Epigenetic Mechanisms Promoting Longevity

Abstract Circulating sRNAs are short non-coding RNAs (typically ~19-25nt in size). They mediate a broad spectrum of biological processes through regulation of gene expression. Experimental evidence indicates that the serum levels of sRNAs change considerably--the vast majority increasing?with age. The ability of circulating miRNAs to travel among tissues enables them to transmit signals and regulate a broad spectrum of biological functions. sRNAs exist in a variety of RNase-insensitive ribonucleoprotein or lipid complexes, or are encapsulated inside different types of extracellular vesicles. Consequently, in contrast to messenger RNA, sRNAs are protected from extracellular RNases and are measurable and stable in samples stored for decades. Despite numerous recent developments, we are far from understanding the role of sRNAs in aging. An understanding of their role in aging mammals, and humans in particular, is still very limited due to the increased complexity and longer life-spans of mammals compared with invertebrates. This project leverages existing human sample resources from three completed NIH-funded studies (EPESE, STRRIDE and CALERIE) to discover and validate longevity-associated sRNAs in humans. Our preliminary analysis of 175 circulating microRNA--in the NIA- funded Duke Established Populations for Epidemiologic Studies of the Elderly (Duke EPESE) community- based cohort of elders--identified 32 differentially expressed circulating miRNAs (p