While this was first discovered over 70 years ago, the mechanism behind increased life span by calorie restriction has eluded us. Here, I discuss the mechanism that I find to be the most consistent and plausible; glucose hysteresis.
Glucose hysteresis was implicated as a possible cause of aging by Mobbs et al. in the 2007 paper, “Glucose Hysteresis as a Mechanism in Dietary Restriction, Aging, and Disease.” Hysteresis describes a state in which certain genes are “switched” on or off by some metabolite, and the genes tend to remain in that state. That is, the genes have a sort of “memory.” In the case of glucose hysteresis, glucose is the metabolite involved in up- or down-regulating the expression of certain genes.
Metabolites, like glucose, can induce changes in an organism’s gene expression in order to make the utilization of that metabolite more efficient (1,2). This allows the organism’s molecular machinery to optimize the metabolism of that fuel source. There is evidence that these genes remain up-regulated even after the fuel source has been used up (3-7). This way, the organism is prepared to efficiently utilize that fuel source in the future.
The body uses different machinery to break down different fuel sources. When carbohydrates are consumed, they are broken down into glucose. Then, glucose is further broken down in a process called glycolysis. The end products of glycolysis are mainly dependent on an enzyme called mitochondrial complex I to complete the metabolism.
When fats are consumed, they undergo beta-oxidation, which can be thought of as the equivalent of glycolysis for fats. The end products of this process are mainly dependent on mitochondrial complex II to complete metabolism.
Complex I (needed for glucose metabolism) produces more reactive oxygen species (ROS) than complex II (needed for fat metabolism) (8-10). ROS are highly reactive molecules that cause oxidative damage and can promote aging. It is thought that life extension through dietary restriction is a result of decreased oxidative damage (11-14).
During dietary restriction, glycolysis is reduced and lipid metabolism is increased. As people age, the opposite occurs (15). Several studies have shown that reducing glycolysis increases life span, while increasing glycolysis decreases life span (16-19).
Metabolism of fats rather than glucose has advantages other than just reducing the amount of ROS produced. The breakdown of fats produces the antioxidant NADPH, which can help prevent oxidative stress in the body. Furthermore, when fat metabolism is up-regulated, there is a greater turnover rate of fats and proteins, thereby reducing the accumulation of oxidized fatty acids (20).
Thus, according to the glucose hysteresis hypothesis, consumption of glucose leads to an up-regulation of the glycolysis machinery. Over time, the body becomes more adapted to metabolizing glucose for fuel rather than fats and proteins. This leads to increased ROS production, reduced antioxidant production, greater accumulation of oxidized fatty acids, and ultimately increases the rate of aging.
According to this hypothesis, by reducing glucose consumption and increasing fat consumption people could “reprogram” their gene expression and increase their life span.
While there is strong evidence backing this hypothesis, the authors note that further study is needed to confirm it. For example, a study should be done where plasma glucose is permanently lowered using genetic manipulation. If the glucose hysteresis hypothesis is accurate, this should produce the same life span increasing effects as dietary restriction.
If proven correct, glucose restriction could offer a promising way to increase life span. However, this hypothesis may be slow to gain traction as it goes directly against the “common knowledge” today that a healthy diet consists primarily of carbohydrates with moderate protein and little fat.
Lastly, I should note that carbohydrates can provide benefits, such as increasing athletic performance. Sources of carbohydrates like fruits and vegetables can provide vitamins and antioxidants. So, a cost-benefit analysis is needed on an individual basis to determine the optimal amount of carbohydrates in the diet.
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