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.

Carnosic Acid - Protects Retina and Supports Healthy Cartilage

Carnosic acid, an extract from the herb Rosemary, is a powerful activator of cellular endogenous antioxidants, through involvement in increasing Nrf2 transcription.  Since carnosic acid crosses the blood-brain barrier, there is significant provisioning of protection of the brain and neural tissue.(1) In addition, the retina is primarily neural tissue, which benefits greatly from carnosic acid.

          RETINA - MITIGATING AGING EYE DETERIORATION

• Reduces Light Induced Damage - Continued light exposure created free  radicals in the retina, which are destructive to the photoreceptors. (1,2)
• Age-Related Macular degeneration (AMD) - Photoreceptors are also loss in AMD. Studies involving lab animals suggest that the addition of carnosic acid (rosemary extract) to other vision supplements, i.e. AREDS, may maximize effectiveness in reducing retinal damage. (3)
• Slows Photoreceptor Degeneration. In mouse models of retinitis pigmentosa, carnosic acid has been shown to slow the loss of photoreceptors.(4)
• Reduces Acyrlamide Toxicity - A toxic compound resulting from the heating of carbohydrates, and occurs in many everyday foods, including potato chips, and other heated foods.Acrylamide crosses the blood-brain barrier and is destructive to the  retina. (5,6)

           CARTILAGE - BENEFICIAL EFFECTS FOR OSTEOARTHRITIS

• Activates Heme-Oxygenase-1  (HO--1). HO-1 promotes reduction of inflammation in the cartilage, which is characteristic of cartilage degeneration.  As such, carnosic acid promotes preservation of cartilage and inhibition of the degenerative process. Researchers concluded that carnosic acid both prevents cartilage degeneration and the severity of osteoarthritis, as evidenced by animal models.(7)
• Chondrocytes, the cartilage producing cells, are negatively impacted by inflammation, and carnosic acid, improves the function and longevity of the chondrocytes. (8)
• Improves  Chondrocyte Gene Expression. Helps maintain the ability of the chondrocyte to produce cartilage.(8). 

 

 VISION VITALITY™    (with CARNOSIC ACID)

 

 

 

REFERENCES:

(1) 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

(2) Contin MA, et al. Light pollution: the possible consequences of excessive illumination on retina. Eye (Lond). 2016 Feb

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

(4) Kang K, et al. Carnosic acid slows photoreceptor degeneration in the Pde6b(rd10) mouse model of retinitis pigmentosa. Sci Rep. 2016 Mar

(5) Albalawi A, et al. Protective effect of carnosic acid against acrylamide-induced toxicity in RPE cells. Food Chem Toxicol. 2017 Oct

(6) Albalawi A, et al. Carnosic acid attenuates acrylamide-induced retinal toxicity in zebrafish embryos. Exp Eye Res. 2018 Oct;

 (6) Ishitobi H, et al. Carnosic acid attenuates cartilage degeneration through induction of heme oxygenase-1 in human articular chondrocytes.

(7) Ravaili S, et al. Recently highlighted nutraceuticals for preventive management of osteoarthritis. World J Orthop. 2018 Nov

(8) Schwager J, et al.  Carnosol and Related Substances Modulate Chemokine and Cytokine Production in Macrophages and Chondrocytes. Molecules. 2016 Apr

 

NEUROTREX™ - DIetary Supplement for Longterm Brain Support

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The Intestine - Axis of Longevity

Aging and health of the intestine appears to be a significant determinant in the lifespan of an organism.  Studies on research animals show that  aging intestine effects on longevity is focused not only in the gut structure and function, but has a systemic effect, modulating aging throughout the body. Aging of the intestine directing correlates to aging of the body. Conclusions reached by researchers is that the intestine is an important target for extreme longevity. (1)

 

Healthy Intestine Equates to Longevity.

• Homeostasis. Maintaining functional and healthy intestinal homeostasis is directly correlated with increased lifespan. Loss of homeostasis is due to Inflammation of the intestine, poor stem cell maintenance of epithelial intestinal lining and dysfunction of the intestinal barrier. Homeostasis depends on the constant turnover and regeneration of  healthy new intestinal epithelial cells.  This is the function of intestinal stem cells.(2)
• Genetic Stability. Genetic mutations accumulate in adult stem cells during the lifespan of an organism. Mutations in the intestine epithelial cells lead to aging of intestine tissue, dysfunction of stem cells and ltumorgenesis. (3)
• Longevity Signaling.  Expression of Foxo / daf-16 longevity factors in the intestines increases longevity factors throughout the body. By invoking the neuro-endorcrine system, the intestine affects systemic body aging. Furthermore, when brain sensors are activated (for example cold temperatures), this is also relayed to the intestine which triggers longevity factors through neuro-endocrine signaling. In lab animals, activation of the daf-16 longevity factor in the intestine increased lifespan of the organism by 50-60% ! (4,5)

 

Anti-Aging Support for Intestine

• Fucoidan - An extract from seaweed, fucoidan is the constituent known as the "Japanese Longevity Secret".
• Strengthens Intestine Barrier. Tight junctures in the intestine epithelial layer provides protection against toxins and other substances,  while reducing risk of inflammatory bowl disease.(6)
• SIRT6.  Protector of the Intestine. Fucoidan is an activator of SIRT6, an anti-aging sirtuin. SIRT6 promotes stem cell maintenance. and importantly protects the intestine epithelial cells against injury.(7)
• SIRT6 suppresses colon cancer proliferation. In contrast, when SIRT6 is depressed, colon cancer cells proliferate.(8, 9)
• Ursolic Acid | Rosmarinic Acid.  As powerful anti-inflammtory and antioxidant compounds, ursolic and rosmarinic acids offer powerful intestine protection. In animal experimentally induced ulcerative colitis, administration of ursolic acid significantly mitigated the inflammation and tissue destruction. (10) Furthermore, replicated in several animal studies, rosmarinic acid was determined to be a potent inhibitor of colon carcinogensis.(11, 12)
• Nrf2 Activation. Inhibits intestinal fibrosis. Intestinal fibrosis. which results in a loss of intestinal tissue,  is frequent complication of inflammatory bowl disease. (13).  Both ursolic acid and rosmarinic acid are Nrf2 activators.
• Nrf2 Supports Intestinal Stem Cell proliferation. In high turnover tissue (e.g. intestine) stem cell regulation is critical for homeostasis. Nrf2 regulates the redox balance in stem cells. Deficient Nrf2 levels  in the stem cells, accelerates aging of the intestinal epithelium . (14)
• Jujube - Enhances the intestinal barrier, and was shown to mitigate experimentally induced inflammatory bowl disease in lab animals.(15) Further, in research with mice,  indicates that daily administration of jujube to  ameliorate the formation of Aberrant Crypt Formation which is a precursor to colon cancer.(16) 
• Icariin - Promotes genetic stability, thereby reducing cellular DNA damage. (17) Stem cells which accumulate DNA mutations age the cell, and may promote  tumor formation.
  
• Fatty Acid Oxidation - Intestinal Regeneration - Enhancement of intestinal stem cell function, and intestine regeneration, may also be achieved by intermittent (short-term) fasting.  Short-term fasting activates fatty acid oxidation, which promotes stem cell function.(18)

 

HYPER LONGEVITY (Fucoidan, Ursolic | Rosmarinic, Jujube., Icariin)

 

REFERENCES:

(1) Reara M, et al. Organ-specific mediation of lifespan extension: more than a gut feeling?  Ageing Res Rev. 2013 Jan

(2) Santos AJM, et al. The Intestinal Stem Cell Niche: Homeostasis and Adaptations. Trends Cell Biol. 2018 Sep

(3) Blokzij G, et al.Tissue-specific mutation accumulation in human adult stem cells during life. Nature 2016.

(4) Fan X, et al. Intestinal Homeostasis and Longevity: Drosophila Gut Feeling. Adv Exp Med Biol. 2018

(5) Zhang Bi, et al. Brain–gut communications via distinct neuroendocrine signals bidirectionally regulate longevity in C. elegans. Genes Dev. 2018.

(6) Iraha Am et al. Fucoidan enhances intestinal barrier function by upregulating the expression of claudin-1. World J Hastroenterol. 2013 Sep.

(7) Liu F, et al, Sirtuin-6 Preserves R-spondin-1 Expression and Increases Resistance of Intestinal Epithelium to Injury in Mice. Mol Med. 2017.

(8) Tian J, et al. Sirtuin 6 inhibits colon cancer progression by modulating PTEN/AKT signaling.  Biomed Pharmacother. 2018 Oct

(9) Li N, et al. Downregulation of SIRT6 by miR-34c-5p is associated with poor prognosis and promotes colon cancer proliferation through inhibiting apoptosis via the JAK2/STAT3 signaling pathway.

(10) Liu B, et al. Ursolic acid protects against ulcerative colitis via anti-inflammatory and antioxidant effects in mice. Mol Med Rep. 2016 Jun

(11) Venkatachajam K, et al. Biochemical and molecular mechanisms underlying the chemopreventive efficacy of rosmarinic acid in a rat colon cancer. Eur J Pharmocol 2016 Nov 

(12) Furtado RA, et al. Chemopreventive effects of rosmarinic acid on rat colon carcinogenesis.  Eur J Cancer Prev. 2015 Mar

(13) Latella G. Redox Imbalance in Intestinal Fibrosis: Beware of the TGFβ-1, ROS, and Nrf2 Connection. Dig Dis Sci. 2018 Feb;

(14) Hotchmuth CE, et al. Redox regulation by Keap1 and Nrf2 controls intestinal stem cell proliferation in Drosophila. Cell Stem Cell. 2011 Feb

(15) Yue Y, et al. Wild jujube polysaccharides protect against experimental inflammatory bowel disease by enabling enhanced intestinal barrier function. Food Funct. 2015 Aug

(16) Periasamy S, et al. Dietary Ziziphus jujuba Fruit Influence on Aberrant Crypt Formation and Blood Cells in Colitis-Associated Colorectal Cancer in Mice. Asian Pac J Cancer Prev. 2015;

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

(18) Mihaylova MM, et al. Fasting Activates Fatty Acid Oxidation to Enhance Intestinal Stem Cell Function during Homeostasis and Aging. Cell Stem Cell.  2018 May

 

Two times Power of Anti-Aging Resveratrol - Ursolic Acid and Rosmarinic Acid

Resveratrol has long been known as an natural anti-aging gene activator. The target of this activation is SIRT1. Research now indicates that another extract  (ursolic acid) is even more powerful than resveratrol in the activation SIRT1. Furthermore, the extracts ursolic acid and rosmarinic acid promote anti-aging in other ways,, including preservation of the functioning of the hypothalamus (implicated as playing a significant role in the aging process), inhibiting fibrosis (amyloid and tau) and inhibiting NOX2 and NOX4.

URSOLIC ACID

• SIRT1 Activator - Ursolic acid is a powerful activator of anti-aging protein SIRT1. In fact, when compared to resveratol, ursolic acid is double the power of activating SIRT1 versus resveratol.(1)

• Hypothalamus Anti-Aging - Recent research indicates that the hypothalamus is an important determinant in longevity, Dysregulation of the hypothalamus during aging affects the neuroendocrine system, and contributes to the exhaustion of stem cells, and the loss of proteostasis.(2) Ursolic acid beneficially supports health of the hypothalamus by enhancing levels of anti-aging SIRT1, SIRT6, PGC-1β and α-Klotho.(3)

• Nrf2 Preservation - Nrf2 is the master protein activator of the endogenous antioxidant system in the body, and is related to increased longevity. Ursolic acid is a potent inhibitor of the degradation of Nrf2, which supports increased level of Nrf2. (4)

ROSMARINIC ACID

• Longevity Extender -  In experimental studies with c. elegans, rosmarinic acid significantly extended lifespan by increasing anti-aging gene expression of daf-16 and other proteins.(5) 

• NOX2 and NOX4 (NADPH oxidases) Inhibitor - NOX2 and NOX4 play critical roles in aging.
• NOX2 - involved in hypertension, atherosclerosis, cardiac hypertrophy, diabetes and aging. The inhibition of NOX-2 is proposed for maintaining cardiovascular homeostasis.(6)
• NOX4 - involved in cellular senescence. The inhibition of NOX-4 may support anti-aging in body, which is expressed in many organs in the body.(7)
• Both NOXs are viewed as potential therapeutic targets to block.
• Rosmarinic acid inhibits both NOX2 and NOX4.(7)

• Amyoid Aggregation Inhibitor  -  An important hallmark of aging, both in the brain (Alzheimers Disease) and throughout the body, is the formation of amyloid fibril aggregates.
• While resveratrol has been shown to be inactive in the inhibition of aggregate formation,  rosmarinic acid, is shown as a powerful inhibitor.(8)
• Tau Aggregation Inhibitor - Insoluble tau protein is another protein abnormality (in conjunction with amyloid) associated with Alzheimer's Disease in the brain. Aging and chronic stress may induce tau aggregation. In lab animals, rosmarinic acid was shown to reduce tau protein aggregation. (9)

• Glycation Inhibitor - Supports Elastic Arteries and Skin. Glycation is the damaging of protein structure, accelerating aging of all protein structures in the body. Includes loss of elasticity of skin and arterial function.
• Glycation results in stiffness of the skin (and old appearance) and arteries. All indicators of significant aging. Rosmarinic acid was shown to improve the parameters of skin and arterial elasticity in human test subjects.(10)

• Insulin Resistance - AMPK. Rosmarinic acid significantly reduced skeletal muscle insulin resistance in insulin resistant lab animals. Rosmarinic acid activated AMPK in the muscle, which resulted in increased mitochondrial biogenesis,(11)

 

HYPER LONGEVITY  (Ursolic Acid | Rosmarinic Acid)

 

REFERENCES:

(1) Bakhtian N, et al. Mounting evidence validates Ursolic Acid directly activates SIRT1: A powerful STAC which mimic endogenous activator of SIRT1. Arch Biochem Biophys. 2018 Jul

(2) Kim K, et al. Role of hypothalamus in aging and its underlying cellular mechanisms. Mech. Ageing Dev. 2018. May.

(3) Bahrami SA, et al Ursolic acid regulates aging process through enhancing of metabolic sensor proteins level. Biomed Pharmacother, 2016 Aug

(4) Kamble SM, et al. In silico Evidence for Binding of Pentacyclic Triterpenoids to Keap1-Nrf2 Protein-Protein Binding Site. Comb Chem High Throughput Screen. 2017

(5) Wang F, et al. The Molecular Mechanism of Rosmarinic Acid Extending the Lifespan of Caenorhabditis elegans. Applied Mechanics and Materilals. 2011.

(6) Forte M, et al. The Pathophysiological Role of NOX2 in Hypertension and Organ Damage. High Blood Press. Cardiovasc Prev. 2016 Dec

(7) Revoltella S, et al. Identification of the NADPH Oxidase 4 Inhibiting Principle of Lycopus europaeus. Molecules. 2018 Mar.

(8) Ramazzotti M, et al, Mechanism for the inhibition of amyloid aggregation by small ligands.Biosci Rep. 2016 Sept.

(9) Shan Y, et al. Aging as a Precipitating Factor in Chronic Restraint Stress-Induced Tau Aggregation Pathology, and the Protective Effects of Rosmarinic Acid.  J Alzheimers Dis. 2016

(10) Yui S, et al. Beneficial Effects of Lemon Balm Leaf Extract on In Vitro Glycation of Proteins, Arterial Stiffness, and Skin Elasticity in Healthy Adults. J Nutr Sci Vitaminol (Tokyo) 2017

(11) Jayanthy G, et al, Rosmarinic Acid Mediates Mitochondrial Biogenesis in Insulin Resistant Skeletal Muscle Through Activation of AMPK. J Cell Biochem. 2017 Jul

Fucoidan - Brown Seaweed Extract to Reverse Aging

Exceptional longevity in the population of Okinawa Japan is believed to be dietary, and most significantly due to their high consumption of brown seaweed. The anti-aging component in seaweed has been identified as fucoidan. Fucoidan is a sulfated molecule which has been studied extensively for health and anti-aging benefits.

• Stem Cell Mobilization -
  Fucoidan supports mobilization of stem cells from bone marrow into blood stream, via increased expression of CXCR4, and may enhance healing throughout body, including vascular and heart.(1)
• SIRT6 Activation - SIRT6 is a longevity promoting sirtuin protein, similar to the better known SIRT1. Fucoidan is an SIRT6 activator.(2) Among the anti-aging benefits, SIRT6 is a key regular of genome and telomere stability, DNA repair, controlling NF-Kappa (inflammation pathway)(3) and supports maintenance of beta cells in the pancreas in type 2 diabetes (5)
• SIRT6 Expression Affects Longevity. Increases in SIRT6 expression is associated with increased longevity. (3) Deficits in SIRT6 are associated with premature aging.(4)
  
• Attenuates Amyloid-beta Accumulation. In experimental aninmal, c. elegans, fucoidan signicantly reduced the accumulation of amyloid-beta, a signifcant factor in Alzheimer's Disease,(6)
• Stimulates Immune Response.  Fucoidans enhance immune reponse which may be beneficial in inhibiting cancer. (7)
• Healthy Intestinal Wall Barrier. The source of much inflammation in the intestine and in the body occurs when the intestine barrier breaks down due to injury or illness. Fucoidan supports the integrity of the intestine wall barrier by increasing levels of claudin-1, an important component of the intestine wall. In experimental studies, fucoidan was shown to repair injured intestines and even gradually restore villi.(8)  Furthermore, authors of another study indicated that by improving the intestinal wall barrier, fucoidan may offer a potential area of treatment for inflammatory bowl diseases whereby the intestinal barrier is impaired.(10)
• Healthy Microbiotic Diversity in Intestine. Fucoidan promotes healthy microbiotic content, including the increase in anti-inflammtory short chain fatty acid producers (e.g. Coprococcus, Rikenella, and Butyricicoccus)(8-9)
  

 

HYPER LONGEVITY (Fucoidan - Brown Seaweed Extract)

 

 

REFERENCES:

(1) Irhimeh MR, et al. Fucoidan ingestion increases the expression of CXCR4 on human CD34+ cells. Exp Hematol. 2007 Jun

(2) Rahnasto-Rilla MK, et al. The Identification of a SIRT6 Activator from Brown Algae Fucus distichus. Mar Drugs. 2017 Jun 

(3) Hirvonen K, et al. SIRT6 polymorphism rs117385980 is associated with longevity and healthy aging in Finnish men. BMC Med Genet. 2017 Apr

(4) Peshti V, et al. Characterization of physiological defects in adult SIRT6-/- mice. PLoS One. 2017 Apr

(5) Qin K, et al. SIRT6-mediated transcriptional suppression of Txnip is critical for pancreatic beta cell function and survival in mice. Diabetologia. 2018 Jan 10

(6) Wang X, et al. Fucoidan inhibits amyloid-β-induced toxicity in transgenic Caenorhabditis elegans by reducing the accumulation of amyloid-β and decreasing the production of reactive oxygen species.  Food Funct. 2018 Jan

(7) Vetvicka V, et al. Fucoidans Stimulate Immune Reaction and Suppress Cancer Growth. Anticancer Res. 2017 Nov

(8) Xue M, et al. The effect of fucoidan on intestinal flora and intestinal barrier function in rats with breast cancer. Food Funct. 2018 Jan 31

(9) Shi H, et al. Dietary fucoidan of Acaudina molpadioides alters gut microbiota and mitigates intestinal mucosal injury induced by cyclophosphamide. Food Funct. 2017 Sep 

 (10) Iraha A, et al. Fucoidan enhances intestinal barrier function by upregulating the expression of claudin-1. World J Gastroenterol. 2013 Sep

 

 

 

 

Higher Brain Glucose | Prediabetes Diabetes - Connection to Dementia - Alzheimer's Disease

Scientific evidence indicates that higher levels of blood glucose in the brain, due to the inability of the brain to process the glucose (impaired fasting glucose metabolism) is strongly linked to cognitive decline including brain shrinkage and dementia including Alzheimer's Disease (AD). Neurons in the brain must have a continuous supply of glucose, which is utilized as their primary energy source. Transport of glucose into the neuron is through the  glucose transport proteins GLUT1 and GLUT3 which are not dependent on insulin. Since the brain is so dependent on GLUT1 and GLUT3 to sustain energy for the function of the neurons, any loss of GLUT functioning results in the death of neurons. Furthermore. the higher levels of uncontrolled glucose causes destructive pathological changes to the brain associated with Alzheimer's Disease. The impaired ability of the brain to properly metabolize glucose is often referred to as "type 3 diabetes". (1-6)

 

HYPERGLYCEMIA (Including High-Normal Glucose Levels). Dysregulation of glucose homeostasis leads to higher levels of glucose in brain tissue including brain shrinkage, and the formation of brain pathologies such as beta amyloid plaques and fibrils. Higher blood sugar levels (including high normal, prediabetes and type 2 diabetes) begin with insulin resistance, whereby blood glucose cannot be adequately absorbed by the cells, and glucose levels in the blood stream increase.

Higher plasma glucose levels is correlated to increases in brain glucose. Furthermore, this continues to be exacerbated when GLUT1 and GLUT3 transporters are decreased in function and/or number, and glucose is unable to reach the neurons. GLUT transporters are affected by glycation in diabetics, and may render the transport mechanism non-functional.  Higher glucose levels correlate to the most severe loss of brain function in Alzheimer's Disease. (11)

Classifications of fasting blood glucose levels:

• Normal Fasting Blood Sugar. 50-100 mg/dL
• Prediabetes: 101-125 mg/dL.

 

AMYLOID PLAQUES AND TAU FIBRIL ENTANGLEMENTS

Impaired glucose metabolism in brain tissue, including reduced levels of GLUT1 and GLUT3, are significantly linked to amyloid plaque accumulation and brain tau fibril entanglements.

Pathological changes in the brain linked to high blood glucose:

• Atrophy of hippocampus and other brain structures (2,3)
• Increases protein glycation, oxidative stress, and inflammation of brain (7)
• Increases amyloid beta aggregation. (7)
• Increases accumulation of tau-containing neurofibrillary tangles (tau).
• Impaired glucose metabolism decreases levels of protein O-GlcNAcylation - a protein regulated by glucose metabolism. Therefore, high glucose results in INCREASED level of tau hyperphosphorylation.  Tau tangles are known as the neurofibrillary degeneration component of Alzheimer's disease.(8-10)

 

GLUCOSE TRANSPORTERS - Impact on Brain Glucose Metabolism

• GLUT1 is the primary method for the transport of glucose to glial cells including  astrocytes as well as brain endothelial (blood vessel) cells. Atsrocytes are a type of glial cell, which plays importance roles in synaptic nerve transmission and preserving the energetics at the blood brain barrier.
• GLUT1 at the endothelium of the blood-brain barrier allows glucose to be transported into the brain.

• GLUT3 is a protein that transports glucose to the neurons, and the neuron generates energy for the cell by a process of glycolysis.

 

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Natural Support for Glucose Homeostasis

• Hericium erinaceus -  Novel mycelium polysaccharides in H. erinaceus protects the structure and function pancreas, in diabetic animal models. Glucose homeostasis is an important function of the beta cells of the pancreas. Diabetic complications are due to increased levels of inflammation, oxidative stress and reduction in antioxidant capacity. H. Erinaceus enhances antioxidant capacity and reduces oxidative stress.(12)  
  
• Wolfberry ( Lycium Barbarum) - Decreases absorption of glucose in the intestine, thereby reducing glucose levels in the blood stream.(13)
  
• Andrographolide - studies inidicate that andrographolide may significantly reduce blood glucose levels, may reverse decreases in critical protective antioxidants in the brain due to diabetes. (14)
• Jujube - Fructose intake promotes hyperglycemia, glycation is a known promoter of insulin resistance, Jujube polysacchardies ameliorate fructose induced insulin resistance.(15)
• Baicalin -  Alleviates obesity induced insulin resistance, through activation of Akt/GLUT4 pathways. GLUT4 reduces plasma glucose levels by increasing removal of glucose by skeletal muscle. (16)
  
• Piperine - Insulin resistance models results demonstrate that piperine reverses glucose impairment in insulin resistance cell lines. Research indicates that piperine increases activity of AMPK signaling, which accounts for glucose improvement,(16) AMPK is involved as an energy sensor, and is also activated by exercise, which also increases insulin sensitivity in exercisers. (17,18)
• Fucoidan - Plays dual role including regulating glucose homeostasis and protecting pancreatic beta cells.(19,20)
• Yellows (Flavonoids Plus) -  Ginger (21), Apigenin and Luteolin (22), Curcumin (23) also baicalin.

 

NEUROTREX (Jujube, Wolfberry, Piperine, more)

                            

HYPER LONGEVITY (Fucoidan, Piperine, more)

                   

YELLOW LONGEVITY (Yellow Glucose Homeostasis)

MEMORY ACTION (Andrographolide, more)

 

REFERENCES:

(1) An Y, et al, Evidence for brain glucose dysregulation in Alzheimer's disease.  Alzheimers Dement. 2017 Oct 19

(2) Cherbuin N, et al. Higher normal fasting plasma glucose is associated with hippocampal atrophy: The PATH Study. Neurology. 2012 Sep

(3) Mortby ME, et al, High "normal" blood glucose is associated with decreased brain volume and cognitive performance in the 60s: the PATH through life study. PLoS One. 2013 Sep

(4) Porter-Turner MM, et al. Relationship between erythrocyte GLUT1 function and membrane glycation in type 2 diabetes.  Br J Biomed Sci. 2011

(5) Barros LF, et al. Near-critical GLUT1 and Neurodegeneration. J Neurosci Res. 2017 Nov

(6) Vogelsang P, et al. Reduced glucose transporter-1 in brain derived circulating endothelial cells in mild Alzheimer's disease patients. Brain Res. 2017 Nov 1

(7) Guo C, et al. Chronic hyperglycemia induced via the heterozygous knockout of Pdx1 worsens neuropathological lesion in an Alzheimer mouse model. Sci Rep. 2016 Jul 

(8) Ying Liu, et al. Brain glucose transporters, O-GlcNAcylation and phosphorylation of tau in diabetes and Alzheimer disease. J Neurochem 2009 Oct.

(9) Liu F, et al. Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease. Brain. 2009.

(10) Gong CX, et al. O-GlcNAcylation: A regulator of tau pathology and neurodegeneration. Alzheimers Dement. 2016 Oct;

(11) Mittal K, et al. Shared links between type 2 diabetes mellitus and Alzheimer's disease: A review. Diabetes Metab Syndr. 2016 Apr-Jun

(12) Zhang, C, et a. Antihyperglycaemic and organic protective effects on pancreas, liver and kidney by polysaccharides from Hericium erinaceus SG-02 in streptozotocin-induced diabetic mice. Scientific Reports 7, Article number: 10847 (2017)  

(13) Cai H, et al. Lycium barbarum L. Polysaccharide (LBP) Reduces Glucose Uptake via Down-Regulation of SGLT-1 in Caco2 Cell. Molecules. 2017 Feb.

(14) Naik RR, et al. Andrographolide reorganise hyperglycaemia and distorted antioxidant profile in streptozotocin-induced diabetic rats. Cardiovasc Hematol Agents Med Chem. 2017 Oct 

 (15) Zhao Y, et al. Preventive effects of jujube polysaccharides on fructose-induced insulin resistance and dyslipidemia in mice. Food Funct. 2014 Aug

(16) Fang P, et al. Baicalin against obesity and insulin resistance through activation of AKT/AS160/GLUT4 pathway.  Mol Cell Endocrinol. 2017 Jun

(17) Wan CP, et al. [Piperine regulates glucose metabolism disorder in HepG2 cells of insulin resistance models via targeting upstream target of AMPK signaling pathway]. Zhongguo Zhong Yao Za Zhi, 2017 Feb

(18) O'Neill HM. AMPK and Exercise: Glucose Uptake and Insulin Sensitivity.  Diabetes Metab J. 2013 Feb

(19) Kim KJ, et al, Fucoidan regulate blood glucose homeostasis in C57BL/KSJ m+/+db and C57BL/KSJ db/db mice. Fitoweapia. 2012 Sep

(20) Yu W, wt al. Fucoidan ameliorates pancreatic β-cell death and impaired insulin synthesis in streptozotocin-treated β cells and mice via a Sirt-1-dependent manner. Mol Butr Food Res. 2017 Oct;

(21) de Las Heras N, et al. Molecular factors involved in the hypolipidemic- and insulin-sensitizing effects of a ginger (Zingiber officinale Roscoe) extract in rats fed a high-fat diet.  Appl Physiol Nutr Metab. 2017 Feb

(22) Bumke-Vogt C, et al. The flavones apigenin and luteolin induce FOXO1 translocation but inhibit gluconeogenic and lipogenic gene expression in human cells. PLoS One. 2014 Aug 

(23) Zhao NJ, et al. Curcumin suppresses Notch‑1 signaling: Improvements in fatty liver and insulin resistance in rats. Mol Med Rep. 2018 Jan;