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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) 

Remarkable Vinpocetine & Citrus Bergamot - Youthful Arteries and Suppressing Atherosclerosis

Arteries degenerate with age, via a process known as vascular remodeling, leading to atherosclerosis, stroke and other cardiovascular diseases.. Therefore, preserving youthful arteries is a very important factor in longevity. Two important supplements which have been shown to suppress degenerative changes to the arteries are vinpocetine and citrus bergamot polyphenols.

VASCULAR AGING - Involves changes to the vascular endothelium and smooth muscle which promotes increased hypertension and stiffness of the arteries. The results is an aged vascular system  which is characterized by inflammation and atherosclerosis. As such, the arteries lose their ability to expand and contract, and becomes stiff, thickened and inflamed. When the vascular system ages it becomes more susceptible to hypertension, ischemic stroke and coronary heart blockage (heart attack). Furthermore, vascular aging in the brain may lead to cognitive disorders due to diminished blood flow.

Key areas of Vascular Aging:

• NF-kB - The master transcription factor for promoting inflammation in the artery and is involved in atherosclerosis plaque progression.
• PDE1 (phosphodiesterase) - An isozyme which plays a key role in the pathological changes which occur in the vascular structure with age. Increased levels of PDE1 are associated with loss of vasodilator function, vascular smooth muscle senescence, increased blood pressure and vascular hypertrophy. (1,2)

VINPOCETINE -
Promotes youthful arteries via two mechanisms. Vinpocetine reduces the release of inflammatory cytokines from endothelial cells and vascular smooth muscle by targeting oxidative stress and inflammation of the arteries. NF-kB. Also, vinpocetine is a powerful inhibitor of PDE1.

• Suppresses Atherosclerosis - Via the inhibition of inflammation transcription factor NF-kB.(3)
• Inhibition of PDE1 - PDE1 is a key regulator in the pathological changes that occur in aging vascular functioning including changes to structure and blockage of blood flow. Aging (senescent) vascular cells are correlated with increased levels of PDE1. (4) Inhibition of PDE1 has been shown to reduce all biomarkers associated with vascular aging.

CITRUS BERGAMOT (Bergamonte®) - The polyphenols in Citrus Bergamot uniquely provide artery anti-aging benefits. Citrus Bergamot provides protection directly to the vascular endothelium, in addition to optimizing cholesterol and triglycerides and inhibiting non alcoholic liver disease.

• Vascular Endothelium Protection.  Targets arterial endothelium cells to reduce inflammation and oxidative stress. Both are associated with vascular aging.
• Inhibits Non Alcoholic Fatty Liver Disease (NAFLD). NAFLD is a common liver disease where fat accumulates in the liver, causing liver dysfunction and is correlated with increased cardiovascular disease and mortality. It is estimated that up to 25% of Americans have NAFLD. Furthermore, excess belly fat not only is predictor of increased cardiovascular risk, but normally indicates high fat in the liver and NAFLD.
• Bergamot polyphenols stimulate lipid metabolism thereby preventing toxic build-up in the liver. Removal of lipids is through enhanced autophagy. (6)
  
• Decreases Oxidized Cholesterol Receptors. LOX-1 is the receptor on the endothelium for oxidized cholesterol. Expression of LOX-1 is increased with pathological conditions including hypertenison, hyperlipidemia, and diabetes.(5, 7)
• Inhibits Phosphodiesterases (PDEs). Offers similar protections as vinpocetine in preventing age-related changes to vascular structure .(7)

 VASCULAR STRENGTH  (with Vinpocetine and Bergamot Polyphenols)

REFERENCES:

(1) Chan S, et al. PDE1 isozymes, key regulators of pathological vascular remodeling. Curr Opin Pharmacol. 2011 Dec

(2) Bautista N, et al. Phosphodiesterase 1 regulation is a key mechanism in vascular aging. Clin Sci (Lond) 2015 Dec

(3) Zhuang J, et al. Inhibitory effects of vinpocetine on the progression of atherosclerosis are mediated by Akt/NF-κB dependent mechanisms in apoE-/- mice. PLoS One. 2013 Dec.

(4) Yan, C. Cyclic nucleotide phosphodiesterase 1 and vascular aging. Clin Sci (Lond). 2015 Dec.

(5) Chen M, et al. LOX-1, the receptor for oxidized low-density lipoprotein identified from endothelial cells: implications in endothelial dysfunction and atherosclerosis. Pharmacol Ther. 2002 Jul

(6) HP Ingredients. Support against NAFLD in those with Metabolic Syndrome. 2016 Apr.

(7) HP Ingredients. 2016.