Caloric restriction modifies small RNA profiles and engages age-related molecular pathways in the CALERIE trial.
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2026-01
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Caloric restriction (CR) extends lifespan and enhances healthspan across species. In humans, the CALERIE Phase 2 trial demonstrated that CR improves inflammation, cardiometabolic health, and molecular aging. To explore underlying mechanisms, we examined CR-induced changes vs. ad libitum (AL) in small non-coding RNAs (smRNAs) across plasma, muscle, and adipose tissue. Using smRNA sequencing, we analyzed microRNAs (miRs) and piwi-interacting RNAs (piRs) over 12 and 24 months, comparing CR levels (%CR) and group assignments (CR vs. AL). We identified 16 smRNAs associated with %CR and 41 with CR vs. AL. Although tissue-specific expression varied, shared pathways emerged, including insulin signaling, circadian rhythm, cell cycle regulation, and stress response. Cross-species analysis revealed 17 miRs altered by CR in both humans and rhesus monkeys. These findings suggest smRNAs are key molecular mediators of CR's effects on aging and longevity, offering insight into biological mechanisms of CR and potential targets for age-related interventions.
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Orenduff, Melissa C, Kim M Huffman, Daniel W Belsky, Carl F Pieper, William E Kraus, Virginia B Kraus and undefined CALERIE™ Investigators (2026). Caloric restriction modifies small RNA profiles and engages age-related molecular pathways in the CALERIE trial. iScience, 29(1). p. 114514. 10.1016/j.isci.2025.114514 Retrieved from https://hdl.handle.net/10161/34038.
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Scholars@Duke
Kim Marie Huffman
Determining the role of physical activity in modulating health outcomes (cardiovascular disease risk) in persons with rheumatologic diseases (rheumatoid arthritis, gout, osteoarthritis)
Integrating clinical rheumatology, basic immunology, metabolism, and exercise science in order to reduce morbidity in individuals with arthritis
Evaluating relationships between circulating and intra-muscular metabolic intermediates and insulin resistance in sedentary as well as individuals engaging in regular exercise
Addressing the role of physical activity in modulating inflammation, metabolism, and functional health in aging populations
Carl F. Pieper
Analytic Interests.
1) Issues in the Design of Medical Experiments: I explore the use of reliability/generalizability models in experimental design. In addition to incorporation of reliability, I study powering longitudinal trials with multiple outcomes and substantial missing data using Mixed models.
2) Issues in the Analysis of Repeated Measures Designs & Longitudinal Data: Use of Hierarchical Linear Models (HLM) or Mixed Models in modeling trajectories of multiple variables over time (e.g., physical and cognitive functioning and Blood Pressure). My current work involves methodologies in simultaneous estimation of trajectories for multiple variables within and between domains, modeling co-occuring change.
Areas of Substantive interest: (1) Experimental design and analysis in gerontology and geriatrics, and psychiatry,
(2) Multivariate repeated measures designs,
William Erle Kraus
My training, expertise and research interests range from human integrative physiology and genetics to animal exercise models to cell culture models of skeletal muscle adaptation to mechanical stretch. I am trained clinically as an internist and preventive cardiologist, with particular expertise in preventive cardiology and cardiac rehabilitation. My research training spans molecular biology and cell culture, molecular genetics, and integrative human exercise physiology and metabolism. I practice as a preventive cardiologist with a focus on cardiometabolic risk and exercise physiology for older athletes. My research space has both a basic wet laboratory component and a human integrative physiology one.
One focus of our work is an integrative physiologic examination of exercise effects in human subjects in clinical studies of exercise training in normal individuals, in individuals at risk of disease (such as pre-diabetes and metabolic syndrome; STRRIDE), and in individuals with disease (such as coronary heart disease, congestive heart failure and cancer).
A second focus of my research group is exploration of genetic determinates of disease risk in human subjects. We conduct studies of early onset cardiovascular disease (GENECARD; CATHGEN), congestive heart failure (HF-ACTION), peripheral arterial disease (AMNESTI), and metabolic syndrome. We are exploring analytic models of predicting disease risk using established and innovative statistical methodology.
A third focus of my group’s work is to understand the cellular signaling mechanisms underlying the normal adaptive responses of skeletal muscle to physiologic stimuli, such as occur in exercise conditioning, and to understand the abnormal maladaptive responses that occur in response to pathophysiologic stimuli, such as occur in congestive heart failure, aging and prolonged exposure to microgravity.
Recently we have begun to investigate interactions of genes and lifestyle interventions on cardiometabolic outcomes. We have experience with clinical lifestyle intervention studies, particularly the contributions of genetic variants to interventions responses. We call this Lifestyle Medicopharmacogenetics.
KEY WORDS:
exercise, skeletal muscle, energy metabolism, cell signaling, gene expression, cell stretch, heart failure, aging, spaceflight, human genetics, early onset cardiovascular disease, lifestyle medicine
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