Epigenetic Mechanisms Promoting Longevity

Abstract
Circulating small regulatory RNAs (sRNAs) are short non-coding RNAs (typically ~19-25nt in size). They mediate
a broad spectrum of biological processes through regulation of gene expression. Our experimental evidence
indicates that serum levels of miRNAs (one form of sRNA) change considerably, the vast majority increasing
with age. The ability of circulating sRNAs 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 in 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 miRNAs 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
(p10 years) compared with age, sex and race matched but short-term survivors (