Lin28 and let-7 in the Metabolic Physiology of Aging

Lin28 and let-7 miRNA mutually suppress each other to form a bistable switch in regulating stem cell fate. The Lin28/let-7 switch regulates a broad network of cellular growth and metabolism regulators, including insulin/IGF-PI3K-mTOR signaling, to regulate self-renewal and oncogenesis. Genetic mutations in Lin28 and the let-7 targets Igf2bp1/2 and Hmga1/2 suggest that this core network of fetal genes modulates muscle growth, overall growth, and systemic glucose homeostasis via insulin/IGF signaling. Lin28 and let-7 regulate the maturation, aging, and dedifferentiation of cardiomyocytes during cardiovascular development and disease. The Lin28/let-7 molecular switch has emerged as a central regulator of growth signaling pathways and metabolic enzymes. Initially discovered to regulate developmental timing in the nematode, the Lin28/let-7 pathway of RNA regulation has gained prominence for its role in mammalian stem cells, cancer cells, tissue development, and aging. By regulating RNAs, the pathway coordinates cellular growth and cellular metabolism to influence metabolic physiology. Here, we review this regulatory mechanism and its impact on cancers, which reactivate Lin28, cardiovascular diseases, which implicate let-7, human genome-wide association studies (GWAS) of growth, and metabolic diseases, which implicate the Lin28/let-7 pathway. We also highlight questions relating to Barker's Hypothesis and the potential actions of the Lin28/let-7 pathway on programming long-lasting epigenetic effects. The Lin28/let-7 molecular switch has emerged as a central regulator of growth signaling pathways and metabolic enzymes. Initially discovered to regulate developmental timing in the nematode, the Lin28/let-7 pathway of RNA regulation has gained prominence for its role in mammalian stem cells, cancer cells, tissue development, and aging. By regulating RNAs, the pathway coordinates cellular growth and cellular metabolism to influence metabolic physiology. Here, we review this regulatory mechanism and its impact on cancers, which reactivate Lin28, cardiovascular diseases, which implicate let-7, human genome-wide association studies (GWAS) of growth, and metabolic diseases, which implicate the Lin28/let-7 pathway. We also highlight questions relating to Barker's Hypothesis and the potential actions of the Lin28/let-7 pathway on programming long-lasting epigenetic effects. in a dynamical system, bistability means the system has two stable equilibrium states. A bistable switch can toggle between either of two states. also known as Barker's Hypothesis proposes that the long-term risk of adult chronic metabolic diseases is influenced by adaptive physiological responses that the fetus or infant makes in response to environmental cues about health or nutritional state. These physiological responses by the fetus or infant may include changes in growth, metabolism, and tissue development patterns, which need not manifest during childhood, but nevertheless cause disease in adulthood. stem cells derived from the inner cell mass of the blastocyst stage of an embryo that show the properties of both pluripotency, or the ability to differentiate into all three germ layers and, thus, every tissue in a fetus, and long-term self-renewal. an examination of many common genetic variants in the DNA of different individuals to see if any variant is statistically associated with a trait. A human GWAS typically includes at least thousands of human subjects, and focuses on associations between SNPs and traits such as height and fasting glucose, or diseases such as type 2 diabetes mellitus (T2DM), coronary heart disease, rheumatoid arthritis, and hypertension. a small noncoding RNA molecule, containing about 22 nucleotides, found in plants, animals, and some viruses, which functions in RNA silencing and post-transcriptional regulation of gene expression. An animal miRNA is initially transcribed as part of a several hundred nucleotides-long miRNA precursor termed a ‘pri-miRNA’, which is then processed in the nucleus to form a pre-miRNA, and finally cleaved in the cytoplasm by Dicer to form a mature miRNA. Lin28, for example, is thought to inhibit both the nuclear and cytoplasmic processing of the let-7 miRNAs. the oxygen-consuming metabolic pathway in which mitochondria use their enzymes and the biochemical energy released by the oxidation of nutrients, in the form of NADH and FADH2 and their resultant high-energy electrons, to synthesize ATP. a form of cell division that maintains the undifferentiated epigenetic state. It is the process by which stem cells divide to make more stem cells, perpetuating the stem cell pool throughout life in vivo or in long-term cultures in vitro. a DNA sequence variation occurring commonly within a population (e.g., 1%) in which a single nucleotide (A, T, C, or G) in the genome differs between members of a biological species or paired chromosomes.