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Calorie Restriction – Interspecies Phenomena!
Posted on: July 15, 2003

Calorie restriction in rodents is already known to slow down aging process. What could be the result of such prescription of healthier life to primates and humans? Does this "anti-aging, health increasing drug" works in all organisms uniformly? Starting with yeast and ending with humans?

Feeding fewer calories to rodents – and likely primates too – make them more stress resistant, they live considerably longer. Several other animal model systems have mutation induced metabolic states that are similar to those produced by caloric restriction and are also designed to withstanding adverse conditions. Scientists compared these long-lived creatures, ranging from yeast to mice and pointed out the commonalities, such as defects in insulin/insulin-like growth factor 1 signaling pathway.

Restriction of caloric intake (CR) extends longevity in organisms from yeast to mice and postpones or prevents a remarkable array of diseases and age-dependent deterioration without causing irreversible developmental or reproductive defects.

CR has remarkably broad effects on increasing the life span and attenuating chronic diseases of aging in rodents. In rodents, caloric restriction decreases the levels of plasma glucose and insulin-like growth factor I (IGF-I) and postpones or attenuates cancer, immunosenescence and inflammation without irreversible side effects. CR increases life span by about 35% and also results in a lower incidence of tumors, kidney disease, vascular calcification and chronic pneumonia. CR acts similarly in most rodent genotypes, extending their life span by slowing mortality rate increases and decreasing strain-specific tumors and other diseases.

The small but persistent decreases in blood glucose, insulin and IGF-I, the increased insulin sensitivity and elevated glucocortocoids may be responsible for the beneficial effects of CR in mice. These changes are homeostatic responses to reduced body stores of fat and the need of increased gluconeogenesis. Monkeys show similar effects of CR on glucose and insulin, as well as indications of reduced mortality. In a small group of healthy non-obese humans, CR also causes physiologic, hormonal and biochemical changes resembling those caused by CR in rodents and monkeys. CR counteracts the general trend for laboratory rodents and primates to progressively add body fat during aging. Laboratory animals have much reduced daily activity as compared to their unlimited food and therefore can be considered as models for sedentary humans who are at high risk for obesity and insulin resistance. CR has few adverse outcomes for confined animals or sedentary obese humans.

In rodents CR increases protein synthesis in liver and probably in skeletal muscle, and it decreases the load of oxidized proteins. These substantial shifts may be due to faster protein turnover (which decreases exposure to endogenous damage), decreased production of metabolic toxins and increase of free-radical scavenging functions.

CR also modulates host defense functions. CR attenuates cellular immune age changes in more than 10 rodent genotypes. For example, lecithin-induced proliferation of splenic lymphocytes, which decreases sharply during aging in mice fed ad libitum, is increased twofold by CR at all ages. CR also enhances the immune responses to influenza during aging, blunts the aging changes in T cell functions by maintaining interleukin 2 (IL-2) production and delays or prevents changes in the proportion of memory cells during aging.

On the other hand, CR strongly inhibits inflammatory responses of aging. Blood levels of IL-6 and tumor necrosis factor-α (TNF-α) (which are both involved in acute phase responses) commonly increase during aging in rodents and humans. CR attenuates inflammatory gene expression throughout the body. CR has anti-inflammatory effects in brain, which normally shows prominent activation of microglia-monocytes during aging and in neurodegenerative diseases. High caloric intake is associated with increased risk of Alzheimer's disease, consistent with a role for CR in protecting against inflammation and neurodegeneration. Alzheimer's disease shows remarkable benefits from a broad group of anti-inflammatory drugs, particularly the nonsteroidal anti-inflammatory drugs. Long-term use of these drugs may be responsible for a reduction in the risk of Alzheimer's diseases, up to 80%. Non-steroidal anti-inflammatory drugs also reduced the risk of breast, colon and other cancers, possibly by inhibiting proliferation and decreasing angiogenesis. Long-term reduction of glucose levels may contribute to the decrease in inflammation and diseases in CR mice. The similarity of the effects of CR and nonsteroidal anti-inflammatory drugs in diseases of aging is consistent with the role of inflammatory mechanisms in vascular disease, Alzheimer's disease and many cancers. Thus, CR may extend life span in mammals by attenuating the major inflammatory diseases of aging.

By contrast, most genetic manipulations that extend life span cause major side effects. In organisms ranging from yeast to mice, mutations in glucose or IGF-I-like signaling pathways (mutations in these signaling pathways may simulate starvation conditions) extend life span but also cause glycogen or fat accumulation and dwarfism.


Fig. 1: WT (right specimen) and long-lived dwarf (left specimen) yeast, flies, and mice with mutations that decrease glucose or insulin/IGF-I like signaling. Yeast sch9 null mutants form smaller colonies (right). Sch9 mutants are also smaller size, grow at a slower rate, and survive three times longer than WT yeast. Chico homozygous mutant female flies are dwarfs and exhibit an increase in life span of up to 50% (center). Chico functions in the fly insulin/IGF-I like signaling pathway. The GHR/BP mice are dwarfs deficient in IGF-I and exhibit a 50% increase life span (left). Other yeast and worm mutants exhibit life-span extension of more than 100% but do not have any detectable growth defects.

Chronological longevity in yeast and worms is extended by inactivation of conserved glucose-dependent and insulin/IGF-I-like pathways that promote growth and, by an increase in protection against oxidative damage, other forms of stress. Systems that repair and replace damaged DNA, proteins and lipids are also likely to play a major role in extending survival. Conserved genes also regulate longevity in fruit flies. Mutations that decrease the activity of the fly insulin/IGF-I-like pathway cause dwarfism but nearly double longevity. A decrease in IGF-I signaling may also extend longevity in mice. Dwarf mice with a 90% lower IGF-I livelonger than the wild type mice.


Fig. 2: Conserved regulation of longevity. In yeast, worms, and flies, the partially conserved glucose or insulin/IGF-I like pathways down regulate antioxidant enzymes and HSP, reduce the accumulation of glycogen or fat, and increase growth and mortality. Mutations that reduce the activity of these pathways appear to extend longevity by stimulating CR or more severe forms of starvation. In yeast and worms, the induction of stress-resistance genes is required for longevity extension. In mice, IGF-I activates signal transduction pathways analogous to the longevity regulatory pathways in lower eukaryotes and increases mortality. However, the intracellular mediators of life-span extension in GH- or IGF-I- deficient mice have not been identified. In humans, mutations or diseases that result in plasma GH or IGF-I deficiencies cause dwarfism, obesity, and other adverse effects, but their effect on longevity is unclear.

Mammals exhibit an association between stress resistance and reduced IGF-I signaling. The storage of fat or glycogen is another aspect of the stress response. In yeast down-regulation of glucose-dependent pathway results in accumulation of glycogen, which is the major carbon source catabolized during periods of starvation. By contrast, in worms, flies and mice, the down-regulation of the insulin/IGF-I-like pathways results in the accumulation of fat. Dwarf mutations cause fat accumulation, which is reversed by administration of growth hormone. IGF-I deficiency also increases fat accumulation in humans. The switch between glycogen storage in yeast and fat storage in metazoans is consistent with the role of longevity regulatory pathway in inducing accumulation of the carbon source that would maximize long-term survival during periods of starvation.

CR, dwarf and IGF-I-deficient mice share a number of biochemical and phenotypic characteristics, including reduced plasma insulin, IGF-I and glucose; reduced fertility and body size and delayed sexual maturation (Table 1). Many of these characteristics are also shared with IGF-I-deficient humans. Mutations in certain pathways in the yeast and worms can extend longevity but can also induce dormant phases that are normally entered during periods of starvation. In fact, these pathways are inactivated under starvation conditions. Thus, the reduced levels of plasma IGF-I in dwarf mice may contribute to disease prevention and life-span extension by simulating CR or more severe starvation conditions (Table 1). Consistent with this notion is the role of IGF-I in reversing the protection of CR against carcinogen induced bladder cancer. Apoptosis in the tumor is decreased 10-fold in CR mice in which the levels of IGF-I are restored, indicating that the activation of antiapoptotic pathways contributes to tumor incidence.

CR extends further the life span of dwarf mice, suggesting that the mechanisms that regulate life-span extension in CR and dwarf mice are not identical. In flies, by contrast dwarf mutations and CR slow aging through overlapping mechanisms. In dwarf mice CR may further increase longevity by preventing fat accumulation and reducing mortality associated with obesity. The obesity caused by growth hormone deficiency in humans may promote cardiovascular diseases and age-dependent mortality.


Table 1: Comparison of CR, dwarf mice, IGF-I deficient mice (GHR/BP), and IGF-I-deficient humans (Laron syndrome). N/A, no available data

Taken together knowledge of the molecular pathways that regulate longevity and CR, we can begin to develop a novel strategy to prevent diseases such as cancer, Alzheimer's and vascular diseases.

Abbreviations:
CR – caloric restriction,
WT – wild type,
HSP – heat shock proteins,
IGF-I – insulin growth factor I

Source: Valter D. Longo and Caleb E. Finch; Evolutionary medicine: from dwarf model systems to healthy centenarians? ; Science, vol. 299; Feb 28, 2003.
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