Life Extension Magazine®

Issue: Sep 2003

Alpha Lipoic Acid, Acetyl-L-Carnitine and Carnosine

A landmark study has found that the combination of alpha lipoic acid, acetyl-L-carnitine and carnosine produces broad spectrum antioxidant activity throughout the body. This powerful supplement combination can be of significant assistance to any serious wellness protocol.

A landmark study published in the Proceedings of the National Academy of Sciences1,2 produced by noted biochemist Bruce Ames and a team of scientists describes the powerful synergistic abilities of lipoic acid and acetyl-l-carnitine to significantly combat aging. Together, these two nutrients are shown to help combat diabetes, maintain proper cognitive function, support heart health, support energy production, protect the body from radiation and chemical toxins, and maintain immunity. And, when combined with carnosine, a powerful trio for longevity is created.

New Findings in the Fight Against Diabetes
The story begins in the 1950’s when Eli Lilly and Company backed the discovery of alpha lipoic acid (ALA) by a team led by Lester Reed in the Department of Chemistry at University of Texas, Austin. More recently a German pharmaceutical company Asta Medica has taken the lead in developing ALA for use in diabetic neuropathy. Today, acetyl-l-carnitine (ALC) and carnosine have joined the ranks of ALA in the fight against diabetes.

This supplement trio goes to the root of the problem of diabetes to control blood sugar levels. One recent study found that ALA increased glucose uptake from 40% (approximately the same amount as insulin) up to an impressive 300% (in insulin resistant muscles) in obese diabetic mice.1 Leading antioxidant authority Lester Packer2 notes that ALA works against insulin resistance by increasing the permeability of cell membranes, which is decreased by hyperglycemia and prevents uptake of glucose. ALC given at 1.0 milligram per kilogram per minute constant infusion increases glucose storage from 3.8 to 5.2 milligrams per kilogram per minute.3 Carnosine also works to lower glucose in cases of hyperglycemia.4

One side effect of high sugar levels is damage to the nervous system, called neuropathy. Packer claims ALA can prevent or slow neuropathy experienced by up to 70% of diabetics5 and it has been used in Germany for over 30 years for this application. ALA and evening primrose oil were found to improve blood flow and nerve function by lowering blood lipid risk factors in a recent study.6 ALA improves circulation to the sciatic nerve, which is crucial for nerve function but is reduced in neuropathy by impaired acetylcholine-mediated vascular relaxation and accumulation of superoxide radicals.7 ALA provides 85% protection against the 31% reduction in maximum endothelium relaxation to acetylcholine that occurs in diabetes by improving nitric oxide levels, vasodilation and cervical ganglion blood flow.8 ALA is shown in another study to reverse the impairment of nitric oxide (NO)-mediated vasodilation in diabetes due to increased vascular oxidative stress.9 In addition, protein glycation (denaturing) or cross linking by excessive glucose damages nervous, vascular, kidney, retinal and other tissues and carnosine is an effect anti-glycating agent due to its hydroxyl radical scavenging ability.10 Carnosine’s anti-protein glycating abilities make it very effective at delaying senescence in nervous system cells and other types of cells.11

High sugar levels can cause extensive damage to other body systems as well. For example, people with diabetes often suffer from a high incidence of eye cataracts (free radical damage to the non renewable proteins of the eye lens) since the cells of the eye lens are very susceptible to glucose damage. Eye lens cells use slower anaerobic (without oxygen) metabolism as transparent structures without mitochondria which puts them at greater risk for free radical damage. Fortunately, ALA can help this condition. Packer and his team suggest that about 60% of diabetes related cataracts can be prevented with ALA.12 ALA works by recharging levels of the potent antioxidant glutathione, which is essential for protecting the eye lens. ALA can also help protect other organs from sugar damage. A recent study found that long term ALA supplementation in rats (30 milligrams per kilogram of body weight per day) prevented kidney injury (depletion of glutathione and accumulation of malondialdehyde) due to high blood sugar levels in people with diabetes.13

Preventing Cognitive Decline
Besides diabetes the other frontline application of ALA, ALC and carnosine has been in preventing disorders of cognitive decline. For example, ALC, first discovered in 1905, has recently become an important new target of drug and biotech companies as an Alzheimer’s treatment block-buster drug. It is manufactured by Italy’s Sigma-Tau as ALCAR, also known as Branigen (Glaxo), Nicetile (Sigma-Tau) and Normobren (Medosan).

ALC works by preventing buildup of amyloid plaque that damages brain tissues and is emerging as a cause of cognitive disorders such as Alzheimer’s. A new study shows that ALC helps control amyloid by inhibiting free radical action and preserving energy production in the brain.14 Similarly, ALA protects rat cortical neurons against cell death induced by amyloid induced free radical damage.15 And carnosine works to inhibit advanced glycation end-products (AGEs), which cross-links proteins, renders them insoluble, accumulates in protein plaques and leads to oxidation of neurons.16 AGE inhibitors such as carnosine may work by chelating copper,17 which is linked to brain disorders such as Alzheimer’s.

Chemical messengers like neurotransmitters are vital to maintaining cognitive function yet often decline with age. Fortunately, a new study shows that ALC improves synthesis of neurotransmitters such as acetylcholine and uptake of choline, both of which increases learning capacity (maze learning was used in this study).18 ALC improves Alzheimer’s by helping to maintain brain energy production, phospholipid metabolism and acetylcoenzyme A levels, the latter being used by the body to re-synthesize acetylcholine.19 Degenerative ataxias are also slowed by ALC due to improved mitochondrial energy production, synthesis of acetylcholine, and antioxidant metabolism.20 ALA also controls excitotoxicity (a condition of excess glutamate, the main excitatory neurotransmitter) and improves survival in animal models of Huntington’s disease.21

ALA, ALC and carnosine work by preventing damage to nervous system tissues by free radicals. For example, one new study found that ALA protects against Alzheimer’s by preventing the oxidative stress and energy depletion caused by deranged glucose metabolism and free radical production. In this study 600 milligrams of ALA was given daily to nine patients with Alzheimer’s and related dementias for roughly a year and led to stabilization of cognitive function.22 ALA and vitamin E work synergistically to prevent free radical damage to brain cells during stroke according to new research.23 And it controls activity of a key enzyme in cell death, caspase-3 (CPP32), which increases in the hippocampus in rats with diabetes and cerebral ischemia by up to 80%.24 Together ALA and ALC improve performance on memory tasks by lowering oxidative damage to mitochondria and improving mitochondrial function.25 ALA and ALC also work synergistically to increase ambulatory activity, restore levels of ascorbate and lower levels of malondialdehyde (a product of lipid oxidation) in old rats more than either supplement alone.26

Keeping Cardiovascular Disease in Check
Cardiovascular disease is the number one killer of Americans. We’ve heard this many times but how many people actually do something to prevent it? Fortunately, ALA, ALC and carnosine provide just the tools we need to take action against this frightening disorder.

High glucose levels oxidize low-density lipoproteins resulting in formation of foam cells and deposits of atherosclerotic plaques. As a result, people with diabetes suffer from higher rates of heart disease, stroke, and hypertension than the general population. Fortunately, ALA inhibits monocyte adhesion and endothelial activation, which leads to atherosclerosis due to oxidative stress.27 Carnosine inhibits oxidation of low-density lipoprotein (LDL), which leads to atherosclerosis, by chelating (removing) copper, which oxidizes ascorbic acid.28

ALA prevents hyperglycemia induced hypertension in rats by lowering free radical production and raising glutathione levels.29 It also prevents hypertension and protects against kidney and vascular injuries in rats by suppressing endothelin-1 (a substance produced in blood vessels that regulates their tone).30 Carnosine is shown to suppress diabetes triggered increases in blood pressure by reacting with small carbonyl compounds (aldehydes and ketones) which accumulate on proteins during aging.31

Heart health is closely tied to how well heart cells can make energy and protect themselves from free radical attack. Recent research suggests that carnosine increases heart contractility by releasing calcium in calcium-regulated proteins in cardiac muscle cells.32 ALA improves numerous functions in the heart including oxygen uptake, ATP levels, cardiac output, pyruvate (energy) production, lactate (a waste product) accumulation and glucose and glycogen (energy) storage and breakdown. It also protects glutathione and controls hydroxyl radicals, which may account for its anti-aging, heart supporting function.33 Finally, ALA is found to protect against reperfusion arrhythmias and lipid peroxidation induced by ferrous ions and ascorbate.34

New Solutions for HIV-AIDS and Cancer
Another recent application of ALA, ALC and carnosine that has caught the attention of drug and biotechnology companies is for immune disorders such as cancer and HIV-AIDS. For example, Polaprezinc an ultra-safe Japanese drug made from carnosine and zinc is shown to help fight certain cancers but has yet to be approved by the FDA for use in the U.S. One recent study noted that ALA is toxic to leukemia cell lines, inhibits proliferation of mitogen-stimulated human peripheral blood lymphocytes, and increases interleukin-2.35 ALA synergistically enhances vitamin C cytotoxicity against hollow fibre tumors and unlike ascorbate, is equally effective against proliferating and non-proliferating cells.36

Alpha Lipoic Acid, Acetyl-L-Carnitine and Carnosine
The Latest Significant Research on This Powerful Life Extension Trio
By Tim Batchelder, B.A.

ALC helps maintain liver function, which is essential for detoxification. One new study found that ALC almost completely restores the age-dependent decline in oxygen consumption, gluconeogenesis, urea synthesis, and ketogenesis found in the liver of old rats to the levels found in young rats.37 ALC also helps prevent hepatoxicity and increases survival during chemotherapy with heptotoxic alkylating agents for cancer.38 ALC and ALA are useful in treating muscle and nerve mitochondrial toxicity caused by nucleoside analog reverse transcriptase inhibitor therapy for HIV-AIDS.39 ALC also enhances detoxification of ethanol in the liver as well as the unpleasant side effects of detoxification. For example, it significantly reduces the onset of tremors in ethanol withdrawal syndrome as well as the level of ethanol intake in alcohol-preferring rats.40 One new study shows that ALA (and its chemical cousin alpha-lipoamide (LM) may work as an antioxidant by chelating iron which is involved in cell death by lysosomal rupture.41 Further, since it has a particular affinity for the liver ALA can also treat liver damage from mushroom poisoning, snake venom, acetaldehyde and viral hepatitis. ALA was studied extensively in the 1950s for radiation protection and was found to be more effective than other common radio-protectants such as cysteamine. It was put to use for victims of Chernobyl, and as a sulfur compound, can bind and eliminate heavy metals. ALA is also shown to decrease smoking-related lipid peroxidation.42 Finally, carnosine is a potent radioprotectant and prevents damage by cold, hyperthermia, and hypoxia.43

Support for Energy, Muscle Recovery and Weight Loss
Exercise creates a heavy load of free radical activity, which makes it a natural target for powerful antioxidants like ALA, ALC and carnosine. Several recent studies have looked at how these compounds work to protect muscle tissue during exercise and maintain energy stores. For example, one study noted that carnosine inhibits lipid peroxidation and oxidative modification of protein in muscle tissue.44 It works as a pH buffer to protect muscle cells from oxidation under the acidic conditions of muscular exertion. Similar, ALA decreases lipid peroxidation and lactic acid accumulation and increases levels of glutathione, vitamins C and E and the activities of mitochondrial enzymes, which prevents tissue damage and improves ATP (energy) synthesis.45 ALA also helps Chronic Fatigue Syndrome.46 Finally, ALA and exercise interact in an additive fashion to improve insulin action in insulin-resistant skeletal muscles in obese rats.47

Conclusion
The surge of recent research on the synergies and anti-aging benefits of ALA, ALC and carnosine is making them an important addition to any supplement plan. What is so exciting is the versatility of these antioxidant compounds, which seem to work in so many body systems, from the nervous system to the cardiovascular, musculoskeletal and immune systems. In doing so they are able to effectively combat the major diseases of our time including diabetes, cognitive decline and Alzheimer’s, heart disease, obesity and immune disorders such as cancer and HIV-AIDS.

References

1. Liu J, et al. Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding aceyl-l-carnitine and/or R-alpha- lipoic acid. Proc Natl Acad Sci USA 2002 Feb 19;99(4):2356-61.

2. Hagen TM, et al. Feeding acetyl-l-carntine and lipoic acid to old rats significantly improves the metabolic function while decreasing oxidative stress. Proc Natl Acad Sci USA 2002 Feb 19;99(4):1870-5.

3. Giancaterini A, et al. Acetyl-L-carnitine infusion increases glucose disposal in type 2 diabetic patients. Metabolism 2000 Jun;49(6):704-8.

4. Yamano T,et al. Effect of L-carnosine on the hyperglycemia caused by intracranial injection of 2-deoxy-D-glucose in rats. Neurosci Lett 2001 Nov 2;313(1-2):78-82.

5. Packer L, et al. Molecular aspects of lipoic acid in the prevention of diabetes complications. Nutrition 2001 Oct;17(10):888-95.

6. Ford I, et al. The effects of treatment with alpha-lipoic acid or evening primrose oil on vascular hemostatic and lipid risk factors, blood flow, and peripheral nerve conduction in the streptozotocin-diabetic rat. Metabolism 2001 Aug;50(8):868-75.

7. Coppey LJ, et al. Effect of antioxidant treatment of streptozotocin-induced diabetic rats on endoneurial blood flow, motor nerve conduction velocity and vascular reactivity of epineurial arterioles of the sciatic nerve. Diabetes 2001 Aug;50(8):1927-37.

8. Cameron NE, et al. Effect of alpha-lipoic acid on vascular responses and nociception in diabetic rats. Free Radic Biol Med 2001 Jul 1;31(1):125-35.

9. Heitzer T, et al. Beneficial effects of alpha-lipoic acid and ascorbic acid on endothelium-dependent, nitric oxide-mediated vasodilation in diabetic patients: relation to parameters of oxidative stress. Free Radic Biol Med 2001 Jul 1;31(1):53-61.

10. Ukeda H, et al. Effect of carnosine and related compounds on the inactivation of human Cu,Zn-superoxide dismutase by modification of fructose and glycolaldehyde. Biosci Biotechnol Biochem 2002 Jan;66(1):36-43.

11. Hipkiss AR. On the “struggle between chemistry and biology during aging”--implications for DNA repair, apoptosis and proteolysis, and a novel route of intervention. Biogerontology 2001;2(3):173-8.

12. Packer Let al. Molecular aspects of lipoic acid in the prevention of diabetes complications. Nutrition 2001 Oct;17(10):888-95.

13. Melhem MF, et al. Alpha-lipoic acid attenuates hyperglycemia and prevents glomerular mesangial matrix expansion in diabetes. J Am Soc Nephrol 2002 Jan;13(1):108-16.

14. Virmani MA, et al. The action of acetyl-L-carnitine on the neurotoxicity evoked by amyloid fragments and peroxide on primary rat cortical neurones. Ann N Y Acad Sci 2001 Jun;939:162-78.

15. Zhang L, et al. Alpha-lipoic acid protects rat cortical neurons against cell death induced by amyloid and hydrogen peroxide through the Akt signalling pathway. Neurosci Lett 2001 Oct 26;312(3):125-8.

16. Dukic-Stefanovic S, et al. AGES in brain ageing: AGE-inhibitors as neuroprotective and anti-dementia drugs? Biogerontology 2001;2(1):19-34.

17. Price DL, et al. Chelating activity of advanced glycation end-product inhibitors. J Biol Chem 2001 Dec 28;276(52):48967-72.

18. Ando S, et al. Enhancement of learning capacity and cholinergic synaptic function by carnitine in aging rats. J Neurosci Res 2001 Oct 15;66(2):266-71.

19. Pettegrew JW, et al. Acetyl-L-carnitine physical-chemical, metabolic, and therapeutic properties: relevance for its mode of action in Alzheimer’s disease and geriatric depression. Mol Psychiatry 2000 Nov;5(6):616-32.

20. Sorbi S, et al. Double-blind, crossover, placebo-controlled clinical trial with L-acetylcarnitine in patients with degenerative cerebellar ataxia. Clin Neuropharmacol 2000 Mar-Apr;23(2):114-8.

21. Andreassen OA, et al. Lipoic acid improves survival in transgenic mouse models of Huntington’s disease. Neuroreport 2001 Oct 29;12(15):3371-3.

22. Hager K, et al. Alpha-lipoic acid as a new treatment option for Azheimer type dementia. Arch Gerontol Geriatr 2001 Jun;32(3):275-282.

23. Gonzalez-Perez O, et al. Beneficial effects of alpha-lipoic acid plus vitamin E on neurological deficit, reactive gliosis and neuronal remodeling in the penumbra of the ischemic rat brain. Neurosci Lett 2002 Mar 15;321(1-2):100-4.

24. Piotrowski P, et al. Neuronal death in the rat hippocampus in experimental diabetes and cerebral ischaemia treated with antioxidants. Folia Neuropathol 2001;39(3):147-54.

25. Liu J, et al. Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-alpha -lipoic acid. Proc Natl Acad Sci U S A 2002 Feb 19;99(4):2356-61.

26. Hagen TM, et al. Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc Natl Acad Sci U S A 2002 Feb 19;99(4):1870-5.

27. Zhang WJ, Frei B. Alpha-lipoic acid inhibits TNF-alpha-induced NF-kappaB activation and adhesion molecule expression in human aortic endothelial cells. FASEB J 2001 Nov;15(13):2423-32.

28. Decker EA, et al. Inhibition of low-density lipoprotein oxidation by carnosine histidine. J Agric Food Chem 2001 Jan;49(1):511-6.

29. El Midaoui A, de Champlain J. Prevention of hypertension, insulin resistance, and oxidative stress by alpha-lipoic acid. Hypertension 2002 Feb;39(2):303-7.

30. Takaoka M, et al. Effects of alpha-lipoic acid on deoxycorticosterone acetate-salt-induced hypertension in rats. Eur J Pharmacol 2001 Jul 20;424(2):121-9.

31. Hipkiss AR, et al. Carnosine, the anti-aging, anti-oxidant dipeptide, may react with protein carbonyl groups. Mech Ageing Dev 2001 Sep 15;122(13):1431-45.

32. Roberts PR, Zaloga GP. Cardiovascular effects of carnosine. Biochemistry (Mosc) 2000 Jul;65(7):856-61.

33. Arivazhagan P, et al. Effect of DL-alpha-lipoic acid on glutathione metabolic enzymes in aged rats. Exp Gerontol 2001 Dec;37(1):81-7.

34. Koufaki M, et al. Novel potent inhibitors of lipid peroxidation with protective effects against reperfusion arrhythmias. J Med Chem 2001 Nov 22;44(24):4300-3.

35. Pack RA, et al. Differential effects of the antioxidant alpha-lipoic acid on the proliferation of mitogen-stimulated peripheral blood lymphocytes and leukaemic T cells. Mol Immunol 2002 Feb;38(10):733-45.

36. Casciari JJ, et al.. Cytotoxicity of ascorbate, lipoic acid, and other antioxidants in hollow fibre in vitro tumours. Br J Cancer 2001 Jun 1;84(11):1544-50.

37. Mollica MP, et al. Acetyl-L-carnitine treatment stimulates oxygen consumption and biosynthetic function in perfused liver of young and old rats. Cell Mol Life Sci 2001 Mar;58(3):477-84.

38. Niang M, Melka M. Effect of acetyl-L-carnitine on leukemia L1210 resistant to mitoxantrone. Acta Medica (Hradec Kralove) 2000;43(4):125-8.

39. Patrick L. Nutrients and HIV: part three - N-acetylcysteine, alpha-lipoic acid, L-glutamine, and L-carnitine. : Altern Med Rev 2000 Aug;5(4):290-305.

40. Mangano NG, et al. Effect of acetyl-L-carnitine on ethanol consumption and alcohol abstinence syndrome in rats. Drugs Exp Clin Res 2000;26(1):7-12.

41. Persson HL, et al. Alpha-lipoic acid and alpha-lipoamide prevent oxidant-induced lysosomal rupture and apoptosis. Redox Rep 2001;6(5):327-34.

42. Dietrich M, et al. Antioxidant supplementation decreases lipid peroxidation biomarker F(2)-isoprostanes in plasma of smokers. Cancer Epidemiol Biomarkers Prev 2002 Jan;11(1):7-13.

43. Akhalaia MIa, et al. Effect of natural radioprotector carnosine on histamine-diamine oxidase system of rat’s myocardium after action of various extreme factors. Radiats Biol Radioecol 2001 Jan-Feb;41(1):56-8.

44. Nagasawa T, et al. In vitro and in vivo inhibition of muscle lipid and protein oxidation by carnosine. Mol Cell Biochem 2001 Sep;225(1-):29-34.

45. Arivazhagan P, et al. Effect of DL-alpha-lipoic acid on mitochondrial enzymes in aged rats. Chem Biol Interact 2001 Nov 28;138(2):189-98.

46. Logan AC, Wong C. Chronic fatigue syndrome: oxidative stress and dietary modifications. Altern Med Rev 2001 Oct;6(5):450-9.

47. Saengsirisuwan V, et al. Interactions of exercise training and lipoic acid on skeletal muscle glucose transport in obese Zucker rats. J Appl Physiol 2001 Jul;91(1):145-53.

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