Book Aubrey de Grey

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Point mutations: mutations that change only one, or a few, of the "letters" in one "word" in the "sentence" of instructions comprising an individual gene. Prodrug: a substances that is inactive until metabolized in some way, whereupon it is chemically transformed into a pharmacologically active product. Proton: an electrically charged particle present in the atom. The flow of protons across the mitochondrial inner membrane through complex V provides the power to drive the storage of cellular energy as ATP. Receptor: a molecular "lock" on the surface of the cell that responds to the correct molecular "key" by performing functions like opening the cell up to a needed nutrient or inducing a signaling cascade. G L O S S A R Y 375 Reductant: a substance that characteristically "wants" to give electrons to other compounds. Retinopathy, diabetic: vision loss in diabetics linked to damage to the fine blood vessels feeding the light-absorbing tissues at the back of the eyeball.more...

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But the fact that the symptoms of an abnormal pathology look a lot like the symptoms of "normal" aging doesn't prove that the mechanisms of one underlie the mechanisms of the other, any more than a wetlawn proves that the same mechanisms govern rainfall patterns and sprinkler systems. Almost anything that messes up normal equilibrium in the body but takes a while to kid you will look like "premature aging;" the question is what if any relationship a given change bears to aging in the rest of us. Evolutionary biologist Michael Rose, a geneticist at the University of California who has himself bred remarkably slow-aging, long-lived fruit flies, puts the point succinctly: "A lot of people can kill things off sooner, by screw-ing around with various mechanisms, but to me that's like killing mice with hammers: it doesn't show that hammers are related to aging." Because we don't have this kind of direct evidence, we normally rely on more indirect, correlative types of evidence of a phenomenon's involvement with aging.more...

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In the Paleolithic environment in which we evolved, that meant about three decadesfar less time than it takes lipofuscin or atherosclerotic cholesterol aggregates to build up to life-threatening levels. For this reason, evolution has never bothered to equip the lysosome with enzymes designed to deal with these wastes, because it has never had U P G R A D I N G T H E B I O L O G I C A L I N C I N E R A T O R S 123 a good reason to do so. But, as we've seen, it seems very likely that evolutionary forces have pushed soil microorganisms to develop these capacities in order to exploit a new fuel sourcean issue, for them, of day-to-day survival. Not only do evolutionary theory and the "microbial infallibility hypothesis" predict this, but it also seems to be confirmed by the absence of large accumulations of lipofuscin in mass grave sites: were it not so, all such locations would have an eerie glow about them, instead of such a phenomenon being confined to cheesy horror flicks. Suddenly it came together.more...

Quote #1933989
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But more important to me, it suggested a biomedical solution to what I was convinced was a major cause of aging damage: With some complex but foreseeable gene therapy, the connection between mitochondrial free radicals and pathology could be severed, without the need to interfere with the mitochondria's normal energy-producing activity. (I'll say a little more about this below, and lots more in Chapter 6.) I had come to the conclusion that, in the best case, my mitochondrial gene therapy proposal might (and I emphasize might) also slow the rate of aging in humans attributable to most other causes by about 50 percent. This would be a massive breakthrough, as it would lead to as good an extension of healthy life as the most severe calorie restriction (even under the CR optimists' scenario) but without CR's side effects. But I was far from sure about that estimate, and in the wee hours of that morning, alone in a hotel room, I was even less confident than usual, because I had spent all day being reminded of just how many things go wrong in an aging body.more...

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When you take in more calories than you expend, your body hangs on to them rather than allowing them to go to waste. This is not the result of perversity on the part of evolution, but a survival strategy: until very recently (by evolutionary standards) there was a good chance that quite soon you'd be in a period of famine, when those stored calories would be your lifeline. If your body isn't under the kinds of challenges (like weight-bearing exercise) that signal the body to build up metabolically expensive muscle or bone tissue, it will take the easy way out by storing the calories as fat. But in an environment where feast is never followed by famine, and where exercise is almost entirely a voluntary affair, we fail to shed that extra fat tissue, and it slowly accumulates as we age. Because this accumulation is a difference of aging versus healthy young bodies, it qualifies as "aging damage" under my engineering definition, even though it might not be considered as such from a purely theoretical point of view.more...

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Some critics hold that alagebrium is not actually an AGE breaker after all, but an AGE inhibitor, just as Ulrich and his colleagues originally designed it to be. There is a certain superficial plausibility to this view, but these arguments can't stand up against the irrefutable fact that, in animal studies, alagebrium doesn't just slow down the development of complications in diabetic rodents on prevent the AGE-related tissue stiffening of the cardiovascular system in normally aging dogs and monkeys: it reverses them. A drug that only inhibited the cross-linking of tissues would be able to reduce the rate at which new cross-links would form, and thereby slow down the degeneration of cross-linked tissuesbut it would not have the kind of rapid restorative effects that have been elicited by alagebrium.more...

Quote #1933986
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The drug development process has been reasonably clear, although technically challenging. In one disease after another, scientists have identified the enzyme whose absence causes the disorder; modified it in various ways to allow it to be injected, taken up by cells, and delivered to the patient's lysosome, where U P G R A D I N G T H E B I O L O G I C A L I N C I N E R A T O R S 1 2 7 they function exactly like the same enzyme does in the rest of us when it is produced by our own cells; and watched as symptoms have disappeared, lives have been extended, and victims have been enabled to live the life that the rest of us take for granted. Of course, the same fundamental problem faces all of us in the case of diseases of long-term lysosomal failure: we will all ultimately suffer from age-related "lysosomal storage diseases" (such as age-related neurodegenerative disease, macular degeneration, and atherosclerosis), even though only a tiny proportion of the population is stricken with the currently recognized congenital ones (Gaucher's disease and the like).more...

Quote #1933985
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All these viruses can be beaten back enough to put an end to active, sympto-matic disease, but they are never completely defeated. A few copies of the virus continue to lurk hidden in some hard-to-reach corner of the body, dormant and out of sight of the immune system, waiting for the day when the tissue or the body as a whole is in such a weakened state that they can flare up again. In fact, the very name "herpes" is taken from the Greek herpein, "to creep," in reference to their ability to sneak about the body while they await conditions favorable to their reactivation. You may never have heard of CMV, even though the odds are good that you are carrying it (up to 85 percent of adults over the age of forty do). That's because CMV rarely causes a recognizable illness, even briefly: about half of those undergoing CMV infection or reactivation suffer no symptoms at all, while the other half are afflicted only with hard-to-diagnose, nonspecific complaints such as general malaise, fever, and sweats.more...

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It does this by interfering with the action of the virus's unusual version of thymidine kinase (TK), an enzyme that is required for the synthesis of DNA. Thymidine kinase's job is to make thymine (a "letter" in the DNA code's "alphabet") available to be added onto the new DNA chain, by joining thymidine to phosphate molecules taken from the "energy currency molecule" ATP. Ganciclovir acts like a molecular impersonator on a mission to sabotage an enemy factory. It first uses its strong structural resemblance P U T T I N G T H E Z O M B I E S T O R E S T 2 2 3 to thymidine to fool the viral TK into thinking that it is that molecule. Duped, TK hands over thymidine's rightful phosphate group to the drug. Ganciclovir then uses its shiny new phosphate group to perpetuate its identity theft, presenting its phony credentials to the cell's DNA synthesis machinery, which unknowingly inserts it into the emerging DNA strand in thymine's place.more...

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Hydrophobicity is no problem for proteins when they are built from DNA that is already located within the mitochondrion, because the final three-dimensional shape of the protein is supposed to be twisted up, and there are special enzymes that guide such proteins into the proper conformation. But it becomes a showstopper when the same protein is constructed from DNA located in the nucleus. The genes for such proteins are translated into their products in the main body of the cell, and the proteins must then be moved from the fluid environment outside of the mitochondrion, through the outer and inner mitochondrial membranes, and into their final location in the mitochondrion's core. Of course, the membranes won't just let proteins pass freely through them, or the integrity of the mitochondrionand its ability to preserve its proton reservoirwould be compromised by the constant leak of material into and out of its chambers. But mitochondria do need to be able to import hundreds of proteins: for example, the dozens of the subunits of the electron transport chain whose genes have already been moved successfully into the bomb shelter of the nucleus by evolution.more...

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