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An intriguing effect of short-term caloric restriction (CR) is the expansion of certain stem cell populations, including muscle stem cells (satellite cells), which facilitate an accelerated regenerative program after injury. Here, we utilized the MetRS L274G (MetRS) transgenic mouse to identify liver-secreted plasminogen as a candidate for regulating satellite cell expansion during short-term CR. Knockdown of circulating plasminogen prevents satellite cell expansion during short-term CR. Furthermore, loss of the plasminogen receptor KT (Plg-R KT) is also sufficient to prevent CR-related satellite cell expansion, consistent with direct signaling of plasminogen through the plasminogen receptor Plg-R KT /ERK kinase to promote proliferation of satellite cells. Importantly, we are able to replicate many of these findings in human participants from the CALERIE trial. Our results demonstrate that CR enhances liver protein secretion of plasminogen, which signals directly to the muscle satellite cell through Plg-R KT to promote proliferation and subsequent muscle resilience during CR. [Display omitted] • Short-term caloric restriction (CR) drastically alters the liver-derived plasma proteome • Circulating plasminogen increases with CR, which is necessary for satellite cell expansion • During CR, plasminogen signals to the satellite cell via the plasminogen receptor Plg-R KT • Loss of Plg-R KT prevents CR-induced SC expansion and associated regenerative enhancements Short-term caloric restriction (CR) has been shown to expand the muscle satellite cell pool and accelerate the early phase of muscle regeneration. Bareja et al. report robust changes in the liver-derived plasma proteome during CR and identify plasminogen as a contributing factor to the satellite cell expansion, signaling through Plg-R KT. [ABSTRACT FROM AUTHOR]

Globally, the aging population is growing rapidly, creating an urgent need to attenuate age-related health conditions, including metabolic disease and disability. A promising strategy for healthy aging based on consistently positive results from studies with a variety of species, including non-human primates (NHP), is calorie restriction (CR), or the restriction of energy intake while maintaining intake of essential nutrients. The burgeoning evidence for this approach in humans is reviewed and the major study to date to address this question, CALERIE (Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy), is described. CALERIE findings indicate the feasibility of CR in non-obese humans, confirm observations in NHP, and are consistent with improvements in disease risk reduction and potential anti-aging effects. Finally, the mechanisms of CR in humans are reviewed which sums up the fact that evolutionarily conserved mechanisms mediate the anti-aging effects of CR. Overall, the prospect for further research in both NHP and humans is highly encouraging. [ABSTRACT FROM AUTHOR]

Calorie restriction (CR), a nutritional intervention of reduced energy intake but with adequate nutrition, has been shown to extend healthspan and lifespan in rodent and primate models. Accumulating data from observational and randomized clinical trials indicate that CR in humans results in some of the same metabolic and molecular adaptations that have been shown to improve health and retard the accumulation of molecular damage in animal models of longevity. In particular, moderate CR in humans ameliorates multiple metabolic and hormonal factors that are implicated in the pathogenesis of type 2 diabetes, cardiovascular diseases, and cancer, the leading causes of morbidity, disability and mortality. In this paper, we will discuss the effects of CR in non-obese humans on these physiological parameters. Special emphasis is committed to recent clinical intervention trials that have investigated the feasibility and effects of CR in young and middle-aged men and women on parameters of energy metabolism and metabolic risk factors of age-associated disease in great detail. Additionally, data from individuals who are either naturally exposed to CR or those who are self-practicing this dietary intervention allows us to speculate on longer-term effects of more severe CR in humans. [ABSTRACT FROM AUTHOR]

Calorie restriction (CR) and time-restricted eating (TRE) are distinctly different dietary management strategies with overlapping health outcomes. After two years of CR, healthy participants in the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) study showed significant weight-loss relative to the ad libitum intake control group and achieved 12% CR on average. Preclinical rodent studies have shown that sustaining a consistent eating interval of 8–12 h between the first and last calories of each day— without reducing daily calorie intake—can impart health benefits that partly overlap with those imparted by CR. Preclinical CR protocols often inadvertently restrict eating interval, and conversely, clinical studies of TRE often inadvertently result in modest CR. Other factors related to daily timing of food intake, such as breakfast skipping, and early food intake also impact health outcomes. These observations have raised the possibility that CR protocols can be further optimized by adopting relevant aspects of eating patterns to boost weight loss and health outcomes. With a goal to inform CR protocols that aim to optimize eating patterns, the objective of this secondary analysis was to test aspects of daily timing of food intake associated with greater weight loss in the CALERIE study participants. We found no difference in the daily time window of energy intake between the CR and control arms. In the CALERIE trial, weight change was used as a proxy for adherence to CR, and hence we used linear models to test the relationships among CR, weight loss, and temporal aspects of daily eating pattern. We found that CR alone could explain 41% of the variance in weight loss. We tested the contribution of eating interval, time to 50% daily calorie intake, and day-to-day shifts in the time of the first (breakfast) or last meal consumed. We found that eating interval and variation in the timing of the first and last meals significantly influenced weight loss after controlling for CR. Our models suggest that shorter eating intervals are associated with greater CR (1% of the variance explained) and facilitate additional weight loss. Our models suggest that less day to day variation in first mealtime is directly associated with weight loss (6% of the variance explained). More regular first meal timing is also associated with greater CR (2% of the variance explained). Likewise, regular timing of the last daily meal is directly associated with weight loss (1% of the variance explained) and greater CR (1% of the variance explained). The time to 50% of daily calorie intake or consuming half the caloric intake earlier in the day is associated with additional CR (2% of the variance explained). In summary, these secondary analyses on CALERIE data suggest that – in order to maximize CR and weight loss – future CR protocols should encourage participants to adopt consistent timing of their first and last meals, a shorter eating window, and earlier consumption of food. [ABSTRACT FROM AUTHOR]

Abstract: This review focuses on research involving calorie restriction (CR) in humans and the resulting changes observed in endocrine and neuroendocrine systems. Special emphasis is given to the clinical science studies designed to investigate the effects of controlled, high-quality, energy-restricted diets on both biomarkers of longevity and on the development of chronic diseases of human aging. Prolonged CR has been shown to extend both the median and maximal lifespan in a variety of lower species such as yeast, worms, fish, rats and mice. The biological mechanisms of this lifespan extension via CR are not fully elucidated, but possibly involve significant alterations in energy metabolism, oxidative damage, insulin sensitivity and functional changes in both neuroendocrine and autonomic nervous systems. Most of the difficulty in characterizing the systemic endocrine and neuroendocrine changes with aging and CR is due to the limited capability to collect large and multiple blood samples from small animals, which are usually shorter lived, and hence the most studied. Ongoing studies of prolonged CR in humans are now making it possible to analyze changes in the “biomarkers of aging” to unravel some of the mechanisms of its anti-aging phenomenon. With the incremental expansion of research endeavors in the area of energy restriction, data on the effects of CR in non-human primates and human subjects are becoming more accessible. Detailed analyses from controlled human trials involving long-term CR will allow investigators to link observed alterations from body composition and endocrine systems down to changes in molecular pathways and gene expression, with their possible effects on aging. [Copyright &y& Elsevier]