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Significance: Aging is a complex trait that is influenced by a combination of genetic and environmental factors. Although many cellular and physiological changes have been described to occur with aging, the precise molecular causes of aging remain unknown. Given the biological complexity and heterogeneity of the aging process, understanding the mechanisms that underlie aging requires integration of data about age-dependent changes that occur at the molecular, cellular, tissue, and organismal levels. Recent Advances: The development of high-throughput technologies such as next-generation sequencing, proteomics, metabolomics, and automated imaging techniques provides researchers with new opportunities to understand the mechanisms of aging. Using these methods, millions of biological molecules can be simultaneously monitored during the aging process with high accuracy and specificity., Critical Issues: Although the ability to produce big data has drastically increased over the years, integration and interpreting of high-throughput data to infer regulatory relationships between biological factors and identify causes of aging remain the major challenges. In this review, we describe recent advances and survey emerging omics approaches in aging research. We then discuss their limitations and emphasize the need for the further development of methods for the integration of different types of data., Future Directions: Combining omics approaches and novel methods for single-cell analysis with systems biology tools would allow building interaction networks and investigate how these networks are perturbed with aging and disease states. Together, these studies are expected to provide a better understanding of the aging process and could provide insights into the pathophysiology of many age-associated human diseases. Antioxid. Redox Signal. 29, 985-1002.

Significance: Redox biology is a rapidly developing area of research due to the recent evidence for general importance of redox control for numerous cellular functions under both physiological and pathophysiological conditions. Understanding of redox homeostasis is particularly relevant to the understanding of the aging process. The link between reactive oxygen species (ROS) and accumulation of age-associated oxidative damage to macromolecules is well established, but remains controversial and applies only to a subset of experimental models. In addition, recent studies show that ROS may function as signaling molecules and that dysregulation of this process may also be linked to aging., Recent Advances: Many protein factors and pathways that control ROS production and scavenging, as well as those that regulate cellular redox homeostasis, have been identified. However, much less is known about the mechanisms by which redox signaling pathways influence longevity. In this review, we discuss recent advances in the understanding of the molecular basis for the role of redox signaling in aging., Critical Issues: Recent studies allowed identification of previously uncharacterized redox components and revealed complexity of redox signaling pathways. It would be important to identify functions of these components and elucidate how distinct redox pathways are integrated with each other to maintain homeostatic balance., Future Directions: Further characterization of processes that coordinate redox signaling, redox homeostasis, and stress response pathways should allow researchers to dissect how their dysregulation contributes to aging and pathogenesis of various age-related diseases, such as diabetes, cancer and neurodegeneration.

Selenium (Se) is an essential trace element in mammals that has been shown to exert its function through selenoproteins. Whereas optimal levels of Se in the diet have important health benefits, a recent clinical trial has suggested that supplemental intake of Se above the adequate level potentially may raise the risk of type 2 diabetes mellitus. However, the molecular mechanisms for the effect of dietary Se on the development of this disease are not understood. In the present study, we examined the contribution of selenoproteins to increased risk of developing diabetes using animal models. C57BL/6J mice (n=6-7 per group) were fed either Se-deficient Torula yeast-based diet or diets supplemented with 0.1 and 0.4 parts per million Se. Our data show that mice maintained on an Se-supplemented diet develop hyperinsulinemia and have decreased insulin sensitivity. These effects are accompanied by elevated expression of a selective group of selenoproteins. We also observed that reduced synthesis of these selenoproteins caused by overexpression of an i(6)A(-) mutant selenocysteine tRNA promotes glucose intolerance and leads to a diabetes-like phenotype. These findings indicate that both high expression of selenoproteins and selenoprotein deficiency may dysregulate glucose homeostasis and suggest a role for selenoproteins in development of diabetes.

Selenium is an essential trace element in mammals. The major biological form of this micronutrient is the amino acid selenocysteine, which is present in the active sites of selenoenzymes. Seven of 25 mammalian selenoproteins have been identified as residents of the endoplasmic reticulum, including the 15-kDa selenoprotein, type 2 iodothyronine deiodinase and selenoproteins K, M, N, S, and T. Most of these proteins are poorly characterized. However, recent studies implicate some of them in quality control of protein folding in the ER, retrotranslocation of misfolded proteins from the ER to the cytosol, metabolism of the thyroid hormone, and regulation of calcium homeostasis. In addition, some of these proteins are involved in regulation of glucose metabolism and inflammation. This review discusses evolution and structure-function relations of the ER-resident selenoproteins and summarizes recent findings on these proteins, which reveal the emerging important role of selenium and selenoproteins in ER function.