Publications by Author: Frank J Slack

MicroRNAs (miRNAs) are a class of short non-coding RNAs that bind mRNAs through partial base-pair complementarity with their target genes, resulting in post-transcriptional repression of gene expression. The role of miRNAs in controlling aging processes has been uncovered recently with the discovery of miRNAs that regulate lifespan in the nematode Caenorhabditis elegans through insulin and insulin-like growth factor-1 signaling and DNA damage checkpoint factors. Furthermore, numerous miRNAs are differentially expressed during aging in C. elegans, but the specific functions of many of these miRNAs are still unknown. Recently, various miRNAs have been identified that are up- or down-regulated during mammalian aging by comparing their tissue-specific expression in younger and older mice. In addition, many miRNAs have been implicated in governing senescence in a variety of human cell lines, and the precise functions of some of these miRNAs in regulating cellular senescence have helped to elucidate mechanisms underlying aging. In this Commentary, we review the various regulatory roles of miRNAs during aging processes. We highlight how certain miRNAs can regulate aging on the level of organism lifespan, tissue aging or cellular senescence. Finally, we discuss future approaches that might be used to investigate the mechanisms by which miRNAs govern aging processes.

In the nematode Caenorhabditis elegans, the let-7 microRNA (miRNA) controls the timing of key developmental events and terminal differentiation in part by directly regulating lin-41. C. elegans lin-41 mutants display precocious cell cycle exit and terminal differentiation of epidermal skin cells. lin-41 orthologues are found in more complex organisms including both mice and humans, but their roles are not known. We generated Mlin41 mouse mutants to ascertain a functional role for Mlin41. Strong loss of function Mlin41 gene-trap mutants demonstrated a striking neural tube closure defect during development, and embryonic lethality. Like C. elegans lin-41, Mlin41 also appears to be regulated by the let-7 and mir-125 miRNAs. Since Mlin41 is required for neural tube closure and survival it points to human lin-41 (HLIN41/TRIM71) as a potential human development and disease gene.

The modulation of gene expression by small non-coding RNAs is a recently discovered level of gene regulation in animals and plants. In particular, microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs) have been implicated in various aspects of animal development, such as neuronal, muscle and germline development. During the past year, an improved understanding of the biological functions of small non-coding RNAs has been fostered by the analysis of genetic deletions of individual miRNAs in mammals. These studies show that miRNAs are key regulators of animal development and are potential human disease loci.

A report of the meeting 'Regulatory RNAs', the 71st Cold Spring Harbor Symposium on Quantitative Biology, Cold Spring Harbor, USA, 31 May-5 July 2006.

Genes that control cell differentiation and development are frequently mutated in human cancer. Micro (mi)RNAs are small regulatory RNAs that are emerging as important regulators of cell division/differentiation and human cancer genes. In this review, the miRNA cancer connection is discussed and the possibility of using this novel, but potentially powerful new therapy, involving miRNAs, to treat cancers is speculated on. For example, lung cancer is the major cause of cancer deaths in the USA, but existing therapies fail to treat this disease in the overwhelming majority of cases. The let-7 miRNA is one of a number of 'oncomirs', natural miRNA tumor suppressors in lung tissue, which may prove useful in treating lung cancer or enhancing current treatments for lung cancer.

In C. elegans, heterochronic genes control the timing of cell fate determination during development. Two heterochronic genes, let-7 and lin-4, encode microRNAs (miRNAs) that down-regulate a third heterochronic gene lin-41 by binding to complementary sites in its 3'UTR. let-7 and lin-4 are conserved in mammals. Here we report the cloning and sequencing of mammalian lin-41 orthologs. We find that mouse and human lin-41 genes contain predicted conserved complementary sites for let-7 and the lin-4 ortholog, mir-125, in their 3'UTRs. Mouse lin-41 (Mlin-41) is temporally expressed in developing mouse embryos, most dramatically in the limb buds. Mlin-41 is down-regulated during mid-embryogenesis at the time when mouse let-7c and mir-125 RNA levels are up-regulated. Our results suggest that mammalian lin-41 is temporally regulated by miRNAs in order to direct key developmental events such as limb formation.

Aging is associated with decreased health span, and despite the recent advances made in understanding the mechanisms of aging, no antiaging drug has been approved for therapy. Therefore, strategies to promote a healthy life in aging are desirable. Previous work has shown that chronic treatment with extracellular vesicles (EVs) from young mice prolongs lifespan in old mice, but the mechanism of action of this effect on liver metabolism is not known. Here we investigated the role of treatment with EVs derived from young sedentary (EV-C) or exercised (EV-EX) mice in the metabolism of old mice and aimed to identify key youthful-associated microRNA (miRNA) cargos that could promote healthy liver function. We found that aged mice treated with either EV-C or EV-EX had higher insulin sensitivity, higher locomotor activity resulting in longer distance traveled in the cage, and a lower respiratory exchange ratio compared to mice treated with EVs from aged mice (EV-A). In the liver, treatment with young-derived EVs reduced aging-induced liver fibrosis. We identified miR-30c in the EVs as a possible youth-associated miRNA as its level was higher in circulating EVs of young mice. Treatment of aged mice with EVs transfected with miR-30c mimic reduced stellate cell activation in the liver and reduced fibrosis compared to EV-negative control by targeting Foxo3. Our results suggest that by delivering juvenile EVs to old mice, we can improve their liver health. Moreover, we identified miR-30c as a candidate for antiaging liver therapy.