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

Abstract

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.

Keywords: acne vulgaris; amino acids; cancer; diabetes mellitus; growth; mTORC1; milk; milk exosomal microRNAs; mortality; neurodegeneration.

Figure 1

Model of milk amino acid signaling activating mTORC1 directly via amino acid-RAG interaction and insulin/IGF-1/PI3K/AKT signaling activating RHEB at the lysosomal membrane. Abbreviations: GH: growth hormone; GHR: growth hormone receptor; 5-HT: 5-hydroxy-tryptamine; INS: insulin gene; IR: insulin receptor; IGF1: IGF-1 gene; IGF-1: insulin-like growth factor 1; IGF1R: IGF-1 receptor; PI3K: phosphoinositide-3-kinase; PTEN: phosphatase and tensin homolog; AKT: Akt kinase (protein kinase B); TSC2: tuberin; SESN2: sestrin 2; SAMTOR: S-adenosylmethionine sensor upstream of mTOR; CASTOR1: cellular arginine sensor for mTORC1; RHEB: ras homolog enriched in brain. RAG: ras-related GTP binding protein; mTORC1: mechanistic target of rapapmycin complex 1; PDCD4: programmed cell death 4, S6K1: ribosomal protein S6 kinase 1; 4EBP1: eukaryotic translation initiationfactor 4E-binding protein 1; eIF4A: eukaryotic translation initiation factor 4A; RPS6: ribosomal protein S6; eIF4B: eukaryotic translation initiation factor 4A; eIF4E: eukaryotic translation initiation factor 4A; Leu: leucine; Met: methionine; Arg: arginine; Glu: glutamine; Trp: tryptophan.

Figure 2

Model of milk miR-mediated epigenetic regulation increasing mTORC1 signaling. Milk-derived exosomal miRs enhance insulin/IGF-1/PI3K/AKT signaling, enhance intracellular levels of BCAAs, and promote mTOR expression. Abbreviations: miR: micro-ribonucleic acid; DNMT1: DNA methyltransferase 1; INS: insulin gene; IR: insulin receptor; IGF1: IGF-1 gene; IGF-1: insulin-like growth factor 1; IGFBP3: IGF binding protein 3; IGF1R: IGF-1 receptor; PI3K: phosphoinositide-3-kinase; PTEN: phosphatase and tensin homolog; AKT: Akt kinase (protein kinase B); AMPK: AMP-activated protein kinase; TSC2: tuberin; RHEB: ras homolog enriched in brain; Leu: leucine; RAG: ras-related GTP binding protein; mTORC1: mechanistic target of rapapmycin complex 1; PDCD4: programmed cell death 4, S6K1: ribosomal protein S6 kinase 1; 4EBP1: eukaryotic translation initiation factor 4E-binding protein 1; eIF4A: eukaryotic translation initiation factor 4A; RPS6: ribosomal protein S6; eIF4B: eukaryotic translation initiation factor 4B; eIF4E: eukaryotic translation initiation factor 4E; NRF2: nuclear factor erythroid 2-related factor 2; TOR: target of rapamycin; FBXW7: F-box and WD40 domain protein 7; DBT: dihydrolipoamide branched-chain transacylase; BCKD: branched-chain alpha-ketoacid dehydrogenase.

Figure 3

Milk-mediated mTORC1 signaling. Upper panel: physiological milk signaling exclusively only during the postnatal breastfeeding period with milk derived from the biological mother (human lactation genome). Lower panel: cow milk-driven overactivation of mTORC1 begins with maternal cow milk consumption during pregnancy, continues with high protein cow milk-based artificial formula, and continues with milk consumption during all age periods of human life. Persistent milk signaling with overactivated mTORC1 modifies growth trajectories during childhood and adolescence and promotes diseases of civilization.