Meso Zeaxanthin - Macular Degeneration Lipofuscin & The Aging Retina

RETINAL AGING. The component of the retina which is essential for maintaining visual function and photoreceptor survival  is the Retinal Pigment Epithelium (RPE).(1)  The RPE provides the homeostasis of the retina, including phagocytosis, a process by which the shedding of the outer segments of photoreceptors is removed and properly disposed as waste products. It is critical that phagocytosis provide daily removal of the shedded segments to maintain vision.  Phagocytosis denote a highly active lysosomal activity in the RPE of the retina. Aging of retinal results in a degression of lysosomal activity and accumulation of waste material (Lipofuscin). (2) Furthermore, age related photooxidation of the cellular membrane of the retina further damages the RPE and retinal function.  

LIPOFUSCIN AND MACULAR DEGENERATION. Lipofuscin is generated through oxidative stress and a result of waste products. When the retina loses phagocytosis, there is photoreceptor degeneration.(1) Diminished phagocytosis results in increased lipofuscin accumulated in the RPE, which in turn negatively affects the RPE and photoreceptors. Lipofuscin levels also increase through oxidative stress in the retina. Accumulation of lipofuscin is an indicator of RPE atrophy and macular degeneration. As powerful antioxidants, lutein and zeaxanthin can reduce formation of lipofuscin. Zeaxanthin in particular can further help by supporting the phagocytosis removal of lipofuscin.(3,4)

The RPE contains the pigments melanin (in melanosomes) and lipofuscin. Melanin is an antioxidant pigment, whereas lipofucsin is the byproduct of waste material from photoreceptor removal and oxidative stress, which increases with dysfunction of phagocytosis. The accumulation of lipofuscin  reduces the protection of melanin and increases oxidative stress of the RPE.(2)  

While melanin is a powerful protector of the retina, aging affects the ability of melanin to protect the eye. Older melanosomes exposed to blue light, significantly inhibited phagocytosis - which accelerated degeneration of photoreceptors.. Therefore, the phototoxicity of melansomes increase with age. However, the antioxidant zeaxanthin has been shown to reduce the phototoxicity potential.(3)

ZEAXANTHIN HELPS PROTECTS AGAINST RETINAL DEGENERATION

(1) By reducing Phototoxicity / Photooxidation damage of retinal cellular membranes associated with aging.

(2) By supporting Phagocytosis.and the Maintenance of the RPE. 

Meso zeaxanthin is the most powerful version of zeaxanthin, and is found in the central macula.

 VISION VITALITY  (MESO ZEAXANTHIN)

REFERENCES:

(1) Valiente-Soriano F, et al. Tracing the retina to analyze the integrity and phagocytic capacity of the retinal pigment epithelium.Sci Rep. 2020.

(2) Bonilha V.. Age and disease-related structural changes in the retinal pigment epithelium. Clin. Ophthalmol. 2008 Jun

(3) Olchawa M, et al. The effect of aging and antioxidants on photoreactivity and phototoxicity of human melanosomes; an in vitro study. Pigment Cell Melanoma Res, 2020 Jul 23.

(4) Olchawa M, et al. Zeaxanthin and α-tocopherol reduce the inhibitory effects of photodynamic stress on phagocytosis by ARPE-19 cells. Free Radic Biol Med. 2015 Dec.

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.

Natural Yellows - For Obesity and Non-Alcoholic Liver Disease

Excess body weight is associated with many health concerns, and is rapidly  becoming the number one health problem worldwide. among the health risks are diabetes, cardiovascular disease, cancer and premature death. (1)  Individuals of the obese classification are especially subject to deleterious health implications. Obesity results in:

• Visceral Fat. Excessive adipose tissue, especially dangerous visceral fat surrounding internal organs, and
• Non-alcoholic fatty liver disease (NAFLD) is the most ubiquitous cause of liver disorder worldwide and is attributed to obesity and diabetes. NAFLD affects approximately 25% of the global population.(22). Insulin resistance is a major contributor to NAFLD. Ultimately, NAFLD may lead to liver cirrhosis and liver failure.

Visceral Fat - Obesity results in increases of visceral fat. Visceral fat (also known as belly fat) is the fat that accumulates around organs in the abdominal cavity and is linked to serious diseases, including type 2 diabetes. metabolic syndrome and those affecting organ functioning. Significant levels of inflammatory proteins are generated by visceral fat. In fact, inflammation of the liver which precedes HDLF, is mediated by visceral fat inflammatory proteins.(2)

• Heart visceral fat - Accumulation of fat surrounding the heart may have profound effects on the myocardium and functioning of the heart. In obese lab animals, the heart visceral fat (white fat) increased inflammation of the heart, including hypertrophy of the cardiomyocytes and fibrosis. Further, these changes to the heart are significantly related to increased rates of heart failure.(3) Such changes were not seen in lean animals which had a significant amount of brown fat adjacent to the heart muscle.
• Kidney visceral fat - Visceral fat deposits around the kidney are associated with both chronic kidney disease as well as cardiovascular disease.(4)
• Pancreatic Visceral Fat - Increased levels of pancreatic fat coincide with pancreatic cancer and pre-cancer lesions.(5)

Nonalcoholic fatty liver disease (NAFLD) - Obesity is a significant risk factor in the development of NAFLD.  Most noteworthy, is the excessive buildup of triglycerides in the liver which causes metabolic disturbances throughout the body. As a result, fatty acid metabolism becomes impaired, which may lead to fatty acid intermediates which causes insulin resistance and cardiovascular disease. 

Adipose Tissue and Aging - White adipose tissue, associated with obesity,  is the most affected tissue in aging. As the adipose tissue ages, there is a significant increase in oxidative stress and the generation of  inflammatory proteins resulting in  chronic low grade inflammation. In turn, this further damages tissue and accelerates aging. (6) 

• Telomere Shortening - Telomere shortening is a marker of aging. (7) Appears to be associated with obesity and increased insulin resistance.
• Insulin Resistance - Insulin resistance prevents blood sugar from being removed from the blood. The result is hyperglycemia which damages structures in the body. Eventually this become diabetes.
• Diminishes Immune Response - Increased inflammation from adipose tissue contributes to loss of innate immunity response during aging.(8)
• Impairs Stem Cell Regenerative Ability - Adipose tissue stem cells are impacted by adipose tissue inflammation. The result is the senescence of the stem cells and loss of tissue repair and regeneration.(9).
• Loss of Healthy Fat Cell (Stromal Cells) Renewal - Healthy adipose tissue requires renewal of adipose stromal cells. The stromal cells ensure the production of new healthy adipose cells. Obesity contributes to the loss of the stromal cells.(10)

INGREDIENTS:

• Berberine - Inhibits the inflammation of the liver associated NAFLD. Inflammation is a key event in the progression of NAFLD. (11) Also enhances brown adipose fat activity, which promotes thermogenesis, which dissipates harmful white adipose tissue,(12) Furthermore, berberine inhibits the proliferation of white fat adipocytes, thereby suppressing the formation of fat associated with obesity.(13) Berberine also reduces insulin resistance which improves glucose tolerance and NAFLD.(14).
• Apigenin - Reduces abdominal visceral obesity and weight. Abdominal visceral fat promotes metabolic syndrome including inhibition of adipocytes  (fat cells). Does not affect subcutaneous fat, which lies just under the skin.(15) Apigenin also improves NAFLD and Insulin resistance.(16) 
• Saffron - Improves insulin sensitivity,(16) Possesses a protective effect against NAFLD and fatty liver induced damage.(17)
• Curcumin - Reduces insulin resistance by enhancing GLUT4 gene expression (the receptor for Glucose transport into the cell).(18)
• Fisetin - Offers protection to suppress NAFLD initiation and progression.(19)
• Rosmarinic Acid - Ameliorates liver damage by NAFLD, by increasing antioxidant enzymes and activating AMPK. inhibiting hepatic fibosis and inflammation of the liver.(20) Rosmarinic acid also acts as an anti-obesity agent by inhibiting adipogenesis (the formation of fat tissue), and increasing lipolysis (the breakdown of fat), Also reduced adipocyte associated inflammation.(21)
• Pterostilbene -  Enhances brown adipose tissue activation. Increases thermogenesis and promotes browning of white adipose tissue,(23) Offers protective effect on liver steatosis.(24)
• Ursolic Acid - Targets insulin resistance and mitigating the effects of liver fibrosis. (25,26) Obesity disrupts insulin signaling, thereby promoting insulin resistance. Furthermore, visceral fat in obesity sets off cascading generation of proinflammatory cytokines. Ursolic acid may improve these conditions. 

YELLOW LONGEVITY® (Berberine | Apigenin | Saffron)

VASCULAR VX™

 CURCUMIN PXC™(Curcumin | Fisetin | Pterostilbene) 

 HYPER LONGEVITY™ (Ursolic Acid | Rosmarinic Acid)

REFERENCES:

(1)  Unamuno Xm et al. Adipokine dysregulation and adipose tissue inflammation in human obesity. Eur J Clin Invest. 2018 Sep

(2)  Casagrande BP, et al. Hepatic inflammation precedes steatosis and is mediated by visceral fat accumulation.  J Endocrinol. 2020 Mar 1

(3) Conceição G, et al. Fat Quality Matters: Distinct Proteomic Signatures Between Lean and Obese Cardiac Visceral Adipose Tissue Underlie its Differential Myocardial Impact. Cell Physiol Biochem. 2020 Apr 23

(4) Huang N, et al. Novel insight into perirenal adipose tissue: A neglected adipose depot linking cardiovascular and chronic kidney disease. World J Diabetes, 2020 Apr 15

(5) Sreedhar UL, et al. A Systematic Review of Intra-pancreatic Fat Deposition and Pancreatic Carcinogenesis. J Gastrointest Surg. 2019 Nov 20

(6) Yu Q, et al. Sample multiplexing for targeted pathway proteomics in aging mice. Proc Natl Acad Sci USA. 2020 Apr 24

(7) Mangge H, et al. Telomere shortening associates with elevated insulin and nuchal fat accumulation. Sci Rep. 2020 Apr 22

(8) Goldberg EL, et al. How Inflammation Blunts Innate Immunity in Aging. Interdiscip Top Gerontol Geiatr.  2020

(9) Conley SM, et al. Human Obesity Induces Dysfunction and Early Senescence in Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells. Front Cell Dev Biol. 2020 Mar 26

(10) Eckel-Mahan K, et al. Adipose Stromal Cell Expansion and Exhaustion: Mechanisms and Consequences. Cells 2020 Apr 2

(11) Wang Y, et al. Berberine inhibits free fatty acid and LPS-induced inflammation via modulating ER stress response in macrophages and hepatocytes. PLoS One. 2020 May 1

(12) Horvath C, et al. Feeding brown fat: dietary phytochemicals targeting non-shivering thermogenesis to control body weight. Proc Nutr Soc, 2020 Apr 

(13) Wang C, et al. Berberine inhibits adipocyte differentiation, proliferation and adiposity through down-regulating galectin-3.

(14) Yu SJ, et al. Berberine alleviates insulin resistance by reducing peripheral branched-chain amino acids.  Am J Physiol Endocrinol Metab. 2019 Jan

(15) Su T, et al. Apigenin inhibits STAT3/CD36 signaling axis and reduces visceral obesity.  Pharmacol Res. 2020 Feb

(16) Jung UJ, et al. Apigenin Ameliorates Dyslipidemia, Hepatic Steatosis and Insulin Resistance by Modulating Metabolic and Transcriptional Profiles in the Liver of High-Fat Diet-Induced Obese Mice.  Nutrients. 2016 May

(16) Yaribeygi H, et al.  Antidiabetic potential of saffron and its active constituents. J Cell Physiol, 2019 Jun

(17) Mashmoul M, et al. Protective effects of saffron extract and crocin supplementation on fatty liver tissue of high-fat diet-induced obese rats. BMC Complement Altern Med. 2016 Oct

(18) Al-Saud NBS.  Impact of curcumin treatment on diabetic albino rats. Saudi J Biol Sci. 2020 Feb;27

(19) Gaballah HH, et al, Mitigative effects of the bioactive flavonol fisetin on high-fat/high-sucrose induced nonalcoholic fatty liver disease in rats. 

(20) Kim M, et al.  Lemon Balm and Its Constituent, Rosmarinic Acid, Alleviate Liver Damage in an Animal Model of Nonalcoholic Steatohepatitis. Nutrients. 2020 Apr 22

(21) Rui Y, et al. Rosmarinic acid suppresses adipogenesis, lipolysis in 3T3-L1 adipocytes, lipopolysaccharide-stimulated tumor necrosis factor-α secretion in macrophages, and inflammatory mediators in 3T3-L1 adipocytes. Food Nutr Res. 2017 Jun

(22) Younossi ZM, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology, 2016 Jul;

(23) Milton-Laskibar L, et al.  Effects of resveratrol and its  derivative pterostilbene on brown adipose tissue thermogenic activation and on white adipose tissue browning process. J Physiol Biochem. 2020 Mar 13

 (24) Gomez-Zorita S, et al. Effects of Pterostilbene on Diabetes, Liver Steatosis and Serum Lipids. Curr Med Chem. 2019 Oct 29

(25) Gonzales-Garibay AS, et al,  Effect of Ursolic Acid on Insulin Resistance and Hyperinsulinemia in Rats with Diet-Induced Obesity: Role of Adipokines Expression.  J Med Food. 2020 Mar;23

(26) 

Atherosclerosis - Pterostilbene & Progression of Artery Disease

Atherosclerosis is a chronic degenerative disease condition which slowly blocks arteries, accelerate aging and is a contributing factor in most age-related deaths.The key event in the  initiation and progression of atherosclerosis is injury and inflammation to the arterial lining (endothelial cells).

• Endothelial Cell Injury Reduction 
• Atherosclerosis is intrinsically linked to damage of the endothelial cells in the artery lining. Such damage is attributed to inflammation and oxidative stress in the arterial wall. In animal models, pterostilbene mitigated the process of atherosclerosis and reduced inflammation in the blood vessels. Importantly, pterostilbene increased levels of protective Nrf2 in the endothelial cells.(1)
• Vascular Inflammation Prevention 
•  In the gut, there are bacteria that convert choline and carnitine into  trimethylamine (TMA). In turn, TMA is converted to  trimethylamine-N-oxide (TMAO).(2) Increased levels of TMAO correlate to cardiovascular disease, by increasing vascular inflammation and endothelial dysfunction.(3)
• Pterostilbene significantly reduces vascular inflammation by:
• altering the composition of gut bacteria, thereby reducing the levels of TMAO
•  decreasing inflammatory vascular markers, including TNF-alpha.(4)
• Protects Against Oxidized Low Density Lipoprotein (LDL) 
• Oxidized LDL targets the endothelium lining of the artery and causes cellular death of the endothelium. This facilitates atherosclerosis development. Pterostilbene inihibits expression of LOX-1, the cellular receptor for oxidized LDL in the endothelium. As such, pterostilbene mitigates the buildup of LDL and subsequent atherosclerosis.(5). 
• Attenuates Heart Aging (Myocardial Fibrosis)
• Oxidative stress negatively impacts heart function and accelerates aging of the heart. As a result of oxidative stress, including inflammation, the heart can become fibrotic, replacing heart tissue with non functional fibrotic tissue.  In lab studies pterostilbene has been shown to mitigate myocardial fibrosis.(6)

CURCUMIN PXC  (Pterostilbene)

REFERENCES

(1) Tang T, et al. Pterostilbene reduces endothelial cell injury in vascular arterial walls by regulating the Nrf2-mediated AMPK/STAT3 pathway in an atherosclerosis rat model. Exp Ther Med. 2020 Jan

(2) Rath S, et al. Potential TMA-Producing Bacteria Are Ubiquitously Found in Mammalia. Front Microbiol. 2020 Jan 

(3) Singh G, et al.  High Mobility Group Box 1 Mediates TMAO-Induced Endothelial Dysfunction. Int J Mol Sci 2019 Jul

(4) Koh YC, et al.  Prevention of Vascular Inflammation by Pterostilbene via Trimethylamine-N-Oxide Reduction and Mechanism of Microbiota Regulation.  Mol Nutr Food Res. 2019 Oct.

(5) Zhang L, et al.  Pterostilbene protects vascular endothelial cells against oxidized low-density lipoprotein-induced apoptosis in vitro and in vivo. Apoptosis. 2012 Jan

(6) Kang LL, et al. Pterostilbene Attenuates Fructose-Induced Myocardial Fibrosis by Inhibiting ROS-Driven Pitx2c/miR-15b Pathway. Oxid Med Cell Longev. 2019 Dec

Oxidative Stress and Inflammation - Pathogenesis in Degeneration of the Retina

Neurodegenerative diseases of the retina are mostly attributable to oxidative stress and inflammation.(1)  Diseases of the retina target the retinal epithelial cells, and photoreceptors. Photoreceptors are the processing centers in the retina, and are the primary area of vision. The retina has the highest metabolic rate of any tissue in the body. Furthermore, the retina must endure oxidative stress from chronic exposure to light, which will damage the retina. In addition, retina degeneration is associated with inflammation. The result is that with age, the retina becomes damaged, and blindness is the end effect in older people.

AGE RELATED MACULAR DEGENERATION. Degeneration of retinal cells (photoreceptor and retinal pigment epitheilium (RPE) cells) by oxidative stress and inflammation is responsible for age-related macular degeneration (AMD).

• PHOTORECEPTORS - Are comprised of rods and cones.  Are under constant threat of oxidative threats, including excessive stress from light, high oxygen requirements, All of which make photo receptors susceptible to degradation and death of the photo receptors.

(1) Oxidative Stress - NrFT2. Cellular Transcription Factor for Endogenous Antioxidant Protective Factors

• CARNOSIC ACID

Carnosic Acid is an electrophilic antioxidant which crosses the blood brain barrier. Carnoisc acid is a potent activator of Nrf2, a transcription factor that causes the increased production of endogenous antioxidants. Additionally, carnoisc acid is unqiue in that it does not deplete endogenous levels of glutathionine, the key cellular antioxidant, unlike other antioxidants.(2) In a study of high intensity lighting on photooxidative damage of the retina, adding carnoisc acid to AREDS ingredients greatly increased protection of retina vs AREDS alone.(3)

• LYCIUM BARBARIM (WOLFBERRY)

Protects the eye and retina in multiple ways. First, lycium bararum protects the photreceptor cells from light-induced retina damage by activating Nrf2.(4)

2) Inflammation - NLRP3 inflammasome activation is involed in the pathogenesis of AMD.

• BLACK CURRANT / BILBERRY EXTRACT (C3G)

C3G is considered the most important anthocyanin in maintaining health of the retina. Recently, research indicates that cyanidin-3-glucoside (C3G) has potent anti-inflammation properties and may inhibit  inflammasome damage to retinal epithelium cells.(5) C3G further reduces oxidative stress of the retina, and light induced retinal degeneration,  by activating Nrf2 endogenous levels.(6)

VISION VITALITY (Carnosic Acid | Lycium Barbarum | C3G)

REFERENCES:
(1) Rohowetz RJ, et al, Reactive Oxygen Species-Mediated Damage of Retinal Neurons: Drug Development Targets for Therapies of Chronic Neurodegeneration of the Retina. Int J Mol Sci. 2018 Oct

(2) Rezaie T, et al. Protective effect of carnosic acid, a pro-electrophilic compound, in models of oxidative stress and light-induced retinal degeneration. Invest Ophthalmol Vis Sci. 2012 Nov

(3) Wong P, et al, Enhancing the efficacy of AREDS antioxidants in light-induced retinal degeneration.  Mol Vis. 2017 Oct

(4)  Tang L, et al. Antioxidant effects of Lycium barbarum polysaccharides on photoreceptor degeneration in the light-exposed mouse retina. Biomed Pharmacother. 2018 Jul

(5) Jin X, et al. Cyanidin-3-glucoside Alleviates 4-Hydroxyhexenal-Induced NLRP3 Inflammasome Activation via JNK-c-Jun/AP-1 Pathway in Human Retinal Pigment Epithelial Cells.  J Immunol Res. 2018

(6) Wang Y, et al. Cyanidin-3-glucoside and its phenolic acid metabolites attenuate visible light-induced retinal degeneration in vivo via activation of Nrf2/HO-1 pathway and NF-κB suppression.  Mol Nutr Food Res. 2016 Jul

Curcumin & Fisetin - Amyloid Autophagy & Senolytics. Implications for Longevity and Brain Health

Protein Homeostasis is a significant determining factor in the longevity of multi-cellular animals.(1) Quality control mechanisms in place to support protein homeostasis include autophagy - the essential degradation of toxic proteins. As an organism ages, protein homeostasis is gradually lost.(2) Autophagy, by lysosomes, plays an active role in protein homeostasis, by eliminating toxic and damaged proteins such as amyloid. Nrf2 activation increases autophagy activity. Reduced levels of autophagy are tied to Alzheimers Disease. Misfolded amyloid beta and tau proteins are involved in the development of Alzheimers Disease.(11) 

Autophagy is not only critical in the deposition of toxic proteins, but is functionally important in the degradation and recycling of defective cellular components. Research now indicates that autophagy is central for maximum longevity.(13)

AUTOPHAGY:  FISETIN and CURCUMIN

• FISETIN - As a potent Nrf2 activator, fisetin supports increased autophagic activity, and therefore clearance of toxic proteins.(3) Fisten supports decreased levels pf tau and amyloid beta, and increased expression of neprilysin, an amyloid beta remover.(4) Further, fisetin is a potent neuroprotective against amyloid beta toxicity(5) and brain aging.(6)
• Fisetin when provided to late in life mice, restored tissue homeostasis and increased median and maximum lifespans.(8)
• CURCUMIN - Increases autophagic activity by increasing biogenesis of lysosomes,which will degrade misfolded and damaged proteins. Furthermore, curcumin facilitates loading of the proteins into the lysosomes by increasing HSP70.(12)
• SENOLYTICS - both Fistein and Curcumin are considered senolytics, having the ability to remove senescent cells. Both are considered significant senolytics, however fisetin is considered most powerful.(8.12)

AGING - LOSS OF PROTEOSTASIS (TOXIC PROTEINS)

• AMYLOID. Amyloid is the resulting end-product of defective protein homeostasis. The ability of an organism to bind and autophagically remove toxic amyloid, supports health of the brain and life extension. Specifically, extracellular amyloid beta plaques in the brain are associated withAlzheimer's Disease.(2) 

• TAU Fibrils. Tau hyperphosphorylation results in toxic fibrils which is integral in the pathogenesis of Alzheimers Disease. Tau fibrils are typically present with amyloid beta in Alzheimers patients. The tau pathology in the brain represents detrimental structural changes, and is present in all adults over 70 years of age.(7)

• LIPOFUSICIN - The brown-yellow age pigment which accumulates in cells, and is considered a hallmark of aging. Intra-neuronal accumulation of lipofuscin is observed in all aged brains. Eventually, lipofusin accumulation will lead to neuron cell death.  Lipofuscin accumulation is also associated with dysfunction autophagic lysosomal functioning. Fisetin, Curcumin, Rosmarinic acid (9), Carnosic acid and Myricetin (11) are active in the removal of cellular lipofuscin. Reductions in lipofsucin are correlated with increased lifespan. Lipofuscin accumulation is also a significant factor in macular degeneration. Lipofuscin is a precursor molecule of amyloid.(10)

CURCUMIN PXC  (Curcumin | Fisetin | Rosmarinic Acid | Carnosic Acid)

HYPER LONGEVITY (Rosmarinic Acid | Myricetin)

NEUROTREX (Rosmarinic Acid | Myricetin)

VISION VITALITY (Carnosic Acid)

REFERENCES:

(1) Alavez A, et al. Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan. Nature. 2011 Apr

(2) Kuang H, et al, Exploring the bi-directional relationship between autophagy and Alzheimer's disease. CNS Neurosci Ther. 2019 Sep

(3) Chen T, et al. Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells.  Aging Cell. 2011 Oct

(4) Yang W, et al. Fisetin improves lead-induced neuroinflammation, apoptosis and synaptic dysfunction in mice associated with the AMPK/SIRT1 and autophagy pathway. Food Chem Toxicol .2019 Sep 

(5) Ahmad A, et al. Neuroprotective Effect of Fisetin Against Amyloid-Beta-Induced Cognitive/Synaptic Dysfunction, Neuroinflammation, and Neurodegeneration in Adult Mice.  Mol Neurobiol. 2017 Apr

(6) Singh S, et al. Fisetin as a caloric restriction mimetic protects rat brain against aging induced oxidative stress, apoptosis and neurodegeneration. Life Sci. 2018 Jan

(7) Ziontz J, et al. Tau pathology in cognitively normal older adults. Alzheimers Dement (Amst). 2019 Sep

(8) Yousefzadeh MJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018 Oct

(9) Lin C, et al. Rosmarinic acid improved antioxidant properties and healthspan via the IIS and MAPK pathways in Caenorhabditis elegans. Biofactors. 2019 Jun 

(10) De Biase D, et al. Amyloid precursor protein, lipofuscin accumulation and expression of autophagy markers in aged bovine brain. BMC VET Res, 2017.

(11) Buchter C, et al. Myricetin-Mediated Lifespan Extension in Caenorhabditis elegans Is Modulated by DAF-16. Int J Mol Sci. 2913 Jun.

(12) Bielak-Zmijewsja A, et al. The Role of Curcumin in the Modulation of Ageing. Int J Mol Sci. 2019 Mar.

(13) Bareja A, et al. Maximizing Longevity and Healthspan: Multiple Approaches All Converging on Autophagy. Front Cell Dev Biol. 2019 Sep

Fisetin - Potent for Anti-Aging Senolytics and Homeostasis

In the field of anti-aging, the flavonoid fisetin is emerging as a potent longevity compound. Fisetin affects the aging process in experimental animals through multiple pathways, including senolytics (removing senescent cells)m SIRT1 activation, calorie restriction mimic and homeostasis.

SENOLYTICS

• Senolytics- the rejuvenation of the cellular environment, by eliminating senescent cells. Aging is characterized by the accumulation of senescent cells. These are cells which are irreversibly unable to grow and function and are resistant to normal cellular clearance. Senescent cells not only interfere with normal tissue functioning, but may also be toxic to neighboring cells. Fisetin, has been shown to be a potent senolytic, with the ability to eliminate senescent cells. (1)

• Scenescent Cells Accelerate Aging. Scenescent cells promote inflammation, stem cell dysfunction, chronic disease, and cellular aging.(2)
• Improve Healthy Lifespan. The elimination of specific age accelerating senescent cell populations is a potential strategy in improving health and longevity.(3)
• Fisetin - was the most potent and selective senolytic among flavonoids tested. Most importantly. fisetin administered to late-life laboratory animals, restored all markers of tissue homeostasis,  and amazingly extended median and maximum lifespans.(4)

REDOX HOMEOSTASIS / IONIC HOMEOSTASIS

• Fisetin Improves Redox Homeostasis. Plasma membranes are affected by increased levels of oxidation and reduced antioxidants in cellular membranes. Fisetin signifcantly increases antioxidants in membranes and activates the redox protection system. (5)
• Fisetin Improves Ionic Homeostasis. Aging affects the plasma membrane of cells, and the membrane transporters. Impairment of the membranes transport function is related to age progression and disease. Specifically, membrane transporters are responsible for ionic homeostasis between intracellular and extracellular environments. Fisetin reverses these aging declines.(6)

SIRTUIN ACTIVATION (SIRT1)

• Fisetin is an SIRT1 activator. Sirtuin activation plays a significant role in longevity. Among the anti-aging benefits include inhibition of cellular senescense, reduced telomere reductions, and enhanced DNA repair. Sirtuins interact with the major longevity pathways, among which is FOXO.(7)

PLURIPOTENT STEM CELLS (Induction)

• Stem cells are the regenerative cells of the body, and represent a primary mechanism for longevity. Fisetin has the unique capablity of converting adult cells (somatic)into pluripotent stem cells. A process known as induced pluripotent stem cells (iPSC). Pluripotent stem cells revert to any specialized cells for tissue repair, organ repair, and  other anti-aging regeneration.(8) Fisetn as a sirtuin activator, enhances the generation of cellular reprogramming.

NRF2 ACTIVATION

• Nrf2 is a powerful antioxidant pathway with strong correlation to longevity.(9)
• Fisetin is a potent activator of Nrf2 and is responsible for the cellular antioxidant activity of fisten.(10)

PROTEOSTASIS - ABNORMAL PROTEIN ACCUMULATION / AUTOPHAGY

• Proteostasis is the homeostasis of protein generation, folding and degradation of proteins. The dysregulation of this process results in aging and disease. Alzheimers Disease (AD) is example of the accumulation of toxic proteins in the brain.
• Fisetn supports reduction in abnormal accumulation and alterations of amyloid and tau in the brain. Fisetin has both antiamyloidogenic and fibril-destabilization activity,(11)
• Alzheimers Disease is characterized by amyoid beta and phosphoryated tau fibrils. FIsetin, through increased Nrf2 activation, enhanced the autophagic removal of phosphorylated tau.(12)

CURCUMIN PXC  (contains Fisetin)

REFERENCES:

(1) Glossmann HH, et al, Metformin and Aging: A Review. Gerontology. 2019. Sept.

(2) Kirkland JL, et al. Cellular Scenescence. A Translational Perspective. EBioMedicine, 2017 

(3) van Deursen JM. The role of Scenescent Cells in Ageing. Nature 2014.

(4) Yousefzadeh MJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine, 2018

(5) Singh S, et al. Fisetin, a potential calorie restriction mimetic, attenuates senescence biomarkers in rat erythrocytes.  Biochem Cell Biol. 2019 Aug

(6) Singh S, et al. Fisetin, a potential calorie restriction mimetic,modulates ionic homeostasis in senescence induced and naturally aged rats.  Biochem Cell Biol. 2019 Sept.

(7) Shin-Hae Lee, et al. Sirtuin signaling in cellular senescence and aging. BMB Rep. 2019 Jan

(8) Chen T, et al. Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells. Aging Cell. 2011.

 (9) Bai, et al. Small Molecules as SIRT Modulators.  Mini Rev Med Chem. 2018.

(10) Zhang H, et al. Nrf2⁻ARE Signaling Acts as Master Pathway for the Cellular Antioxidant Activity of Fisetin. Molecules. 2019 Feb.

(10) Zheng W, et al. Fisetin inhibits IL-1β-induced inflammatory response in human osteoarthritis chondrocytes through activating SIRT1 and attenuates the progression of osteoarthritis in mice. Int Immunopharmacol. 2017 Apr

(11) Simunkova M, et al. Management of oxidative stress and other pathologies in Alzheimer's disease. Arch Toxicol. 2019 Aug

(12) Sunhyo K, et al. Fisetin stimulates autophagic degradation of phosphorylated tau via the activation of TFEB and Nrf2 transcription factors Sci Rep. 2016.