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Mitochondria Damage & Aging
  from Jules: if mitochondrial damage is a cause of aging this may be related to what I recall from early HIV research that HIV accelerates aging. HIV may cause inflammation, as perhaps many chronic diseases apparently do. Perhaps both HIV as well as nukes cause mitochondrial damage, so we should study the effects of nukes and nuke-sparing regimens in the context of aging and inflammation and neurologic disorders including Parkinsons & Alzheimers.
"It is generally accepted that oxidative mitochondrial decay is a major contributor to aging."
Cell Mutations Spark Aging

Aging may begin in the mitochondria-the powerplants of the cells
by Jocelyn Selim
published online January 2, 2005
Molecular biologists may be on the brink of unleashing a cellular fountain of youth. In May Nils-Goran Larsson of the Karolinska Institute in Sweden pinpointed where the process of aging begins in a cell-the mitochondria-and thus where it may be slowed.
In their efforts to conquer the aging process, researchers are zeroing in on one specific part of the cell: mitochondria, the energy-generating organelles that control our metabolism and, it seems, help regulate how long we live.
Mitochondria are tiny organelles that harness energy and turn it into a usable form. They are also the only structures outside a cell's nucleus that contain their own DNA, and that turns out to be important. While DNA in the nucleus has an extensive system of proofreading and repairing enzymes, mitochondria depend mostly on a single protein to patch up mutations. When Larsson engineered mice with a defective, error-prone version of the protein, mice accumulated mutations unchecked. The results were startling. At young adulthood, Larsson's mice resembled those three times their age, with bone and muscle loss, heart disease-even baldness.
The study is the first hard evidence that these mutations are a cause of aging rather than just a sign, like wrinkles. When mitochondria begin to break down, they run less efficiently, creating more toxic free radicals. The process resembles an inefficient engine producing more smoke. Larsson's research suggests that the damage from these free radicals-either to the mitochondria or other parts of a cell-is what triggers the aging process.
Mitochondrial mutations may also underlie Alzheimer's, Parkinson's, and other diseases that are common among senior citizens, says Doug Wallace, director of the University of California at Irvine's new Center for Molecular and Mitochondrial Medicine and Genetics. "If we could find a way to protect mitochondrial DNA, either with drugs or by using gene therapy to transplant it to the nucleus, it could not only extend our life spans but prevent many of the diseases we associate with aging as well."
Larsson wanted to see what happens when that enzyme fails to catch a glitch, so he and his collaborators engineered mice with a defective, error-prone version of the enzyme. The modified mice developed muscle and hair loss, spine curvature, and loss of fertility at a greatly accelerated pace. "People have noticed a striking correlation between mitochondrial DNA damage and aging, but before it was impossible to be certain if it was causative," Larsson says. Mutations may cause the mitochondria to operate less efficiently, producing more free radicals-reactive molecules-as a waste product. Free radicals are known to damage and weaken cells. Alternatively, flagging mitochondria might simply cause cells to run out of steam.
In parallel work, Scottish biochemists led by John Speakman at the University of Aberdeen found that mice with hyperactive mitochondria live exceptionally long. "We have this expectation that our bodies are like machines-the more we use them, the faster they will wear out," Speakman says. "We were very surprised when we found that the mice with the fastest metabolisms outlast the others by about a third."
He, too, suspects free radicals lie behind the aging effects: "Mice with faster metabolisms have cleaner-running mitochondria. They form fewer free radicals in the process." The results might seem to clash with the discovery that caloric restriction, which is associated with reduced metabolism, also extends life span. Speakman theorizes that the efficiency of the mitochondria is more important than their total output: Mice on calorie-restricted diets seem to show the same mitochondria-mediated reduction in free radicals as do animals with high metabolisms.
Although mitochondria are certainly not the sole cause of aging, the findings suggest that they exert a surprisingly powerful influence. The discoveries also hint at ways to hold on to youth by altering mitochondrial activity. "If we can find a way to manipulate how they work," Speakman says, "it could well be the new path to powerful life-prolonging drugs."

Key To Aging: Mitochondrial DNA
Study Could Help Explain The Mechanics Of The Human Aging Process

PORTLAND, Ore., May 26, 2004
(AP) Gray hair - or no hair - wrinkles and creaky joints are obvious reminders that you're not getting any younger.
Scientists in Sweden say aging begins in a more fundamental way - in the accumulation of tiny changes to a mysterious genetic component in cells called mitochondrial DNA.
Researchers describe the study as the first experimental evidence of this theory - at least in laboratory mice. They believe the finding could explain how humans age and how the body's systems begin to misfire, although more tests must bear out them out. The mouse results appear in the current issue of the journal Nature.
"It seems to be a universal phenomenon in mammals that you have this damage to mitochondrial DNA as you get older," said the study's senior author, Nils-Goran Larsson at the Karolinska Institute in Stockholm.
"But I and many others thought this was just a secondary phenomenon," Larsson said. "I think the importance of our paper is that we actually show these mutations can indeed cause several changes associated with aging."
Other scientists say the Swedish experiments clearly show that a high rate of mutation in mitochondrial DNA has an effect on aging.
"But that does not mean all aging is caused by mutations in mitochondrial DNA," said David Finkelstein of the U.S. National Institute on Aging, part of the National Institutes of Health.
In the experiments, the Swedish team used mice bred with a defective version of an enzyme responsible for maintaining mitochondrial DNA.
Mitochondria are tiny biochemical power plants in cells that convert food into energy. Mitochondria contain strands of their own DNA that are separate from the cell nucleus where the body's genes reside.
The deterioration in the experimental mice started at 25 weeks - young adulthood in normal mice. They prematurely experienced a range of familiar age-related complaints, including baldness, osteoporosis, anemia, curvature of the spine and reduced fertility. The lifespan of the experimental mice was markedly reduced, with the median age of death at 48 weeks. The oldest of the experimental mice died before 61 weeks.
In normal mice, early aging signs appear at about 40 weeks. Emaciation and other signs of old age accumulate by 1.5 years, and lab mice typically live a little over 2 years.
In an accompanying commentary in Nature, George Martin and Lawrence Loeb of the University of Washington said the results are also consistent with the theory that so-called "free radicals" play a role in aging.
Free radicals typically are oxygen molecules that lack an electron, often setting up a corrosive chain reaction that can damage other cells.
Regardless of how aging begins, researchers said the steps to extend a healthy, youthful life are familiar and simple.
"Watch what you eat, exercise, don't smoke, keep your mind active," Finkelstein said, "and you're more likely to live longer."

By James South MA
The mitochondrial theory of aging (MTA) was first proposed in 1972 by Denham Harman, the "father" of the free radical theory of aging (FRTA) (1). The MTA was further refined and developed in 1980 by Jaime Miquel (2). There is such a strong connection between the MTA and the FRTA that they are often discussed together as if the MTA was just one form or specific development of the FRTA (3). Yet the MTA concerns far more than free radicals. The MTA involves three other major biological topics as well: genetics, membranes, and bioenergetics. To understand the MTA, it is first necessary to have an overview of the mitochondrion and its pivotal role in the life of biological organisms - including us.
Mitochondria are organelles ("little organs") found in virtually all cells in the human, (and animal) body except red blood cells. There may be from 20 to 2500 per cell (4). Mitochondria are the energy generators of the cell. They typically produce 90% or more of all the ATP bioenergy made in the body (4). The production of ATP within the mitochondria occurs from the interaction of two metabolic cycles - the tricarboxylic acid (TCA) cycle, (also called the "Krebs" or "citric acid" cycle) and the oxidative phosphorylation (OXPHOS) electron transport chain (ETC) (4). The TCA cycle occurs in the matrix of the mitochondria, while the ETC is a series of five multi-enzyme complexes which form an integral part of the inner mitochondrial membrane (4). (See diagram 1.) Products of the TCA cycle - NADH, FADH2, succinate - are connected to the ETC to activate the first two enzyme complexes (I and II), which transfer electrons down the chain, eventually combining oxygen and hydrogen to make water, and producing ATP at complex II (ATP synthase) (4). The mitochondrion is essential for life. It generates the energy (from the food we eat) that powers cellular activity, muscular activity, heart and brain activity, breathing, walking, talking etc. Without ATP there is no life, and without well-functioning mitochondria, there is (almost) no ATP.
One of the unique features of mitochondria is that they contain their own DNA - mitochondrial DNA (mtDNA). All the other DNA of a cell is found in the nucleus (nDNA). The mitochondrial DN is a closed circular molecule. It encodes 13 ETC enzyme proteins, 2 ribosomal RNAs, and 22 transfer RNAs, all needed to form the mitochondrial ETC protein synthesis system (5). The remainder of the ETC enzymes and other mitochondrial components are encoded by nDNA. Each mitochondrion contains 5 to 10 mtDNA molecules (6). A mitochondrion reproduces itself by first increasing in size through integration of newly synthesized molecules, then eventually dividing to form two mitochondria (7).
The very feature that makes mitochondria unique among the various cell organelles - having their own DNA - gives rise to a major problem. nDNA is protected by histone proteins and various repair enzymes, which minimizes damage to nDNA from free radicals/oxidants. mtDNA has no histone protection or significant enzymes repair systems to offer free radical protection (6). Therefore, mtDNA is far more subject to free radical damage than nDNA. The commonest form of free radical damage to mtDNA molecules is the production of 80HdG, an oxidized guanine base. Even in young (3 month old) rats, the level of 80HdG is already 16 times higher in mtDNA than nDNA (6). Mecocci and colleagues investigated ten normal humans aged 42 to 97 years, checking three brain regions. A 10-fold increase in 80HdG in mtDNA as compared to nDNA was found in the entire group of samples, with a 15-fold increase in persons over 70 (6). And, high 80HdG levels in mtDNA is strongly correlated with mtDNA deletions (damage) (6).
As mtDNA damage accumulates over the lifetime of an individual, the functionality of the ETC enzyme complexes that produce ATP, and are encoded for (in part) by mtDNA, decreases dramatically and gradually produces a cellular energy crisis. Linnane and associates found that in a 90 year old man, only 5% of the total mtDNA from muscle tissue was still in the form of full-length, normal mtDNA (5). Along with this cumulative mtDNA damage, there was a large percentage of cells lacking cytochrome oxidase (COX), complex IV of the ETC (5). And 3 of 13 proteins of complex IV are encoded for by mtDNA, so the low COX activity is hardly surprising.
To make matters worse, the mitochondrial ETC is the main source of cellular free radicals/oxidants, especially superoxide radical (SOR), hydrogen peroxide (H2O2) and hydroxyl radical (8). [See my Free Radical Theory of Aging article in this issue for more detail on free radicals.] mtDNA is at least transiently attached to the inner mitochondrial membrane, where the ETC is located and from which free radicals/oxidants are continuously released. It is generally estimated that 1-2% of oxygen consumed by mitochondria (and they consume 85% of all body oxygen) in ETC activity is converted to SOR (8). Much of this SOR is converted by mitochondrial superoxide dismutase (SOD) to H2O2 (9). Yet H2O2 causes scissions (breaks) and cross linking of DNA (9). (Ed.- See Dr. Kyriazis article in the Spring 2003 Anti-Aging Bulletin about the problems associated with cross-linking). Thus, in the very act of doing its job-making ATP - the ETC inadvertently damages mtDNA, on which the viability of current and future mitochondria depends. As Linnane notes: "As tissues age, mtDNA mutations accumulate in individual cells; eventually some cells will reach the point at which the ability to make the mtDNA - encodes components of the mitochondrial energy generation system is seriously impaired. If mtDNA mutations occur in a significant number of cells in a tissue, the function of that tissue will be comprised and consequently will contribute to such age-associated pathologies as skeletal muscular and neurological degeneration, heart failure, strokes, ... other diseases [and death!]." (5) That, in brief, is the MTA.
In the past 30 years of MTA research, a vast amount of evidence has accumulated that tends to validate the MTA. This prompted MTA/FRTA researcher Bruce Ames and colleagues to state in 2002: "It is generally accepted that oxidative mitochondrial decay is a major contributor to aging." (10)
Sastre and co-workers point out that "The role of old mitochondria in cell aging has been emphasized by the finding that cells microinjected with mitochondria isolated from fibroblasts of old rats degenerate to a much greater extent than those microinjected with mitochondria from young rats." (11)
One area of evidence for MTA comes from the morphological (structural) differences between young and old mitochondria. Studies with both humans (9) and rats (7, 11) show a similar picture. In young organisms, there are a large number of small mitochondria that provide needed ATP. In aged rats and humans, however, there are a smaller number of large mitochondria. The total volume of the cell that consists of mitochondria, (up to 20% of cell volume), remains roughly the same in young and old rats/humans. These larger mitochondria are not as bio-energetically efficient as the youthful, normal, small mitochondria (7, 11). A key aspect of the ETC is the mitochondrial membrane potential, which is produced by the electron and proton pumping activity of the ETC. As Sastre and colleagues note: "... mitochondrial size increases and mitochondrial membrane potential decreases with age in brain and liver. This may reduce the energy supply in old cells since the mitochondrial membrane potential is the driving force for ATP synthesis." (12) Reviewing the evidence on the large size of aged mitochondria, Bertoni Freddari et al remark that in old organisms "... the genesis of new mitochondria appears to stop at the intermediate step of accretion in size of the organelles, but it is not followed by their division [due to mtDNA damage]." (7) Hence the fewer but longer mitochondria of old organisms.
Linnane and colleagues compared skeletal muscle tissue samples from a 5 year old and 90 year old human. Using the extra-long PCR technique, they analyzed the samples for mtDNA content. They also used a staining technique to measure COX (ETC complex IV) activity in the muscle cells. They found that less than 5% of the total mtDNA from the 90 year old was still in the form of full-length mtDNA, while the bulk of mtDNA molecules was made up of deletion products and oversized mtDNA rearrangements - i.e. seriously mutated mtDNA. The 5 year olds mtDNA was almost entirely normal mtDNA. There were only rare COX-deficient muscle fibers in the 5 year old, but COX-deficient muscle fibers were common in the 90 year old. They conclude that "This result establishes the relationship between age-associated accumulation of mtDNA mutation and COX activity and provides compelling support for the hypothesis of mtDNA mutation-driven bioenergy degradation as a key feature of the aging process...." (5).
In a review of the MTA, Barja reports that "Many different laboratories have consistently shown that mtDNA mutations (deletions, point mutations, gross DNA rearrangements, etc.) increase with age in mammals, specially in post-mitotic highly aerobic tissues [i.e. brain, heart, skeletal muscle] ... and affect up to 50% of the mtDNA molecules in the mtDNA control region of fibroblasts from old humans [; the mtDNA control region is essential for mitochondrial reproduction]. Accumulation of mtDNA mutations with age have been reported also in the brain, heart, or skeletal muscle of three mammalian species with widely different MLSP [maximum life span potentials], mice (3.5 years), chimpanzees (59 years), and humans (122 years)...." (13) Barja also notes that 8-oxodG, a free radical-damaged DNA base, can cause DNA mutation during DNA replication. Levels of 8-oxodG were measured in the heart and brain mtDNA and nDNA of eight different mammal species differing 13-fold in MLSP. The results indicated that 8-oxodG levels in both organs were inversely correlated with MLSP, while there was no correlation between 8-oxodG in nDNA and MLSP (13). 8-oxodG is found four-nine-fold higher in mtDNA compared to nDNA in eight mammal and three bird species so far studied (13).
A comparison of three bird species to rats and mice also provides support for the MTA. Pigeons have a body size and basal metabolism similar to rats. Yet pigeons have a nine-fold higher MLSP (35 years) than rats (4 years). It was discovered that pigeons had significantly less mitochondrial free radical/oxidant generation than rats in all organs studied-brain, liver, lung, heart and kidney (13). It was also found that parakeets (21 years MLSP), and canaries (24 years MLSP) have similar body size and oxygen consumption to mice (3.5 years MLSP), yet also have much lower mitochondrial oxidant generation (13). Less mitochondrial oxidant generation = less mtDNA damage, and less mtDNA damage = more normal mitochondrial bioenergetics throughout a longer life.
Glutathione (GSH) plays a key role in protecting mitochondria and mtDNA from oxidative damage. GSH protects against mtDNA-damaging lipid peroxidation in the inner mitochondrial membrane, where the ETC is located (14). GSH also breaks down H2O2, another oxidant normally produced within mitochondria and which damages mtDNA (9). Unfortunately, "Glutathione oxidation increases with age in mitochondria from liver, kidney, and brain of rats. It is striking that this increase was much higher in mitochondria than in whole cells." (12) And mitochondria are at special risk with regard to GSH, because they lack the ability to synthesize GSH or to rid themselves of oxidized glutathione (GSS) (10). Sastre and colleagues found that GSSG levels doubled in old rats compared to young rats, while GSH levels dropped 40% and H2O2 generation increased 22% (11). GSH levels and peroxide production may also explain the differential in life spans that occurs between males and females in many species, including humans and rats and mice. Brain and liver mitochondria from male rats have higher H2O2 production than females, yet GSH levels in mitochondria of male rats were lower than females (12). Thus females should suffer less mtDNA damage, with consequent slower aging.
Mitochondria can function in five different energy states, with state 3 and state 4 being the main ones. State 4 is a resting or basal energy production state, when cellular energy needs are modest. State 3 is the active energy production state, when the mitochondria are rapidly producing ATP to fuel heightened cellular energy needs. Tzu Chen Yen and colleagues studied 35 Chinese subjects, ages 31 to 76 years old. They found a sharp drop with aging in both state 3 and state 4 activity in liver mitochondria, but with a lesser drop in state 4 levels. The sharp drop in state 3/state4 energy production with aging is indicative of significant mitochondrial ETC damage. The study authors note that the lesser drop in state 4 activity indicates that aged liver cells could still maintain basic "housekeeping" activity, but would not do as well as young liver cells when presented with an energy-consuming toxicological challenge. Shigenaga et al also point out the shift to state 4 dominance with aging (8). At the organismic level, consider most elderly humans. Do they spend more time at rest (state 4), or in activities such as walking, running, dancing, swimming, etc. (state 3)? Yen and colleagues conclude their study with the remark that "Our results strongly support the hypothesis recently proposed by Linnane and colleagues which maintains that ageing may be due to somatic gene mutations that occur at a substantial rate in the mtDNA and its accumulation during the life-span of the subject." (15)
In Harman's original MTA (1), he assumed that all cell types were equally subject to mtDNA/mitochondrial damage with aging. Miquel's reformulation of the MTA (2,9) maintains that it is primarily to "fixed post-mitotic" cells that MTA applies. Fixed post mitotic cells are those that no longer divide after early childhood, and thus are irreplaceable. They are primarily brain, heart, and skeletal muscle cells. Yet the finding in the Yen study that liver mitochondrial energy production drops sharply with age seems to indicate that at least some mitotic, (dividing) cells also suffer aging mtDNA/mitochondrial damage, since liver cells are able to divide and replicate throughout life.
The preceding evidence for the MTA is just a brief "snapshot" of the vast array of evidence accumulated in the past 30 years that supports the MTA. In preparing this article I studied far more scientific papers on the MTA than I can refer to in this brief article. Having looked carefully into the MTA, I am personally convinced that the MTA represents the single most important cause of aging and age-related diseases.
Fortunately, there are various practical measures that we can take to minimize or reduce mtDNA/mitochondrial damage and aging. Caloric restriction is the best-proven anti-aging regimen, and also significantly reduces mtDNA/mitochondrial oxidant damage (13). Please see the "caloric restriction" section of my accompanying article on the free radical theory of aging for more detail. What follows are some of the nutrients and anti-aging drugs that will combat mtDNA/mitochondrial oxidative damage, and thus aging itself.
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