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Genetically Engineered Mice Defy Aging Process
Scientists have prolonged the lives of laboratory mice by 20 percent using a technique that boosts the natural antioxidants of the body.

Scientists Find Anti-Aging Gene in Mice
The discovery was triggered by a study Kuro-o and his colleagues published in 1997. That study identified a gene in mice that, when damaged, caused the animals to experience all the hallmarks of aging in humans -- hardening of the arteries, thinning bones, withered skin, weak lungs -- and to die prematurely. They dubbed the gene Klotho, for the Greek goddess who spins the thread of life.

Suspecting the gene may play a role in regulating life span, Kuro-o and his colleagues genetically engineered mice with overactive Klotho genes. In the latest experiments, they found that these animals lived an average of 20 to 30 percent longer than normal -- 2.4 to 2.6 years vs. a normal life span of about two years -- without any signs of ill effects, according to the new report.
The researchers then identified a small protein component, called a peptide, that the gene produces and found it circulating in the animals' blood at double the normal level.

After isolating and purifying the substance and reproducing it through genetic engineering techniques, the researchers injected the substance into normal mice. Tests on those animals, combined with experiments involving cells in the laboratory, indicate that the substance modulates [the insulin/insulin-like growth factor-1 signaling] pathway involved in an array of basic metabolic functions that has become the focus of aging research in recent years.

Mechanisms of Aging

The "mitochondrial theory of aging" postulates that damage to Mitochondrial DNA (mtDNA) and organelles by free radicals leads to loss of mitochondrial function and loss of cellular energy (with loss of cellular function). Mutations in mtDNA occur at 16 times the rate seen in nuclear DNA. Unlike nuclear DNA, mtDNA has no protective histone proteins. And DNA repair is less efficient in mitochondria than in the nucleus. These factors account for the more rapid aging seen with Complex I & III as compared to Complex II & IV. Aging mitochondria become enlarged and, if they can be engulfed by lysosomes, are resistant to degredation and contribute to lipofuscin formation [EUROPEAN JOURNAL OF BIOCHEMISTRY; Brunk,UT; 269(8):1996-2002 (2002)].

A comparison of 7 non-primate mammals (mouse, hamster, rat, guinea-pig, rabbit, pig and cow) showed that the rate of mitochondrial superoxide and hydrogen peroxide production in heart & kidney were inversely correlated with maximum life span [FREE RADICAL BIOLOGY & MEDICINE 15:621-627 (1993)]. A similar study of 8 non-primate mammals showed a direct correlation between maximum lifespan and oxidative damage to mtDNA in heart & brain. There was a 4-fold difference in levels of oxidative damage and a 13-fold difference in longevity, supportive of the idea that mtDNA oxidative damage is but one of several causes of aging [THE FASEB JOURNAL; Barja,G; 14(2):312-318 (2000)].

A comparison of the heart mitochondria in rats (4-year lifespan) and pigeons (35-year lifespan) showed that pigeon mitochondria leak fewer free-radicals than rat mitochondria, despite the fact that both animals have similar metabolic rate and cardiac output. Pigeon heart mitochondria (Complexes I & III) showed a 4.6% free radical leak compared to a 16% free radical leak in rat heart mitochondria [MECHANISMS OF AGING AND DEVELOPMENT 98:95-111 (1997)]. Hummingbirds use thousands of calories in a day (more than most humans) and have relatively long lifespans (the broad-tailed hummingbird Selasphorus platycerus has a maximum lifespan in excess of 8 years). Birds have less unsaturation (oxidizability) in their mitochondrial membranes and have higher levels of small-molecule antioxidants, such as ascorbate & uric acid. Even for mammals there is a direct relationship between mitochondrial membrane saturation and lifespan [JOURNAL OF LIPID RESEARCH 39:1989-1994 (1998)].

Free-radicals from mitochondria result in damage to cellular protein, lipids and DNA throughout the cell. This damage has been implicated as a cause of aging. If the fatty acids entering the mitochondria for energy-yielding oxidation have been peroxidized in the blood, this places an additional burden on antioxidant defenses. The greatest damage occurs in the mitochondria themselves, including damage to the respiratory chain protein complexes (leading to higher levels of superoxide production), damage to the mitochondrial membrane (leading to membrane leakage of calcium ions and other substances) and damage to mitochondrial DNA (leading to further damage to mitochondrial protein complexes). An experiment in yeast that improved the accuracy of mitochondrial protein synthesis demonstrated a 27% longer mean life span [JOURNAL OF GERONTOLOGY 57A(1):B29-B36 (2002)].

The first test-tube baby was nick-named Pandora's baby. I have a hunch that the first application of genetic engineering to humans that will make the concept compelling will be to offer parents the option of longer life for their child at the in vitro fertilization stage.


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