeding, the birthright of all mammals.

The impact of isotretinoin on the pituitary-ovarian axis: An interpretative review of the literature.

Isotretinoin (13-cis-retinoic acid), a derivative of vitamin A, is used in the treatment of severe acne resulting in sebum suppression induced by sebocyte apoptosis. Isotretinoin treatment is associated with several adverse effects including teratogenicity, hepatotoxicity, and dyslipidemia. Isotretinoin's effects on endocrine systems and its potential role as an endocrine disruptor are not yet adequately investigated. This review presents clinical, endocrine, and molecular evidence showing that isotretinoin treatment adversely affects the pituitary-ovarian axis and enhances the risk of granulosa cell apoptosis reducing follicular reserve. Isotretinoin is associated with pro-apoptotic signaling in sebaceous glands through upregulated expression of p53, forkhead box O transcription factors (FOXO1, FOXO3), and tumor necrosis factor-related apoptosis inducing ligand (TRAIL). Two literature searches including clinical and experimental studies respectively support the hypothesis that isotretinoin's toxicological mode of action on the pituitary-ovarian axis might be caused by over-expressed p53/FOXO1 signaling resulting in gonadotropin suppression and granulosa cell apoptosis. The reduction of follicular reserve by isotretinoin treatment should be especially considered when this drug will be administered for the treatment of acne in post-adolescent women, in whom fertility may be adversely affected. In contrast, isotretinoin treatment may exert beneficial effects in states of hyperandrogenism, especially in patients with polycystic ovary syndrome.

Dairy consumption and hepatocellular carcinoma risk.

This review provides epidemiological and translational evidence for milk and dairy intake as critical risk factors in the pathogenesis of hepatocellular carcinoma (HCC). Large epidemiological studies in the United States and Europe identified total dairy, milk and butter intake with the exception of yogurt as independent risk factors of HCC. Enhanced activity of mechanistic target of rapamycin complex 1 (mTORC1) is a hallmark of HCC promoted by hepatitis B virus (HBV) and hepatitis C virus (HCV). mTORC1 is also activated by milk protein-induced synthesis of hepatic insulin-like growth factor 1 (IGF-1) and branched-chain amino acids (BCAAs), abundant constituents of milk proteins. Over the last decades, annual milk protein-derived BCAA intake increased 3 to 5 times in Western countries. In synergy with HBV- and HCV-induced secretion of hepatocyte-derived exosomes enriched in microRNA-21 (miR-21) and miR-155, exosomes of pasteurized milk as well deliver these oncogenic miRs to the human liver. Thus, milk exosomes operate in a comparable fashion to HBV- or HCV- induced exosomes. Milk-derived miRs synergistically enhance IGF-1-AKT-mTORC1 signaling and promote mTORC1-dependent translation, a meaningful mechanism during the postnatal growth phase, but a long-term adverse effect promoting the development of HCC. Both, dietary BCAA abundance combined with oncogenic milk exosome exposure persistently overstimulate hepatic mTORC1. Chronic alcohol consumption as well as type 2 diabetes mellitus (T2DM), two HCC-related conditions, increase BCAA plasma levels. In HCC, mTORC1 is further hyperactivated due to RAB1 mutations as well as impaired hepatic BCAA catabolism, a metabolic hallmark of T2DM. The potential HCC-preventive effect of yogurt may be caused by lactobacilli-mediated degradation of BCAAs, inhibition of branched-chain α-ketoacid dehydrogenase kinase via production of intestinal medium-chain fatty acids as well as degradation of milk exosomes including their oncogenic miRs. A restriction of total animal protein intake realized by a vegetable-based diet is recommended for the prevention of HCC.

Lifetime Impact of Cow's Milk on Overactivation of mTORC1: From Fetal to Childhood Overgrowth, Acne, Diabetes, Cancers, and Neurodegeneration.

The consumption of cow's milk is a part of the basic nutritional habits of Western industrialized countries. Recent epidemiological studies associate the intake of cow's milk with an increased risk of diseases, which are associated with overactivated mechanistic target of rapamycin complex 1 (mTORC1) signaling. This review presents current epidemiological and translational evidence linking milk consumption to the regulation of mTORC1, the master-switch for eukaryotic cell growth. Epidemiological studies confirm a correlation between cow's milk consumption and birthweight, body mass index, onset of menarche, linear growth during childhood, acne vulgaris, type 2 diabetes mellitus, prostate cancer, breast cancer, hepatocellular carcinoma, diffuse large B-cell lymphoma, neurodegenerative diseases, and all-cause mortality. Thus, long-term persistent consumption of cow's milk increases the risk of mTORC1-driven diseases of civilization. Milk is a highly conserved, lactation genome-controlled signaling system that functions as a maternal-neonatal relay for optimized species-specific activation of mTORC1, the nexus for regulation of eukaryotic cell growth, and control of autophagy. A deeper understanding of milk´s impact on mTORC1 signaling is of critical importance for the prevention of common diseases of civilization.

[Health risks related to milk consumption: a critical evaluation from the medical perspective]. / Gesundheitsrisiken durch Milchkonsum : Eine kritische Bewertung aus ärztlicher Sicht.

BACKGROUND: Recent epidemiological studies associate the consumption of non-fermented cow's milk, but not fermented milk products, with an increased risk of diseases of civilization. OBJECTIVES: Presentation of epidemiological and pathophysiological data on health risks associated with milk consumption. METHOD: Selective PubMed surveys between 2005-2020 considering epidemiological studies which clearly differentiate between non-fermented versus fermented milk and its potential health risks. RESULTS: Epidemiological studies confirm a correlation between milk consumption and birthweight, linear growth during puberty, acne vulgaris, type 2 diabetes mellitus, prostate cancer, breast cancer, hepatocellular carcinoma, non-Hodgkin lymphoma, Parkinson's disease and over-all mortality. In comparison to milk consumption, the intake of fermented milk/milk products exhibits neutral to beneficial health effects, which are explained by attenuated mTORC1 signaling due to bacterial fermentation of milk. CONCLUSIONS: Long-term persistent consumption of non-fermented milk, but not fermented milk/milk products, might increase the risk of diseases of civilization. The avoidance of milk, especially pasteurized fresh milk, may enhance the prevention and reduce the recurrence of common Western diseases of civilization.

Pasteurized non-fermented cow's milk but not fermented milk is a promoter of mTORC1-driven aging and increased mortality.

Recent epidemiological studies in Sweden, a country with traditionally high milk consumption, revealed that the intake of non-fermented pasteurized milk increased all-cause mortality in a dose-dependent manner. In contrast, the majority of epidemiological and clinical studies report beneficial health effects of fermented milk products, especially of yogurt. It is the intention of this review to delineate potential molecular aging mechanisms related to the intake of non-fermented milk versus yogurt on the basis of mechanistic target of rapamycin complex 1 (mTORC1) signaling. Non-fermented pasteurized milk via its high bioavailability of insulinotropic branched-chain amino acids (BCAAs), abundance of lactose (glucosyl-galactose) and bioactive exosomal microRNAs (miRs) enhances mTORC1 signaling, which shortens lifespan and increases all-cause mortality. In contrast, fermentation-associated lactic acid bacteria metabolize BCAAs and degrade galactose and milk exosomes including their mTORC1-activating microRNAs. The Industrial Revolution, with the introduction of pasteurization and refrigeration of milk, restricted the action of beneficial milk-fermenting bacteria, which degrade milk's BCAAs, galactose and bioactive miRs that synergistically activate mTORC1. This unrecognized behavior change in humans after the Neolithic revolution increased aging-related over-activation of mTORC1 signaling in humans, who persistently consume large quantities of non-fermented pasteurized cow's milk, a potential risk factor for aging and all-cause mortality.

Synergistic Effects of Milk-Derived Exosomes and Galactose on α-Synuclein Pathology in Parkinson's Disease and Type 2 Diabetes Mellitus.

Epidemiological studies associate milk consumption with an increased risk of Parkinson's disease (PD) and type 2 diabetes mellitus (T2D). PD is an α-synucleinopathy associated with mitochondrial dysfunction, oxidative stress, deficient lysosomal clearance of α-synuclein (α-syn) and aggregation of misfolded α-syn. In T2D, α-syn promotes co-aggregation with islet amyloid polypeptide in pancreatic ß-cells. Prion-like vagal nerve-mediated propagation of exosomal α-syn from the gut to the brain and pancreatic islets apparently link both pathologies. Exosomes are critical transmitters of α-syn from cell to cell especially under conditions of compromised autophagy. This review provides translational evidence that milk exosomes (MEX) disturb α-syn homeostasis. MEX are taken up by intestinal epithelial cells and accumulate in the brain after oral administration to mice. The potential uptake of MEX miRNA-148a and miRNA-21 by enteroendocrine cells in the gut, dopaminergic neurons in substantia nigra and pancreatic ß-cells may enhance miRNA-148a/DNMT1-dependent overexpression of α-syn and impair miRNA-148a/PPARGC1A- and miRNA-21/LAMP2A-dependent autophagy driving both diseases. MiRNA-148a- and galactose-induced mitochondrial oxidative stress activate c-Abl-mediated aggregation of α-syn which is exported by exosome release. Via the vagal nerve and/or systemic exosomes, toxic α-syn may spread to dopaminergic neurons and pancreatic ß-cells linking the pathogenesis of PD and T2D.

Milk Exosomes Prevent Intestinal Inflammation in a Genetic Mouse Model of Ulcerative Colitis: A Pilot Experiment.

BACKGROUND: Milk is rich in nutrients and anabolic mediators rendering it essential for postnatal growth and metabolic programming. However, in adults, excessive consumption of milk is controversial as civilization disorders such as diabetes or prostate cancer may be promoted. A cytoprotective effect of milk could be utilized in inflammatory conditions, that is, chronic colitis. OBJECTIVE: To evaluate the effect of bovine milk exosomes on intestinal inflammation in a genetic mouse model of ulcerative colitis. METHODS: Intestinal-specific kindlin 2 knockout (KO) mice were exposed for 4 days to tamoxifen for induction of an ulcerative colitis phenotype. At the same time 4 other kindlin 2 KO mice were exposed to 33 µg/g cow milk derived exosomes in PBS by oral gavage. Both groups were compared to untreated wild-type controls. RESULTS: Milk exosomes prevented the appearance of a severe ulcerative phenotype. The macroscopic colitis score dropped from a mean of 3.33 in untreated mice to 0.75 index points (p < 0.01) in exosome-treated mice, which included significant improvement of the subscores of stool improvement and colon weight and length. Treated mice featured a noninflamed appearance of the intestinal mucosa. KEY MESSAGE: Milk exosomes have cytoprotective/anti-inflammatory activity in a genetic mouse model of ulcerative colitis. The mechanisms behind this need to be elucidated. This pilot study needs verification before a therapeutic strategy is developed.

MicroRNA-21-Enriched Exosomes as Epigenetic Regulators in Melanomagenesis and Melanoma Progression: The Impact of Western Lifestyle Factors.

DNA mutation-induced activation of RAS-BRAF-MEK-ERK signaling associated with intermittent or chronic ultraviolet (UV) irradiation cannot exclusively explain the excessive increase of malignant melanoma (MM) incidence since the 1950s. Malignant conversion of a melanocyte to an MM cell and metastatic MM is associated with a steady increase in microRNA-21 (miR-21). At the epigenetic level, miR-21 inhibits key tumor suppressors of the RAS-BRAF signaling pathway enhancing proliferation and MM progression. Increased MM cell levels of miR-21 either result from endogenous upregulation of melanocytic miR-21 expression or by uptake of miR-21-enriched exogenous exosomes. Based on epidemiological data and translational evidence, this review provides deeper insights into environmentally and metabolically induced exosomal miR-21 trafficking beyond UV-irradiation in melanomagenesis and MM progression. Sources of miR-21-enriched exosomes include UV-irradiated keratinocytes, adipocyte-derived exosomes in obesity, airway epithelium-derived exosomes generated by smoking and pollution, diet-related exosomes and inflammation-induced exosomes, which may synergistically increase the exosomal miR-21 burden of the melanocyte, the transformed MM cell and its tumor environment. Several therapeutic agents that suppress MM cell growth and proliferation attenuate miR-21 expression. These include miR-21 antagonists, metformin, kinase inhibitors, beta-blockers, vitamin D, and plant-derived bioactive compounds, which may represent new options for the prevention and treatment of MM.

Milk exosomal miRNAs: potential drivers of AMPK-to-mTORC1 switching in ß-cell de-differentiation of type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) steadily increases in prevalence since the 1950's, the period of widespread distribution of refrigerated pasteurized cow's milk. Whereas breastfeeding protects against the development of T2DM in later life, accumulating epidemiological evidence underlines the role of cow's milk consumption in T2DM. Recent studies in rodent models demonstrate that during the breastfeeding period pancreatic ß-cells are metabolically immature and preferentially proliferate by activation of mechanistic target of rapamycin complex 1 (mTORC1) and suppression of AMP-activated protein kinase (AMPK). Weaning determines a metabolic switch of ß-cells from a proliferating, immature phenotype with low insulin secretion to a differentiated mature phenotype with glucose-stimulated insulin secretion, less proliferation, reduced mTORC1- but increased AMPK activity. Translational evidence presented in this perspective implies for the first time that termination of milk miRNA transfer is the driver of this metabolic switch. miRNA-148a is a key inhibitor of AMPK and phosphatase and tensin homolog, crucial suppressors of mTORC1. ß-Cells of diabetic patients return to the postnatal phenotype with high mTORC1 and low AMPK activity, explained by continuous transfer of bovine milk miRNAs to the human milk consumer. Bovine milk miRNA-148a apparently promotes ß-cell de-differentiation to the immature mTORC1-high/AMPK-low phenotype with functional impairments in insulin secretion, increased mTORC1-driven endoplasmic reticulum stress, reduced autophagy and early ß-cell apoptosis. In contrast to pasteurized cow's milk, milk's miRNAs are inactivated by bacterial fermentation, boiling and ultra-heat treatment and are missing in current infant formula. Persistent milk miRNA signaling adds a new perspective to the pathogenesis of T2DM and explains the protective role of breastfeeding but the diabetogenic effect of continued milk miRNA signaling by persistent consumption of pasteurized cow's milk.

Exosomes of pasteurized milk: potential pathogens of Western diseases.

Milk consumption is a hallmark of western diet. According to common believes, milk consumption has beneficial effects for human health. Pasteurization of cow's milk protects thermolabile vitamins and other organic compounds including bioactive and bioavailable exosomes and extracellular vesicles in the range of 40-120 nm, which are pivotal mediators of cell communication via systemic transfer of specific micro-ribonucleic acids, mRNAs and regulatory proteins such as transforming growth factor-ß. There is compelling evidence that human and bovine milk exosomes play a crucial role for adequate metabolic and immunological programming of the newborn infant at the beginning of extrauterine life. Milk exosomes assist in executing an anabolic, growth-promoting and immunological program confined to the postnatal period in all mammals. However, epidemiological and translational evidence presented in this review indicates that continuous exposure of humans to exosomes of pasteurized milk may confer a substantial risk for the development of chronic diseases of civilization including obesity, type 2 diabetes mellitus, osteoporosis, common cancers (prostate, breast, liver, B-cells) as well as Parkinson's disease. Exosomes of pasteurized milk may represent new pathogens that should not reach the human food chain.