Obviously, it's vital to protect energy production in crisis situations like the simulated heart attack in these experiments. But when you take the long view, what's of even greater significance is maintaining - or, if possible, restoring - the energy supply you have every day. Damage to mitochondria, and loss of mitochondrial function with age, is now believed by almost all investigators into the biology of aging to be central to the loss of function and resilience that we experience as "aging." 57, 70 , 71 , 72
When older people feel their get-up-and-go has got up and went, it's no illusion: it's a real loss of cellular bioenergetics, spread across the entire organism. And because ATP is required for essentially all cellular functions, this loss of energy impacts all aspects of life, from the shaping of vital enzymes to the repair of the thousands of injuries, great and small, that we suffer every day. We've already seen the effects of R(+)-Lipoic Acid in a crisis. How does it impact the quiet desperation and gradual loss of function - the quiet desperation - of aging?
Dr. Tory Hagen and his fellow researchers at the Molecular and Cell Biology department of UC Berkeley asked themselves just these questions - and decided to find out.
The Hagen team 73 first determined just how big a gap there was between young and old lab animals, so that they could later determine how much of a difference R(+)-Lipoic Acid would make in the old animals. As you'd expect, the old animals looked like they were running on empty, at all levels.
Down at the cellular level, the "depth" of older animals' mitochondrial "reservoirs" was less than half (40%) of what it was in young animals. As a result, their mitochondrial production of ATP (which can be measured using cellular oxygen consumption) was also about half (58.5%) of what it was in youths. And, as you'd expect by now, the old animals' mitochondria had become very polluting sources of energy for the cell: for every unit of ATP produced, old animals were producing nearly twice as many free radicals as young animals did.
The increase in free radical production exacted a serious toll on the overall antioxidant defense system of old animals, lowering their levels of reduced glutathione by nearly a quarter (23%) and slashing their vitamin C levels in half. You can't solve the problem just by supplementing with more vitamin C and glutathione precursors like n-acetylcysteine (NAC), by the way: Dr. Hagen and his research team have indicated that the evidence suggests that the ability of the cell to both take in 74, 77 and effectively recycle 75 vitamin C (which happens using enzymes in the mitochondria 76 ) and glutathione precursors, 77 is weakened with age.
As a result of the increased production of - and relative defenselessness against - free radicals, the membranes of old animals' cells were literally turning rancid, as measured by levels of malondialdehyde (MDA), a chemical marker of lipid peroxidation. MDA levels were five times higher in old animals' cells, as compared to young ones. In later work, 74 Hagen's team showed that free radical damage in the DNA of old animals' hearts was also considerably higher, being almost exactly double what's seen in young animals.
Meanwhile, up at the level of the whole organism, scientists were able to monitor how active the animals were, using video cameras linked to computers running special digitizing software. This monitoring system revealed the real impact of reduced mitochondrial function in the old animals: they were hardly moving. While young animals actively sniffed about in their cages, traveling an average of more than 500 centimeters each hour, old animals were only managing to get up the energy to haul their aging bodies a third as far. They also appeared to be less active in other ways, such as in spending less energy in grooming themselves. R(+)-lipoic acid acid changed all that.
Hagen's group specifically used R(+)-lipoic acid, because (in their words) of the "evidence that R(+)-lipoic acid supplementation may be more potent than either the racemic mixture (the form sold commercially as alpha-lipoic acid) or (S)-enantiomer". 73 After just two weeks on an R(+)-Lipoic Acid supplemented diet, the old animals' mitochondrial function and antioxidant defenses were dramatically improved. Their levels of reduced glutathione and vitamin C were no longer significantly different from the young animals'.
Dr. Hagen link this restoration back to lipoic acid's known ability to increase recycling of these antioxidants, but has also now stated 77 that his group - and Dr. Lester Packer - have found evidence that R(+)-Lipoic Acid also increases the ability of cells to abosorb vitamin C from the plasma. And even more excitingly, consuming supplemental R(+)-Lipoic Acid brought the level of free radical production in old animals down to levels not significantly different from the young ones.
This change was reflected in levels of fatty peroxidation, as MDA levels dropped by over 40%. In a new study published just this spring, 74Hagen's team not only confirmed these results, but also showed that supplementing old animals with R(+)-Lipoic Acid also wiped out the age-associated increase in DNA damage in the heart, bringing levels back to those seen in young animals!
ATP production had been boosted, too, so that the mitochondrial ion "reservoir" of animals getting the R(+)-Lipoic Acid supplements was fully half again as high as it was in unsupplemented animals. In parallel, the cellular oxygen consumption data indicated that the mitochondria of R(+)-Lipoic Acid supplemented old animals produced as much ATP as did young animals.
The change could be seen in the old animals' appearance and in their activity. "Anecdotally," Dr. Hagen has stated, "these animals are looking a whole lot better. 77 And they were acting a lot healthier, too: old animals supplemented with R(+)-Lipoic Acid doubled the amount of exploring they did in their cages, and also appeared to be otherwise more active than the animals eating an unsupplemented diet.
Bottom line: giving old animals R(+)-Lipoic Acid is like installing a mitochondrial turbocharger, which soups up the engine's power while making it run more cleanly and efficiently. All the evidence says that S(-)-lipoic acid does not have this power, and may even be counterproductive.
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