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Caloric restriction to prevent age-related disorders and extend lifespan

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Hypotheses of anti-aging effect by caloric restriction

The underlying mechanisms of the effects of caloric restriction on longevity have not yet been definitely demonstrated. Indeed, there are hundreds of hypotheses that still must be tested before the mechanism responsible for extended lifespan in response to reduced food intake is fully understood.

The most reliable hypothesis of the anti-aging effect of caloric restriction is associated with the reduction of oxidative stress. The oxygen that enters the body is changed into reactive oxygen species (ROS) through cellular respiration, which subsequently attacks the macromolecules in the cells, resulting in the onset of age-associated changes. Caloric restriction is thought to reduce ROS production, which delays the aging processes.

Caloric restriction also reduces body temperature, and this decreased body temperature has been shown to be one of the mechanisms contributing to lifespan extension by caloric restriction.

Molecular signals associated with caloric restriction

Although the mechanisms of caloric restriction have not been clearly defined, most gerontologists believe that the effects of caloric restriction on longevity are associated with nutrient-triggered signaling cascades, such as insulin/insulin-like growth factor-1 (IGF) signaling, and the target of rapamycin (TOR) pathway. Lifespan extension and retardation of aging processes are observed when the activity of these nutrient-triggered signaling pathways is reduced by mutations or chemical inhibitors.

Insulin/IGF signaling

Over intake of glucose, a major energy source in a variety of model animals, induces age-related diseases such as diabetes and cardiovascular disease. Increased glucose levels in serum followed by food intake promote the secretion of insulin hormone, which in turn activates insulin/IGF signaling. After binding with insulin, insulin receptor activates downstream factors such as PI3K/Akt/Ras and/or represses forkhead box O (FOXO) transcription factor, which is well-known to regulate stress response genes. Modulation of organismal longevity by insulin/IGF signaling has been well defined in various animals from yeast to mammals. Under caloric restriction conditions, systemic levels of insulin/IGF signaling are definitely decreased in many species. Thus, insulin/IGF signaling has been proposed as a mediator of longevity benefit by caloric restriction. However, it is still not clear whether the longevity extension effect of caloric restriction is dependent on the insulin/IGF signaling pathway. Flies containing the FOXO mutation still responded to caloric restriction, and the lifespan of long lived-Ames dwarf mice generated by mutation of growth hormone was also extended by caloric restriction.

TOR pathway

The other nutrient sensor signaling pathway known to regulate longevity is the TOR pathway, which is a well-known amino acid sensor that is evolutionally conserved from yeast to mammals. Activation of TOR by amino acids promotes protein synthesis via the activation of S6K and/or the inhibition of 4EBP, and the inactivation of TOR promotes the degradation of damaged proteins and intracellular organelles via autophagy. Thus, decreased expression or activity of the TOR signaling pathway is known to extend lifespan in nematodes, flies, and rodents. Since it plays a role as an amino acid sensor, the TOR pathway has been proposed as a mediator of caloric restriction. However, there are conflicting reports of the effects of caloric restriction on TOR expression in rodents. Thus, further intensive investigations are required to enable a precise understanding of the mediators of caloric restriction.

Caloric restriction also reduces body temperature. Image Source: Imago Images

Adenosine Monophosphate -activated Protein Kinase (AMPK) signaling

AMPK is emerging as a key nutrient-triggered signaling pathway underlying the lifespan extension effect of caloric restriction. Under energy deprivation conditions, LKB phosphorylates and activates AMPK, which in turn stimulates the processes to generate ATP. The nematode model system has generated evidence in support of the function of AMPK on lifespan extension by caloric restriction. Worms overexpressing AMPK (aak-2) lived longer than controls, and glucose restriction increased aak-2 activity. Furthermore, it was reported that the lifespan extension effect by caloric restriction was dependent on aak-2 in a C. elegans model. In the Drosophila model system, activation of AMPK activity via the overexpression of LKB1 extended the lifespan. In addition, a recent study showed that the tissue-specific overexpression of AMPK in muscle and abdominal fat body extended the fly lifespan and that supplementation of adenosine could modulate the beneficial effects of caloric restriction, which are associated with the activation of AMPK. However, it is still not clear whether AMPK is a mediator of the effects of caloric restriction on longevity in mammalian systems.

Sirtuin

At the beginning of the 21st century, a new factor, Sirtuin, gained a great deal of attention as a mediator of caloric restriction. Sirtuins are evolutionally conserved nicotine amide (NAD)-dependent histone deacetylases. In calorie-restricted environments, the expression and activity of Sirtuin is increased in many tissues, including adipose and brain tissue. The overexpression of Sirtuin in worms and flies increased lifespan, and mutants of Sirtuin do not show lifespan extension by caloric restriction. The roles of Sirtuin as a mediator of caloric restriction have also been shown in the mammalian model animal. Transgenic mice expressing SIRT1, which is the most thoroughly investigated mammalian Sirtuin, showed similar phenotypes to that of food-restricted mice. In addition, the extension of longevity in response to caloric restriction was not observed in mice from which SIRT1 had been deleted. However, there is conflicting evidence regarding the role of Sirtuin as a caloric restriction mediator. Indeed, some studies showed that various caloric restriction conditions did not activate Sirtuins, and the phenotype of Sirtuin overexpression did not exactly coincide with that of caloric restriction.

Although the beneficial effects of caloric restriction on lifespan and health have been clearly demonstrated, it is difficult to implement a rigid dietary regimen at a larger scale. To overcome difficulties associated with changing eating habits, gerontologists and biologists have been attempting to develop drugs to mimic the beneficial effects of caloric restriction without the need for embarking on a strict diet. Such medicines are known as caloric restriction mimetics (CRM).

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