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)

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)

• 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.