Sunday, May 18, 2025
5/18/2025
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.
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