Oxidative Stress and Inflammation - Pathogenesis in Degeneration of the Retina

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).

• PHOTORECEPTORS - Are comprised of rods and cones.  Are under constant threat of oxidative threats, including excessive stress from light, high oxygen requirements, All of which make photo receptors susceptible to degradation and death of the photo receptors.

(1) Oxidative Stress - NrFT2. Cellular Transcription Factor for Endogenous Antioxidant Protective Factors

• CARNOSIC ACID

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)

• LYCIUM BARBARIM (WOLFBERRY)

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.

• BLACK CURRANT / BILBERRY EXTRACT (C3G)

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)

VISION VITALITY (Carnosic Acid | Lycium Barbarum | C3G)

REFERENCES:
(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

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.

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;

Cardiac Aging - Heart Failure and Limits of Longevity

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:

• Increased injury and loss of cardiac muscle due to inflammation and injury,
• Increased fibrosis and scarring of heart muscle
• Loss of regenerative ability (cardiomyocytes)
• Loss of cardiomyocyte homeostasis
• Reduction in contractile strength of myocytes
• Increased thickening of muscle (cardiac hypertrophy) - commonly caused by hypertension
• Diabetes accelerates aging of the heart muscle, and is directly causative of cardiomyopathy - a damaging condition of the heart muscle which leads to heart failure.

Key Conditions of the Aging Heart

• Atrial Fibrillation
• Heart Failure (1)

• Heart failure is primarily the result of insufficient ability to regenerate heart tissue by cardiomyoctes and the replacement of muscle with scar tissue.

• Inhibiting Cardiac Fibrosis and Inflammation supports maintenance of Heart Function with aging.

• Atrial fibrillation. Changes to the heart through aging, alters the ability of the left atrium to properly conduct the critical electrical impulses, which can cause an abnormal heart beat. Atrial fibrillation results from increased fibrosis in the heart muscle and a remodeling of the heart muscle. Nrf2 activation, which is potently activated by sulforaphane and andrographolide, may reduce fibrosis. 

• Cardiomyocyte Regeneration and Maintenance (Homeostasis) - Mammal adult heart cells display very poor regenerative ability after incurring inflammation or injury. Instead of regenerating, hearts undergo extensive scarring - reducing functional ability. In order to properly regenerate, there must be a proliferation of cardio myocytes. Hypertension can result in increased cellular death of the cardiomyocytes. An extract of epimedium (icariin) may mitigate the loss of heart muscle due to hypertension.(12) Furthermore, as demonstrated in lab animals, curcumin also may prevent loss of cardiac muscle due to myocardial infarction (heart attack).(16)
• Cardiomyocyte homeostasis ensures that the heart muscle stays healthy and strong. Cardiac aging leads to a gradual loss of homeostasis, which leads to the death of the cardiomyocyte and eventual heart failure. An important mechanism for maintaining homeostasis is regulated autophagy in the cardiomyocyte. Autophagy eliminates defective proteins and recycles components into new structures.

• Cardiac scarring is the development of fibrosis in response to an attempt to repair damaged tissue (including inflammation and heart attack). Fibrosis can be reduced by nrf2 activation.

• Cardiac hypertrophy - is the result of scarring which eventually can lead to cardiac failure. Andrographolide and arjuna have been shown in lab research to inhibit hypertrophy.(2)

• Contractibility of Cardiomyocytes. Healthy cardiomyocytes have strong contraction capability which may be loss with age and is  factor in heart failure. Luteolin can improve contraction and ameliorate myocardium fibrosis which may improve heart failure.

• Reducing Myocardial Damage. Carnosic Acid may reduce myocardial damage through properties of anti-inflammatory and antioxidant effects on the heart.(9)

• Chronic Inflammation - Coronary Artery Disease. Coronary artery disease creates conditions of pervasive inflammation which also affect the heart. Lutein is not only important for vision health, but has potent anti-inflammatory effect in coronary artery patients.(4)

•  Nrf2 for Oxidative Homeostasis - Aging results in lower levels of nrf2. As a master antioxidant factor, nrf2 is essential to maintain homeostasis of a protective oxidative state for the heart. Increased nrf2 may also protective against cardio fibrosis.

 Natural support for Cardio Anti-aging

• Terminalia Arjuna (bark extract) - Indian medicine has long recognized arjuna as a cardio tonic and now modern research is supporting this. In young fitness participants, an arjuna extract significantly improved cardiovascular strength and efficiency. Arjuna has also shown potential benefit in heart failure in research animals.(5)
• Terminalia Arujuna - supports heart function in diabetic rats. Myocardium function improved, as hypothesized by the study researchers, as a result of increased in endogenous antioxidant enzymes.(17)
• Benefits of Terminalia Arjuna:
• Improved Diabetic heart function
• Improved exercise capacity via cardiovascular efficiency
• Strong improvement of left ventricle output in individuals with cardiovascular ailments.
• Reduction in mass of cardiac hypertrophy
• May have beneficial effects on pulmonary hypertension - which is a fatal disease characterized by right ventricular hypertrophy and right heart failure.(20)
• Protection of cardiac muscle from injury
• Cardio tonic effect - i.e. positively affecting heart function

•  Apigenin - Provides supports for hypertrophy and diabetic cardiomyopathy.(2.3)
•  Luteolin - Supports improved heart muscle contraction in lab animal models of heart failure.(4) Furthermore, in research simulated myocardial infarction (heart attack), luteolin increased autophagy of the heart muscle, increasing mitochondrial biogenesis, thereby lessening subsequent cardiac dysfunction.
•  Icariin (Epimedium) - helps mitigate hypertension induced cellular death of the   cardiomyocytes.(12)
•  Lutein - Provides powerful anti-inflammatory action in cardiovascular disease, thereby reducing potential for fibrosis. Lutein is further supportive by acting as an nrf2 activator.  
• Sulforaphane - Inhibits diabetic cardiomyopathy via the effects as a powerful Nrf2 activator.(13) Experimental research has shown that sulforaphane inhibited cardiomyopathy in both type 1 and type 2 diabetes. In experimental models of cardiac infarctions (heart attack), sulforaphane inhibited changes to the heart muscle, in particular the fibrosis that occurs post-injury.(23)
• EGCG (Green Tea Extract) - Has an inhibitory effect on myocardial fibrosis.(14)
• Andrographolide - Nrf2 activator, significantly reducing oxidative stress and potent ant-inflammation agent.(15, 22) Also upregulates glutathione levels in cardiomyocytes, which offers powerful protection against oxygen deprived injury (such as a myocardial infarction). (21) 
• Curcumin - Regulates autophagy of cardiomyocytes, which supports the degradation and recycling of cardiomyocyte components, such as mis-folded proteins. Autophagy is an essential process in supporting cardiomyocyte homeostasis. When autophagy is dysregulated, the muscle cell dies and may lead to atrophy of the heart and eventually heart failure. In addition to curcumin, resveratrol and berberine also regulate autophagy,(18)

CARDIO VITALITY (Terminalia Arjuna (Rejuna))

YELLOW LONGEVITY (Curcumin, EGCG, Apigenin, Luteolin, Icariin, Carnosic Acid)*

YELLOW NATURALLY (Curcumin, EGCG, Apigenin, Luteolin, Icariin, Carnosic Acid)*

VISION VITALITY MAX (Lutein, Meso Zeaxanthin)

XGEVITY (Glucoraphanin precursor to Sulforaphane)*

 *Andrographolide is also included

REFERENCES:

(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

Electronic Technology - Eye Protection from Blue Light - Role of Lutein Mesozeaxanthin & Zeaxanthin

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)

• LED (light Emitting Diodes) - Due to their emitting of blue light, may damage the retina if viewed for long periods of time at close distances. White LEDs have an intense amount of blue light. Blue light is very high energy and as such can cause oxidative stress and tissue damage (including the retina). 
• Some researchers recommend restricting internal LED lamps to "white warmth" - 2700K, which is closer to that of traditional incandescent.
• Avoid "cool white" 5000K - 6500K. The brighter the light the more potential for harm to the retina.

 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

• Mesozeaxanthin. Zeaxanthin. Lutein.
  

• Macular Density.
  

   Additionally, lutein, repairs light induced damage to the retinal pigment epithelium (RPE) kayer, which is disrupted by the oxidative stress. Much like the protection of the retina cells, lutein repairs the RPE via invoking the Nrf2 endogenous antioxidant system,(10)

FURTHER PROTECTION

• 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)

VISION VITALITY MAX (Mesozeaxanthin | Zeaxanthin | Lutein | Bilberry)

XGEVITY (Glucoraphinin percursor to Sulforaphane)

REFERENCES:

(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

(13) Sachdeva MM, et al. Nrf2 signaling is impaired in the aging RPE given an oxidative insult. Exp Eye Res. 2014 Feb;

(14) Chen WJ, et al. Nrf2 protects photoreceptor cells from photo-oxidative stress induced by blue light. Exp Eye Res. 2016 Dec

Mitophagy - Maintaining Mitochondria & Stem Cell Renewal for Regenerative Longevity

MITOPHAGY AND  LONGEVITY

• Cellular homeostasis, which significantly includes mitochondria function, is critical for longevity. Mitochondria are the energy powerhouses of the cell and are essential cellular elements for health and longevity. As part of aging, the mitochondria accumulate damage which decreases cellular vitality while increasing dysfunction. Mitophagy is the ability to clean the cell of damaged mitochondria which, if left to accumulate, would cause irreversible loss of cellular energy. Dysfunctional mitochondria can lead to cellular death, degenerative diseases and shorten the lifespan.

• Mitophagy is essential for longevity. Higher activity levels of  mitophagy in the cell has been linked to significant increases in longevity in research animals. Improved aging and extended longevity is correlated with a proper balance of mitochondria biogenesis and mitophagy.(1) Age-related decreases in mitophagy result in the accumulation of damaged mitochondria and a decrease in mitochondria biogenesis, 

• Mitophagy and Autophagy. Mitophagy is the selective degradation of the mitochondria by cellular process known as autophagy. Autophagy is the cellular process used to remove damaged cellular organelles and debris. Increased autophagy is known as a critical component in cellular survival and longevity. Enhanced levels of autophagy is considered a major factor in the  increased longevity in long lived animals.(2)

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).

• Nrf2 Increases Mitochondria Biogenesis and Mitophagy. .

• Stem Cells - The basis for extreme longevity. Extreme lifespans are based on the ability to regenerate new cells to replace damaged cells. This is the function of stem cells. Stem cells are undifferentiated cells which, when needed, can differentiate into replacement cells in the body. Examples where stem cells differentiate into new functional cells include cardiomyoctyes (heart cells) and neurons in the brain. Sources of stem cells include a stem cell pool, whereby stem cells undergo a self-renewal (making new stem cell cells) which supply this pool. Additionally there are specific stem cells such as neural stem cells which can produce new neurons in the brain. Aging, and the dysfucntion of stem cell mitochondria, decrease the functional ability of stem cell self renewal and the regeneration ability of stem cells into cells such as neurons.

• Nrf2 Protects Stem Cells Capacity for Self-Renewal and Differentiation, When levels of Nrf2 are decreased, stem cells and progenitor cells, lose their function for the self renewal and regeneration of cells.. An example of this is seen in neural stem cells in the brain where the ability to stimulate new neuron growth from stem cells  is inhibited when nrf2 levels are low. Researchers believe that nrf2 promotes healthy mitochondria in the stem cells which in turn reverses age related decline in stem cell ability to self-renew and to regenerate new cells. Therefore, nrf2 activation is significant in stem cell self renewal as well as cellular regeneration, including cardiomyocyte regeneration and preserving the function of neural stem cells.(5,6)  

• SULFORAPHANE is a natural and potent Nrf2 Activator and helps maintain youthful and healthy mitochondria. (4, 7)
• SULFORAPHANE - BEYOND Nrf2. In addition to providing Nrf2 activation, sulforaphane helps block damage to the mitochondria through non-Nrf2 mechanisms. Sulforaphane supports mitochondria hyperfusion, which is cytoprotective and prevents the formation of pores in the mitochondria.(8)

REFERENCES:

(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 Outdoor Indoor Exercising - Detoxification

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:

• Indoor environment (Fitness Centers, Home)
• Outdoor environment (Suburban - Urban - Transit areas)
• Ambient Air
• Automobiles
• Buses / trucks (Diesel Exhaust)
• Airports / Airplanes
• Factories

SULFORAPHANE DETOXIFICATION

 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)

XGEVITY   (Sulforaphane precursor Glucoraphanin)

REFERENCES:

(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