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
CARTILAGE - BENEFICIAL EFFECTS FOR OSTEOARTHRITIS
(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
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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.
Anti-Aging Support for Intestine
(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
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.
(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
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.
(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
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:
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:
GLUCOSE TRANSPORTERS - Impact on Brain Glucose Metabolism
Natural Support for Glucose Homeostasis
YELLOW LONGEVITY (Yellow Glucose Homeostasis)
MEMORY ACTION (Andrographolide, more)
(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
(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;
The hypothalamus is a small structure in the brain which is involved in important physiological functions including homeostasis and systemic energy balance, which support health and longevity. Recent research indicates that the neural stem cells found within hyopathalamus may be key to slowing the aging process. However, this not through neurogenesis, but by the secretion of exosomes and microRNA content. (1) Exosomes are vesicles released by the stem cells into the cerebrospinal fluid. Exosomes are an important mechanism for cell-to-cell communications. communication. The content of exsomes include microRNAs, which modifies the expression of genes in the recipient cell.
Inflammation and the Hypothalamus
Longevity of Hypothalamus Neural Stem Cells (Hnsc). With aging there is a significant increase in inflammation, which negatively affects the pool of neural stem cells in the hypothalamus, decreasing their numbers, thereby reducing release of exosomes and microRNA. Most importantly, microRNAs slows aging by inhibiting inflammatory gene expression, thereby improving health of the hypothalamus (3). In experimental animals, the start of aging in the animals began with the loss of hypothalamus stem cells.(4)
Next Article: Supplements supporting health of Hypothalamus and longevity
(1) Mendelsohn AR, et al. Inflammation, Stem Cells, and the Aging Hypothalamus. Rejuvenation Res. 2017 Aug
(2) Santos CL, et al, Age-Dependent Neurochemical Remodeling of Hypothalamic Astrocytes. Mol Neurobiol, 2017 Oct 4
(3) Meyer K, et al. Slowing Down Aging. Cell Metabb. 2017 Oct 3
(4) Zhang Y, et al, Hypothalamic stem cells control ageing speed partly through exosomal miRNAs. Nature. 2017 Aug 3