Metabolic and Neuropsychiatric Effects of Calorie Restriction and Sirtuins

Abstract

Most living organisms, including humans, age. Over time the ability to do physical and intellectual work deteriorates, and susceptibility to infectious, metabolic, and neurodegenerative diseases increases, which leads to general fitness decline and ultimately to death. Work in model organisms has demonstrated that genetic and environmental manipulations can prevent numerous age-associated diseases, improve health at advanced age, and increase life span. Calorie restriction (CR) (consumption of a diet with fewer calories but containing all the essential nutrients) is the most robust manipulation, genetic or environmental, to extend longevity and improve health parameters in laboratory animals. However, outside of the protected laboratory environment, the effects of CR are much less certain. Understanding the molecular mechanisms of CR may lead to the development of novel therapies to combat diseases of aging and to improve the quality of life. Sirtuins, a family of NAD+-dependent enzymes, mediate a number of metabolic and behavioral responses to CR and are intriguing targets for pharmaceutical interventions. We review the molecular understanding of CR; the role of sirtuins in CR; and the effects of sirtuins on physiology, mood, and behavior.

Ketogenic diets, mitochondria, and neurological diseases

“…Finally, there is CR, a dietary practice known to reduce the progression of many age-related diseases. Interestingly, this particular dietary strategy, which the KD was originally designed to mimic, has been an intense focus for researchers interested in the mechanisms underlying aging/longevity, neurological diseases, and a host of other conditions (58)(59)(60).…”

“…CR involves a reduction in total daily caloric intake below the ad libitum level without the risk of malnutrition ( 58,66 ). CR is well-known to ameliorate many age-related and metabolic diseases, and is the only natural method known to increase life-span across multiple species ( 60 ). As such, comparisons of the KD and CR on seizure control have been performed in animal concentrations ( 78 ).…”

“…It is well-established that multiple signaling pathways have evolved to sense states of diminished energy stores, such as seen during exercise and CR, and that activation of these pathways results in restoration of cellular homeostasis and integrity ( 60,130 ). Data regarding the association of the KD with these energy-sensing pathways are limited, but the similarities between the protective mechanisms evoked by the KD and those known to be infl uenced by these pathways indicates substantial overlap in their mechanisms and downstream effects.…”

Calorie Restriction, Longevity and Cognitive Function

“…CR in Huntington mutant mice increased the level of Brainderived neurotrophic factor (BDNF) and the protein chaperone heat-shock-protein-70 in the stratum and cortex, which were depleted in HD mice fed a normal diet.CR promotes neuronal degeneration by impairing cellular resistance (21). Underlying mechanisms: There is ample evidence that the mechanisms involve significant alterations in energy metabolism; response to oxidative damage, insulin sensitivity, inflammation, and changes in the neuroendocrine, paracrine and reproductive systems (22) .CR induces a down-regulation of inflammatory pathways (e.g., nuclear factor kB), and an up-regulation of genes that enhance protection against molecular damage (e.g., Nrf2 (nuclear factor-erythroid 2), heat shock protein70 (HSP70)) (23). Similar to other organ systems, cells in the brain encounter a cumulative burden of oxidative and metabolic stress that may be universal feature of the aging process and neurodegenerative disorders.…”

“…In AD, SIRTUN can deacetylate retinoic receptor β; this in turn results in encoding α-secretase, which can reduce the formation of toxic Aβ. Increasing level of heat shock protein due to higher amount of SIRT1 can have protective role in PD, and eventually SIRT1 in HD activates the target of rapamysin complex1(TORC1) that interacts with cAMPresponsive element binding protein (CREB), resulting in higher levels of BDNF, a neuroprotective factor in HD (22). BDNF: Neurotrophins are critical for development and maintenance of the mammalian central nervous system.…”