A Selection of Recent Calorie Restriction Research

Calorie restriction is a growing area of research these days, linked to diverse fields ranging from aging to diabetes to pharmaceutical development, and above all to the overarching quest to produce a grand map of cellular metabolism. Calorie restriction is of greatest interest outside the scientific community for the fact that it reliably slows aging and extends healthy life in most species and lineages tested to date. This effect, like all methods of slowing aging through altered metabolic state, is much more pronounced in short-lived species. The additional life gained as a proportion of life span falls as the species life span increases: we all know that calorie restriction in humans, while it produces impressive short-term benefits for basically healthy individuals that have yet to be matched by medical science, doesn't extend human life span by 40% or more as it does in mice. We would have noticed by now.

Messing with metabolism, however it is done, isn't a great approach to life extension. It has a limited upside, and has proven very hard and very expensive to achieve successfully via drug development. Calorie restriction itself already exists, however, is reliable, and even though it has a limited upside, it is free. Just as for exercise, it seems silly not to take advantage. The cost-benefit analysis for metabolic alteration via drugs is terrible because it will cost an enormous amount of time and money to produce results, and those resources would be better devoted to SENS rejuvenation research. The cost-benefit analysis for calorie restriction is completely different because it costs nothing and is here now - something for nothing, even if it is not much of a benefit in the grand scheme of things.

Moving away from considerations of enhanced longevity, inside the scientific community calorie restriction is perhaps of greatest interest as a reliable tool with which to interrogate the operation of cellular metabolism. The ability to reliably adjust that operation into a different stable state is very useful if the aim is to try to understand the function of this complex system. Two operating states provides points of comparison and analysis that don't exist for one state. This is of particular interest in aging research, and calorie restriction is used by some groups in much the same way as comparisons between species with different life spans: to try to identify important mechanisms relevant to aging and understand how the operation of metabolism determines natural variations in life span.

Nevertheless, some research groups are attempting to refine the application of calorie restriction as a formal treatment, largely to augment existing approaches to diabetes and cancer, as that is where the ability to raise funding best overlaps with potential benefits for patients. This involves a lot more careful categorization of short-term results for human calorie restriction, and a classification of different types of calorie restriction, some of which don't involve a reduction in overall calorie intake at all, but rather focus on timing and dietary content, such as intermittent fasting or protein restriction. The first of the papers linked here is a review along these lines:

Dietary restriction with and without caloric restriction for healthy aging

Caloric restriction is the most effective and reproducible dietary intervention known to regulate aging and increase the healthy lifespan in various model organisms, ranging from the unicellular yeast to worms, flies, rodents, and primates. However, caloric restriction, which in most cases entails a 20-40% reduction of food consumption relative to normal intake, is a severe intervention that results in both beneficial and detrimental effects. Specific types of chronic, intermittent, or periodic dietary restrictions without chronic caloric restriction have instead the potential to provide a significant healthspan increase while minimizing adverse effects. Improved periodic or targeted dietary restriction regimens that uncouple the challenge of food deprivation from the beneficial effects will allow a safe intervention feasible for a major portion of the population. Here we focus on healthspan interventions that are not chronic or do not require calorie restriction.

Newer antidiabetic drugs and calorie restriction mimicry

In rhesus monkeys unsurprisingly one of the most potent mechanisms of longevity was the reduction of cardiovascular risk factors and glucose intolerance in calorie-restricted monkeys. In the University of Wisconsin cohort, none of the individual calories restricted animals developed any degree of glucose impairment at the time of the interim analysis in contrast with the control monkeys who developed diabetes in a fairly good number. The animal data suggests the long-term CR in adult animals is a potent way to prevent the development of glucose impairment.

There are no comparable human studies with CR. Type 2 diabetes mellitus in humans is currently described as a progressive disease with a pathophysiology that involves over eight different organ systems. However, this understanding of disease does not really give a valid explanation to the reversibility and induction of normal glucose tolerance in patients with type 2 diabetes who undergo bariatric surgery. The improvements in glucose control happen within a few days after surgery much before there is any significant reduction in body weight. There are many explanations offered for early improvement in glucose tolerance like changes in gut hormone profile, changes in gut bacteria, etc., Both these overlook the most logical explanation for the phenomenon which is an acute profound decrease in calorie intake.

However, considering the difficulties in getting healthy adults to limit food intake science has focused on understanding the biochemical processes that accompany calorie restriction (CR) to formulate drugs that would mimic the effects of CR without the need to actually restrict calories. Drugs in this emerging therapeutic field are called CR mimetics. Some of the currently used anti-diabetic agents may have some CR mimetic like effects. This review focuses on the CR mimetic properties of the currently available anti-diabetic agents.

Sex difference in pathology of the ageing gut mediates the greater response of female lifespan to dietary restriction

Women live on average longer than men, but have greater levels of late-life morbidity. We have uncovered a substantial sex difference in the pathology of the ageing gut in Drosophila. The intestinal epithelium of the ageing female undergoes major deterioration, driven by intestinal stem cell (ISC) division, while lower ISC activity in males associates with delay or absence of pathology, and better barrier function, even at old ages. Males succumb to intestinal challenges to which females are resistant, associated with fewer proliferating ISCs, suggesting a trade-off between highly active repair mechanisms and late-life pathology in females. Dietary restriction reduces gut pathology in ageing females, and extends female lifespan more than male. By genetic sex reversal of a specific gut region, we induced female-like ageing pathologies in males, associated with decreased lifespan, but also with a greater increase in longevity in response to dietary restriction.

The effects of graded levels of calorie restriction: VI. Impact of short-term graded calorie restriction on transcriptomic responses of the hypothalamic hunger and circadian signaling pathways

Food intake and circadian rhythms are regulated by hypothalamic neuropeptides and circulating hormones, which could mediate the anti-ageing effect of calorie restriction (CR). We tested whether these two signaling pathways mediate CR by quantifying hypothalamic transcripts of male C57BL/6 mice exposed to graded levels of CR (10 % to 40 %) for 3 months. Hunger signaling, circadian rhythms and their downstream effects are far more complex than the results described here. Although limited by using a knowledge based signaling network, we were able to gain insights into the potential mechanisms underpinning the action of CR. Associations between gene expression and physiological outcomes such as body temperature and food anticipatory activity established by linear models and correlations are obviously only descriptive and causality cannot be assumed. Nevertheless these individual mice have been subjected to an unprecedented level of phenotyping allowing us to tie together the complex transcriptomic changes to alterations in body composition, circulating hormones and physiological outcomes.

Overall, our study has demonstrated that increasing levels of CR lead to a graded expression of genes involved in both hunger signaling and circadian rhythms. The expression of genes in these pathways wwere correlated with circulating levels of leptin, insulin, TNF-α and IGF-1, but not resistin or IL-6. We also demonstrated the phenotypic responses to CR (body temperature and physical activity) were significantly associated with the key hunger and core clock genes. Our results suggest that under CR modulation of the hunger and circadian signaling pathways, in response to altered levels of circulating hormones, drive some of the key phenotypic outcomes, such as activity and body temperature, which are probably important components of the longevity effects of CR.


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