Hwa Jin Jung

MicroRNA in aging: From discovery to biology

MicroRNAs (miRNAs) are small non-coding RNA molecules that negatively regulate gene expression of their targets at the post-transcriptional levels. A single miRNA can target up to several hundred mRNAs, thus capable of significantly altering gene expression regulatory networks. In-depth study and characterization of miRNAs has elucidated their critical functions in development, homeostasis, and disease. A link between miRNAs and longevity has been demonstrated in C. elegans, implicating their role in regulation of lifespan and in the aging process. Recent years have witnessed unprecedented technological advances in studies of miRNAs, including ultra-high throughput sequencing technologies that allow comprehensive discovery of miRNAs and their targets. Here we review the latest experimental approaches from the perspective of understanding miRNA gene expression regulatory networks in aging. We provide a methodological work flow that can be employed to discover aging-related miRNAs and their targets, and to functionally validate their roles in aging. Finally, we review the links between miRNAs known to act in the conserved pathways of aging and major aging-related diseases. Taken together, we hope to provide a focused review to facilitate future endeavor of uncovering the functional role of miRNA in aging.

Comprehensive microRNA profiling in B-cells of human centenarians by massively parallel sequencing.

BackgroundMicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression and play a critical role in development, homeostasis, and disease. Despite their demonstrated roles in age-associated pathologies, little is known about the role of miRNAs in human aging and longevity.ResultsWe employed massively parallel sequencing technology to identify miRNAs expressed in B-cells from Ashkenazi Jewish centenarians, i.e., those living to a hundred and a human model of exceptional longevity, and younger controls without a family history of longevity. With data from 26.7 million reads comprising 9.4 × 108 bp from 3 centenarian and 3 control individuals, we discovered a total of 276 known miRNAs and 8 unknown miRNAs ranging several orders of magnitude in expression levels, a typical characteristics of saturated miRNA-sequencing. A total of 22 miRNAs were found to be significantly upregulated, with only 2 miRNAs downregulated, in centenarians as compared to controls. Gene Ontology analysis of the predicted and validated targets of the 24 differentially expressed miRNAs indicated enrichment of functional pathways involved in cell metabolism, cell cycle, cell signaling, and cell differentiation. A cross sectional expression analysis of the differentially expressed miRNAs in B-cells from Ashkenazi Jewish individuals between the 50th and 100th years of age indicated that expression levels of miR-363* declined significantly with age. Centenarians, however, maintained the youthful expression level. This result suggests that miR-363* may be a candidate longevity-associated miRNA.ConclusionOur comprehensive miRNA data provide a resource for further studies to identify genetic pathways associated with aging and longevity in humans.

The potential roles of p53 tumor suppressor in nucleotide excision repair (NER) and base excision repair (BER)

The p53 tumor suppressor has long been envisaged to preserve genetic stability by the induction of cell cycle checkpoints and apoptosis. More recently, p53 has been implicated to play roles in DNA repair responses to genotoxic stresses. UV-damage and the damage caused by certain chemotherapeutics including cisplatin and nitrogen mustards are known to be repaired by the nucleotide excision repair (NER) pathway which is reportedly regulated by p53 and its downstream genes. There are evidences to suggest that the base excision repair (BER) induced by the base-damaging agent methyl methanesulfonate (MMS) is partially deficient in cells lacking functional p53. This result suggests that the activity of BER might be also dependent on the p53 status. In this review, we discuss the possibilities that p53 regulates BER as well as NER; these are one of the most significant potentials of p53 tumor suppressor for repairing the vast majority of DNA damages that is incurred from various environmental stresses.

Circulating miRNAs in Ageing and Ageing-Related Diseases

MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. They are involved in important biological processes including development, homeostasis, and ageing. Recently, extracellular miRNAs have been discovered in the bloodstream and bodily fluids. These miRNAs are shown to be secreted and circulating in microvesicles (MVs), or in complex with other factors such as RNA-binding proteins and high-density lipoprotein (HDL) particles. These cell-free, circulating miRNAs can be taken into and function as negative regulators of target genes in recipient cells. Here we review the biogenesis and uptake of circulating miRNAs as well as their profiles in ageing and ageing-related diseases. We discuss the emerging role of circulating miRNAs as biomarkers and therapeutic targets.

Regulation of IGF -1 signaling by microRNAs

The insulin-like growth factor 1 (IGF-1) signaling pathway regulates critical biological processes including development, homeostasis, and aging. Dysregulation of this pathway has been implicated in a myriad of diseases such as cancers, neurodegenerative diseases, and metabolic disorders, making the IGF-1 signaling pathway a prime target to develop therapeutic and intervention strategies. Recently, small non-coding RNA molecules in ∼22 nucleotide length, microRNAs (miRNAs), have emerged as a new regulator of biological processes in virtually all organ systems and increasing studies are linking altered miRNA function to disease mechanisms. A miRNA binds to 3’UTRs of multiple target genes and coordinately downregulates their expression, thereby exerting a profound influence on gene regulatory networks. Here we review the components of the IGF-1 signaling pathway that are known targets of miRNA regulation, and highlight recent studies that suggest therapeutic potential of these miRNAs against various diseases.

Current issues of selenium in cancer chemoprevention

The element selenium (Se) was identified, nearly 40 years ago, as being essential in the nutrition of animals and humans. In addition, antitumorigenic effects of Se compounds have been described in a variety of in vitro and animal models, suggesting that supplemental Se in human diets may reduce cancer risk. Apparent mechanisms underlying the potential of Se compounds as cancer chemopreventive agents have been suggested. Some recent clinical trials, however, have shed doubt on the anticancer effects of Se. The contradictory findings and consequent controversy might be due to the lack of understanding of the mechanisms underlying Se biology. This article reviews current knowledge on this topic and addresses the disparate viewpoints on the chemopreventive effects of Se, the human populations.

A novel chemopreventive mechanism of selenomethionine: Enhancement of APE1 enzyme activity via a Gadd45a, PCNA and APE1 protein complex that regulates p53-mediated base excision repair

Organic selenium compounds have been documented to play a role in cancer prevention. Our previous study showed that selenomethionine (SeMet) induces p53 activation without genotoxic effects including apoptosis and cell cycle arrest. In this study, we investigated the mechanism by which organic selenium compounds promote p53-mediated base excision repair (BER) activity. Our data demonstrated for the first time that the interaction between growth arrest and DNA damage-inducible protein 45A (Gadd45a), which is a p53-activated downstream gene, and two BER-mediated repair proteins, proliferating cell nuclear antigen (PCNA) and apurinic/apyrimidinic endonuclease (APE1/Ref-1), was significantly increased in a p53-dependent manner following treatment with organic selenium compounds. Furthermore, we observed that the activity of APE1 was significantly increased in a p53-dependent manner in response to the organic selenium compounds. These results suggest that BER activity is dependent on wild-type p53 activity and is mediated by the modulation of protein interactions between Gadd45a and repair proteins in response to organic selenium compounds. We propose that p53-dependent BER activity is a distinct chemopreventive mechanism mediated by organic selenium compounds, and that this may provide insight into the development of effective chemopreventive strategies against various oxidative stresses that contribute to a variety of human diseases, particularly cancer.

Circulating miRNAs and miRNA shuttles as biomarkers: Perspective trajectories of healthy and unhealthy aging.

Human aging is a lifelong process characterized by a continuous trade-off between pro-and anti-inflammatory responses, where the best-adapted and/or remodeled genetic/epigenetic profile may develop a longevity phenotype. Centenarians and their offspring represent such a phenotype and their comparison to patients with age-related diseases (ARDs) is expected to maximize the chance to unravel the genetic makeup that better associates with healthy aging trajectories. Seemingly, such comparison is expected to allow the discovery of new biomarkers of longevity together with risk factor for the most common ARDs. MicroRNAs (miRNAs) and their shuttles (extracellular vesicles in particular) are currently conceived as those endowed with the strongest ability to provide information about the trajectories of healthy and unhealthy aging. We review the available data on miRNAs in aging and underpin the evidence suggesting that circulating miRNAs (and cognate shuttles), especially those involved in the regulation of inflammation (inflamma-miRs) may constitute biomarkers capable of reliably depicting healthy and unhealthy aging trajectories.

Enhancement of methyl methanesulfonate-induced base excision repair in the presence of selenomethionine on p53-dependent pathway.

Selenomethionine (SeMet) has been identified as a chemopreventive antioxidant to activate p53-mediated nucleotide excision repair. In this study, we examined whether p53-mediated base excision repair (BER) might be induced by SeMet. When methyl methanesulfonate, a BER-inducing agent, was treated in the cells, DNA damage was rapidly decreased in the presence of SeMet. In addition, our data showed that the removal of apurinic/apyrimidinic sites was significantly enhanced in the presence of SeMet. Furthermore, we observed that the expression of gadd45a, known to involve BER as one of the p53 downstream genes, was increased by SeMet in p53 wild-type RKO cells. Those results supported the proposal that BER activity might be dependent on wild-type p53 under the modulation of gadd45a expression in response to SeMet. We suggested that p53-dependent BER activity as a distinct mechanism of SeMet might play an important role to prevent cancer caused by various oxidative stresses.

Comprehensive miRNA Profiling of Skeletal Muscle and Serum in Induced and Normal Mouse Muscle Atrophy During Aging

Age-associated loss of muscle mass and function is a major cause of morbidity and mortality in the elderly adults. Muscular atrophy can also be induced by disuse associated with long-term bed rest or disease. Although miRNAs regulate muscle growth, regeneration, and aging, their potential role in acute muscle atrophy is poorly understood. Furthermore, alterations in circulating miRNA levels have been shown to occur during aging but their potential as noninvasive biomarkers for muscle atrophy remains largely unexplored. Here, we report comprehensive miRNA expression profiles by miRNA-seq analysis in tibialis anterior muscle and serum of a disuse-induced atrophy mouse model, mimicking the acute atrophy following long-term bed rest, as compared to those of young and old mice. Comparative analysis and validation studies have revealed that miR-455-3p was significantly decreased in muscle of both induced-atrophy model and old mice, whereas miR-434-3p was decreased in both serum and muscle of old mice, as compared to young mice. Furthermore, upregulation of miR-455-3p in fully differentiated C2C12 myoblasts induced a hypertrophic phenotype. These results suggest that deregulation of miR-455-3p may play a functional role in muscle atrophy and miR-434-3p could be a candidate serum biomarker of muscle aging.