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

Melnik, Bodo C.

doi:10.3390/biom11030404

Cited by 25 publications

(24 citation statements)

References 548 publications

(732 reference statements)

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“…Some reviews have raised concerns about the possible deleterious effects of milk exosome intake. Accordingly, milk exosomes would contribute to the development of diabetes, atherosclerosis, osteoporosis, Parkinson’s disease, diverse types of cancer, and even all-cause mortality mediated by different mechanisms such as over-activation of the mechanistic target of rapamycin complex 1 (mTORC1), among others [ 210 , 211 , 212 , 213 , 214 ]. These effects would not be attributed to fermented milk because fermented milk displays reduced exosome miRNA, branched-chain amino acids, and protein content due to bacterial activity [ 212 ].…”

Section: Limitationsmentioning

confidence: 99%

Beneficial Effects of Bovine Milk Exosomes in Metabolic Interorgan Cross-Talk

et al. 2022

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Extracellular vesicles are membrane-enclosed secreted vesicles involved in cell-to-cell communication processes, identified in virtually all body fluids. Among extracellular vesicles, exosomes have gained increasing attention in recent years as they have unique biological origins and deliver different cargos, such as nucleic acids, proteins, and lipids, which might mediate various health processes. In particular, milk-derived exosomes are proposed as bioactive compounds of breast milk, which have been reported to resist gastric digestion and reach systemic circulation, thus being bioavailable after oral intake. In the present manuscript, we critically discuss the available evidence on the health benefits attributed to milk exosomes, and we provide an outlook for the potential future uses of these compounds. The use of milk exosomes as bioactive ingredients represents a novel avenue to explore in the context of human nutrition, and they might exert important beneficial effects at multiple levels, including but not limited to intestinal health, bone and muscle metabolism, immunity, modulation of the microbiota, growth, and development.

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Section: Limitationsmentioning

confidence: 99%

Beneficial Effects of Bovine Milk Exosomes in Metabolic Interorgan Cross-Talk

et al. 2022

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“…In the time scale of human evolution, the consumption of cow milk is a novel behavioral change of humans [ 477 ], modifying human physiology, such as accelerated linear growth [ 478 ]. Cow milk signaling affects a large spectrum of tissues in the human body likely including the pancreatic islets [ 479 ]. Western societies are exposed to substantial daily amounts of pasteurized cow milk [ 480 , 481 , 482 , 483 ].…”

Section: Bovine Mex Mir Signaling During Adult Human Lifementioning

confidence: 99%

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

Melnik

Schmitz

2022

IJMS

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Pancreatic β 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 β cells. This review elucidates the potential role of milk-derived exosomes (MEX) and their microRNAs (miRs) on pancreatic β 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 β cell proliferation and glycolysis, but attenuate β 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 β cells from proliferation to TGF-β/AMPK-mediated cell differentiation, whereas continued exposure of adult humans to bovine MEX miRs via intake of pasteurized cow milk may reverse β cell differentiation, promoting β cell de-differentiation. Whereas MEX miR signaling supports postnatal β cell proliferation (diabetes prevention), persistent bovine MEX exposure after the lactation period may de-differentiate β cells back to the postnatal phenotype (diabetes induction).

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“…Despite recent progress in milk's molecular biology and its sophisticated physiological functions [20,152,153] , nutrition science and dairy industry-supported reviews present a positive view on milk as a nutrient for metabolic health, providing valuable proteins, macronutrients, oligosaccharides, calcium, vitamins, and other micronutrients [155][156][157][158][159] . None of those studies in the field of nutrition and epidemiological research appreciates milk's biological role as an mTORC1-driving system of mammalian evolution physiologically restricted to the postnatal growth period [20,152,153,160] .…”

Section: Calcium-independent Milk-induced Mtorc1 Activationmentioning

confidence: 99%

The endocrine and epigenetic impact of persistent cow milk consumption on prostate carcinogenesis

Melnik¹,

John²,

Weiskirchen³

et al. 2022

jtgg

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This review analyzes the potential impact of milk-induced signal transduction on the pathogenesis of prostate cancer (PCa). Articles in PubMed until November 2021 reporting on milk intake and PCa were reviewed. Epidemiological studies identified commercial cow milk consumption as a potential risk factor of PCa. The potential impact of cow milk consumption on the pathogenesis of PCa may already begin during fetal and pubertal prostate growth, critical windows with increased vulnerability. Milk is a promotor of growth and anabolism via activating insulin-like growth factor-1 (IGF-1)/phosphatidylinositol-3 kinase (PI3K)/AKT/mechanistic target of rapamycin complex 1 (mTORC1) signaling. Estrogens, major steroid hormone components of commercial milk of persistently pregnant dairy cows, activate IGF-1 and mTORC1. Milk-derived signaling synergizes with common driver mutations of the PI3K/AKT/mTORC1 signaling pathway that intersect with androgen receptor, MFG-E8, MAPK, RUNX2, MDM4, TP53, and WNT signaling, respectively. Potential exogenously induced drivers of PCa are milk-induced elevations of growth hormone, IGF-1, MFG-E8, estrogens, phytanic acid, and aflatoxins, as well as milk exosome-derived oncogenic microRNAs including miR-148a, miR-21, and miR-29b. Commercial cow milk intake, especially the consumption of pasteurized milk, which represents the closest replica of native milk, activates PI3K-AKT-mTORC1 signaling via cow milk’s endocrine and epigenetic modes of action. Vulnerable periods for adverse nutrigenomic impacts on prostate health appear to be the fetal and pubertal growth periods, potentially priming the initiation of PCa. Cow milk-mediated overactivation of PI3K-AKT-mTORC1 signaling synergizes with the most common genetic deviations in PCa, promoting PCa initiation, progression, and early recurrence.

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

Cited by 25 publications

References 548 publications

Beneficial Effects of Bovine Milk Exosomes in Metabolic Interorgan Cross-Talk

Beneficial Effects of Bovine Milk Exosomes in Metabolic Interorgan Cross-Talk

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

The endocrine and epigenetic impact of persistent cow milk consumption on prostate carcinogenesis

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