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YELLOW LONGEVITY® - The Yellows for Longevity Support

Yellow Longevity® is a high quality supplement which contains the most important natural yellows found in nature for health and anti-aging.

Key ingredients:

• CURCUGEN® - from Dolcas-Biotech, is a next generation curcumin complex,  which is an oleoresin-sourced turmeric active. The result is significantly enhanced bioavailability of free curcumin. Tests proved a 39x enhanced bioavailability vs regular 95% Curcumin extract,(1)
• TETRAHYDROCURCUMIN (THC) - Further, Curcugen® is unique in being able to significantly enhance endogenously produced THC bioavailability (by a factor of 31xs more bioavailability vs placebo). THC is stronger antioxidant than curcumin. (2) Additional benefits from THC include cardioprotective against pathological cardiac hypertrophy (enlargement) and fibrosis(3),  and increases lifespan in research animals by increasing FOXO gene factor.(4)
• BERBERINE - Many significant antiaging benefits. Through various pathways, has anti-cancer potential.  Is anti-diabetic and may be beneficial for colitis.(6)  Acts as a protective of retina epithelial cells, and Age-related macular degeneration (AMD)(7). Supports inhibition of atherosclerosis by increasing SIRT1, thereby activating autophagy and apoptosis of peritoneal macrophages. Researchers suggest that this may be a therapeutic for atherosclerosis.(8) 
• SAFFRON - The emerging roles of saffron in degenerative diseases, and anti-aging. Benefits includes, eye protection, depression (anti-neuroinflammation), anti-stress, support for sleep and cardiovascular health.(9) Ameliorates cardiac hypertrophy.(10) 
• APIGENIN - Compelling animal research indicates a potent anti-cancer effect of apigenin. Part of this effect is due to apigenin being a strong antioxidant. Apigenin also effects other pathways involved in cancer development.(11) Slow clearance by the liver enables long lasting effect of apigenin in the body. New research indicates that apigenin may provide  endothelium restoration in aging blood vessels.(12) Aging blood vessels include aorta stiffening and vascular inflammation. Apigenin may prevents foam cell formation (initial step in atherosclerosis), reverse aortic stiffening, and promote normal collagen elastin in arteries as well as reversing arterial inflammation. Researchers indicate that apigenin may provide an effective mechanism in reversing arterial dysfunction.  

 YELLOW LONGEVITY (Curcugen®  | Berberine | Saffron | Apigenin)

REFERENCES:

(1) Dolcas-Biotech Research. 2021

(2) Sanjib K, et al. The enhanced bioavailability of free curcumin and bioactive-metabolite tetrahydrocurcumin from a dispersible, oleoresin-based turmeric formulation. Medicine (Baltimore). 2021 Jul.

(3) Zhang B, et al. Novel PGC-1 α/ATF5 Axis Partly Activates UPR ^mt and Mediates Cardioprotective Role of Tetrahydrocurcumin in Pathological Cardiac Hypertrophy. Oxid Med Cell Longev. 2020 Dec

(4) Shen L, et al. Curcumin and Aging.Biofactors. Jan-Feb 2013 

(5) Samadi P, et al. Berberine: A novel therapeutic strategy for cancer. IUBMB Life. 2020 Oct.

(6) Ashrafizadeh M, et al. Berberine Administration in Treatment of Colitis: A Review. Curr Drug Targets. 2020.

(7) Li, S. et el. Protective Mechanism of Berberine on Human Retinal Pigment Epithelial Cells against Apoptosis Induced by Hydrogen Peroxide via the Stimulation of Autophagy. Oxid Med Cell Longev. 2021 Aug.

(8) Zheng Y, et al Berberine-induced TFEB deacetylation by SIRT1 promotes autophagy in peritoneal macrophages. Aging (Albany NY) 2021 Feb

(9) Roshanravan N, et al. The therapeutic potential of Crocus sativus Linn.: A comprehensive narrative review of clinical trials. Phytother Res. 2021 Sep

(10) Lin C, et al. IGF-II-induced hypertrophy in H9c2 cardiomyocytes is ameliorated by saffron by regulation of calcineurin/NFAT abd CaMKII signaling. Environ Toxicol. 2021 Sep.

 (11) Kashyap P, et al. Functionality of apigenin as a potent antioxidant with emphasis on bioavailability, metabolism, action mechanism and in vitro and in vivo studies: A review. J Food Biochem. 2021 Sep

(12) Clayton Z, et al. Apigenin restores endothelial function by ameliorating oxidative stress, reverses aortic stiffening, and mitigates vascular inflammation with aging. Am J Physiol Heart Circ Physiol. 2021 Jul.

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

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