A Discussion of the Effects of Calorie Restriction

Calorie restriction, reducing calorie intake while maintaining optimal levels of micronutrients, produces beneficial alterations in near all aspects of metabolism. It extends healthy life spans in near all species investigated to date, through this effect is much larger in short-lived species that have evolved a greater plasticity of life span in response to circumstances. In humans the consensus is that it might make a difference of a few years to overall life span, but it certainly greatly improves measures of health and lowers risk of age-related disease, suggesting the effect on healthspan is probably larger. Here, researchers discuss the effects of calorie restriction and some of the candidate calorie restriction mimetic drugs. It is a lengthy paper, but worth reading if you'd like a comprehensive overview of past investigations:

The aging process is undoubtedly the single most significant contributor to disease and death. Although this has been the inevitable outcome of all life on this planet, is aging an unavoidable consequence or can it be treated and potentially cured? As of yet this question remains unanswered, but many believe that the aging process is essentially a disease. Environmental conditions, including lifestyle, can greatly affect the rate of aging. For example, obesity or excessive ingestion of calories has been linked to increased incidents of age-related pathologies. Several lines of research indicate that certain behaviors can increase our health and potentially lifespan, such as exercise and regimes to improve cardiovascular function. One such intervention is the use of dietary/caloric restriction (CR); the reduced intake of calories/nutrients without causing malnutrition. In recent years, this observation has been verified across a large number of model organisms. These observations not only demonstrated an increase in the lifespan, but also in healthspan (time spent being healthy) of these organisms coincident with a significant decrease in age-related pathologies such as cardiovascular disease, diabetes and a number of cancers. For example, when fed a diet consisting of 35% of the ad libitum intake but enriched with vitamins and minerals, mice lived an average of 53 months, compared to 35 months in the control ad libitum-fed group.

Several drugs or naturally occurring compounds in food have been found to "mimic" the phenotypes of CR and could be potential alternatives to this somewhat difficult to follow dietary regime. An obvious first question: Do these compounds mirror the effects of CR? A large body of outstanding research focuses on the impact of CR and mimetics on autophagy in the regulation of longevity and in promoting apoptosis in cancer cells; however, the mechanism and impact on genome function (gene expression) and organization (epigenetic changes and physical genome folding) are less well understood. The oxidative damage attenuation hypothesis states that increased metabolism from high levels of nutrients/calories leads to higher rates of reactive oxygen species (ROS) and that lowering these levels will prevent lipid, protein and DNA damage. Damage such as this would lead to decreased function of cellular components as well as to increased rates of mutation. However, the other side of this hypothesis states that lower metabolic rates results in decreased rates of DNA damage and increased genome stability, and thus in fewer incidents of cancer. Although this is logical, some data does indicate that there is not a significant enough change in free radical production upon CR to significantly decrease ROS levels indicating that the benefits of CR might not be elicited through this mechanism. Although CR increases lifespan, it may not be due to a reduction of the ROS levels produced by mitochondria, but may result from an increase in the expression of enzymes that protect against these highly reactive molecules, reducing net oxidative stress. However, in D. melanogaster exposed to CR, no link between lifespan extension and increased resistance to oxidative stress has been found.

The altered glucose-insulin hypothesis indicates that CR causes a decrease in the circulating levels of both insulin and glucose, leading to decreased insulin signaling. This is based on observations that decreased insulin signaling promotes increased lifespan in a variety of model organisms. Increased glucose and insulin in the circulatory system will cause peripheral cells to absorb this glucose and convert it to ATP. In addition, insulin will also send positive growth and proliferative signals, pushing cellular balance toward growth and cell division. Therefore, CR may promote increased lifespan by decreasing rates of cell division and favoring repair and maintenance. The growth hormone-IGF-1 axis hypothesis states that increased signaling through these pathways advances the aging process by promoting cell growth and proliferation. Similarly to the glucose-insulin level hypothesis, CR causes the reduction of growth hormone/IGF-1 signaling, favoring a switch from cell growth and proliferation to maintenance and repair in mice. However, in human studies over a 2 year period of CR, no change in circulating IGF-1 levels were observed. These findings hint at two potential conclusions; (1) CR does not work in humans, only in mice, or (2) CR does not impact IGF-1 levels; however, it does impact other pathways, leading to at least increased healthspan, if not lifespan.

The hormesis hypothesis states that low levels or intensity of stress leads to "priming" in which cells/tissues/organs can then withstand other stresses that would normally prove terminal. It is thought that with hormesis, cells move from active growth and proliferation to a state that favors repair and maintenance. CR may prime cells by activating stress pathways to deal with later assault such as DNA damage. Other specific observations appear to favor this model, activating transcription factors and mechanisms controlling gene expression leading to increased levels of proteins mediating cellular stress responses. A large number of gene expression studies have been performed in order to determine the impact of CR on genome function. CR is well known to elicit a change in cell behavior marked by a decrease in cell proliferation and shift to cellular maintenance and repair. Changes in phenotype are accompanied by changes in gene expression; therefore, what impact does CR have on gene expression from across the genome?

It is clear that CR results in decreased energy and changes in cellular AMP:ATP and NAD:NADH ratios. Compounds that mimic CR do so by impacting cellular function resulting energy readouts or interfering with signaling down-stream cellular energy levels. The main proteins that appear central to mediating this response are AMPK and SIRT1 which regulate cycles of deacetylation and phosphorylation of a large number of proteins to control gene expression and cellular functions. Many of the CR mimetics of naturally occurring compounds identified either modulate SIRT1/AMPK function or, for example with rapamycin, target downstream signaling hubs to mediate potential health and lifespan effects. Of these targets NF-κB and the FOXO family of transcription factors, are pivotal in promoting decreased cell proliferation and increased maintenance in normal cells, while facilitating apoptosis and cell death in cancer cells. Furthermore, although all compounds appear to confer life and healthspan extending impacts across numerous cell types and model organisms via this SIRT1/AMPK interaction, the downstream impact on genome function (gene expression) is varied, across cell-type, organism-type, and compound-type in addition to variations in experimental details (such as exposure times, drug concentrations). This suggests that although mechanisms mediating health and lifespan in response to CR and these compounds are similar, the effects on gene expression mean that these compounds may not be direct mimetics of CR or of one another.

Link: http://dx.doi.org/10.3389/fgene.2016.00142


This year's Nobel prize in medicine has been awarded for research on autophagy.

Posted by: Antonio at October 3rd, 2016 4:26 PM
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