Caloric Restriction-Regulated Non-Coding RNAs as Modulators of Adipose Tissue Aging and Senescence - Project Summary Caloric restriction (CR) is one of the most robust and evolutionarily conserved interventions known to extend lifespan and delay age-associated functional decline across species, including humans. It confers both systemic and tissue-specific benefits in aging. The CALERIE-2TM study, the first and longest randomized controlled trial of CR in non-obese individuals, provided strong evidence that moderate, sustained CR over 24 months can improve a variety of aging-related biomarkers without adversely affecting psychological or behavioral health. Adipose tissue plays a central role in systemic metabolic regulation and is a key modulator of age-related health. CR has been shown to enhance adipose tissue function, as demonstrated in the CALERIE-2™ study, where CR participants exhibited reduced fat mass and organ size, with follow-up analyses revealing transcriptomic remodeling. Adipocyte senescence is a critical driver of age-related adipose dysfunction, and CR is also known to modulate both cellular senescence and inflammation in adipose tissue. However, the molecular mechanisms underlying these protective effects remain poorly understood. Moreover, long-term CR remains difficult to implement on a broad scale, particularly in non-obese individuals, due to challenges related to adherence, ethical concerns, and an unfavorable risk-to-benefit ratio. This highlights the urgent need to identify novel, druggable molecular targets that can replicate the beneficial effects of CR without requiring sustained dietary restriction. Emerging evidence highlights the importance of non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), as key regulators of gene expression in aging tissues. These molecules are attractive therapeutic targets due to their specificity, ease of synthesis, and efficient delivery to tissues. This K01 proposal aims to identify key ncRNAs regulated by CR and investigate their roles in adipose tissue senescence and aging in humans. Utilizing transcriptomic data from the CALERIE-2TM study, we will perform in-silico identification and functional annotation of CR-responsive ncRNAs in adipose tissue. This will enable us to construct a regulatory network of CR-modulated ncRNAs and uncover potential biomarkers linked to age related functional decline in adipose tissue and overall organismal health-span. Following this, we will prioritize adipose-enriched ncRNAs to assess their roles in regulating adipocyte senescence in-vitro. Finally, we will evaluate conserved murine miRNAs as potential therapeutic targets for extending adipose tissue health-span, focusing on their roles in glucose metabolism, lipolysis, mitochondrial function, and ROS metabolism in mice. This research will uncover CR-regulated ncRNAs that influence adipose tissue function, identifying novel therapeutic targets to delay tissue’s functional decline and enhance metabolic health.
