contentLife Extension Magazine May 2014 How Lipoic Acid Preserves Critical Mitochondrial Function By Megan M. Mitzelfelt, PhD References Andreux PA, Houtkooper RH, Auwerx J. Pharmacological approaches to restore mitochondrial function. Nat Rev Drug Discov. 2013 Jun;12(6):465-83. Available at: http://www.umdf.org/site/pp.aspx?c=8qKOJ0MvF7LUG&b=7934637. Accessed February 18, 2014. Kaki SS, Grey C, Adlercreutz P. Bioorganic synthesis, characterization and antioxidant activity of esters of natural phenolics and alpha-lipoic acid. J Biotechnol. 2012 Jan 20;157(2):344-9. Koufaki M, Detsi A, Kiziridi C. Multifunctional lipoic acid conjugates. Curr Med Chem. 2009;16(35):4728-42. Barbiroli B, Medori R, Tritschler HJ, et al. Lipoic (thioctic) acid increases brain energy availability and skeletal muscle performance as shown by in vivo 31P-MRS in a patient with mitochondrial cytopathy. J Neurol. 1995 Jul;242(7):472-7. Available at: http://clinicaltrials.gov/ct2/results?term=lipoic+acid&Search=Search. Accessed February 24, 2014. Available at: http://www.thorne.com/altmedrev/.fulltext/11/3/232.pdf. Accessed February 24, 2014. Available at: http://www.cdc.gov/diabetes/pubs/estimates11.htm#12. Accessed February 18, 2014. Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiol Rev. 2013 Jan;93(1):137-88. Barshes NR, Sigireddi M, Wrobel JS, Mahankali A, Robbins JM, Kougias P, et al. The system of care for the diabetic foot: objectives, outcomes, and opportunities. Diabet Foot Ankle. 2013;4. Available at: http://www.mayoclinic.org/diseases-conditions/diabetic-neuropathy/basics/treatment/con-20033336. Acessed February 18, 2014. Ziegler D, Reljanovic M, Mehnert H, Gries FA. Alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: current evidence from clinical trials. Exp Clin Endocrinol Diabetes. 1999;107(7):421-30. Ziegler D. Thioctic acid for patients with symptomatic diabetic polyneuropathy: a critical review. Treat Endocrinol. 2004;3(3):173-89. Han T, Bai J, Liu W, Hu Y. A systematic review and meta-analysis of alpha-lipoic acid in the treatment of diabetic peripheral neuropathy. Eur J Endocrinol. 2012 Oct;167(4):465-71. Ziegler D, Low PA, Litchy WJ, Boulton AJ, Vinik AI, Freeman R, et al. Efficacy and safety of antioxidant treatment with alpha-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care. 2011 Sep;34(9):2054-60. Cummings BP, Stanhope KL, Graham JL, et al. Dietary fructose accelerates the development of diabetes in UCD-T2DM rats: amelioration by the antioxidant, alpha-lipoic acid. Am J Physiol Regul Integr Comp Physiol. 2010 May;298(5):R1343-50. Ansar H, Mazloom Z, Kazemi F, Hejazi N. Effect of alpha-lipoic acid on blood glucose, insulin resistance and glutathione peroxidase of type 2 diabetic patients. Saudi Med J. 2011 Jun;32(6):584-8. Kandeil MA, Amin KA, Hassanin KA, Ali KM, Mohammed ET. Role of lipoic acid on insulin resistance and leptin in experimentally diabetic rats. J Diabetes Complications. 2011 Jan-Feb;25(1):31-8. Udupa A, Nahar P, Shah S, Kshirsagar M, Ghongane B. A comparative study of effects of omega-3 Fatty acids, alpha lipoic Acid and vitamin e in type 2 diabetes mellitus. Ann Med Health Sci Res. 2013 Jul;3(3):442-6. Qin ZY, Zhang M, Guo XR, Wang YM, Zhu GZ, Ni YH, et al. alpha-Lipoic acid ameliorates impaired glucose uptake in LYRM1 overexpressing 3T3-L1 adipocytes through the IRS-1/Akt signaling pathway. J Bioenerg Biomembr. 2012 Oct;44(5):579-86. Porasuphatana S, Suddee S, Nartnampong A, Konsil J, Harnwong B, Santaweesuk A. Glycemic and oxidative status of patients with type 2 diabetes mellitus following oral administration of alpha-lipoic acid: a randomized double-blinded placebo-controlled study. Asia Pac J Clin Nutr. 2012;21(1):12-21. Arambasic J, Mihailovic M, Uskokovic A, Dinic S, Grdovic N, Markovic J, et al. Alpha-lipoic acid upregulates antioxidant enzyme gene expression and enzymatic activity in diabetic rat kidneys through an O-GlcNAc-dependent mechanism. Eur J Nutr. 2013 Aug;52(5):1461-73. Feng B, Yan XF, Xue JL, Xu L, Wang H. The protective effects of alpha-lipoic acid on kidneys in type 2 diabetic goto-kakisaki rats via reducing oxidative stress. Int J Mol Sci. 2013;14(4):6746-56. Wang L, Wu CG, Fang CQ, et al. The protective effect of alpha-lipoic acid on mitochondria in the kidney of diabetic rats. Int J Clin Exp Med. 2013;6(2):90-7. Yi X, Xu L, Hiller S, et al. Reduced expression of lipoic acid synthase accelerates diabetic nephropathy. J Am Soc Nephrol. 2012 Jan;23(1):103-11. Chen CL, Cheng WS, Chen JL, Chiang CH. Potential of nonoral alpha-lipoic acid aqueous formulations to reduce ocular microvascular complications in a streptozotocin-induced diabetic rat model. J Ocul Pharmacol Ther. 2013 Oct;29(8):738-45. Nebbioso M, Pranno F, Pescosolido N. Lipoic acid in animal models and clinical use in diabetic retinopathy. Expert Opin Pharmacother. 2013 Sep;14(13):1829-38. Santos JM, Kowluru RA. Role of mitochondria biogenesis in the metabolic memory associated with the continued progression of diabetic retinopathy and its regulation by lipoic acid. Invest Ophthalmol Vis Sci. 2011;52(12):8791-8. Naser N, Januszewski AS, Brown BE, Jenkins AJ, Hill MA, Murphy TV. Advanced glycation end products acutely impair ca(2+) signaling in bovine aortic endothelial cells. Front Physiol. 2013;4:38. Koh EH, Lee WJ, Lee SA, et al. Effects of alpha-lipoic Acid on body weight in obese subjects. Am J Med. 2011 Jan;124(1):85 e81-8. Carbonelli MG, Di Renzo L, Bigioni M, Di Daniele N, De Lorenzo A, Fusco MA. Alpha-lipoic acid supplementation: a tool for obesity therapy? Curr Pharm Des. 2010;16(7):840-6. Kim E, Park DW, Choi SH, Kim JJ, Cho HS. A preliminary investigation of alpha-lipoic acid treatment of antipsychotic drug-induced weight gain in patients with schizophrenia. J Clin Psychopharmacol. 2008 Apr;28(2):138-46. Pershadsingh HA. Alpha-lipoic acid: physiologic mechanisms and indications for the treatment of metabolic syndrome. Expert Opin Investig Drugs. 2007 Mar;16(3):291-302. Available at: http://www.nhlbi.nih.gov/health/health-topics/topics/ms/. Accessed February 18, 2014. Jung TS, Kim SK, Shin HJ, Jeon BT, Hahm JR, Roh GS. alpha-lipoic acid prevents non-alcoholic fatty liver disease in OLETF rats. Liver Int. 2012 Nov;32(10):1565-73. Butler JA, Hagen TM, Moreau R. Lipoic acid improves hypertriglyceridemia by stimulating triacylglycerol clearance and downregulating liver triacylglycerol secretion. Arch Biochem Biophys. 2009 May 1;485(1):63-71. Chen WL, Kang CH, Wang SG, Lee HM. alpha-Lipoic acid regulates lipid metabolism through induction of sirtuin 1 (SIRT1) and activation of AMP-activated protein kinase. Diabetologia. 2012 Jun;55(6):1824-35. Deiuliis JA, Kampfrath T, Ying Z, Maiseyeu A, Rajagopalan S. Lipoic acid attenuates innate immune infiltration and activation in the visceral adipose tissue of obese insulin resistant mice. Lipids. 2011 Nov;46(11):1021-32. Prieto-Hontoria PL, Perez-Matute P, Fernandez-Galilea M, Alfredo Martinez J, Moreno-Aliaga MJ. Effects of lipoic acid on AMPK and adiponectin in adipose tissue of low- and high-fat-fed rats. Eur J Nutr. 2013 Mar;52(2):779-87. Yi X, Pashaj A, Xia M, Moreau R. Reversal of obesity-induced hypertriglyceridemia by (R)-alpha-lipoic acid in ZDF (fa/fa) rats. Biochem Biophys Res Commun. 2013 Sep 27;439(3):390-5. Kim MS, Park JY, Namkoong C, et al. Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nat Med. 2004 Jul;10(7):727-33. Gianturco V, Bellomo A, D’Ottavio E, et al. Impact of therapy with alpha-lipoic acid (ALA) on the oxidative stress in the controlled NIDDM: a possible preventive way against the organ dysfunction? Arch Gerontol Geriatr. 2009;49 Suppl 1:129-33. Zamora PL, Villamena FA. Pharmacological approaches to the treatment of oxidative stress-induced cardiovascular dysfunctions. Future Med Chem. 2013 Mar;5(4):465-78. Dhalla NS, Temsah RM, Netticadan T. Role of oxidative stress in cardiovascular diseases. J Hypertens. 2000 Jun;18(6):655-73. Lee WR, Kim A, Kim KS, et al. Alpha-lipoic acid attenuates atherosclerotic lesions and inhibits proliferation of vascular smooth muscle cells through targeting of the Ras/MEK/ERK signaling pathway. Mol Biol Rep. 2012 Jun;39(6):6857-66. Ying Z, Kherada N, Farrar B, et al. Lipoic acid effects on established atherosclerosis. Life Sci. 2010 Jan 16;86(3-4):95-102. Amom Z, Zakaria Z, Mohamed J, et al. Lipid lowering effect of antioxidant alpha-lipoic Acid in experimental atherosclerosis. J Clin Biochem Nutr. 2008 Sep;43(2):88-94. Zulkhairi A, Zaiton Z, Jamaluddin M, et al. Alpha lipoic acid possess dual antioxidant and lipid lowering properties in atherosclerotic-induced New Zealand White rabbit. Biomed Pharmacother. 2008 Dec;62(10):716-22. Deng C, Sun Z, Tong G, et al. alpha-Lipoic acid reduces infarct size and preserves cardiac function in rat myocardial ischemia/reperfusion injury through activation of PI3K/Akt/Nrf2 pathway. PLoS One. 2013;8(3):e58371. Rocamonde B, Paradells S, Barcia JM, et al. Neuroprotection of lipoic acid treatment promotes angiogenesis and reduces the glial scar formation after brain injury. Neuroscience. 2012 Nov 8;224:102-15. Connell BJ, Saleh TM. Co-administration of apocynin with lipoic acid enhances neuroprotection in a rat model of ischemia/reperfusion. Neurosci Lett. 2012 Jan 17;507(1):43-6. Connell BJ, Saleh MC, Khan BV, Rajagopal D, Saleh TM. UPEI-100, a conjugate of lipoic acid and apocynin, mediates neuroprotection in a rat model of ischemia/reperfusion. Am J Physiol Regul Integr Comp Physiol. 2012 Apr;302(7):R886-95. Connell BJ, Khan BV, Rajagopal D, Saleh TM. Novel neurovascular protective agents: Effects of INV-155, INV-157, INV-159, and INV-161 versus lipoic acid and captopril in a rat stroke model. Cardiol Res Pract. 2012;2012:319230. Richard MJ, Connell BJ, Khan BV, Saleh TM. Cellular mechanisms by which lipoic acid confers protection during the early stages of cerebral ischemia: a possible role for calcium. Neurosci Res. 2011 Apr;69(4):299-307. Connell BJ, Saleh M, Khan BV, Saleh TM. Lipoic acid protects against reperfusion injury in the early stages of cerebral ischemia. Brain Res. 2011 Feb 23;1375:128-36. Yan MH, Wang X, Zhu X. Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease. Free Radic Biol Med . 2013 Sep;62:90-101. Available at: http://www.alz.org/alzheimers_disease_facts_and_figures.asp#quickFacts. Accessed February 18, 2014. Shinto L, Quinn J, Montine T, et al. A randomized placebo-controlled pilot trial of omega-3 fatty acids and alpha lipoic acid in Alzheimer’s disease. J Alzheimers Dis. 2013 Sep 27. Sancheti H, Akopian G, Yin F, Brinton RD, Walsh JP, Cadenas E. Age-dependent modulation of synaptic plasticity and insulin mimetic effect of lipoic acid on a mouse model of Alzheimer’s disease. PLoS One. 2013;8(7):e69830. Head E, Murphey HL, Dowling AL, et al. A combination cocktail improves spatial attention in a canine model of human aging and Alzheimer’s disease. J Alzheimers Dis. 2012;32(4):1029-42. Farr SA, Price TO, Banks WA, Ercal N, Morley JE. Effect of alpha-lipoic acid on memory, oxidation, and lifespan in SAMP8 mice. J Alzheimers Dis. 2012;32(2):447-55. Koriyama Y, Nakayama Y, Matsugo S, Kato S. Protective effect of lipoic acid against oxidative stress is mediated by Keap1/Nrf2-dependent heme oxygenase-1 induction in the RGC-5 cellline. Brain Res. 2013 Mar 7;1499:145-57. Koriyama Y, Nakayama Y, Matsugo S, et al. Anti-inflammatory effects of lipoic acid through inhibition of GSK-3beta in lipopolysaccharide-induced BV-2 microglial cells. Neurosci Res. 2013 Jul 24. Zara S, De Colli M, Rapino M, et al. Ibuprofen and lipoic acid conjugate neuroprotective activity is mediated by Ngb/Akt intracellular signaling pathway in Alzheimer’s disease rat model. Gerontology. 2013;59(3):250-60. Parachikova A, Green KN, Hendrix C, LaFerla FM. Formulation of a medical food cocktail for Alzheimer’s disease: beneficial effects on cognition and neuropathology in a mouse model of the disease. PLoS One. 2010;5(11):e14015. Li DW, Li GR, Lu Y, et al. alpha-lipoic acid protects dopaminergic neurons against MPP+-induced apoptosis by attenuating reactive oxygen species formation. Int J Mol Med. 2013 Jul;32(1):108-14. Jalali-Nadoushan M, Roghani M. Alpha-lipoic acid protects against 6-hydroxydopamine-induced neurotoxicity in a rat model of hemi-parkinsonism. Brain Res. 2013 Apr 10;1505:68-74. de Araújo DP, De Sousa CN, Araujo PV, et al. Behavioral and neurochemical effects of alpha-lipoic Acid in the model of Parkinson’s disease induced by unilateral stereotaxic injection of 6-ohda in rat. Evid Based Complement Alternat Med. 2013;2013:571378. Zaitone SA, Abo-Elmatty DM, Shaalan AA. Acetyl-L-carnitine and alpha-lipoic acid affect rotenone-induced damage in nigral dopaminergic neurons of rat brain, implication for Parkinson’s disease therapy. Pharmacol Biochem Behav. 2012 Jan;100(3):347-60. Abdin AA, Sarhan NI. Intervention of mitochondrial dysfunction-oxidative stress-dependent apoptosis as a possible neuroprotective mechanism of alpha-lipoic acid against rotenone-induced parkinsonism and L-dopa toxicity. Neurosci Res. 2011 Dec;71(4):387-95. Karunakaran S, Diwakar L, Saeed U, , et al. Activation of apoptosis signal regulating kinase 1 (ASK1) and translocation of death-associated protein, Daxx, in substantia nigra pars compacta in a mouse model of Parkinson’s disease: protection by alpha-lipoic acid. FASEB J. 2007 Jul;21(9):2226-36. Feuerecker B, Pirsig S, Seidl C, et al. Lipoic acid inhibits cell proliferation of tumor cells in vitro and in vivo. Cancer Biol Ther. 2012 Dec;13(14):1425-35. Choi SY, Yu JH, Kim H. Mechanism of alpha-lipoic acid-induced apoptosis of lung cancer cells. Ann N Y Acad Sci. 2009 Aug;1171:149-55. Yoo TH, Lee JH, Chun HS, Chi SG. alpha-Lipoic acid prevents p53 degradation in colon cancer cells by blocking NF-kappaB induction of RPS6KA4. Anticancer Drugs. 2013 Jul;24(6):555-65. Hiratsuka T, Inomata M, Kono Y, Yokoyama S, Shiraishi N, Kitano S. DHLTauZnNa, a newly synthesized alpha-lipoic acid derivative, induces autophagy in human colorectal cancer cells. Oncol Rep. 2013 Jun;29(6):2140-6. Michikoshi H, Nakamura T, Sakai K, et al. alpha-Lipoic acid-induced inhibition of proliferation and met phosphorylation in human non-small cell lung cancer cells. Cancer Lett. 2013 Jul 28;335(2):472-8. Kono Y, Inomata M, Hagiwara S, et al. Antiproliferative effects of a new alpha-lipoic acid derivative, DHL-HisZnNa, in HT29 human colon cancer cells in vitro. Expert Opin Ther Targets. 2012 Mar;16 Suppl 1:S103-9. Guerriero E, Sorice A, Capone F, et al. Effects of lipoic acid, caffeic acid and a synthesized lipoyl-caffeic conjugate on human hepatoma cell lines. Molecules. 2011;16(8):6365-6377. Zachar Z, Marecek J, Maturo C, et al. Non-redox-active lipoate derivates disrupt cancer cell mitochondrial metabolism and are potent anticancer agents in vivo. J Mol Med (Berl). 2011 Nov;89(11):1137-48. Bernini R, Crisante F, Merendino N, Molinari R, Soldatelli MC, Velotti F. Synthesis of a novel ester of hydroxytyrosol and alpha-lipoic acid exhibiting an antiproliferative effect on human colon cancer HT-29 cells. Eur J Med Chem. 2011 Jan;46(1):439-46. Dozio E, Ruscica M, Passafaro L, et al. The natural antioxidant alpha-lipoic acid induces p27(Kip1)-dependent cell cycle arrest and apoptosis in MCF-7 human breast cancer cells. Eur J Pharmacol. 2010 Sep 1;641(1):29-34. Selvakumar E, Hsieh TC. Regulation of cell cycle transition and induction of apoptosis in HL-60 leukemia cells by lipoic acid: role in cancer prevention and therapy. J Hematol Oncol. 2008;1:4. Lee HS, Na MH, Kim WK. alpha-Lipoic acid reduces matrix metalloproteinase activity in MDA-MB-231 human breast cancer cells. Nutr Res. 2010 Jun;30(6):403-9. Berkson BM, Rubin DM, Berkson AJ. Revisiting the ALA/N (alpha-lipoic acid/low-dose naltrexone) protocol for people with metastatic and nonmetastatic pancreatic cancer: a report of 3 new cases. Integr Cancer Ther. 2009 Dec;8(4):416-22. Schwartz L, Abolhassani M, Guais A, et al. A combination of alpha lipoic acid and calcium hydroxycitrate is efficient against mouse cancer models: preliminary results. Oncol Rep. 2010 May;23(5):1407-16. Lee KC, Shorr R, Rodriguez R, Maturo C, Boteju LW, Sheldon A. Formation and anti-tumor activity of uncommon in vitro and in vivo metabolites of CPI-613, a novel anti-tumor compound that selectively alters tumor energy metabolism. Drug Metab Lett. 2011 Aug;5(3):163-82. Ramachandran L, Nair CK. Protection against genotoxic damages following whole body gamma radiation exposure in mice by lipoic acid. Mutat Res. 2011 Sep 18;724(1-2):52-8. Ramachandran L, Krishnan CV, Nair CK. Radioprotection by alpha-lipoic acid palladium complex formulation (POLY-MVA) in mice. Cancer Biother Radiopharm. 2010 Aug;25(4):395-9. Davis GD, Masilamoni JG, Arul V, et al. Radioprotective effect of DL-alpha-lipoic acid on mice skin fibroblasts. Cell Biol Toxicol. 2009 Aug;25(4):331-40. Manda K, Ueno M, Moritake T, Anzai K. alpha-Lipoic acid attenuates x-irradiation-induced oxidative stress in mice. Cell Biol Toxicol. 2007 Mar;23(2):129-37. Trevisan G, Materazzi S, Fusi C, et al. Novel therapeutic strategy to prevent chemotherapy-induced persistent sensory neuropathy by TRPA1 blockade. Cancer Res. 2013 May 15;73(10):3120-31. Goraca A, Huk-Kolega H, Piechota A, Kleniewska P, Ciejka E, Skibska B. Lipoic acid - biological activity and therapeutic potential. Pharmacol Rep. 2011;63(4):849-58. Morikawa T, Yasuno R, Wada H. Do mammalian cells synthesize lipoic acid? Identification of a mouse cDNA encoding a lipoic acid synthase located in mitochondria. FEBS Lett. 2001 Jun 1;498(1):16-21. Rochette L, Ghibu S, Richard C, Zeller M, Cottin Y, Vergely C. Direct and indirect antioxidant properties of alpha-lipoic acid and therapeutic potential. Mol Nutr Food Res. 2013 Jan;57(1):114-25. Suzuki YJ, Tsuchiya M, Packer L. Thioctic acid and dihydrolipoic acid are novel antioxidants which interact with reactive oxygen species. Free Radic Res Commun. 1991;15(5):255-63. Kagan VE, Shvedova A, Serbinova E, et al. Dihydrolipoic acid--a universal antioxidant both in the membrane and in the aqueous phase. Reduction of peroxyl, ascorbyl and chromanoxyl radicals. Biochem Pharmacol. 1992 Oct 20;44(8):1637-49. Ghibu S, Lauzier B, Delemasure S, et al. Antioxidant properties of alpha-lipoic acid: effects on red blood membrane permeability and adaptation of isolated rat heart to reversible ischemia. Mol Cell Biochem. 2009 Jan;320(1-2):141-8. Fujii Y, Segawa R, Kimura M, et al. Inhibitory effect of alpha-lipoic acid on thioacetamide-induced tumor promotion through suppression of inflammatory cell responses in a two-stage hepatocarcinogenesis model in rats. Chem Biol Interact. 2013 Sep 25;205(2):108-18. Lin YC, Lai YS, Chou TC. The protective effect of alpha-lipoic Acid in lipopolysaccharide-induced acute lung injury is mediated by heme oxygenase-1. Evid Based Complement Alternat Med. 2013;2013:590363. Miao Y, Ren J, Jiang L, Liu J, Jiang B, Zhang X. alpha-lipoic acid attenuates obesity-associated hippocampal neuroinflammation and increases the levels of brain-derived neurotrophic factor in ovariectomized rats fed a high-fat diet. Int J Mol Med. 2013 Nov;32(5):1179-1186. Park SJ, Lee KS, Lee SJ, et al. L-2-oxothiazolidine-4-carboxylic acid or alpha-lipoic acid attenuates airway remodeling: Involvement of nuclear factor-kappaB (NF-kappaB), nuclear factor erythroid 2p45-related factor-2 (Nrf2), and hypoxia-inducible factor (HIF). Int J Mol Sci. 2012;13(7):7915-37. Polat B, Halici Z, Cadirci E, et al. The effect of alpha-lipoic acid in ovariectomy and inflammation-mediated osteoporosis on the skeletal status of rat bone. Eur J Pharmacol. 2013 Jul 30. Suzuki YJ, Aggarwal BB, Packer L. Alpha-lipoic acid is a potent inhibitor of NF-kappa B activation in human T cells. Biochem Biophys Res Commun. 1992 Dec 30;189(3):1709-15. Smith JR, Thiagaraj HV, Seaver B, Parker KK. Differential activity of lipoic acid enantiomers in cell culture. J Herb Pharmacother. 2005;5(3):43-54. Streeper RS, Henriksen EJ, Jacob S, Hokama JY, Fogt DL, Tritschler HJ. Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle. Am J Physiol. 1997 Jul;273(1 Pt 1):E185-91. Available at: http://link.springer.com/article/10.1007%2Fs00018-012-0962-0. Accessed February 24, 2014. Sherif S, Bendas ER, Badawy S. The clinical efficacy of cosmeceutical application of liquid crystalline nanostructured dispersions of alpha lipoic acid as anti-wrinkle. Eur J Pharm Biopharm. 2013 Sep 18. Tsuji-Naito K, Ishikura S, Akagawa M, Saeki H. alpha-Lipoic acid induces collagen biosynthesis involving prolyl hydroxylase expression via activation of TGF-beta-Smad signaling in human dermal fibroblasts. Connect Tissue Res. 2010 Oct;51(5):378-87. Pandel R, Poljsak B, Godic A, Dahmane R. Skin photoaging and the role of antioxidants in its prevention. ISRN Dermatol. 2013;2013:930164. Campos PM, de Camargo Junior FB, de Andrade JP, Gaspar LR. Efficacy of cosmetic formulations containing dispersion of liposome with magnesium ascorbyl phosphate, alpha-lipoic acid and kinetin. Photochem Photobiol. 2012 May-Jun;88(3):748-52.