Atherosclerosis is a chronic degenerative disease condition which slowly blocks arteries, accelerate aging and is a contributing factor in most age-related deaths.The key event in the initiation and progression of atherosclerosis is injury and inflammation to the arterial lining (endothelial cells).
REFERENCES
(1) Tang T, et al. Pterostilbene reduces endothelial cell injury in vascular arterial walls by regulating the Nrf2-mediated AMPK/STAT3 pathway in an atherosclerosis rat model. Exp Ther Med. 2020 Jan
(2) Rath S, et al. Potential TMA-Producing Bacteria Are Ubiquitously Found in Mammalia. Front Microbiol. 2020 Jan
(3) Singh G, et al. High Mobility Group Box 1 Mediates TMAO-Induced Endothelial Dysfunction. Int J Mol Sci 2019 Jul
(4) Koh YC, et al. Prevention of Vascular Inflammation by Pterostilbene via Trimethylamine-N-Oxide Reduction and Mechanism of Microbiota Regulation. Mol Nutr Food Res. 2019 Oct.
(5) Zhang L, et al. Pterostilbene protects vascular endothelial cells against oxidized low-density lipoprotein-induced apoptosis in vitro and in vivo. Apoptosis. 2012 Jan
(6) Kang LL, et al. Pterostilbene Attenuates Fructose-Induced Myocardial Fibrosis by Inhibiting ROS-Driven Pitx2c/miR-15b Pathway. Oxid Med Cell Longev. 2019 Dec
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)
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
Protein Homeostasis is a significant determining factor in the longevity of multi-cellular animals.(1) Quality control mechanisms in place to support protein homeostasis include autophagy - the essential degradation of toxic proteins. As an organism ages, protein homeostasis is gradually lost.(2) Autophagy, by lysosomes, plays an active role in protein homeostasis, by eliminating toxic and damaged proteins such as amyloid. Nrf2 activation increases autophagy activity. Reduced levels of autophagy are tied to Alzheimers Disease. Misfolded amyloid beta and tau proteins are involved in the development of Alzheimers Disease.(11)
Autophagy is not only critical in the deposition of toxic proteins, but is functionally important in the degradation and recycling of defective cellular components. Research now indicates that autophagy is central for maximum longevity.(13)
AUTOPHAGY: FISETIN and CURCUMIN
AGING - LOSS OF PROTEOSTASIS (TOXIC PROTEINS)
CURCUMIN PXC (Curcumin | Fisetin | Rosmarinic Acid | Carnosic Acid)
HYPER LONGEVITY (Rosmarinic Acid | Myricetin)
NEUROTREX (Rosmarinic Acid | Myricetin)
VISION VITALITY (Carnosic Acid)
REFERENCES:
(1) Alavez A, et al. Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan. Nature. 2011 Apr
(2) Kuang H, et al, Exploring the bi-directional relationship between autophagy and Alzheimer's disease. CNS Neurosci Ther. 2019 Sep
(3) Chen T, et al. Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells. Aging Cell. 2011 Oct
(4) Yang W, et al. Fisetin improves lead-induced neuroinflammation, apoptosis and synaptic dysfunction in mice associated with the AMPK/SIRT1 and autophagy pathway. Food Chem Toxicol .2019 Sep
(5) Ahmad A, et al. Neuroprotective Effect of Fisetin Against Amyloid-Beta-Induced Cognitive/Synaptic Dysfunction, Neuroinflammation, and Neurodegeneration in Adult Mice. Mol Neurobiol. 2017 Apr
(6) Singh S, et al. Fisetin as a caloric restriction mimetic protects rat brain against aging induced oxidative stress, apoptosis and neurodegeneration. Life Sci. 2018 Jan
(7) Ziontz J, et al. Tau pathology in cognitively normal older adults. Alzheimers Dement (Amst). 2019 Sep
(8) Yousefzadeh MJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018 Oct
(9) Lin C, et al. Rosmarinic acid improved antioxidant properties and healthspan via the IIS and MAPK pathways in Caenorhabditis elegans. Biofactors. 2019 Jun
(10) De Biase D, et al. Amyloid precursor protein, lipofuscin accumulation and expression of autophagy markers in aged bovine brain. BMC VET Res, 2017.
(11) Buchter C, et al. Myricetin-Mediated Lifespan Extension in Caenorhabditis elegans Is Modulated by DAF-16. Int J Mol Sci. 2913 Jun.
(12) Bielak-Zmijewsja A, et al. The Role of Curcumin in the Modulation of Ageing. Int J Mol Sci. 2019 Mar.
(13) Bareja A, et al. Maximizing Longevity and Healthspan: Multiple Approaches All Converging on Autophagy. Front Cell Dev Biol. 2019 Sep
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)
REDOX HOMEOSTASIS / IONIC HOMEOSTASIS
SIRTUIN ACTIVATION (SIRT1)
PLURIPOTENT STEM CELLS (Induction)
NRF2 ACTIVATION
PROTEOSTASIS - ABNORMAL PROTEIN ACCUMULATION / AUTOPHAGY
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, 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
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
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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
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