Neurodegenerative diseases of the retina are mostly attributable to oxidative stress and inflammation.(1) Diseases of the retina target the retinal epithelial cells, and photoreceptors. Photoreceptors are the processing centers in the retina, and are the primary area of vision. The retina has the highest metabolic rate of any tissue in the body. Furthermore, the retina must endure oxidative stress from chronic exposure to light, which will damage the retina. In addition, retina degeneration is associated with inflammation. The result is that with age, the retina becomes damaged, and blindness is the end effect in older people.
AGE RELATED MACULAR DEGENERATION. Degeneration of retinal cells (photoreceptor and retinal pigment epitheilium (RPE) cells) by oxidative stress and inflammation is responsible for age-related macular degeneration (AMD).
(1) Oxidative Stress - NrFT2. Cellular Transcription Factor for Endogenous Antioxidant Protective Factors
Carnosic Acid is an electrophilic antioxidant which crosses the blood brain barrier. Carnoisc acid is a potent activator of Nrf2, a transcription factor that causes the increased production of endogenous antioxidants. Additionally, carnoisc acid is unqiue in that it does not deplete endogenous levels of glutathionine, the key cellular antioxidant, unlike other antioxidants.(2) In a study of high intensity lighting on photooxidative damage of the retina, adding carnoisc acid to AREDS ingredients greatly increased protection of retina vs AREDS alone.(3)
Protects the eye and retina in multiple ways. First, lycium bararum protects the photreceptor cells from light-induced retina damage by activating Nrf2.(4)
2) Inflammation - NLRP3 inflammasome activation is involed in the pathogenesis of AMD.
C3G is considered the most important anthocyanin in maintaining health of the retina. Recently, research indicates that cyanidin-3-glucoside (C3G) has potent anti-inflammation properties and may inhibit inflammasome damage to retinal epithelium cells.(5) C3G further reduces oxidative stress of the retina, and light induced retinal degeneration, by activating Nrf2 endogenous levels.(6)
(1) Rohowetz RJ, et al, Reactive Oxygen Species-Mediated Damage of Retinal Neurons: Drug Development Targets for Therapies of Chronic Neurodegeneration of the Retina. Int J Mol Sci. 2018 Oct
(2) 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
(3) Wong P, et al, Enhancing the efficacy of AREDS antioxidants in light-induced retinal degeneration. Mol Vis. 2017 Oct
(4) Tang L, et al. Antioxidant effects of Lycium barbarum polysaccharides on photoreceptor degeneration in the light-exposed mouse retina. Biomed Pharmacother. 2018 Jul
(5) Jin X, et al. Cyanidin-3-glucoside Alleviates 4-Hydroxyhexenal-Induced NLRP3 Inflammasome Activation via JNK-c-Jun/AP-1 Pathway in Human Retinal Pigment Epithelial Cells. J Immunol Res. 2018
(6) Wang Y, et al. Cyanidin-3-glucoside and its phenolic acid metabolites attenuate visible light-induced retinal degeneration in vivo via activation of Nrf2/HO-1 pathway and NF-κB suppression. Mol Nutr Food Res. 2016 Jul
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- 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)
REDOX HOMEOSTASIS / IONIC HOMEOSTASIS
SIRTUIN ACTIVATION (SIRT1)
PLURIPOTENT STEM CELLS (Induction)
PROTEOSTASIS - ABNORMAL PROTEIN ACCUMULATION / AUTOPHAGY
(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.
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.
Other FOXO Activators and Longevity Pathways:
(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.
(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;
While we live in an age where people are living longer, an important limiting factor on longevity is the ability of the heart to maintain function. Known causes of death for the oldest people on record (over 110 years old) were recorded as heart failure. Heart failure is due to the gradual loss of cardiomyocytes (heart muscle cells) and the increase in scarring of the heart muscle. The process may take place due to low grade inflammation of the muscle, which progresses with age, or injury (such as a heart attack) which may cause a more sudden loss of heart function. Inflammation in the cardiovascular system is common with the aging process, being the result of hypertension, high blood glucose, trigylcerides, or oxidized VDL cholesterol.
Cardiac Aging Characteristics:
Key Conditions of the Aging Heart
Natural support for Cardio Anti-aging
*Andrographolide is also included
(1) Steenman M, et al. Cardiac aging and heart disease in humans. Biophys Rev. 2017 Apr;
(2) Zhu ZY, et al. Apigenin ameliorates hypertension-induced cardiac hypertrophy and down-regulates cardiac hypoxia inducible factor-lα in rats. Food Funct. 2016 Apr;7
(3) Liu HJ, et al. Apigenin alleviates STZ-induced diabetic cardiomyopathy. Mol Cell Biochem. 2017 Apr
(4) Hu W, et al. Luteolin improves cardiac dysfunction in heart failure rats by regulating sarcoplasmic reticulum Ca2+-ATPase 2a. Sci Rep. 2017 Jan
(5) Oberoi L, et al. The aqueous extract, not organic extracts, of Terminalia arjuna bark exerts cardiotonic effect on adult ventricular myocytes. Phytomedicine. 2011 Feb 15
(6) Parveen A, et al. Terminalia arjuna enhances baroreflex sensitivity and myocardial function in isoproterenol-induced chronic heart failure rats. J Cardiovasc Pharmacol Ther. 2012 Jun
(7) Kaliq F, et al, Improvement in myocardial function by Terminalia arjuna in streptozotocin-induced diabetic rats: possible mechanisms. J Cardiovasc Pharmacol Ther. 2013 Sept.
(8) Kumar S, et al. Proteomic analysis of the protective effects of aqueous bark extract of Terminalia arjuna (Roxb.) on isoproterenol-induced cardiac hypertrophy in rats. J Ethnopharmacol. 2017 Feb 23
(9) Kocak C, et al, Molecular and biochemical evidence on the protective effects of embelin and carnosic acid in isoproterenol-induced acute myocardial injury in rats. Life Sci. 2016 Feb 15
(10) Chung RWS, et al. Lutein exerts anti-inflammatory effects in patients with coronary artery disease. Atherosclerosis. 2017 May 6;
(11) Girandola RN, et al. Effect of E-OJ-01 on Cardiac Conditioning in Young Exercising Adults: A Randomized Controlled Trial. Am J Ther. 2017 May
(12) Qian ZQ, et al. Icariin prevents hypertension-induced cardiomyocyte apoptosis through the mitochondrial apoptotic pathway. Biomed Pharmacother. 2017 Apr.
(13) Gu J, et al. Metallothionein Is Downstream of Nrf2 and Partially Mediates Sulforaphane Prevention of Diabetic Cardiomyopathy. Diabetes. 2017 Feb;
(14) Lin CM, et al. Suppressive effect of epigallocatechin-3-O-gallate on endoglin molecular regulation in myocardial fibrosis in vitro and in vivo. J Cell Mol Med. 2016 Nov;
(15) Tan WS, et al. Is there a future for andrographolide to be an anti-inflammatory drug? Deciphering its major mechanisms of action. Biochem Pharmacol. 2017 Apr 2
(16) Lv FH, et al. Effects of curcumin on the apoptosis of cardiomyocytes and the expression of NF-κB, PPAR-γ and Bcl-2 in rats with myocardial infarction injury. Exp Ther Med. 2016 Dec
(17) Khaliq F, et al. Improvement in myocardial function by Terminalia arjuna in streptozotocin-induced diabetic rats: possible mechanisms. J Cardiovasc Pharmacol Ther, 2013 Sep
(18) Hashemzaei M, et al. Regulation of autophagy by some natural products as a potential therapeutic strategy for cardiovascular disorders. Eur J Pharmacol. 2017 May
(19) Hu J, et al. Luteolin alleviates post-infarction cardiac dysfunction by up-regulating autophagy through Mst1 inhibition. J Cell Mol Med, 2016 Jan
(20) Meghwani H, et al. Beneficial effects of aqueous extract of stem bark of Terminalia arjuna (Roxb.), An ayurvedic drug in experimental pulmonary hypertension. J Ethnopharmocol. 2017 Feb 2
(21) Woo AY, et al. Andrographolide up-regulates cellular-reduced glutathione level and protects cardiomyocytes against hypoxia/reoxygenation injury. J Pharmacol Exp Ther. 2008 Apr
(22) Zhang J, et al. Andrographolide Attenuates LPS-Induced Cardiac Malfunctions Through Inhibition of IκB Phosphorylation and Apoptosis in Mice. Cell Physiol Biochem. 2015
(23) Fernandes RO, et al. Sulforaphane effects on postinfarction cardiac remodeling in rats: modulation of redox-sensitive prosurvival and proapoptotic proteins. J Nutr Biochem. 2016 Aug
Blue Light from Electronic Technology. Eye Damaging? That is the concern. Everywhere we are constantly exposed to electronic sources of blue light, including smart phones, computer displays, LED and OLED televisions and car lights. While the light emitted from a smartphone is thought to be in the visible spectrum, there is a very high amount of short wave blue light that is also emitted. LED from cars lights, especially at night, may also pose a problem for the retina. Since we are living longer and are exposed continuously to LED lights, there is real danger the retina may be irrevocably harmed.
Natural sunlight (blue light) also causes light-induced damage to the retina, but are less intense than blue light emissions from LED devices. Therefore LED lights significantly increases the potential for toxicity to the retina. (1-4)
BLUE LIGHT DAMAGES RETINA
Photoreceptors (cones and rods) in the retina provide the neuron interface to convert light to images. These photoceptors reside on the outermost parts of the retina, and are nourished and maintained by an underlying layer termed the Retinal Pigment Epithelium (RPE). Photo induced stress directly affects the health of the retina. The blue light is especially damaging, increasing oxidative stress and can lead to cellular death to either the photoreceptors or the Retinal Epithelium.
Age-Related Macular Degeneration (AMD) involves the progressive degradation of the photoreceptors and the RPE. Blue light can damage and cause cellular death of these critical structures. Oxidative stress and inflammation are believed to be key factors in the development of AMD.
NATURAL PROTECTION AGAINST DAMAGING BLUE LIGHT
Bilberry Anthocyanins. Increases Antoxidant Protection of Retina. An experimental model of retinal degeneration, produced by visible-light damage, was ameliorated by the protective antioxidant effects of bilberry anthocyanins. (11)
Sulforaphane. Most potent Nfr2 Activator.
In studies involving the Retinal Pigment Epithelium (RPE), and oxidative stress, sulforaphane was shown to significantly up regulate antioxidant protection of the RPE by activating Nrf2 and HO-1. (12)
Aging Increases Damage from Blue Light in PhotoReceptor cells. Normal protection of the photoreceptor cells and the supporting retiinal epithelium layer, is provided by the cells inherent Nrf2 antioxidant protection against oxidative stress. However, aging is known to deplete the protective Nrf2 response, leaving the retina even more susceptible to damage by oxidative insults such as blue light. Therefore, not only does blue light inherently stress the retina and may cause cellular death, but this response is greatly amplified with retinal aging.(13-14)
(1) Coleman S. LED Lights Dangerous on Roadways and Off. 2015 Jan.
(2) Renard G, et al. The dangers of blue light. True story. J Fr Ophtalmol.2016 May.
(3) Jaadane I, et al.Retinal damage induced by commercial light emitting diodes (LEDs) Free Radic Biol Med. 2015 Jul.
(4) Krigel A, et al. Light-induced retinal damage using different light sources, protocols and rat strains reveals LED phototoxicity.Neuroscience, 2016 Dec.
(5) Lima VC, et al. Macular pigment in retinal health and disease. Int J Retina Vitreous. 2016 Aug
(6) Nolan JM, et al. The impact of supplemental macular carotenoids in Alzheimer's disease: a randomized clinical trial. J Alzheimers Dis. 2015
(7) Orthan, et al. Mesozeaxanthin Protects Retina from Oxidative Stress in a Rat Model. Ocul Pharmacol Ther. 2016 Nov
(8) Miyake S, et al. Phase II enzyme induction by a carotenoid, lutein, in a PC12D neuronal cell line. Biochem Biophys Res Commun. 2014 Apr
(9) Zou X, et al. Zeaxanthin induces Nrf2-mediated phase II enzymes in protection of cell death. Cell Death Dis. 2014 May
(10) Kamoshita M, et al. Lutein acts via multiple antioxidant pathways in the photo-stressed retina. Sci Rep. 2016 Jul.
(11) Wang Y, et al. Retinoprotective Effects of Bilberry Anthocyanins via Antioxidant, Anti-Inflammatory, and Anti-Apoptotic Mechanisms in a Visible Light-Induced Retinal Degeneration Model in Pigmented Rabbits. Molecules. 2015 Dec
(12) Ye L, et al, Sulforaphane enhances the ability of human retinal pigment epithelial cell against oxidative stress, and its effect on gene expression profile evaluated by microarray analysis. Oxid Med Cell Longev, 2013
MITOPHAGY AND LONGEVITY
NRF2 - THE ROLE IN MITOPHAGY AND LONGEVITY Nrf2 is a latent protein in the cell, which upon activation, regulates the activation of genes which produce antioxidant proteins for cellular protection, reduction of inflammation and reduction of mitochondrial toxins (via glutathione induction).
(1) Palikaras K, et al. Mitophagy: In sickness and in health. Mol Cell Oncol. 2015 Jun.
(2) Palikaras K, et al. Coupling mitogenesis and mitophagy for longevity. Autophagy. 2015.
(3) LaPierre L, et al. Transcriptional and epigenetic regulation of autophagy in aging. Autophagy. 2015 Jun
(4) Greco T, et al. Sulforaphane Inhibits Mitochondrial Permeability Transition and Oxidative Stress. Free Radic Biol Med, 2012 Dec
(5) Holstrom Kira, et al. The multifaceted role of Nrf2 in mitochondrial function. Curr Opin Toxicol. 2016 Dec
(6) Wang K, et al. Redox homeostasis: the linchpin in stem cell self-renewal and differentiation. Cell Death Dis. 2013 Mar
(7) Russo M, et al. Nrf2 targeting by sulforaphane: a potential therapy for cancer treatment. Crit Rev Food Sci Nutr. 2016 Dec
(8) O'Mealey GB, et al. Sulforaphane is a Nrf2-independent inhibitor of mitochondrial fission. Redox Biol. 2016 Nov
Air pollutants are harmful and affect everyone, but may be additionally detrimental for people who exercise at higher levels (with higher inhalation rates) both outdoors and indoors. Since runners, bikers, aerobics class participants and other fitness buffs, require more oxygen and deeper inhalation. they typically inhale higher level of pollutants. For example, a fitness center study comparing the inhalation of pollutants of indoor aerobics class vs. less intense activity, showed 2x's the amount of pollutants inhaled by the higher intensity aerobics class. (1) Moreover, the air pollutants tend to become trapped deeper into the lung tissue. Furthermore, air pollutants are most often not apparent and the fitness ethusiast is unlikely to be aware of the inhalation hazard.
Air pollutants have been associated with respiratory mortality (3), development of atherosclerosis (2), diabetes (5) and neuropatholgies (via increased neuro inflammation) (4). While doctors support the need for exercise, many will caution about exercising outdoors, especially where air pollution levels may be higher.
SOURCES OF AIR POLLUTION:
Sulforaphane is a powerful phase 2 detoxifier, which enables the detoxfication and excretion of harmful pollutants and toxins. In a clinical trial in china, glucoraphain in broccoli sprout (beverage), which contains the powerful precursor of sulforaphane, was shown to effectively detoxify several major air pollutants.(6) Compared to placebo, the broccoli sprout beverage showed "rapid and sustained increases in the levels of excretion of the glutathione-derived conjugates of benzene (61%), acrolein (23%)". Another study, also showed increased excretion of the air pollutant crotonaldehyde.(7)
Effective results showed detoxification of airborne pollutants from study participants.(6,7) Sulforaphane may also have an inhibitory effect against cancer, including lung cancer, via activation of Nrf2 antioxidant pathway. (10)
Diesel Exhaust Fine Particles - The fine particles form diesel exhaust are considered a significant health hazard which impacts especially outdoor exercise. At high cardiac output, diesel increased pulmonary vasoconstriction (8) and increased oxidative stress and allergic inflammatory response.(9) Sulforaphane induces phase II enzymes which can block the oxidant and allergic inflammation harmful effect of the diesel exhaust particles. (9)
(1) Ramos CA, et al. Estimating the inhaled dose of pollutants during indoor physical activity. Sci Total Environ. 2015 Sep 15
(2) Bai Y, et al. Fine particulate matter air pollution and atherosclerosis: Mechanistic insights. Biochim Biophys Acta. 2016 May 6.
(3) Brunekreef B, et al. Effects of long-term exposure to traffic-related air pollution on respiratory and cardiovascular mortality in the Netherlands: the NLCS-AIR study. Res Rep Health Eff Inst. 2009 Mar
(4) Jørgensen JT, et al. Long-term exposure to ambient air pollution and incidence of brain tumours: The Danish Nurse Cohort. Neurotoxicology. 2016 Jun 2
(5) Hansen AB, et al. Long-term exposure to fine particulate matter and incidence of diabetes in the Danish Nurse Cohort. Environ Intl 2016 May;
(6) Egner PA, et al. Rapid and sustainable detoxication of airborne pollutants by broccoli sprout beverage: results of a randomized clinical trial in China. Cancer Prev Res (Phila). 2014 Aug
(7) Kensler TW, et al. Modulation of the metabolism of airborne pollutants by glucoraphanin-rich and sulforaphane-rich broccoli sprout beverages in Qidong, China. Carcinogenesis. 2012 Jan
(8) Wauters A, et al. At high cardiac output, diesel exhaust exposure increases pulmonary vascular resistance and decreases distensibility of pulmonary resistive vessels.
(9) Wan J, et al. Antioxidant enzyme induction: a new protective approach against the adverse effects of diesel exhaust particles. Inhal Toxicol. 2007
(10) Yang L, et al. Frugal chemoprevention: targeting Nrf2 with foods rich in sulforaphane. Semin Oncol. 2016 Feb