How does caloric restriction slow down aging?

Overview
Caloric restriction seems to slow down some of the destructive processes that take place in cells and tissues with aging. Scientists don't yet know exactly how or why it works, but have developed several theories.

First of all, caloric restriction seems to reduce damage from chemical metabolic processes, particularly oxidative and glycation damage, thought to be leading causes of cell aging and death.

On a larger scale, caloric restriction slows the effects of aging on the nervous system, the reproductive organs and the production of hormones in some animals. It has been shown to boost the immune system and delay the onset of certain age-related cancers.

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Reducing cellular damage
Oxidative damage results when free radicals, the potentially toxic byproducts of cell energy production, break down DNA, cell walls, and mitochondria, the energy factories of cells. Caloric restriction has been observed to retard and even reverse oxidative damage in aging animals.

Glycation is the addition or insertion of sugar molecules into DNA and proteins that takes place in a variety of physiological reactions. Glycation causes damage to proteins and DNA and is thought to be a major cause of degeneration associated with diabetes and other diseases. Caloric restriction also reduces glycation damage in tissues.

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Hormonal effects

Insulin
Caloric restriction in animals also has potent effects on glucose and insulin regulation. Glucose is a simple sugar that is one of the major sources of energy for mammals. It enters the circulation after food is digested and circulates until the hormone insulin assists its movement into cells to be turned into fuel, or into the liver, to be stored for future use. With age and obesity, mammals such as mice, monkeys and humans develop insulin resistance, which is a drop-off in the ability of insulin to push glucose into cells. With insulin resistance, blood glucose (blood sugar) levels rise, blood insulin levels rise, and cells and tissues are damaged. Diabetes, high blood pressure, hardening of the arteries, heart disease and stroke are some of the consequences of insulin resistance in humans.

Caloric restriction protects against insulin resistance. The tissues of an animal whose total calorie (and thus energy) intake is limited become more sensitive to insulin for driving glucose into cells. This has been observed in numerous species of laboratory mice and rats; recent studies in non-human primates have also demonstrated caloric restriction's beneficial effects on reducing insulin resistance.

Glucocorticoids
Caloric restriction has been shown to increase the ability of aging rodents to produce glucocorticoids, which are natural steroids produced when the body is under stress. They help stop glucose from being stored and instead redirect it into tissues that need it. As mammals age, the neurotransmission of signals between the brain and the adrenal gland is altered and the release of these stress hormones falters. Caloric restriction increases the blood level of glucocorticoids.

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Protection against temperature effects
Another interesting cellular change noted in aging rodents subjected to caloric restriction is their ability to resist the damaging effects of hyperthermia, or elevated body temperature.

Calorie restricted rodents are harder to kill by hyperthermia. The mechanism that confers this protection on calorie-restricted rodents is not yet clear, however. Some scientists speculate that this protection may be conferred because older mammals are less likely to produce protective substances called heat shock proteins. Others say that a rodent’s ability to cope with hyperthermia may not involve heat shock proteins at all. Instead, it might be related to weight. Calorie restricted rats are extremely lean and this helps them to stay cooler even in a hot room. Control rats, in contrast, are obese. Obesity interferes with heat loss in a hot environment.

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Downsides
Caloric restriction leads to reduced ability to deal with hypothermia (lowered body temperature)—possibly associated with the individual's lower body fat content. Another problem is that wounds don't heal as quickly in calorie-restricted animals as in normal-fed laboratory animals.

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