This Project Grant award from the National Institute on Aging (CFDA 93.866 - Aging Research) provides $386,900.00 to the University of Texas Health Science Center at Houston (UTHealth) to study the role of the circadian clock and retinoid acid receptor-related orphan receptor (ROR) proteins in regulating metabolic function and healthy aging. The key objectives are to: 1) Evaluate the impact of ROR proteins on healthspan and lifespan using mice with skeletal muscle-specific ROR knockout, 2)...
The U.S. National Institute on Aging awarded a $467,416 Project Grant (R21AG085086) to Tufts University School of Medicine to investigate the effects of calorie restriction on mitochondrial DNA integrity and its relationship to biological aging and cardiometabolic health. The study will analyze mitochondrial DNA heteroplasmy changes over two years in participants from the CALERIE clinical trial, which examined the long-term effects of calorie restriction. The project aims to determine if calorie...
This federal Project Grant award from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847), provides $772,246 to The Salk Institute for Biological Studies to conduct a clinical study on the effects of time-restricted eating (TRE) and TRE with a low-glycemic snack (TRE-LGS) as dietary interventions to improve the health of overweight and obese night shift workers. The study will...
This Project Grant award from the National Institute on Aging (CFDA 93.866 - Aging Research) in the amount of $425,958 supports research to understand the role of the hormone glucagon in the health benefits of calorie restriction. The study aims to: Measure serum levels of glucagon, GLP-1, and FGF21 in participants of the CALERIE trial (a long-term calorie restriction study in humans) at baseline, 12 months, and 24 months. This will assess changes in glucagon sensitivity during calorie...
This Project Grant award from the National Heart, Lung, and Blood Institute (NHLBI) under the Cardiovascular Diseases Research Program (CFDA 93.837) provides $691,124 to the Regents of the University of Michigan to study the relationship between circadian disruption and cardiometabolic risk during the transition from adolescence to young adulthood. The key objectives are to: 1) Test the hypothesis that persistent circadian disruption, including misaligned sleep, eating, and activity timing, will...
This Cooperative Agreement award from the National Institute on Aging (CFDA 93.866 - Aging Research) provides $2,015,766 in funding to the University of Texas Health Science Center at Houston to study the impact of circadian-microbiome interactions on the gut-pancreas axis in aging. The project aims to investigate how disruptions to circadian rhythms affect the intestinal barrier, gut microbiome, and pancreatic health, with the goal of identifying novel anti-aging mechanisms that could be...
This Project Grant award from the National Institute on Aging (CFDA 93.866 - Aging Research) provides $123,309 to The Regents of the University of California, San Francisco (UCSF) to fund research on the role of fatty acid signaling in modulating gene expression and metabolic pathways during fasting and aging. The key objectives are to: 1) Identify the molecular mechanisms by which fatty acids induce specific changes in mRNA translation, including determining the regulatory motifs and upstream...
This R21 project grant of $241,500 awarded by the National Institute on Aging under the Aging Research program (CFDA 93.866) will investigate the role of nutrient-sensitive post-translational modifications (PTMs) in regulating daily biological rhythms. The key objectives are to: 1) Identify proteins that are rhythmically modified by O-GlcNAcylation and phosphorylation in major mammalian organs, and determine how timing of metabolic input impacts these rhythmic PTM profiles; and 2) Incorporate...
This $406,250 project grant awarded on June 12, 2025 by the National Institute of General Medical Sciences (NIGMS) under the Biomedical Research and Research Training Program (CFDA 93.859) supports research to mechanistically understand how circadian and metabolic rhythms shape the maturation and maintenance of fully differentiated cells. The key products and services to be delivered under this 5-year project include: (1) using single-cell multimodal mapping to determine how circadian clock...
This Project Grant award of $752,588 from the National Cancer Institute (CFDA 93.395 - Cancer Treatment Research) will support a 12-week randomized controlled trial to evaluate the effects of time-restricted eating on cancer-related fatigue among survivors of hematological malignancies. The study will assess the impact of a 10-hour daytime feeding window with 14-hour overnight fasting on patient-reported fatigue, circadian rhythms, and glucose metabolism. The University of Maryland, Baltimore...
CIRCADIAN RHYTHM AND LIFESPAN - HEALTHY AGING IS A CRITICAL GOAL FOR THE HUMAN POPULATION, AND ONE SOLUTION TO THIS PROBLEM IS TO EXTEND HEALTHSPAN AND LIFESPAN. IN MODEL ORGANISMS INCLUDING RODENTS AND NON-HUMAN PRIMATES, CALORIC RESTRICTION (CR) IS THE MOST EFFECTIVE INTERVENTION FOR IMPROVING AGING-RELATED DETERIORATION OF BIOLOGICAL FUNCTIONS AND FOR EXTENDING LIFESPAN. HOWEVER, DESPITE MORE THAN 80 YEARS SINCE ITS DISCOVERY, THE UNDERLYING MECHANISMS FOR HOW CALORIC RESTRICTION EXTENDS LIFESPAN ARE STILL LARGELY UNKNOWN. A NUMBER OF PATHWAYS HAVE BEEN ASSOCIATED WITH LONGEVITY INCLUDING THOSE INVOLVED WITH NUTRIENT SIGNALING, METABOLISM, GROWTH, GENOME STABILITY AND OXIDATIVE STRESS. OUR LABORATORIES HAVE BEEN STUDYING THE BEHAVIORAL EFFECTS OF CALORIC RESTRICTION IN MICE AND HAVE FOUND THAT CR LEADS TO DRAMATIC CHANGES IN THE PATTERN OF FOOD INTAKE. IN CONTRAST TO NORMALLY FED MICE, WHICH DISTRIBUTE THEIR FOOD INTAKE OVER THE 24-HOUR DAY, MICE ON CALORIC RESTRICTION ADOPT A SEVERE FEEDING AND FASTING PATTERN IN WHICH THEY CONSUME ALL OF THEIR FOOD WITHIN A FEW HOURS EACH DAY. IN ORDER TO DISENTANGLE THE CONTRIBUTION OF CALORIES, FASTING AND CIRCADIAN ALIGNMENT OF EATING ON LONGEVITY, WE RECENTLY SHOWED THAT CR IS SUFFICIENT TO EXTEND LIFESPAN BUT THAT THE PATTERN AND CIRCADIAN-ALIGNMENT OF FEEDING UNDER CR ACTS SYNERGISTICALLY TO EXTEND LIFESPAN IN MALE C57BL/6J MICE. CALORIE REDUCTION ALONE INCREASES LIFESPAN ONLY BY ~10%, WHILE TIME-RESTRICTED CR DURING THE ACTIVE PHASE EXTENDS LIFESPAN MORE THAN 3 TIMES LONGER (35%). CIRCADIAN ALIGNMENT OF FEEDING ENHANCES CR-MEDIATED BENEFITS ON SURVIVAL INDEPENDENTLY OF FASTING DURATION AND BODY WEIGHT. IN AIM 1, BECAUSE WE HAVE FOUND THAT CR WITH TIME-RESTRICTED FEEDING (TRF) EXTENDS LIFESPAN FROM 10% TO 35%, WE WILL TEST WHETHER TRF WITHOUT CR CAN EXTEND LIFESPAN. IN AIM 2, WE WILL TEST WHETHER ENHANCED CLOCK GENE EXPRESSION CAN RESCUE THE AGE-RELATED DECLINE IN CIRCADIAN GENE EXPRESSION AND CAN IMPROVE HEALTH AND EXTEND LIFESPAN. AGING PROMOTES WIDESPREAD INCREASES IN INFLAMMATION AND DECREASES IN METABOLISM IN THE LIVERS FROM AD LIB (AL) FED MICE; WHEREAS CR AT NIGHT AMELIORATES THESE AGING-RELATED CHANGES. IN OUR PREVIOUS WORK, WE FOUND THAT THE GENE EXPRESSION OF THE CYTOKINE, INTERLEUKIN-1 BETA (IL-1B), IS DIRECTLY CORRELATED WITH LIFESPAN ACROSS 6 FEEDING CONDITIONS (AL VS. 5 CR GROUPS). IN AIM 3, WE WILL TEST THE HYPOTHESIS THAT IL-1B IS NECESSARY FOR THE EFFECTS OF CR ON LIFESPAN AND WHETHER CALORIES, FASTING AND CIRCADIAN ALIGNMENT OF FEEDING DIFFERENTIALLY EFFECT LIFESPAN IN IL-1B NULL MICE. IN SUMMARY, WE WILL TEST: WHETHER CIRCADIAN INTERVENTIONS SUCH AS TRF OR GENETIC ENHANCEMENT OF CLOCK TRANSCRIPTION CAN EXTEND HEALTHSPAN AND LIFESPAN AND WHETHER IL-1B IS CRITICAL FOR THESE EFFECTS.