and Calorie Restriction - Page 3
Reprinted by permission from Bill Faloon of The Life Extension Foundation
A lean body may be more significant in determining life span in mice than a calorie-restricted diet (Bluher et al. 2003). The mice ate whatever they wanted and stayed slim because their fat tissue had been altered and could not respond to insulin.
Insulin is the primary hormone that transports sugar into the cells and facilitates storage of fat in adipose cells. Altered mice ate 55% more food per their body weight than normal mice, yet they had 70% less body fat at three months of age. Essentially, these mice were protected against obesity. These mice increased mean life span (134 days or 18%), median and maximum life spans. A reduction of fat mass (even without caloric restriction) was associated with increased longevity, possibly through effects mediated by insulin. These findings raise the possibility that a new drug for obesity and diabetes mellitus Type-2 (DM-2) might act by blocking insulin receptors in fat tissue. The drug would need to target fat tissue only because a loss of insulin sensitivity throughout the body would mimic DM-2 (Bluher et al. 2003; Mercola 2003b). The dangers of hyperinsulinemia (high blood insulin) are well-established (many degenerative diseases develop secondary to an excess of insulin).
Immune System Responds to Calorie Restriction
Restriction and Malignancies
Even moderate dietary restriction is an effective antiangiogenic (anti-canc) therapy against recurrent brain cancs. Dietary restriction shifted the tumor vascular environment from pro-angiogenic (favoring a well-developed vascular system to nurture the growing tumor) to an anti-angiogenic state through multiple effects on tumor cells and tumor-associated host cells (Mukherjee et al. 2002).
Calorie restriction favors apoptosis (programmed cell death) of damaged cells. Damaged cells either undergo repair or trigger apotosis. Chaperones are stress proteins that enable polypeptides to assume their proper shape (quaternary structure) and participate in mechanisms of apoptosis by secretion of proteins that inhibit apoptosis. High levels of chaperone occur with aging and prevents the useful induction of apotosis. Calorie restriction lowers chaperone levels, favoring apotosis of damaged and pre-cancous cells. A balance must exist in the need to maintain sufficient cell numbers for a particular tissue function and the need to eliminate damaged, potentially toxic cells. Non-dividing cells, such as neurons, cannot be replaced. Calorie restriction induces chaperone expression in neuronal cells and may delay the onset of neurologic disorders of aging, including Alzheimer's disease, Parkinson's disease and stroke. Rapidly dividing cells, such as liver cells, has shown that calorie restriction reduces chaperones, encouraging the death of aged and pre-cancous cells (Wickner et al. 1999;Spindler, 2001a; Suh et al. 2002; Ken t, 2003).
Although the anti-canc effects of calorie restriction are well-established, Spindler (BioMarker Pharmaceuticals) does not recommend calorie restriction for individuals with canc. There is no question that calorie-restriction improves health, but it is impractical to try to improve the health of very sick people by under-feeding them.
Effects of Calorie Restriction on p53, IGF- 1, and Leptin
The following technical comments explain how caloric restriction (acting upon p53, IGF-1, and leptin) might influence life span.
(The Guardian of the Genome)
Most natural systems function best when in balance, neither showing hyper nor hypo-responsiveness to any natural stimulus. High activity of the tumor-suppressing p53 genes lowers canc rates, but causes premature aging. This finding suggests that aging might relate to the body's innate vigilance against canc. Mutant mice with over-active p53 genes were more resistant to canc than normal mice, but had a 20% shorter life span. Instead of canc, these animals showed bone thinning, organ breakdown, vulnerability to physical stress, sagging skin, and balding. Hyperactivity of the p53 gene may prematurely compromise the body's reserve of stem cells. This might prevent undifferentiated stem cells from replenishing necessary tissues and lead to premature tissue degeneration (Ferbeyre et al. 2002; infoaging.org 2003).
Growth Factor-1 (IGF-1)
Hyperleptinemia is linked with cardiovascular disease. Moderate increases in the level of leptin enhance the relative risk of a cardiovascular event by 25%. Leptin is a novel, independent risk factor for coronary heart disease (Wallace et al. 2001). Levels of leptin are increased in obesity. This hormone may play a role in the development of insulin resistance and non-insulin dependent diabetes mellitus (Haque et al. 2003).
Restriction and the Heart
At least a 30% reduction in calories is necessary to realize significant health advantages. Such austerity requires a psychological profile that only 1 person in 1000 possesses. Thus, the best objective may not be to develop another diet that people will not follow, but rather to develop a medicine that mimics the beneficial effects of calorie restriction (Taubes, 2000). An agent that mimics the function of a compound called PPAR-delta seems to provide similar benefits to calorie restriction (at least in monkeys).
Middle-aged, insulin-resistant, male monkeys (with imbalances in blood lipids) were administered an agent that mimics PPAR. PPAR-delta activates genes that regulate fat transport and insulin sensitivity. After four weeks of treatment with this PPAR imitator, monkeys showed higher HDL cholesterol levels (79%), lower triglycerides (56%), and increased insulin sensitivity. It is unknown whether the drug mimicking PPAR-delta would lengthen life span in humans through actions on insulin sensitivity and cholesterol levels, particularly in people that are not at risk for developing diabetes or heart disease (Christensen 2001).
Many "longevity medicines" have yielded disappointing results. For example, 2-deoxy-D-glucose (2-DG), a compound that inhibits glucose metabolism, was toxic for some animals even at low levels or when given over long periods. The narrowness of this range of safety (low therapeutic index) precludes it from human use, although studies provide some clues that inhibition of glucose metabolism can mimic some effects of caloric restriction (Lane et al. 2002).
BioMarker Pharmaceuticals has discovered that metformin (Glucophage), a drug used to treat diabetes, can mimic many of the changes in gene expression found in calorie-restricted mice (Kent 2003). Metformin has a unique mechanism of action compared to many antidiabetic agents; it does not increase insulin production; rather it lowers blood sugar by decreasing sugar production, absorption, while increasing insulin sensitivity. Metformin was more effective in mimicking the genetic responses to caloric-restriction than Glucotrol (Glipizide), which stimulates the pancreas to secrete more insulin, or Rosiglitazone, which reduces resistance to insulin. A number of studies have linked aging to poor glucose control, lack of insulin sensitivity, and hyperinsulinemia. Metformin impacts genes involved in (drug) metabolism and detoxification, energy metabolism, protein biosynthesis and degradation, cell growth and proliferation, and in the formation of the cytoskeleton.
The cytoskeleton is an internal reinforcement of the cytoplasm of a cell. Microtubules contained in the cytoskeleton of most cells, provide structure to the cell and a conduit for intracellular transport. It is speculated that microtubules act as processors of electrical information. When a cell divides, it may pass on genetic information, not just in the form of DNA, but also in the form of microtubules, integral to the mechanics of cell division.
Metformin has been shown to increase the life span of mice by 20%. BioMarker Pharmaceuticals is conducting a life span study using metformin to see if they can replicate this study. The results of multiple studies suggest that metformin needs to be evaluated as a longevity medicine. (Visit www.lef.org to read The Multiple Benefits of Metformin, September 2001 Life Extension Magazine for dosing instructions and caveats. For additional information about BioMarker Pharmaceuticals, contact www.biomarkerinc.com.)
to Support Longevity
Glycemic Index and Glycemic Load
The glycemic index does not indicate the level of carbohydrate contained in food. While the carbohydrates in carrots have a high glycemic index, carrots contain relatively fewer carbohydrates than corn chips. The unfavorably high glycemic index of carrots (131%) is based on the blood-sugar response to eating 50 grams of carbohydrate (or a pound and a half of carrots), which few people would consume. The net effect of carrots on blood sugar levels is considerably less than corn chips, even though the glycemic indices are similar.
The glycemic load is calculated by taking the amount of carbohydrate in a serving of food multiplied by that food's glycemic index. A half-cup serving of carrots (which has 8 grams of carbohydrate) has a glycemic load of about 10 (8 131% or 1.31 = 10.48). Many advocate assessing the overall glycemic load of a diet, rather than focusing too much on any one food. Increased risk for cardiovascular disease begins at a daily glycemic load of 161 (Faloon, 2002; Harvard Women's Health Watch, 2002).
It is obvious that living to the maximum (well beyond 100 years) is no longer just a whim, but rather a cooperative effort, one pursued by committed individuals and scientists. It is reassuring to know that one can influence the odds of living long and living well (through mind-set, diet, and exercise), and that the scientific community is passionate about helping achieve this objective.
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