Intermittent Fasting and Longevity
Research has suggested that intermittent fasting may have a positive effect on longevity. The restriction of caloric intake from intermittent fasting can lead to benefits including improved insulin sensitivity, increased sirtuin levels, and increased DNA repair. These changes in turn lead to improved stem cell function, improved mitochondrial function, and increased autophagy and tissue repair, all of which are crucial for improvements in longevity.1
Dietary restriction can lead to several physiological changes that lead to improved organ function, and improved resistance to stress, which would lead to improved longevity.
Research in humans
Retrospective epidemiological studies on human populations may gives us insight into the positive effects that may occur in humans.
Prospective studies on humans have yielded some promising effects of intermittent fasting and caloric restriction on longevity. There has been a growing interest in analyzing expression of biomarkers for longevity while undergoing intermittent fasting. In a study involving 11 non-obese subjects between BMI 20 to 30 kg/m^2, it was fond that after 3 weeks of alternate day fasting, there was a positive trend of increase in CPT1 expression in response to the alternate day fasting. In this study, a gene for longevity, SIRT1, was found to have increased expression.2
In humans, sirtuins including SIRT1 play a role in regulating the functions of the hypothalamus, a structure in the brain that plays a central role in maintaining homeostatic function with regards to circadian rhythm, feeding behavior, energy expenditure, and body temperature.3
SIRT1 modulates various functions of the hypothalamus.
The reasoning for why intermittent fasting and caloric restriction can impact sirtuin levels and activation is not scientifically clear, however some evidence suggests that caloric restriction induces cellular respiration in cells, which leads to increased levels of NAD+ and reduced levels of NADH. Since NADH is a competitive inhibitor to Sir2 and SIRT1.4
Research in animals
There is a growing body of scientific knowledge showing the effects of intermittent fasting on longevity in animal models. Studies have shown that prolonged fasting can result in longer lifespan by anywhere from 10% to 30%, in addition to other benefits such as lower levels of body fat and serum glucose in mice.5Furthermore, lifespan has been known to be increased by over 100% in bacteria and yeast (see Figure 1).6
From an evolutionary perspective, it is possible that the link between fasting and longevity arose over billions of years, as early organisms attempted to survive in nutrient-devoid environments, while simultaneously avoiding age-dependent damage.6
Fasting can increase lifespan in yeast, worms, and mice.
Biomarkers for longevity
There are various molecular biomarkers which have been suggested to play a role in longevity. Sirtuins, which are a class of proteins which carry antioxidative potential via mono-ADP-ribosyltransferase or deacylase properties. Furthermore, research shows that intermittent fasting and caloric restriction can play a role in upregulating sirtuins.3One of the most widely studied sirtuin genes in animals is Sirt1 (known as Sirt1 in yeast and bacteria, SIRT1 in mammals), which has been found to modulate various molecular pathways that are implicated in aging. For example, Sirt1 activity has been reported to activate PGC-1α, which is involved in inducing mitochondrial biogenesis in yeast.7,8,9,10This is important because mitochondria play a central role in maintenance and regulation of metabolic state. In addition, Sirt3, Sirt5, and Sirt6 have also been associated with improvements in mitochondrial function.7With regard to insulin sensitivity, Sirt6 was found to affect levels of insulin-like growth factor 1 (IGF1) expression, as well as bone density, in transgenic mice.11Such discoveries substantiate the broad affect of sirtuins on various aspects of aging.
Sirt6 knockout mice show significantly lower bone density, implicating a role of sirtuins in maintaining bone health, which becomes vital in old age.
Heilbronn, L. K., Civitarese, A. E., Bogacka, I., Smith, S. R., Hulver, M., & Ravussin, E. (2005). Glucose tolerance and skeletal muscle gene expression in response to alternate day fasting. Obesity research, 13(3), 574-581.
Brandhorst, S., Choi, I. Y., Wei, M., Cheng, C. W., Sedrakyan, S., Navarrete, G., ... & Di Biase, S. (2015). A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan. Cell metabolism, 22(1), 86-99.
Nemoto, S., Fergusson, M. M., & Finkel, T. (2005). SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1α. Journal of Biological Chemistry, 280(16), 16456-16460.
Rodgers, J. T., Lerin, C., Haas, W., Gygi, S. P., Spiegelman, B. M., & Puigserver, P. (2005). Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature, 434(7029), 113-118.
Gerhart‐Hines, Z., Rodgers, J. T., Bare, O., Lerin, C., Kim, S. H., Mostoslavsky, R., ... & Puigserver, P. (2007). Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC‐1α. The EMBO journal, 26(7), 1913-1923.
Mostoslavsky, R., Chua, K. F., Lombard, D. B., Pang, W. W., Fischer, M. R., Gellon, L., ... & Mills, K. D. (2006). Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell, 124(2), 315-329.
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