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Glycation - Implications for Proteostasis (Autophagy) and Extracellular Matrix Aging

Aging is a complex consequence of many factors. Cellular age post-translational non-enzymatic protein modifications is considered as critical in this model. Glycation is damaging of protein structures ,via non-enzymatic binding of glucose to protein. Glycation results in damaged proteins which affects functioning inside the cell and outside the cell. Advanced glycation end products (AGEs) are subsequently formed, and trigger oxidative stress and inflammation. Furthermore, inflammation, age-related oxidative stress, as well as decreased levels of NAD+ in the cell all affect proteostasis, a critical factor in longevity.(1,2) An important function of proteostasis is autophagic clearance of damaged and toxic proteins, such as amyloid.

GLYCATION - INTRACELLULAR AGING

With age, there is a buildup of advanced glycation end products (AGEs) in the cell. AGEs  create additional oxidative stress and inflammation in the cell. AGEs also reduce cellular proteostasis, which further reduces the cells ability to eliminate AGE complexes through autophagy. The accumulation of AGEs in cardiac and vascular cells, lead to inflammation and fibrosis, causing atherosclerosis and cardiac diseases. (3)

GLYCATION - EXTRACELLULAR  AGING

In particular, modifications such as cross-linking of long-lived molecules with slow turnover. In the extracellular matrix (ECM), the cross-linking of molecules such as collagen and elastin, create loss of cellular homeostasis, especially proteostasis. The cross-linking of these long-lived molecules occur through processes such as glycation. Creates an abnormal stiffness and hardening from which cannot be recovered. Stiffness of the ECM contributes to hypertension, rigidity of arteries, atherosclerosis and cancer.(4)

Perhaps most important, these alterations of ECM reduce viability of the cell, reducing longevity.  Due to the diminishing amount of functional elastin, it has been suggested that the maximum limit for elastin dependent cardiovascular and respiratory systems is 100-120 years.(5)

ECM aging is also linked to stem-cell aging, and exhaustion of the stem cell supply. (4)  Interestingly, older mouse cells transplanted into younger mice, may outlive the maximum lifespan of an organism by three-fold! This exemplifies the importance of the extracellular environment and how stiff ECM affects cellular lifespan.

Further linkage between ECM stiffness and cellular senescence. Which may also be associated with increased fibrosis. FIBROSIS. Is another key aging indicator. Mitochondrial dysfunction also increases in frequency in a aged (stiff) ECM. Skin aging is accelerated by ECM stiffness, which causes increase in breakdown of skin layers.

ATRIAL FIBRILLATION. Advanced glycation endproducts are involved in the pathogenesis of Atrial fibrillation. (6) Suggested modes of treatment include lowering AGE levels and increasing levels of antioxidants.(9)

 

BOTANICAL EXTRACTS FOR AGING INHIBITION

  • APIGENIN / ANTI-GLYCATION

Apigenin prevents the formation of AGEs by trapping methylglyoxal (MGO), which is a precursor molecule. Through inhibiting MGO, AGEs will not be formed, thereby reducing oxidative stress and inflammation. In turn, this allows for increased proteostasis in the cell.(6)  

    • APIGENIN / CD38 (NAD)
      An important anti-aging molecule NAD signicantly decrease in aging cells. An enzyme CD38, an enzyme found inflammatory cells,  is responsible for decreasing levels of cellular NAD, In fact, older humans were found to have almost three times the levels of CD38 versus younger counterparts.  Apigenin inhibits CD38, thereby increasing levels of NAD+.

      Sufficient levels of cellular NAD+ are required for anti-aging cellular        functions, including proteostasis. (7,8) The principal regular for cellular NAD+ in cells is CD38.

      • BERBERINE  (ANTI-GLYCATION / ANT-FIBRIL / ANTI-AMYLOID)

      In animal research experiments, berberine reduced glycation levels. (10) In the brain of Alzheimers Disease mice, berberine invoked autophagic clearance of amyloid beta deposits.(11)  Also has been shown to reduce the formation of amyloid beta oligomer formation, this is the prior step  before amyloid beta fibril formation. (12) When combined with curcumin, there is a synergistic reduction in amyloid beta production.(13)

      • ROSMARINIC ACID (ANTI-GLYCATION / ANTI-AGGREGATION)

      Research indicates that rosmarinic acid both inhibits glycation and prevents protein aggregation. Both are correlated to aging pathologies.(14).

      • CURCUMIN  (ANTI-GLYCATION / AUTOPHAGY / ELASTIN MATRIX)
      Curcumin has been shown to markedly lower AGE levels in lab animals.(15) Specific studies animal models showed significant increases in antioxidant levels and an increase in the AGE detoxification system.
      AMYLOID INHIBITION - Inhibits production of amyloid and increases autophagic removal of amyloid. Acts synergistically with berberine.(13)
      ELASTIN MATRIX. Curcumin enhances production of elastin fbers (Elastiin and fibrillin-1) which are components of the extracellular matrix (along with collagen). Studies indicate that curcumin supports arterial and lung elasticity.(16).
      • FISETIN (Traps MGO which prevents AGE formation)(17)
      • PTEROSTILBENE (Traps MGO which prevents AGE formation )(18)
      • RUTIN (inhibits generation of AGEs)(19)

       

       YELLOW LONGEVITY®  (APIGENIN | BERBERINE | FISETIN | CURCUMIN)

       CURCUMIN PXC®  (CURCUMIN | ROSMARINIC | FISETIN |PTEROSTILBENE)

       

      REFERENCES:

      (1) Baldensperger T, et al. Comprehensive Analysis of Posttranslational Protein Modifications in Aging of Subcellular Compartments. Sci Rep. 2020 May.

      (2) Rudzinnska M, et al. Cellular Aging Characteristics and Their Association With Age-Related Disorders. Antioxidants (Basel). 2020 Jan.

      (3) Neviere R, et al. Implication of Advanced Glycation End Products (Ages) and Their Receptor (Rage) on Myocardial Contractile and Mitochondrial Functions. Glycoconj J. 2016 Aug.

      (4) Fedintsev, A. et al. Stochastic non-enzymatic modification of long-lived macromolecules - A missing hallmark of aging. Ageing Research Reviews. Volume 62. September 2020.

      (5) Robert L, et al. Rapid Increase in Human Life Expectancy: Will It Soon Be Limited by the Aging of Elastin? Biogerontology. 2008. Apr.

      (6) Zhou, Q. et al. Apigenin and Its Methylglyoxal-Adduct Inhibit Advanced Glycation End Products-Induced Oxidative Stress and Inflammation in Endothelial Cells. Biochem Pharmacol. 2019 Aug.

      (7) Griffiths H, et al. Nicotinamide Adenine Dinucleotide (NAD+): Essential Redox Metabolite, Co-Substrate and an Anti-Cancer and Anti-Ageing Therapeutic Target

      (8) Ogura Y, et al. CD38 Inhibition by Apigenin Ameliorates Mitochondrial Oxidative Stress Through Restoration of the Intracellular NAD +/NADH Ratio and Sirt3 Activity in Renal Tubular Cells in Diabetic Rats. Aging (Albany NY). 2020 Jun

      (9) Prasad K. AGE-RAGE Stress in the Pathophysiology of Atrial Fibrillation and Its Treatment. Int J Angiol. 2020 Jun.

      (10) Zych M, et al. Effect of Berberine on Glycation, Aldose Reductase Activity, and Oxidative Stress in the Lenses of Streptozotocin-Induced Diabetic Rats In Vivo-A Preliminary Study. Int J Mol Sci. 2020 Jun.

      (11) Huang M, et al. Berberine Improves Cognitive Impairment by Promoting Autophagic Clearance and Inhibiting Production of β-amyloid in APP/tau/PS1 Mouse Model of Alzheimer's Disease. Exp Gerontol, 2017 May.

      (12) Fawver J, et al. Probing and Trapping a Sensitive Conformation: Amyloid-β Fibrils, Oligomers, and Dimers. J Alzheimers Dis. 2012.

      (13) Lin L, et al.  Synergic Effects of Berberine and Curcumin on Improving Cognitive Function in an Alzheimer's Disease Mouse Model. Neurochem Res. 2020 May.

      (14) Shamsi A, et al. Rosmarinic Acid Restrains Protein Glycation and Aggregation in Human Serum Albumin: Multi Spectroscopic and Microscopic Insight - Possible Therapeutics Targeting Diseases. Int J Biol Macromol. 2020 Jun.

      (15) Lima T, et al. Curcumin, Alone or in Combination With Aminoguanidine, Increases Antioxidant Defenses and Glycation Product Detoxification in Streptozotocin-Diabetic Rats: A Therapeutic Strategy to Mitigate Glycoxidative Stress. Oxid Med Cell Longev. 2020 May.

      (16) Lee S, et al. Curcumin Enhances the Production of Major Structural Components of Elastic Fibers, Elastin, and fibrillin-1, in Normal Human Fibroblast Cells. Biosci Biotechnol Biochem. 2015.

      (17) Maher P, et al. Fisetin Lowers Methylglyoxal Dependent Protein Glycation and Limits the Complications of Diabetes. PLoS One. 2011.

      (18) Lv, L, et al. Stilbene Glucoside From Polygonum Multiflorum Thunb.: A Novel Natural Inhibitor of Advanced Glycation End Product Formation by Trapping of Methylglyoxal. J Agric Food Chem. 2010 Feb.

      (19) Liang W, et al. Protective Effects of Rutin on Liver Injury in Type 2 Diabetic db/db Mice. Biomed Pharmacother. 2018 Nov.

       

      Cardiac Aging - Heart Failure and Limits of Longevity

      While we live in an age where people are living longer, an important limiting factor on longevity is the ability of the heart to maintain function.  Known causes of death for the oldest people on record (over 110 years old) were recorded as heart failure. Heart failure is due to the gradual loss of cardiomyocytes (heart muscle cells) and the increase in scarring of the heart muscle. The process may take place due to low grade inflammation of the muscle, which progresses with age, or injury (such as a heart attack) which may cause a more sudden loss of heart function. Inflammation in  the cardiovascular system is common with the aging process, being the result of hypertension, high blood glucose, trigylcerides, or oxidized VDL cholesterol.

      Cardiac Aging Characteristics:

      • Increased injury and loss of cardiac muscle due to inflammation and injury,
      • Increased fibrosis and scarring of heart muscle
      • Loss of regenerative ability (cardiomyocytes)
      • Loss of cardiomyocyte homeostasis
      • Reduction in contractile strength of myocytes
      • Increased thickening of muscle (cardiac hypertrophy) - commonly caused by hypertension
      • Diabetes accelerates aging of the heart muscle, and is directly causative of cardiomyopathy - a damaging condition of the heart muscle which leads to heart failure.

      Key Conditions of the Aging Heart

      • Atrial Fibrillation
      • Heart Failure (1)
      • Heart failure is primarily the result of insufficient ability to regenerate heart tissue by cardiomyoctes and the replacement of muscle with scar tissue.

       

      • Inhibiting Cardiac Fibrosis and Inflammation supports maintenance of Heart Function with aging.
      • Atrial fibrillation. Changes to the heart through aging, alters the ability of the left atrium to properly conduct the critical electrical impulses, which can cause an abnormal heart beat. Atrial fibrillation results from increased fibrosis in the heart muscle and a remodeling of the heart muscle. Nrf2 activation, which is potently activated by sulforaphane and andrographolide, may reduce fibrosis. 
      • Cardiomyocyte Regeneration and Maintenance (Homeostasis) - Mammal adult heart cells display very poor regenerative ability after incurring inflammation or injury. Instead of regenerating, hearts undergo extensive scarring - reducing functional ability. In order to properly regenerate, there must be a proliferation of cardio myocytes. Hypertension can result in increased cellular death of the cardiomyocytes. An extract of epimedium (icariin) may mitigate the loss of heart muscle due to hypertension.(12) Furthermore, as demonstrated in lab animals, curcumin also may prevent loss of cardiac muscle due to myocardial infarction (heart attack).(16)
      • Cardiomyocyte homeostasis ensures that the heart muscle stays healthy and strong. Cardiac aging leads to a gradual loss of homeostasis, which leads to the death of the cardiomyocyte and eventual heart failure. An important mechanism for maintaining homeostasis is regulated autophagy in the cardiomyocyte. Autophagy eliminates defective proteins and recycles components into new structures.
      • Cardiac scarring is the development of fibrosis in response to an attempt to repair damaged tissue (including inflammation and heart attack). Fibrosis can be reduced by nrf2 activation.
      • Cardiac hypertrophy - is the result of scarring which eventually can lead to cardiac failure. Andrographolide and arjuna have been shown in lab research to inhibit hypertrophy.(2)
      • Contractibility of Cardiomyocytes. Healthy cardiomyocytes have strong contraction capability which may be loss with age and is  factor in heart failure. Luteolin can improve contraction and ameliorate myocardium fibrosis which may improve heart failure.
      • Reducing Myocardial Damage. Carnosic Acid may reduce myocardial damage through properties of anti-inflammatory and antioxidant effects on the heart.(9)
      • Chronic Inflammation - Coronary Artery Disease. Coronary artery disease creates conditions of pervasive inflammation which also affect the heart. Lutein is not only important for vision health, but has potent anti-inflammatory effect in coronary artery patients.(4)
      •  Nrf2 for Oxidative Homeostasis - Aging results in lower levels of nrf2. As a master antioxidant factor, nrf2 is essential to maintain homeostasis of a protective oxidative state for the heart. Increased nrf2 may also protective against cardio fibrosis.

       Natural support for Cardio Anti-aging

      • Terminalia Arjuna (bark extract) - Indian medicine has long recognized arjuna as a cardio tonic and now modern research is supporting this. In young fitness participants, an arjuna extract significantly improved cardiovascular strength and efficiency. Arjuna has also shown potential benefit in heart failure in research animals.(5)
      • Terminalia Arujuna - supports heart function in diabetic rats. Myocardium function improved, as hypothesized by the study researchers, as a result of increased in endogenous antioxidant enzymes.(17)
      • Benefits of Terminalia Arjuna:
        • Improved Diabetic heart function
        • Improved exercise capacity via cardiovascular efficiency
        • Strong improvement of left ventricle output in individuals with cardiovascular ailments.
        • Reduction in mass of cardiac hypertrophy
        • May have beneficial effects on pulmonary hypertension - which is a fatal disease characterized by right ventricular hypertrophy and right heart failure.(20)
        • Protection of cardiac muscle from injury
        • Cardio tonic effect - i.e. positively affecting heart function
      •  Apigenin - Provides supports for hypertrophy and diabetic cardiomyopathy.(2.3)
      •  Luteolin - Supports improved heart muscle contraction in lab animal models of heart failure.(4) Furthermore, in research simulated myocardial infarction (heart attack), luteolin increased autophagy of the heart muscle, increasing mitochondrial biogenesis, thereby lessening subsequent cardiac dysfunction.
      •  Icariin (Epimedium) - helps mitigate hypertension induced cellular death of the   cardiomyocytes.(12)
      •  Lutein - Provides powerful anti-inflammatory action in cardiovascular disease, thereby reducing potential for fibrosis. Lutein is further supportive by acting as an nrf2 activator.  
      • Sulforaphane - Inhibits diabetic cardiomyopathy via the effects as a powerful Nrf2 activator.(13) Experimental research has shown that sulforaphane inhibited cardiomyopathy in both type 1 and type 2 diabetes. In experimental models of cardiac infarctions (heart attack), sulforaphane inhibited changes to the heart muscle, in particular the fibrosis that occurs post-injury.(23)
      • EGCG (Green Tea Extract) - Has an inhibitory effect on myocardial fibrosis.(14)
      • Andrographolide - Nrf2 activator, significantly reducing oxidative stress and potent ant-inflammation agent.(15, 22) Also upregulates glutathione levels in cardiomyocytes, which offers powerful protection against oxygen deprived injury (such as a myocardial infarction). (21) 
      • Curcumin - Regulates autophagy of cardiomyocytes, which supports the degradation and recycling of cardiomyocyte components, such as mis-folded proteins. Autophagy is an essential process in supporting cardiomyocyte homeostasis. When autophagy is dysregulated, the muscle cell dies and may lead to atrophy of the heart and eventually heart failure. In addition to curcumin, resveratrol and berberine also regulate autophagy,(18)

           

          CARDIO VITALITY (Terminalia Arjuna (Rejuna))

          YELLOW LONGEVITY (Curcumin, EGCG, Apigenin, Luteolin, Icariin, Carnosic Acid)*

          YELLOW NATURALLY (Curcumin, EGCG, Apigenin, Luteolin, Icariin, Carnosic Acid)*

          VISION VITALITY MAX (Lutein, Meso Zeaxanthin)

          XGEVITY (Glucoraphanin precursor to Sulforaphane)*

           *Andrographolide is also included

           

          REFERENCES:

          (1) Steenman M, et al. Cardiac aging and heart disease in humans. Biophys Rev. 2017 Apr;

          (2) Zhu ZY, et al. Apigenin ameliorates hypertension-induced cardiac hypertrophy and down-regulates cardiac hypoxia inducible factor-lα in rats. Food Funct. 2016 Apr;7

          (3) Liu HJ, et al. Apigenin alleviates STZ-induced diabetic cardiomyopathy.  Mol Cell Biochem. 2017 Apr

          (4) Hu W, et al. Luteolin improves cardiac dysfunction in heart failure rats by regulating sarcoplasmic reticulum Ca2+-ATPase 2a. Sci Rep. 2017 Jan

          (5) Oberoi L, et al. The aqueous extract, not organic extracts, of Terminalia arjuna bark exerts cardiotonic effect on adult ventricular myocytes. Phytomedicine. 2011 Feb 15

          (6) Parveen A, et al. Terminalia arjuna enhances baroreflex sensitivity and myocardial function in isoproterenol-induced chronic heart failure rats. J Cardiovasc Pharmacol Ther. 2012 Jun

          (7) Kaliq F, et al, Improvement in myocardial function by Terminalia arjuna in streptozotocin-induced diabetic rats: possible mechanisms. J Cardiovasc Pharmacol Ther. 2013 Sept.

          (8) Kumar S, et al. Proteomic analysis of the protective effects of aqueous bark extract of Terminalia arjuna (Roxb.) on isoproterenol-induced cardiac hypertrophy in rats. J Ethnopharmacol. 2017 Feb 23

          (9) Kocak C, et al, Molecular and biochemical evidence on the protective effects of embelin and carnosic acid in isoproterenol-induced acute myocardial injury in rats. Life Sci. 2016 Feb 15

          (10) Chung RWS, et al. Lutein exerts anti-inflammatory effects in patients with coronary artery disease. Atherosclerosis. 2017 May 6;

          (11) Girandola RN, et al. Effect of E-OJ-01 on Cardiac Conditioning in Young Exercising Adults: A Randomized Controlled Trial. Am J Ther. 2017 May

          (12) Qian ZQ, et al. Icariin prevents hypertension-induced cardiomyocyte apoptosis through the mitochondrial apoptotic pathway. Biomed Pharmacother. 2017 Apr.

          (13) Gu J, et al. Metallothionein Is Downstream of Nrf2 and Partially Mediates Sulforaphane Prevention of Diabetic Cardiomyopathy. Diabetes. 2017 Feb;

          (14) Lin CM, et al. Suppressive effect of epigallocatechin-3-O-gallate on endoglin molecular regulation in myocardial fibrosis in vitro and in vivo. J Cell Mol Med. 2016 Nov;

          (15) Tan WS, et al. Is there a future for andrographolide to be an anti-inflammatory drug? Deciphering its major mechanisms of action. Biochem Pharmacol. 2017 Apr 2

          (16) Lv FH, et al. Effects of curcumin on the apoptosis of cardiomyocytes and the expression of NF-κB, PPAR-γ and Bcl-2 in rats with myocardial infarction injury. Exp Ther Med. 2016 Dec

          (17) Khaliq F, et al. Improvement in myocardial function by Terminalia arjuna in streptozotocin-induced diabetic rats: possible mechanisms. J Cardiovasc Pharmacol Ther, 2013 Sep

          (18) Hashemzaei M, et al. Regulation of autophagy by some natural products as a potential therapeutic strategy for cardiovascular disorders. Eur J Pharmacol. 2017 May

          (19) Hu J, et al. Luteolin alleviates post-infarction cardiac dysfunction by up-regulating autophagy through Mst1 inhibition. J Cell Mol Med, 2016 Jan

          (20) Meghwani H, et al. Beneficial effects of aqueous extract of stem bark of Terminalia arjuna (Roxb.), An ayurvedic drug in experimental pulmonary hypertension.  J Ethnopharmocol. 2017 Feb 2

          (21) Woo AY, et al. Andrographolide up-regulates cellular-reduced glutathione level and protects cardiomyocytes against hypoxia/reoxygenation injury. J Pharmacol Exp Ther. 2008 Apr

          (22) Zhang J, et al. Andrographolide Attenuates LPS-Induced Cardiac Malfunctions Through Inhibition of IκB Phosphorylation and Apoptosis in Mice. Cell Physiol Biochem. 2015

          (23) Fernandes RO, et al. Sulforaphane effects on postinfarction cardiac remodeling in rats: modulation of redox-sensitive prosurvival and proapoptotic proteins. J Nutr Biochem. 2016 Aug