MicroRNAs and the metabolic hallmarks of aging

Abstract

Aging, the natural process of growing older, is characterized by a progressive deterioration of physiological homeostasis at the cellular, tissue, and organismal level. Metabolically, the aging process is characterized by extensive changes in body composition, multi-tissue/multi-organ insulin resistance, and physiological declines in multiple signaling pathways including growth hormone, insulin/insulin-like growth factor 1, and sex steroids regulation. With this review, we intend to consolidate published information about microRNAs that regulate critical metabolic processes relevant to aging. In certain occasions we uncover relationships likely relevant to aging, which has not been directly described before, such as the miR-451/AMPK axis. We have also included a provocative section highlighting the potential role in aging of a new designation of miRNAs, namely fecal miRNAs, recently discovered to regulate intestinal microbiota in mammals.

Keywords: Aging; Inflammation; Metabolism; Microbiome; Mitochondria; miRNA.

Figure 1. A maximalist view of microRNAs (miRNAs) in nutrient sensing, mitochondrial metabolism, and aging

This figure highlights the broad and generalized involvement of miRNAs in the regulation of multiple important signaling events related to nutrient sensing and mitochondrial metabolism relevant to mammalian aging (for additional details, references, abbreviation meaning, please refer to the main text). A theme “observable” in the milieu of cellular signaling and regulatory relationships presented on this cartoon is the apparently redundant “modus-operandi” of miRNAs while controlling homeostasis-promoting biological processes that would wreck havoc cellular and organismal life if left adrift. These processes ensure healthy living when harmonically coupled. Deviances from a “regulatory equilibrium” would induce the system to readjust (thanks, at least in part, to the above mentioned redundancy) and efficiently recover back to the original steady state or related new state of “benign” equilibrium. These balancing acts of regulation would perform adequately until enough uncompensated regulatory damage accumulates and turns the system unstable, triggering a self-destructive chain of events. We think this is an expression of the robustness that characterizes miRNA regulation in metazoans. We reason that by better understanding these regulatory mechanisms, we will eventually be capable of automatically manipulating damaged regulatory events to exogenously contribute to cellular and organismal homeostasis, therefore improving animal and human healthspan. Drawings were done using BioDraw Ultra version 12.0.3.1216 (CambridgeSoft, Waltham, MA)

Figure 2. Fecal microRNAs as mediators of symbiotic relationships among microbiota and animal host: Potential impact in aging

This cartoon summarizes recent advances in the study of the mammalian microbiota in the context of symbiotically interacting with its animal host. The relationship host-microbiota has been shown critical for healthy living and also proven causative of pathological conditions when unbalanced or affected by dysbiosis. Specific host-microbiota interactions are mediated by the action of miRNAs. On one direction, microbiota may influence host gene expression through the regulation of host miRNAs. On the other, host microRNAs (fecal miRNAs secreted by intestinal epithelial cells) can control the gut microbiota through inter-species gene regulation (S. Liu et al., 2016). These host miRNAs can enter bacteria and specifically regulate bacterial transcripts that affect bacterial growth, therefore changing both the relative proportions and the absolutes amounts of microbes in the gut. Commensal microbiota has been shown to impact host aging; therefore, we reason that fecal miRNA regulation of intestinal flora could be relevant to aging. Intriguingly, the regulation mediated by fecal miRNAs acting on gut microflora to activate expression of bacterial genes appear different from the traditional post-transcriptional repression in eukaryotic cells. Drawings were done using BioDraw Ultra version 12.0.3.1216 (CambridgeSoft, Waltham, MA). Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (http://www.servier.com/Powerpoint-image-bank).