Recent Calorie Restriction Research: Monkeys, Squirrels, Mice, and Yeast

Researchers around the world are examining the effects of calorie restriction in many different species, and have been for years. In near all species reducing calorie intake while maintaining optimal levels of vital nutrients extends life and provides numerous health benefits. Spectacular improvements in general health and lowered risk of disease are observed in human practitioners, far more than any presently available medical technology can offer a basically healthy individual, but the jury is still out on the degree to which calorie restriction can extend maximum life span in our species and other longer-lived primates. In part this is due to a lack of data: it takes a long time to run such a study when the only reliable way to measure life extension is to wait and see, and there is little in the way of large sets of historical data to mine. Researchers currently expect calorie restriction to extend human life by only a few years, and the historical absence of evidence bears this out: if calorie restriction with adequate nutrition could significantly extend human life - such as by the 40% seen in laboratory mice - then our ancestors would have found out a long time ago, and at the very least within the last few hundred years of more advanced technology and greater wealth.

Investigations into the biology of calorie restriction induced health and longevity are really only a sideshow in the grand scheme of longevity science. Radical life extension can only arrive from rejuvenation biotechnologies - therapies that can repair the low-level biological damage that causes aging. If you restrict your calories you can expect to have a much healthier life, on average, than would otherwise be the case, something that has great merit in and of itself. But don't expect it to add decades to your overall life span, because it probably won't. For that sort of result, you need to look to the Strategies for Engineered Negligible Senescence (SENS) or other similar programs aiming for new medical technologies to reverse the root causes of aging.

Nonetheless, it will be interesting to see how researchers reconcile the fact that short-term health benefits due to calorie restriction are large and similar in mice and humans, yet calorie restricted mice live for much longer, while humans probably don't. Here are a few recent papers from the breadth of ongoing research into the effects of a lower calorie intake on aging and longevity:

Long-term calorie restriction decreases metabolic cost of movement and prevents decrease of physical activity during aging in the rhesus monkeys

Short-term (less than 1 year) calorie restriction (CR) has been reported to decrease physical activity and metabolic rate in humans and non-human primate models; however, studies examining the very long-term (greater than 10 year) effect of CR on these parameters are lacking. The objective of this study was to examine metabolic and behavioral adaptations to long-term CR longitudinally in rhesus macaques.

Eighteen (10 male, 8 female) control (C) and 24 (14 male, 10 female) age matched CR rhesus monkeys between 19.6 and 31.9 years old were examined after 13 and 18 years of moderate adult-onset CR. Energy expenditure (EE) was examined by doubly labeled water (DLW; TEE) and respiratory chamber (24h EE). Physical activity was assessed both by metabolic equivalent (MET) in a respiratory chamber and by an accelerometer. Metabolic cost of movements during 24h was also calculated. Age and fat-free mass were included as covariates.

Adjusted total and 24h EE were not different between C and CR. Sleeping metabolic rate was significantly lower, and physical activity level was higher in CR than in C independent from the CR-induced changes in body composition. The duration of physical activity above 1.6 METs was significantly higher in CR than in C, and CR had significantly higher accelerometer activity counts than C. Metabolic cost of movements during 24h was significantly lower in CR than in C. The accelerometer activity counts were significantly decreased after seven years in C animals, but not in CR animals. The results suggest that long-term CR decreases basal metabolic rate, but maintains higher physical activity with lower metabolic cost of movements compared with C.

Molecular signatures of mammalian hibernation: comparisons with alternative phenotypes

Mammalian hibernators display phenotypes similar to physiological responses to calorie restriction and fasting, sleep, cold exposure, and ischemia-reperfusion in non-hibernating species. Whether biochemical changes evident during hibernation have parallels in non-hibernating systems on molecular and genetic levels is unclear.

We identified the molecular signatures of torpor and arousal episodes during hibernation using a custom-designed microarray for the Arctic ground squirrel (Urocitellus parryii) and compared them with molecular signatures of selected mouse phenotypes. Our results indicate that differential gene expression related to metabolism during hibernation is associated with that during calorie restriction and that the nuclear receptor protein PPARĪ± is potentially crucial for metabolic remodeling in torpor. Sleep-wake cycle-related and temperature response genes follow the same expression changes as during the torpor-arousal cycle. Increased fatty acid metabolism occurs during hibernation but not during ischemia-reperfusion injury in mice and, thus, might contribute to protection against ischemia-reperfusion during hibernation.

SIRT1 but not its increased expression is essential for lifespan extension in caloric restricted mice

The SIRT1 deacetylase is one of the best-studied potential mediators of some of the anti-aging effects of calorie restriction (CR); but its role in CR-dependent lifespan extension has not been demonstrated. We previously found that mice lacking both copies of SIRT1 displayed a shorter median lifespan than wild type mice on an ad libitum diet. Here we report that median lifespan extension in CR heterozygote SIRT1+/- mice was identical (51%) to that observed in wild type mice but SIRT1+/- mice displayed a higher frequency of certain pathologies. Although larger studies in different genetic backgrounds are needed, these results provide strong initial evidence for the requirement of SIRT1 for the lifespan extension effects of CR, but suggest that its high expression is not required for CR-induced lifespan extension.

Maintenance of cellular ATP level by caloric restriction correlates chronological survival of budding yeast

The free radical theory of aging emphasizes cumulative oxidative damage in the genome and intracellular proteins due to reactive oxygen species (ROS), which is a major cause for aging. Caloric restriction (CR) has been known as a representative treatment that prevents aging; however, its mechanism of action remains elusive. Here, we show that CR extends the chronological lifespan (CLS) of budding yeast by maintaining cellular energy levels. CR reduced the generation of total ROS and mitochondrial superoxide; however, CR did not reduce the oxidative damage in proteins and DNA. Subsequently, calorie-restricted yeast had higher mitochondrial membrane potential (MMP), and it sustained consistent ATP levels during the process of chronological aging. Our results suggest that CR extends the survival of the chronologically aged cells by improving the efficiency of energy metabolism for the maintenance of the ATP level rather than reducing the global oxidative damage of proteins and DNA.
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