CURCUMIN PXC® - The Proteostasis Curcumin® and Fisetin for Longevity

PROTEOSTASIS. Defines the ability of the body to maintain the fidelity of  biogenesis of protein (non-defective proteins), folding. movement, and removal of old protein aggregates. Especially significant is the removal of old damaged protein aggregates, which are detrimental to the functioning of the cell. Clearing old cellular debris, through a process called autophagy, greatly enhances the youthful functioning of the cell. 

CURCUMIN ENHANCES AUTOPHAGY. Lifespan and autophagy are strongly
 associated with one another.  Calorie restriction, resveratrol and curcumin are known to improve autophagy and increase lifespan. In fact, all life extension mechanisms depend upon the importance of autophagy for clearing cellular damage.(1,2)

Aging affects molecular pathways that influence health and longevity. As a result, there is a reduction of cellular debris clearance (autophagy), decreased  the pool of stem cells, increase in inflammation and cellular senescence. 

CURCUMIN has been shown to by positively regulate longevity by through important molecular pathways, including IIS, mTOR and FOXO. Curcumin is a powerful activator of the body's antioxidant defense system, as an Nrf2 activator. As an antioxidant, curcumin stabilizes and protects telomeres. Inflammation is also a powerful promoter of aging. Curcumin inhibits the powerful inflammation transcription factor NF-κB and is associated with reduced levels of inflammation.(3)  PROTEOSTASIS is impacted by all these aging pathways.(4) Therefore, curcumin supports longevity via aging signaling and proteostasis (autophagy).

• NEURODEGENERATION AND AUTOPHAGY.

Misfolded proteins in the brain are associated with poorly functioning autophagy. Autophagy removes aggregate protein accumulations which is responsible for neurodegeneration. Curcumin, research indicates, may help restore autophagy in the brain, to clear these misfolded proteins. (5) Oleuropein, a component of Olive Oil, in addition to curcumin, is implicated in mitophagy in the brain, removing old and dysfunction mitochondria. (6)

• SIRT1 (SIRTUINS) ENHANCES PROTEOSTASIS

SIRT1 is an enzyme which regulates cellular processes relative to longevity. SIRT1 INCREASES PROTEOSTASIS ,which is an important component of the longevity effect. Natural activators of SIRT1 include Curcumin, Fisetin, Quercetin and Resveratrol.(15)

• ATRIAL FIBRILLATION: PROTEOSTASIS AUTOPHAGY & INFLAMMATION

Cardiac remodeling through failure of autophagy, proteostasis and inflammation are believed to be a root cause of atrial fibrillation. Cardiomyocytes are replaced by non-functional proteins..(12. 13)  

• PROTEOSTASIS DECLINE SIGNIFICANTLY IMPACTS AGING. (7)

With age, cells become replicative scenescent - losing ability to produce new cells. Furthermore, scenescent cells are old cells. Old cells have been shown to lose proteostasis, which further limit the abilty of the cell to respond to external threats and maintain function. Curcumin and pterostilbene(11) helps inhibit cellular scenescence. Fisetin and quercetin are considered senolytics, which are capable of removing scenescent cells. (10)  Importantly, recent research also indicates that curcumin also removes scenescent cells.(14)

CURCUMIN PXC® - Incorporates highly bioavailable curcumin  Furthermore, Curcumin PXC also includes powerful supplemental ingredients in support of proteostasis.

• AUTOPHAGIX™ Complex - Rutin, Lonicera japonica (8), Oleuropein, Quercetin. 
• ROSEMARY PROTEOSTASIS™ COMPLEX (9)
• FISETIN (10)
• TRANS-PTEROSTILBENE

CURCUMIN PXC® - THE PROTEOSTASIS CURCUMIN® 

REFERENCES:

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) 

Yellows - Activating FOXO Longevity Factors and Longevity Pathways

It is known that the activation of FOXO transcription factors promote extreme longevity, which has been demonstrated in research animals as well as in animals such as the multi-cell animal hydra. In  human longevity, those with gene variants which activate higher levels of FOXO are also the longest lived with least amounts of illness and disease.

Despite years of research declaring that antioxidants, such as vitamins C and E, promoted longevity, none have been shown to activate the longevity factors FOXO or Nrf2. Rather, potent longevity factor activation has been shown by many plant based flavonoids. (1) Flavonoids are yellow in nature, and the word is derived from the latin flavus, which means yellow.

• FLAVONOIDS - APGEININ & LUTEOLIN
• In a comprehensive study comparing flavonoids to antioxidative vitamins, determined that flavonoids are very potent activators of longevity factors, versus antioxidants. Antioxidants, including Vitamin C and E, did not trigger activation of any longevity factors.
• The flavonoids Apigenin and Luetolin were shown to be the most active longevity triggers of the flavonoids tested.
• Apigenin and Luteolin highly activate Nrf2, FOXO and PPARγ.

• EGCG (Green Tea)  - Life extending properties include upregulation of DAF-16 (the longevity factor equivalent to FOXO) and endogenous superoxide dismutase (SOD),
• ICARIIN (Epimedium) - Inihibits the pathway ISS (Insulin Signaling) which causes an activation of DAF-16 (analogous to FOXO). Also facilitates genome stability by reducing the DNA strand breaks.

•  MYRICETIN (Bayberry extract) - A longevity enhancing and mitochondrial activating flavonoid. Mitichondria activation improves respiration, endurance and activity levels by increasing the density of mitochondria. Myricetin positively impacts cellular mitochondria through activating PGC-1α and SIRT1. SIRT1 is believed to play a major role in mitochondrial biogenesis and mitophagy (mitichondrial turnover).3

 Other FOXO Activators and Longevity Pathways:

• TETRAHYDROCURCUMIN - A metabolite of curcumin, tetrahydrocurcumin has unque anti-aging properties including the activation of FOXO. In aging studies using Drosophila melanogaster , tetrahydrocurcumin extended the lifespan, by the involvement of both longevity factors FOXO and Sir2.
• CURCUMIN -  Increases lifespan in laboratory animals by affecting age-related genes. Enhances gene expression of endogenous antioxidant system, increasing superoxide dismutase (SOD) and reducing lipid peroxidation.

YELLOW LONGEVITY

YELLOW NATURALLY

REFERENCES:

(1) Pallauf K, et al. Flavonoids as Putative Inducers of the Transcription Factors Nrf2, FoxO, and PPARγ. Oxid Med Cell Longev. 2017

(2)  Paredes-Gonzales X, et al. Induction of NRF2-mediated gene expression by dietary phytochemical flavones apigenin and luteolin. Biopharm Drug Dispos.  2015 Oct

(3) Zhang L, et al. Significant longevity-extending effects of EGCG on Caenorhabditis elegans under stress Free Radic Biol Med. February 2009

(4)  Wai-Jiao Cai, et al. Icariin and its Derivative Icariside II Extend Healthspan via Insulin/IGF-1 Pathway in C. elegans. PLoS One, 2011

(5) Zhang SQ, et al. Icariin, a natural flavonol glycoside, extends healthspan in mice. Exp Gerontol. 2015 Sep;

 (6) Jung HY, et al. Myricetin improves endurance capacity and mitochondrial density by activating SIRT1 and PGC-1α. Sci Rep. 2017 Jul 24

(7) Tang BL. Sirt1 and the Mitochondria. Mol Cells. 2016 Feb

(8) Xiang L, et al. Tetrahydrocurcumin extends life span and inhibits the oxidative stress response by regulating the FOXO forkhead transcription factor. Aging (Albany NY) 2011 Nov

(9) Shen LR, et al. Curcumin-supplemented diets increase superoxide dismutase activity and mean lifespan in Drosophila. Age (Dordr) 2013 Aug;

Herbal Extracts - Neurogenesis & Recovery of Cognition Impairments

Aging of the brain involves the loss of neurons (hippocapmus shrinkage), loss of synapse integrity between neurons, build-up of toxic amyloid proteins, neuron tangles, defects in blood flow  and chronic inflammation. Under normal age progression, these events do not happen over night and may take years before impairments in cognition become noticed.

Ultimate anti-aging strategies for the brain and memory should target the progressive decline of the brain and promote reversal and recovery of some cognition impairments.

Emerging research in the study of herbal ingredients show their tremendous potential use in mitigating the decline in brain function with age.

• NEUROGENESIS - is the formation of new neurons, specifically in the hippocampus area in the brain.The hippocampus is essential in providing the capacity for memory and learning. Dementia and Alzheimer's disease are associated with brain shrinkage which is correlated to the loss of neurons in the hippocampus. The formation of new neurons may reverse brain shrinkage.

                    Herbs and Extracts

•  Andrographolide - As an extract from Andrographis Paniculata. Lab research has shown stimulation of neurogenesis in the hippocampus by andorgrapholide. Specifically " increased cell proliferation and the density of immature neurons in the dentate gyrus." (1) The dentate gyrus is an area of the hippocampus involved in memory formation.
• Centella asiatica - Acts as a potent memory enhancer, via  increasing hippocampus neurogenesis and support for brain tissue regeneration. (2)
• Baicalin (3)
• Panax Ginseng (4)
  
• Curcumin (5)
• Epimedium (Icariin)  (6)
• Apigenin (7)
  

• BRAIN TISSUE REGENERATION. While in the same theme as neurogenesis, brain tissue regeneration refers to the enhancement and regeneration of critical neuron structures - axons and dendrites. Dendrites transmit signals from the synapse to the body of the neuron. Axons transmit signals away from the body of the neuron and are covered with a myelin sheath which increase speed of the impulse providing rapid impulse transmission. Aging degenerates the structural integrity of dendrites and axon/myelin complex.
  

                     Herbs and Extracts

•  Centella asiatica - Improves structural integrity of axons / myelination and proliferation of dendritic branching and length. Such improvements have been shown to enhance learning and improve memory. (8) Centella asiatica also has been shown to improve learning and memory in normal lab mice.
• Luteolin - Baicalin - promote neuronal survival and neuron differentiation through the outgrowth of neurites  (axons and dendrites) from the neuron.(9.10)
• Rosemary (Carnosic Acid) - Strongly promotes neurite outgrowth as a function of powerful Nrf2 activity. Suppressed Nrf2 activation suppresses neuron differentiation.(11)

• RECOVERY OF COGNITIVE IMPAIRMENT - the  to reversal of certain functional impairments which may improve cognitive function. Many research animal models for cognitive impairment are characteristically similar to Alzheimer's disease (AD). Impairment usually involves cerebral vascular disease, synaptic dysfunction. and more.

          Herbs and Extracts

• Andrographolide - Impairment of synaptic function between neurons plays a significant role in the loss of cognitive function. This is seen in the progression of AD. In research animals with AD-like cognitive disease, the treatment of andrographolide over a 3 month span imporved synaptic function and protected important synaptic proteins.
• Furthermore, andrographolide has been shown to reduce inflammation in the brain and levels of pathological tau protein and beta amyloid in animal models.(12)
• Andrographolide reduces inflammation and dysfunction of the cerebral endothelial cells, which may affect vascular flow to the brain.(13)
• Centella asiactica - in senescence-accelerated lab mice, which had accelerated aging of the brain, administration of centella asiatica significantly improved synaptic plasticity and reduced beta amyloid build-up. Such treated mice showed significant benefits in memory and learning. (14)

• NEUROPROTECTION - AMYLOID & NON-AMYLOID (α-synuclein) TOXICITY | CHRONIC INFLAMMATION - The aging brain is under continual assault and must be protected to prevent cognitive decline and loss of neurons. Key areas of protection include the build-up of amyoid plaques which are toxic to neurons and synapses. Moreover, chronic inflammation in the brain accelerates destruction of the brain and is believed to be the facilitator of degenerative brain diseases.
• Centella asiatica (15)
  
• Epimedium (Icariin)(16,17)
• Apigenin and luteolin (18,19)
  
• Baicalin (20)
  
• Schisandra (21)
• Rosemary (Carnosic Acid)(22)

• REVERSES INSULIN RESISTANCE IN BRAIN NEURONS - Aging brains become increasingly incapable of using glucose as an energy source. Without this energy neurons age faster and die. Reversing the insulin resistance maintains healthy neurons. Brain insulin resistance is associated with Alzheimer's Disease.
• Further reduction in glucose availability is caused by methylglyoxal - a powerful intermediate in the formation of Advanced Glycation End Products (AGEs).
• Curcumin - Improves insulin sensitivity in neurons. (23)
• Sulforaphane - Reverses reduction of glucose uptake by neurons caused by methylglyoxal (a precusor of advanced glycation end products). Sulforaphane also normalizes brain-derived neurotrophic factor (BDNF) signaling, which is critical for maintaining brain function. BDNF pathways are disrupted in Alzheimer's Disease. (24)

YELLOW LONGEVITY

YELLOW NATURALLY

MEMORY ACTION

XGEVITY

LONGEVITY NATURALLY

REFERENCES:

NEUROGENESIS

(1)   Varela-Nallar L, et al. Andrographolide Stimulates Neurogenesis in the Adult Hippocampus. Neural Plast, 2015.

(2)  Sirichoat A, et al. Effects of Asiatic Acid on Spatial Working Memory and Cell Proliferation in the Adult Rat Hippocampus. Nutrients. 2015 Oct 5

(3) Zhang K, et al. Baicalin promotes hippocampal neurogenesis via SGK1- and FKBP5-mediated glucocorticoid receptor phosphorylation in a neuroendocrine mouse model of anxiety/depression. Sci Rep. 2016 Aug 9

(4) Jiang B, et al.  Antidepressant-like effects of ginsenoside Rg1 are due to activation of the BDNF signalling pathway and neurogenesis in the hippocampus. Br J Pharmacol. 2012 Jul;

 (5) Pluta R, et al. Neurogenesis and neuroprotection in postischemic brain neurodegeneration with Alzheimer phenotype: is there a role for curcumin? Folia Neuropathol. 2015

(6) Li F, et al. Icariin decreases both APP and Aβ levels and increases neurogenesis in the brain of Tg2576 mice. Neuroscience. 2015 Sep 24

(7) Taupin P. Apigenin and related compounds stimulate adult neurogenesis. Mars, Inc., the Salk Institute for Biological Studies: WO2008147483. Expert Opin Ther Pat. 2009 Apr

BRAIN TISSUE REGENERATION

(8) Yogeswarin L, et al. Recent Updates in Neuroprotective and Neuroregenerative Potential of Centella asiatica. Malays J Med Sci 2016 Jan.

(9) Chen PY, et al. Up-Regulation of miR-34a Expression in Response to the Luteolin-Induced Neurite Outgrowth of PC12 Cells. J Agric Food Chem. 2015 Apr

(10) Li M, et al. Neuronal differentiation of C17.2 neural stem cells induced by a natural flavonoid, baicalin. Chembiochem. 2011 Feb 11;

(11) Kosaka K, et al. Role of Nrf2 and p62/ZIP in the neurite outgrowth by carnosic acid in PC12h cells. J Biochem. 2010 Jan;

RECOVERING COGNITIVE DYSFUNCTION

(12) Rivera DS, et al. Andrographolide recovers cognitive impairment in a natural model of Alzheimer's disease (Octodon degus). Neurobiol Aging. 2016 Jul 5

(13) Chang CC, et al. Andrographolide, a Novel NF-κB Inhibitor, Inhibits Vascular Smooth Muscle Cell Proliferation and Cerebral Endothelial Cell Inflammation. Acta Cardiol Sin. 2014 Jul;

(14) Xing L, et al. Beneficial effects of asiaticoside on cognitive deficits in senescence-accelerated mice. Fitoterapia. 2013 Jun.

NEUROPROTECTION - AMYLOID TOXICITY AND INFLAMMATION

(15) Gray NE, et al. Centella asiatica Attenuates Amyloid-β-Induced Oxidative Stress and Mitochondrial Dysfunction. J Alzheimers Dis. 2015

(16) Zhang L, et al. Icariin reduces α-synuclein over-expression by promoting α-synuclein degradation. Age (Dondr.) 2015 Aug

(17) Chen YJ, et al. Neuroprotective Effects of Icariin on Brain Metabolism, Mitochondrial Functions, and Cognition in Triple-Transgenic Alzheimer's Disease Mice. CNS Neurosci Ther, 2016 Jan

(18) Dirscherl K, et al. Luteolin triggers global changes in the microglial transcriptome leading to a unique anti-inflammatory and neuroprotective phenotype. J Neuroinflammation 2010 Jan

(19) Rezai-Zedeh K, et al. Apigenin and luteolin modulate microglial activation via inhibition of STAT1-induced CD40 expression. J Neuroinflammation. 2008 Sep

(20) Chen C, et al. Baicalin attenuates alzheimer-like pathological changes and memory deficits induced by amyloid β1-42 protein.  Metab Brain Dis. 2015 Apr

(21) Song F, et al. Schizandrin A Inhibits Microglia-Mediated Neuroninflammation through Inhibiting TRAF6-NF-κB and Jak2-Stat3 Signaling Pathways. PLoS One. 2016 Feb 26;

(22) Habtemariam S. The Therapeutic Potential of Rosemary (Rosmarinus officinalis) Diterpenes for Alzheimer's Disease. Evid Based Complement Alternat Med, 2016

REVERSES BRAIN INSULIN RESISTANCE IN BRAIN NEURONS

(23) Feng HL, et al. Curcumin ameliorates insulin signalling pathway in brain of Alzheimer's disease transgenic mice. Int J Immunopathol. 2016 Jul 27

(24) Angeloni C, et al. Neuroprotective effect of sulforaphane against methylglyoxal cytotoxicity. Chem Res Toxicol, 2015 Jun 15

Brown Adipose Tissue - Support for Obesity Diabetes and Longevity

 In humans, there are two types of adipose tissue. White adipose tissue and brown adipose tissue. White adipose tissue is associated with excessive fat storage, obesity, insulin resistance and diabetes. Whereas, brown adipose tissue has the opposite effect - producing energy, reducing fat storage and obesity, while increasing insulin sensitivity and reducing diabetes. Further, increasing expression of brown adipose tissue (adipocytes) may also be correlated with increases in longevity.

Newborns have the greatest amount of brown fat, which helps provide a source of heat, but gradually decreases with age. Adults have a predominance of white adipose tissue which correlate with America's obesity epidemic.

ADIPOCYTES COMPARISON

• White Adipocytes. Store fat (triglycerides) and is linked to obesity and associated metabolic disorders such as diabetes.
• Brown and Beige Adipocytes. Energy and thermogenic producing cells. Activation of these cells offer a possible course of treatment for obesity and diabetes.(1)

BROWN ADIPOSE TISSUE

• Health benefits. Studies altering white adipocytes, into adipocytes with brown adipose tissue characteristics show dramatic changes. Includes improvement in increased energy expenditure, improved insulin sensitivity, and protection against diet-induced obesity and diabetes. (2)

• Longevity and UPC1. Aging studies involving animals, showed that increased expression of brown fat increases levels of UCP1 (uncoupling protein 1). UCP1 is contained in the membranes of mitochondria only in brown fat. When UCP1 is activated is provides an enormous source of heat energy.  Increased energy expenditure is recognized as a positive association with longevity.(3) Also UCP1 provides an alternative. less damaging path, for energy generation by the mitochondria. (see below). UCP1 protects the mitochondria from damaging oxidative stress and over a lifetime can have significant effect on lifespan.

• Mitochondrial Uncoupling -Mitochondrial respiration, the process through which mitochondria produces energy,  also results in damaging end-products which promote cellular damage and death via free radicals - reactive oxygen species (ROS). The free radical theory of aging proposes that the free radicals produced by energy metabolism is linked to the aging process. Mitochondrial uncoupling describes anything which bypasses the normal electron chain which generates ATP energy and high levels of free radicals. Brown adipose tissue produces UCP1 - an important biological protein which enables mitochondrial uncoupling and reduction in damaging ROS generation.(3)
  

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NUTRITION SUPPLEMENT SUPPORT:

Research indicates that fat storing white adipocytes may be altered to take on the characteristics of energy producing brown adipocytes. Such changes to white adipocytes may be an effective strategy for reducing obesity and obesity related disorders (such as insulin resistance and diabetes). Improving insulin sensitivity is a factor not only in diabetes, but also considered significant in longevity.

• Sulforaphane - In vitro experiments showed an increase in UCP1 expression (the marker for brown adipose tissue activity), in addition to increasing glucose uptake. (4)
• Curcumin - Curucmin induces browning of white adipocytes as well as inhibition of new fat cell generation. (5)
• Andrographolide - Enhances brown adipose tissue gene activation attenuating obesity. Improves insulin sensitivity.(6)

Improvement in number and function of mitochondria during brown fat adipogenesis. This may result in higher energy brown adipose tissue enabling even a stronger thermogenic response

• Anthocyanins (C3G) - Anthocyanins, and in particular the anthocyanin C3G, has been shown to have beneficial effects towards obesity via brown adipose tissue. The effect is believed to be enhanced through increased mitochondria biogenesis during the formation of brown adipose tissue. (7)

XGEVITY   Glucoraphanin (precursor of Sulforaphane)

CURCUMIN XTRA-MAX  (includes Andrographolide)

BLUE NATURALLY   (high anthocyanins and C3G)

REFERENCES:

(1) Inagaki T, et al. Transcriptional and epigenetic control of brown and beige adipose cell fate and function. Nat Rev Mol Cell Biol. 2016 Jun 2

(2) Qian SW, et al. BMP4-mediated brown fat-like changes in white adipose tissue alter glucose and energy homeostasis. Proc Natl Acad Sci USA. 2013 Feb

(3) Mookerjee SA, et al. Mitochondrial Uncoupling and Lifespan. Mech Ageing Dev. 2010 Jul - Aug.

(4) Zhang HQ, et al. Sulforaphane induces adipocyte browning and promotes glucose and lipid utilization. Mol Nutr Food Res. 2016 May 24

(5) Lone J, et al. Curcumin induces brown fat-like phenotype in 3T3-L1 and primary white adipocytes. J Nutr Biochem. 2016 Jan

(6) Ding L, et al. Andrographolide prevents high-fat diet-induced obesity in C57BL/6 mice by suppressing the sterol regulatory element-binding protein pathway. J Pharmacol Exp Ther. 2014 Nov

(7) You Y, et al. Mulberry and mulberry wine extract increase the number of mitochondria during brown adipogenesis. Food Funct. 2015 Feb

Natural Support for Inflammatory Skin Diseases - Psoriasis and Eczema

INFLAMMATION OF THE SKIN Common forms of inflammatory skin diseases include psoriasis and eczema. Primary common features of these diseases include chronic inflammation, including break down of the skin barrier, dryness and redness and itchiness. Hyper proliferation of skin cells, adding a thickness to the affected areas, is also common, and caused by inflammatory factors.

Psoriasis and eczema are both immune initiated diseases involving lymphocytes (T-Cells: TH1. TH2 and TH17), which cause the secretion of pro-inflammatory factors (called cytokines). The T-cells migrate into the skin where they chronically secret inflammatory factors which inflame the skin. Among the methods to reduce skin inflammation is to decrease the proliferation of T-cells in the skin and to prevent the secretion of pro-inflammatory cytokines.  While both psoriasis and eczema are immune T-cell based diseases, the causative basis of the immune response are not the same, and therefore the effects and targets are different.(1)

• PSORIASIS. An autoimmune disease, which is associated with activation of the TH1 and TH17 lymphocytes. The presence of TH1/TH17 occur is high amounts in autoimmune diseases. Inflammatory skin diseases are characterized by dry, itchy and red skin are caused by an abnormal inflammation response in the body.  Psoriasis is a common form of inflammatory skin disease and is symptomatic of an autoimmune disease and may further indicate the presence of other autoimmune conditions such as rheumatoid arthritis.
• ECZEMA. An allergic response of lymphocytes in the skin. In contrast with psoriasis, eczema is characterized by activation of TH2 lymphocytes. Also inflammatory cytokines IL-4, IL-6 and IL-13 are increased in eczema (atopic dermatitis).
  

• Inflammatory Factors. While there are a number of inflammatory cytokines involved in the inflammation of the skin, a particular key one is TNF-α (TNF-alpha). Studies show high levels of TNF-alpha in the inflamed skin. Not only is TNF-alpha derived from the immune cells, but also has a feedback mechanism which further strengthens the pathological response of the activated T-cells (especially increasing differentiation of TH17). (2)

INGREDIENT SUPPORT:

• Curcumin - Significantly inhibted T-cell secretion of pro-inflammatory factors, including TNF-alpha, by 30-60%. Furthermore, inhibited 50% T-cell proliferation.(3) Oral treatment with curcumin significantly reduced a key psoriasis inflammation factor IL-22. Keratinocyte (skin cell) proliferation in psoriasis is due to IL-22. (4,5) No side effects reported from curcumin (3). Also shown to suppress TH1 induce inflammation in skin cells.(6)
• Andrographolide Supports homeostasis of TH1 / TH2 /TH17 (11). Also effective against rheumatoid arthritis (an autommune disease by suppressing TH17)(8, 9)
• Schisandra Supports suppression of Th2 invoking an anti-allergic effect.(10) Further, schisandra effectively reduced inflammatory Th2 inflammatory cytokines IL-4 and IL-13 as well as TNF-alpha and IL-6 in research studies on inflammatory skin disease.(11). In particular IL-4 and IL-13 are the focus of new drug development for atopic dermatitis.(12)
  
• Anthocyanins with C3G (Blueberry, other dark berries) 
  Suppresses levels of TH2 cytokines and TH17.(13-15)

NOTE: In contrast to natural ingredients, standard immunosuppressive drugs (which reduce the immune response, and are marketed for psoriasis) may have side effects, including kidney fibrosis.(16)

CURCUMIN XTRA-MAX (BCM-95 Curcumin, Andrographolide, Schisandra)

BLUE NATURALLY (C3G and other anthocyanins)

REFERENCES:

(1) Coimbra S, et al. A specific molecular signature for psoriasis and eczema. Annals of Translational Medicine. 2015 Apr.

(2) Ke F, et al. Soluble Tumor Necrosis Factor Receptor 1 Released by Skin-Derived Mesenchymal Stem Cells Is Critical for Inhibiting Th17 Cell Differentiation. Stem Cells Transl Med. 2016 Jan 27

(3) Kang D, et al. Curcumin shows excellent therapeutic effect on psoriasis in mouse model. Biochimie. 2016 January 27.

(4) Zhao Y, et al. Curcumin inhibits proliferation of interleukin-22-treated HaCaT cells. Int J Clin Exp Med. 2015 Jun 

(5) Antiga E, et al. Oral Curcumin (Meriva) Is Effective as an Adjuvant Treatment and Is Able to Reduce IL-22 Serum Levels in Patients with Psoriasis Vulgaris. Biomed Res Int. 2015.

(6) Sun J, et al. Curcumin relieves TPA-induced Th1 inflammation in K14-VEGF transgenic mice. Int. Immunopharmacol. 2015 Apr.

(7) Zhang C, et al. Preventive effects of andrographolide on the development of diabetes in autoimmune diabetic NOD mice by inducing immune tolerance. Int. Immunopharmacol. 2013 Aug.

(8) Liu W, et al. Andrographolide sulfonate ameliorates experimental colitis in mice by inhibiting Th1/Th17 response. Int Immunopharmacol. 2014 Jun

(9) Ku CM, et al. Anti-inflammatory effects of 27 selected terpenoid compounds tested through modulating Th1/Th2 cytokine secretion profiles using murine primary splenocytes. Food Chem. 2013 Nov 15

(10) Lee KP. et al. Anti-allergic effect of α-cubebenoate isolated from Schisandra chinensis using in vivo and in vitro experiments. J Ethnopharmacol. 2015 Sep

(11) Lee HJ, et al. Effects of Schisandra chinensis Turcz. fruit on contact dermatitis induced by dinitrofluorobenzene in mice. Mol Med Rep. 2015 Aug

(12) Lauffer F, et al. Target-oriented therapy: Emerging drugs for atopic dermatitis. Expert Opin Emerg. Drugs. 2016 Jan 25.

(13) Pyo MY, et al. Cyanidin-3-glucoside suppresses Th2 cytokines and GATA-3 transcription factor in EL-4 T cells. Biosci Biotechnol Biochem 2014

(14) Kim MJ, et al. Mixture of Polyphenols and Anthocyanins from Vaccinium uliginosum L. Alleviates DNCB-Induced Atopic Dermatitis in NC/Nga Mice. Evid. Based Complement Alternat. Med. 2012.

(15) Min HK, et al. Anthocyanin Extracted from Black Soybean Seed Coats Prevents Autoimmune Arthritis by Suppressing the Development of Th17 Cells and Synthesis of Proinflammatory Cytokines by Such Cells, via Inhibition of NF-κB. PLoS One. 2015 Nov 6

(16)  Kedzierska K, et al. The effect of immunosuppressive therapy on renal cell apoptosis in native rat kidneys. Histol Histopathol. 2015 Jan.