Novel modulators of senescence, aging, and longevity: Small non-coding RNAs enter the stage.

During the last decade evidence has accumulated that the aging process is driven by limited allocation of energy to somatic maintenance resulting in accumulation of stochastic damage. This damage, affecting molecules, cells, and tissues, is counteracted by genetically programmed repair, the efficiency of which thus importantly determines the life and 'health span' of organisms. Therefore, understanding the regulation of gene expression during cellular and organismal aging as well as upon exposure to various damaging events is important to understand the biology of aging and to positively influence the health span. The recent identification of small non-coding RNAs (ncRNAs), has added an additional layer of complexity to the regulation of gene expression with the classes of endogenous small inhibitory RNAs (siRNAs), PIWI-interacting RNAs (piRNAs), QDE1-interacting RNAs (qiRNAs) and microRNAs (miRNAs). Some of these ncRNAs have not yet been identified in mammalian cells and are dependent on RNA-dependent RNA polymerases. The first mammalian enzyme with such activity has only now emerged and surprisingly consists of the catalytic subunit of telomerase (hTERT) together with RMPR, an alternative RNA component. The so far most studied small non-coding RNAs, miRNAs, however, are now increasingly found to operate in the complex network of cellular aging. Recent findings show that (i) miRNAs are regulated during cellular senescence in vitro, (ii) they contribute to tissue regeneration by regulation of stem cell function, and (iii) at least one miRNA modulates the life span of the model organism C. elegans. Additionally, (iv) they act as inhibitors of proteins mediating the insulin/IGF1 and target of rapamycin (TOR) signalling, both of which are conserved modulators of organism life span. Here we will give an overview on the current status of these topics. Since little is so far known on the functions of small ncRNAs in the context of aging and longevity, the entry of the RNA world into the field of biogerontology certainly holds additional surprises and promises. Even more so, as miRNAs are implicated in many age-associated pathologies, and as RNAi and miRNA based therapeutics are on their way to clinics. 2010 Elsevier Inc. All rights reserved.