Life Extension Magazine June 2002
As We See It
DO ANTI-AGING SUPPLEMENTS REALLY WORK?
Consumers take dietary supplements for a variety of reasons. Some only seek to avoid acute deficiency or reduce their risk of degenerative disease. A growing number of users, however, expect that certain supplements will help to slow aging.
Those who believe that supplements may retard aging base their reliance on scientific studies demonstrating specific mechanisms of action. Examples are the anti-glycating properties of carnosine, the methylation-enhancing effects of folic acid and the ability of fish oil to suppress pro-inflammatory cytokines.[1-13]
Another basis for these anti-aging theories is that certain supplements replace what was naturally produced in youth. For instance, low levels of DHEA and melatonin are associated with a host of age-related disorders.[14-25] Restoring these hormones to youthful ranges has produced promising results.[26-42]
Critics of anti-aging supplements remain unconvinced. They demand proof that ingestion of these supplements actually deters biologic aging.
The National Academy of Sciences has published three new reports showing that aging may be partially reversible with currently available supplements. These new reports corroborate previous findings indicating that we already have some control over how aging affects us.
Restoring cell function
In the first study published by the National Academy of Sciences, young and old rats were supplemented with acetyl-l-carnitine and lipoic acid for up to one month before their death. The results showed a partial reversal in the decline of mitochondrial membrane function while consumption of oxygen significantly increased. This means that acetyl-l-carnitine and lipoic acid improved cellular metabolic function. The improvement was substantially greater in old rats compared to young rats.
We know that aging results in the decline of the ability of cells to generate energy. This impairment is caused by the failure of the mitochondria-the cell's energy factory. Aged cells also generate more damaging free radicals (oxidative stress), even though less oxygen is consumed.
Since acetyl-l-carnitine and lipoic acid cause aged cells to produce more energy, a logical question to ask is whether more toxic free radicals are being generated. Remember, when energy is produced in the mitochondria, a byproduct is oxidative stress (excess free radical formation). Young cells contain natural antioxidants such as glutathione to control free radical reactions, but aged cells are vulnerable because they are deficient in endogenous antioxidants. This new study showed that the combination of lipoic acid and acetyl-l-carnitine reduced a marker (malondialdehyde) of free radical damage.
Another way of ascertaining whether older cells are able to resist free radicals is to measure their vitamin C levels. The findings of this study showed that the combination of acetyl-l-carnitine and lipoic acid restored vitamin C levels in the livers of old rats to those seen in the young rats.
What may impress skeptics most about this study is that the combination of acetyl-l-carnitine and lipoic acid improved ambulatory activity, with a significantly greater degree of improvement in the old rats compared to the young ones.
Human aging is characterized by lethargy, infirmity and weakness. We now have conclusive evidence that supplementation with two over-the-counter nutrients can produce a measurable anti-aging effect.
Reversing memory loss
The second study published by the National Academy of Sciences evaluated the effects of supplemental acetyl-l-carnitine and lipoic acid on the brains of old rats. The scientists evaluated cognitive function, mitochondrial structure and markers of oxidative damage in these old rats.
In two different types of cognitive tests, supplementation with acetyl-l-carnitine and lipoic acid resulted in improved memory. Electron microscopic studies in the hippocampus region of the brain showed that acetyl-l-carnitine and lipoic acid reversed age-associated mitochondrial structural decay.
The brains of the aged rats showed the expected increase in oxidative damage, but supplementation with acetyl-l-carnitine and lipoic acid protected against much of this free radical attack. The conclusion of the scientists who conducted this study was:
|"These results suggest that feeding acetyl-l-carnitine and lipoic acid to old rats improves performance on memory tasks by lowering oxidative damage and improving mitochondrial function."|
A hallmark consequence of aging is a decline in mental function. This study confirms a mechanism by which age-associated cognitive impairment and mitochondrial structural dysfunction can be controlled.
Protecting mitochondrial "fuel"
In the third National Academy of Sciences study, scientists tested acetyl-l-carnitine and lipoic acid to see if an enzyme used by the mitochondria as biologic fuel could be restored in old rats. The name of this enzyme is carnitine acetyltransferase.
As expected, old rats had low levels of this enzyme compared to young rats. However, after seven weeks of supplementation with acetyl-l-carnitine and lipoic acid, levels of carnitine acetyltransferase were significantly restored in the aged rats. Supplementation also inhibited free radical-induced lipid peroxidation.
The scientists concluded that feeding old rats acetyl-l-carnitine and lipoic acid can ameliorate oxidative damage, along with enzyme and mitochondrial dysfunction.
Where we stand today
There is more anti-aging research being conducted today than at any other time in history.
Some scientists are optimistic that significant breakthroughs are on the horizon. Other experts disagree and want more resources allocated to finding a cure for aging. We prefer to err on the pessimistic side and battle for more money to be spent on controlling aging in our lifetime.
The Life Extension Foundation is the largest scientific organization dedicated to eradicating the miseries of human aging. We fund millions of dollars for pioneering research each year. Every time you buy a product from us or renew your membership, you help support our goal of breaking down the genetic barriers that put a finite limit on how long we can exist.
In this issue of Life Extension we report on several anti-aging discoveries, some that Foundation members can take advantage of today!
For longer life,
1. Hipkiss AR, Brownson C, Carrier MJ. Carnosine, the anti-ageing, anti-oxidant dipeptide, may react with protein carbonyl groups. Mech Ageing Dev 2001 Sep 15;122(13):1431-45.
2. Hipkiss AR. Carnosine and protein carbonyl groups: a possible relationship. Biochemistry (Mosc) 2000 Jul;65(7):771-8.
3. Preston JE, Hipkiss AR, Himsworth DT, et al. Toxic effects of beta-amyloid(25-35) on immortalised rat brain endothelial cell: protection by carnosine, homocarnosine and beta-alanine. Neurosci Lett 1998 Feb 13;242(2):105-8.
4. Kuleva NV, Kovalenko ZS. Change in the functional properties of actin by its glycation in vitro. Biochemistry (Mosc) 1997 Oct;62(10):1119-23.
5. Fang JY, Xiao SD, Zhu SS, et al. Relationship of plasma folic acid and status of DNA methylation in human gastric cancer. J Gastroenterol 1997 Apr;32(2):171-5.
6. Cravo M, Fidalgo P, Pereira AD, et al. DNA methylation as an intermediate biomarker in colorectal cancer: modulation by folic acid supplementation. Eur J Cancer Prev 1994 Nov;3(6):473-9.
7. Newman PE. Can reduced folic acid and vitamin B12 levels cause deficient DNA methylation producing mutations which initiate atherosclerosis? Med Hypotheses 1999 Nov;53(5):421-4.
8. Watanabe S, Katagiri K, Onozaki K, et al. Dietary docosahexaenoic acid but not eicosapentaenoic acid suppresses lipopolysaccharide-induced interleukin-1 beta mRNA induction in mouse spleen leukocytes. Prostaglandins Leukot Essent Fatty Acids 2000 Mar;62(3):147-52.
9. Kelley VE, Ferretti A, Izui S, et al. A fish oil diet rich in eicosapentaenoic acid reduces cyclooxygenase metabolites, and suppresses lupus in MRL-lpr mice. J Immunol 1985 Mar;134(3):1914-9.
10. Calder PC. Polyunsaturated fatty acids, inflammation, and immunity. Lipids 2001 Sep;36(9):1007-24.
11. Tomobe YI, Morizawa K, Tsuchida M, et al. Dietary docosahexaenoic acid suppresses inflammation and immunoresponses in contact hypersensitivity reaction in mice. Lipids 2000 Jan;35(1):61-9.
12. McCarty MF. Interleukin-6 as a central mediator of cardiovascular risk associated with chronic inflammation, smoking, diabetes, and visceral obesity: down-regulation with essential fatty acids, ethanol and pentoxifylline. Med Hypotheses 1999 May;52(5):465-77.
13. Raederstorff D, Pantze M, Bachmann H, et al. Anti-inflammatory properties of docosahexaenoic and eicosapentaenoic acids in phorbol-ester-induced mouse ear inflammation. Int Arch Allergy Immunol 1996 Nov;111(3):284-90.
14. Vermeulen A. [Juvenile hormones, reality or myth?] Verh K Acad Geneeskd Belg 1997;59(1):19-33.
15. Barry NN, McGuire JL, van Vollenhoven RF. Dehydroepiandrosterone in systemic lupus erythematosus: relationship between dosage, serum levels, and clinical response. J Rheumatol 1998 Dec;25(12):2352-6.
16. van Vollenhoven RF, Morabito LM, Engleman EG, et al. Treatment of systemic lupus erythematosus with dehydroepiandrosterone: 50 patients treated up to 12 months. J Rheumatol 1998 Feb;25(2):285-9.
17. No Authors listed. DHEA. Monograph. Altern Med Rev 2001 Jun;6(3):314-8.
18. Straub RH, Scholmerich J, Zietz B. Replacement therapy with DHEA plus corticosteroids in patients with chronic inflammatory diseases--substitutes of adrenal and sex hormones. Z Rheumatol 2000;59 Suppl 2:II/108-18.
19. Salek FS, Bigos KL, Kroboth PD. The influence of hormones and pharmaceutical agents on DHEA and DHEA-S concentrations: a review of clinical studies. J Clin Pharmacol 2002 Mar;42(3):247-66.
20. Reiter RJ, Tan D, Kim SJ, et al. Augmentation of indices of oxidative damage in life-long melatonin-deficient rats. Mech Ageing Dev 1999 Oct 22;110(3):157-73.
21. Turek FW, Zee P, Van Reeth O. Melatonin and aging. Adv Exp Med Biol 1999;460:435-40.
22. Srinivasan V. Melatonin, biological rhythm disorders and phototherapy. Indian J Physiol Pharmacol 1997 Oct;41(4):309-28.
23. Grad BR, Rozencwaig R. The role of melatonin and serotonin in aging: update. Psychoneuroendocrinology 1993;18(4):283-95.
24. Sandyk R. Possible role of pineal melatonin in the mechanisms of aging. Int J Neurosci 1990 May;52(1-2):85-92.
25. Rozencwaig R, Grad BR, Ochoa J. The role of melatonin and serotonin in aging. Med Hypotheses 1987 Aug;23(4):337-52.
26. Formiga F, Moga I, Nolla JM, et al. The association of dehydroepiandrosterone sulphate levels with bone mineral density in systemic lupus erythematosus. Clin Exp Rheumatol 1997 Jul-Aug;15(4):387-92.
27. Morales AJ, Nolan JJ, Nelson JC, et al. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. J Clin Endocrinol Metab 1994 Jun;78(6):1360-7.
28. Labrie F, Diamond P, Cusan L, et al. Effect of 12-month dehydroepiandrosterone replacement therapy on bone, vagina, and endometrium in postmenopausal women. J Clin Endocrinol Metab 1997 Oct;82(10):3498-505.
29. Cogan E. DHEA: orthodox or alternative medicine? Rev Med Brux 2001 Sep;22(4):A381-6.
30. Villareal DT, Holloszy JO, Kohrt WM. Effects of DHEA replacement on bone mineral density and body composition in elderly women and men. Clin Endocrinol (Oxf) 2000 Nov;53(5):561-8.
31. Porsova-Dutoit I, Sulcova J, Starka L. Do DHEA/DHEAS play a protective role in coronary heart disease? Physiol Res 2000;49 Suppl 1:S43-56.
32. Baulieu EE, Thomas G, Legrain S, et al. Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: contribution of the DHEAge Study to a sociobiomedical issue. Proc Natl Acad Sci U S A 2000 Apr 11;97(8):4279-84.
33. Acuna CD, Escames G, Carazo A, et al. Melatonin, mitochondrial homeostasis and mitochondrial-related diseases. Curr Top Med Chem 2002 Feb;2(2):133-51.
34. Karbownik M, Reiter RJ. Melatonin protects against oxidative stress caused by delta-aminolevulinic acid: implications for cancer reduction. Cancer Invest 2002;20(2):276-86.
35. Konecna I, Holecek V, Racek J, et al. [Antioxidant effects of melatonin] [Article in Czech] Cas Lek Cesk 2001 May;140(9):262-6.
36. Zhang Z, Inserra PF, Liang B, et al. Melatonin, immune modulation and aging. Autoimmunity 1997;26(1):43-53.
37. Pang SF, Pang CS, Poon AM, et al. Melatonin: a chemical photoperiodic signal with clinical significance in humans. Chin Med J (Engl) 1998 Mar;111(3):197-203.
38. Sandyk R. Possible role of pineal melatonin in the mechanisms of aging. Int J Neurosci 1990 May;52(1-2):85-92.
39. Pierpaoli W, Maestroni GJ. Melatonin: a principal neuroimmunoregulatory and anti-stress hormone: its anti-aging effects. Immunol Lett 1987 Dec;16(3-4):355-61.
40. Armstrong SM, Redman JR. Melatonin: a chronobiotic with anti-aging properties? Med Hypotheses 1991 Apr;34(4):300-9.
41. Zhang Z, Inserra PF, Liang B, et al. Melatonin, immune modulation and aging. Autoimmunity 1997;26(1):43-53.
42. Tan DX, Reiter RJ, Manchester LC, et al. Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem 2002 Feb;2(2):181-97.
43. Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress Mitochondrial-supported bioenergetics decline and oxidative stress increases during aging. Proc. Natl. Acad. Sci. USA, Vol. 99, Issue 4, 1870-1875, February 19, 2002 Biochemistry.
43. Hagen TM, Liu J, Lykkesfeldt J, 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.
44. Liu J, Head E, Gharib AM, 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. USA, Vol. 99, Issue 4, 2356-2361, February 19, 2002.
45. Liu J, Killilea DW, Ames BN. Age-associated mitochondrial oxidative decay: improvement of carnitine acetyltransferase substrate-binding affinity and activity in brain by feeding old rats acetyl-L- carnitine and/or R-alpha -lipoic acid. Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):1876-81.