Lets take a breath here people!
I'm not yet a scientist, but I DID read michael's analysis carefully, and from what he said, when metabolically scaled, the doses were within the therapeutic range for people (about 950 mg/day racemic).
Secondly, I think it's a bit innaccurate to state that ALA was
life shortening in the study. The real conclusion was that ALA when supplemented in early life, "exerts a stable, epigenetic effect on REDOX-sensitive transcription factors, and thus prevents the shift into the alternative metabolic state." In other words, if you eat ad-libitum with ALA for many years, then switch to CR, your body will not undergo (all) the beneficial metabolic changes characteristic of CR. Which is a bummer if you plan on restricting your calories, but just fine if you plan to eat ad libitum - like most people here do. Here's the appropriate lifespan comparison from the study:
Lifelong AL: 926 - 854 - 1100
Lifelong AL + lipoic: 900 - 858 - 1105
Also, AL + ALA followed by CR did not
shorten lifespan, it just reduced the beneficial effects of CR. Again quoting michael here, whose invaluable reading we are indebted to:
"It's interesting that this [AL + ALA --> CR] group had an
intermediate LS, better than lifelong AL (± LA) but not as good as AL ---> unsupplemented CR at the same, youthful age; note, especially, that that the survival curve shows typical AL mortality during AL and continuing for some months after the switch to the CR + LA diet, but that they did eventually enter into a more CR-like pattern (see Fig 4b), suggesting a memory effect that was overcome with enough time and initial youthful metabolic flexibility."
So the long and short of it is: if you plan to practice CR, don't consume therapeutic doses of ALA until you've successfully made the transition. Otherwise, it's fair game, and probably a very beneficial nutrient.
Hope this helps clear things up!
@ OP: I don't think you've got anything to worry about WRT receptor downregulation - in fact, I've never heard of someone going through withdrawal from a cholinergic chemical, though anything's possible. I just ran accross this study, which may be more pertinent to iron-go
bbling oxidatively-challenged mice, but I liked it anyway:
Effects of dietary supplementation with N-acetyl cysteine, acetyl-L-carnitine and S-adenosyl methionine on cognitive performance and aggression in normal mice and mice expressing human ApoE4. Chan A,
Shea TB. Center for Cellular Neurobiology & Neurodegeneration Research, University of Massachusetts Lowell, Lowell, MA 01854, USA. Thomas_shea@uml.edu
In addition to cognitive impairment, behavioral changes such as aggressive behavior, depression, and psychosis accompany Alzheimer's Disease. Such symptoms may arise due to imbalances in neurotransmitters rather than overt neurodegeneration. Herein, we demonstrate that combined administration of N-acetyl cysteine (an antioxidant and glutathione precursor that protects against A beta neurotoxicity), acetyl-L-carnitine (which raises ATP levels, protects mitochondria, and buffers A beta neurotoxicity), and S-adenosylmethionine (which facilitates glutathione usage and maintains acetylcholine levels) enhanced or maintain cognitive function, and attenuated or prevented aggression, in mouse models of aging and neurodegeneration. Enhancement of cognitive function was rapidly reversed upon withdrawal of the formulation and restored following additional rounds supplementation. Behavioral abnormalities correlated with a decline in acetylcholine, which was also prevented by this nutriceutical combination, suggesting that neurotransmitter imbalance may contribute to their manifestation. Treatment with this nutriceutical combination was able to compensate for lack of dietary folate and vitamin E, coupled with administration of dietary iron as a pro-oxidant (which collectively increase homocysteine and oxidative damage to brain tissue), indicating that it provided antioxidant neuroprotection. Maintenance of neurotransmitter levels and prevention of oxidative damage underscore the efficacy of a therapeutic approach that utilizes a combination of neuroprotective agents.
