Calorie Restriction Reduces Inflammation via Moderate Hyperadrenocorticism

The metabolic response to calorie restriction, a sustained reduction in calorie intake while maintaining optimal micronutrient intake, is sweeping and complex. It also extends life span quite dramatically in short-lived species. Near everything changes, which makes it a challenge to characterize the few important mechanisms early in the chain of cause and effect. It also makes it a very fruitful area of study from the pure science perspective, as there is always something new to be discovered, as illustrated by the research results reported here.

While calorie restriction itself is widely studied, and a good lifestyle choice in this modern world of cheap calories and their consequences, I remain unconvinced that the biochemistry of calorie restriction is the road to therapies capable of meaningful extension of the healthy human life span. The gain might be a few years, and better health along the way. This is not to be rejected if that were the outer limits of what is possible, but it is not. It is a poor strategy in a world in which we could plausibly gain decades of additional time in good health by focusing on repair of the damage that causes aging, rather than trying to pick apart the evolved responses to diet.

Calorie restriction (CR) is among the most robust ways to extend lifespan and delay age-related diseases in mammals. Considerable evidence indicates that cell nonautonomous factors, often driven by neuroendocrine signaling, play an essential role in mediating the life- and health-span enhancing effects of CR. Less is known about the specific hormone targets of these neuroendocrine factors that ultimately promote the health-enhancing CR state. CR lowers plasma concentrations of numerous anabolic hormones, including growth hormone (GH), insulin, and insulin-like growth factor 1 (IGF1), which may be contributors.

By contrast, glucocorticoids, which play a major role in responding to stressors, are elevated in CR animals, although again their roles have not be delineated. Glucocorticoids are anti-inflammatory, and attenuated inflammation is widely observed in CR animals. These observations have led to the hypothesis that the hyperadrenocorticism of CR contributes to the attenuation of inflammation in CR animals. Here, we tested this hypothesis directly using a corticotropin-releasing hormone knockout (CRHKO) mouse, which is glucocorticoid deficient and has increased inflammation following allergen exposure.

There were four control groups: CRHKO mice and wild-type (WT) littermates fed either ad libitum (AL) or CR (60% of AL food intake), and three experimental groups: (a) AL-fed CRHKO mice given corticosterone (CORT) in their drinking water titrated to match the integrated 24-hr plasma CORT levels of AL-fed WT mice, (b) CR-fed CRHKO mice given CORT to match the 24-hr CORT levels of AL-fed WT mice, and (c) CR-fed CHRKO mice given CORT to match the 24-hr CORT levels of CR-fed WT mice. Inflammation was measured volumetrically as footpad edema induced by carrageenan injection. As previously observed, CR attenuated footpad edema in WT mice. This attenuation was significantly blocked in CORT-deficient CR-fed CRHKO mice. Replacement of CORT in CR-fed CRHKO mice to the elevated levels observed in CR-fed WT mice, but not to the levels observed in AL-fed WT mice, restored the anti-inflammatory effect of CR. These results indicate that the hyperadrenocorticism of CR contributes to the anti-inflammatory action of CR, which may in turn contribute to its life-extending actions.

Paradoxically, hyperadrenocorticism is well known to be detrimental to health and lifespan. In humans, chronically elevated glucocorticoids are associated with insulin resistance and are the cause of Cushing's syndrome, a life-threatening disorder of glucocorticoid overproduction. Chronic elevation of CORT levels increases the risk of hypertension, hyperkalemia, diabetes, atherosclerosis, osteoporosis, glaucoma, and impairment of the immune and reproductive systems. Elevation of CORT damages hippocampal cells in rats, which in turn is associated with neurodegeneration and cognitive impairment in rodents.

However, all evidence for deleterious effects of hyperadrenocorticism occurs under conditions of ad libitum food intake. There is no evidence that the hyperadrenocorticism associated with CR is deleterious. The results of this study suggest that it may be beneficial - to the extent that resilience against inflammatory stressors is advantageous for the organism. These results not only suggest glucocorticoids are necessary for the anti-inflammatory actions of CR in mice but also buttress previous results that hyperadrenocorticism of CR may be involved in the retardation of aging by CR.



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