Yellow Support for Slowing Aging & Reducing Levels of Advanced Glycation End-Products (AGEs)
o Advanced Glycation End-Products | Accelerating the Aging Process
Diabetes is a serious health problem in our modern society and is responsible not only for accelerated aging but also health complications of the entire body. Uncontrolled blood sugar, brought on by diabetes, damages the cardiovascular system, kidneys, eyes and brain. Furthermore, brain and nerve damage caused by diabetes can greatly impact quality of life areas such as loss of limbs (especially feet), affect coordination and motor skills and bring on early dementia. Exercise, loss of weight, and proper diet all are important elements in controlling diabetes and slowing down accelerated aging process. However, research now indicates that yellow natural extracts may play an important role in attenuating and intervening in the many of the deleterious aging effects brought on by diabetes.
Age accelerating pathologies in diabetes, and increased rates of morbidity and mortality, are primarily due to the formation and accumulation of molecules in the body known as Advanced Glycation End-Products (AGEs). When blood sugar levels are elevated, the excessive amounts of blood sugar attaches to protein structures in the body, including the vascular wall of arteries, which are both destructive to and inhibit the functioning of the structure. The initial binding of protein to sugar is termed glycation. Subsequently, through a chain of additional chemical reactions, the end result is the formation of AGEs. AGEs affect every cell in the body and are considered a significant contributor to age related diseases including cardiovascular disease, Alzheimer’s Disease and many others. AGE formation is an aging process that occurs in everyone, but is most pronounced in diabetics.
Diabetes Factors Involved in AGE Formation:
METHYLGLYOXAL. In the body a substance known as methylglyoxal (MG), has been proven to be the most important agent for the formation of AGEs. MG has a very high toxicity level to cells. Furthermore, MG levels are significantly higher in diabetics (due to higher sugar levels) and substantially increases the risk of cardiovascular disease ,through the glycation of LDL. (1,2)
GLYOXIDASE 1 – LOWERING LEVELS OF MG. Glyoxidase 1 is the enzyme required for the removal of MG. Since increasing the levels of glycosidase 1 reduces levels of MG in the body, there is also an effect of reducing the formation and accumulation of AGEs. Therefore, higher levels of glyoxidase 1 may play an important role in attenuating AGE facilitated complications in diabetes. Clinical patient observations showed a correlation between low levels of glycoxidase 1 with very HIGH levels of AGEs.(3)
o Fisetin– Increasing levels of Glyoxidase 1 | Reducing Diabetic Complications and Aging • Increasing Glyoxidase-1. In a research study using mice model of a type 1 diabetes, fisetin was shown to reduce two major diabetic complications, including kidney hypertrophy and maintenance of normal locomotion capabilities. Fisetin treated mice resulted in increased levels of glyoxidase 1 enzymes, which caused decreases in AGE forming methyglyoxal. Authors of the study conclude that fisetin may have potential therapeutic value in the treatment and prevention of diabetic complications. (4)
o Luetolin – AGE Inhibition | Protection Against Complications • Inhibition of AGE Formation. Luteolin displayed protein glycation on early stage, middle stage and late stages of protein glycation. In middle stages, luteolin had an inhibitory effect on the modification of protein by methylglyoxal. During late stage, luteolin helped prevent the formation of AGEs and cross-linking of collagen. (5) • Kidney Protection. Protection against high glucose diabetic kidney injury (diabetic nephropathy) through increased antioxidant expression, including the potent Heme Oxygenase-1 (HO-1) enzyme.(6) • Preserving Arterial Function. High glucose levels causes significant vascular endothelium impairment, affecting the ability of healthy arterial relaxation. Vasorelalaxation is critical to the functioning of the cardiovascular system, and is important for maintaining normal blood pressure. Administration of luteolin to test rat aorta showed a marked reversal the impairment. (7)
o Apigenin– Modulation of Diabetic Hormonal & Vascular Dysfunction • Increases Insulin and Thyroids Hormones. Diabetic induced animals show significant alterations in hormone levels, decreasing insulin and thyroid hormones (T3 and T4), with an associated increase in blood sugar levels. In research studies, after 10 days of apigenin administration, the diabetic animals showed an increase in insulin and thyroid hormone levels. Furthermore, blood sugar levels also were lowered. In fact, most parameters of the diabetic animals, including decreases in cellular antioxidant levels, were reversed to those of non-diabetic animals.(8, 9) • Inhibition of High Glucose Induced Vascular Endothelium Cell Dysfunction. Cardiovascular problems are common among diabetics, with high glucose levels stimulation expression of genes which increases gene expression of LOX-1 – the major receptor in endothelium cells for oxidized LDL (LOX-1 plays a critical role in the development of atherosclerotic plaques).(10) Apigenin has been shown to inhibit LOX-1 expression, and inhibit endothelium dysfunction and slow the progression of atherosclerosis.(11)
o Ginger– Improve Insulin Sensitivity | AGE Inhibition | Neuroprotective | Kidney Protection • Enhancement of Insulin Sensitivity. A significant problem among diabetics is the loss of tissue sensitivity to insulin, which results in excessive levels of glucose EVEN IF IN THE PRESENCE OF SUFFICIENT LEVELS OF INSULIN. Experiments with ginger, demonstrated that pretreatment with ginger showed increased cellular insulin sensitivity, increasing glucose uptake.(12) • AGE Formation Inhibition. Laboratory studies show that ginger is an effective AGE inhibitor. Among the many diabetic complications of AGEs are diabetic cataracts. In further studies, ginger was shown to effectively delay the formation of AGE derived cataracts in diabetic lab rats (13) • Protects Brain By Increasing Antioxidant Defense. Diabetes causes neuronal injury by high blood sugar induced oxidative stress. Ginger was shown to increase the antioxidant defense system, thereby conferring significant neuroprotective activity.(14)• Protection of Kidney. In a study involving diabetic rats, administration of ginger was able to protect and reverse kidney complications due to high glucose levels, as shown in histopathological analysis. Conclusions by authors of the study were that "results suggest that ginger extracts could be used as a nephro-protective supplement particularly to reverse diabetic-induced complications".(17)
o Green Tea Extract – AGE Inhibition | Vascular Protective • Inhibition of AGE and Collagen-Cross Linking. Green tea extract decreased AGE formation and collagen cross-linking in diabetic rats.(15) • Protects Vascular Function. In a study involving human endothelium cells, treatment of the cells with green tea showed remarkable protective effects to inhibit cellular impairment in a dose dependent manner. Authors of the study conclude that green tea may be a therapeutic alternative for protecting against vascular complications in diabetics.(16)
o Curcumin Suppresses Gene Expression of AGEs | Inhibits AGE Mediated Damage The formation of AGEs stimulates a cascade of increased oxidative stress, inflammation and accelerated aging. These effects are mediated by AGEs by increasing the expression of genes at the cellular AGE receptor site. Curcumin acts at the receptor site, and suppresses the gene expression which causes so many of the problems which occur due to high blood sugar. (18)
1. Rabbani N, et al. Glycation of LDL by methylglyoxal increases arterial atherogenicity. A possible contributor to increased risk of cardiovascular disease in diabetes. Diabetes. 2011 Jul;60(7):1973-80. 2. Rabbani N, et al. Glyoxalase in diabetes, obesity and related disorders. Semin Cell Dev Biol. 2011 May;22(3):309-17. 3. Miyata T, et al. Glyoxalase I deficiency is associated with an unusual level of advanced glycation end products in a hemodialysis patient. Kidney Int. 2001 Dec;60(6):2351-9. 4. Maher P. et al. Fisetin lowers methylglyoxal dependent protein glycation and limits the complications of diabetes. PLoS One. 2011;6(6):e21226. 5. Wu CH, et al. Inhibitory effect of naturally occurring flavonoids on the formation of advanced glycation endproducts. J Agric Food Chem. 2005 Apr 20;53(8):3167-73. 6. Wang GG, et al. Protective Effects of Luteolin on Diabetic Nephropathy in STZ-Induced Diabetic Rats. Evid Based Complement Alternat Med. 2011;2011:323171. 7. Qian LB, et al. Luteolin reduces high glucose-mediated impairment of endothelium-dependent relaxation in rat aorta by reducing oxidative stress. Pharmacol Res. 2010 Apr;61(4):281-7. 8. Panda S, et al. Apigenin (4',5,7-trihydroxyflavone) regulates hyperglycaemia, thyroid dysfunction and lipid peroxidation in alloxan-induced diabetic mice. J Pharm Pharmacol. 2007 Nov;59(11):1543-8. 9. Rauter AP, et al. Antihyperglycaemic and protective effects of flavonoids on streptozotocin-induced diabetic rats. Phytother Res. 2010 Jun;24 Suppl 2:S133-8. 10. Lu J, et al. Oxidative Stress and Lectin-Like Ox-LDL-Receptor LOX-1 in Atherogenesis and Tumorigenesis. Antioxid Redox Signal. 2011 May 25. 11. Yamagata K, et al. Apigenin inhibits tumor necrosis factor alpha plus high glucose-induced LOX-1 expression in human endothelial cells. Microvasc Res. 2011 Jan;81(1):60-7. 12. Sekiva K, et al. Enhancement of insulin sensitivity in adipocytes by ginger. Biofactors. 2004;22(1-4):153-6. 13. Saraswat M, et al. Antiglycating potential of Zingiber officinalis and delay of diabetic cataract in rats. Mol Vis. 2010 Aug 10;16:1525-37. 14. Shanmugam KR, et al. Neuroprotective effect of ginger on anti-oxidant enzymes in streptozotocin-induced diabetic rats. Food Chem Toxicol. 2011 Apr;49(4):893-7. 15. Babu PV, et al. Effect of green tea extract on advanced glycation and cross-linking of tail tendon collagen in streptozotocin induced diabetic rats. Food Chem Toxicol. 2008 Jan;46(1):280-5. 16. Chen X, et al. Green tea polysaccharide-conjugates protect human umbilical vein endothelial cells against impairments triggered by high glucose. Int J Biol Macromol. 2011 Jul 1;49(1):50-4. 17. Ramudu SK, et al. Nephro-protective effects of a ginger extract on cytosolic and mitochondrial enzymes against streptozotocin (STZ)-induced diabetic complications in rats. Chin J Physiol. 2011 Apr 30;54(2):79-86. 18. Lin J, et al. Curcumin inhibits advanced glycation end-products (AGEs)-induced gene expression of receptor for AGEs (RAGE) in hepatic stellate cells in vitro by elevating PPARγ activity and attenuating oxidative stress. Br J Pharmacol. 2012 Feb 21.
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