Lin28 and let-7 in the Metabolic Physiology of Aging

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.

TrendsLin28 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.