Atherosclerosis - Pterostilbene & Progression of Artery Disease

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).

• Endothelial Cell Injury Reduction 
• Atherosclerosis is intrinsically linked to damage of the endothelial cells in the artery lining. Such damage is attributed to inflammation and oxidative stress in the arterial wall. In animal models, pterostilbene mitigated the process of atherosclerosis and reduced inflammation in the blood vessels. Importantly, pterostilbene increased levels of protective Nrf2 in the endothelial cells.(1)
• Vascular Inflammation Prevention 
•  In the gut, there are bacteria that convert choline and carnitine into  trimethylamine (TMA). In turn, TMA is converted to  trimethylamine-N-oxide (TMAO).(2) Increased levels of TMAO correlate to cardiovascular disease, by increasing vascular inflammation and endothelial dysfunction.(3)
• Pterostilbene significantly reduces vascular inflammation by:
• altering the composition of gut bacteria, thereby reducing the levels of TMAO
•  decreasing inflammatory vascular markers, including TNF-alpha.(4)
• Protects Against Oxidized Low Density Lipoprotein (LDL) 
• Oxidized LDL targets the endothelium lining of the artery and causes cellular death of the endothelium. This facilitates atherosclerosis development. Pterostilbene inihibits expression of LOX-1, the cellular receptor for oxidized LDL in the endothelium. As such, pterostilbene mitigates the buildup of LDL and subsequent atherosclerosis.(5). 
• Attenuates Heart Aging (Myocardial Fibrosis)
• Oxidative stress negatively impacts heart function and accelerates aging of the heart. As a result of oxidative stress, including inflammation, the heart can become fibrotic, replacing heart tissue with non functional fibrotic tissue.  In lab studies pterostilbene has been shown to mitigate myocardial fibrosis.(6)

CURCUMIN PXC  (Pterostilbene)

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

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

Curcumin & Fisetin - Amyloid Autophagy & Senolytics. Implications for Longevity and Brain Health

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

• FISETIN - As a potent Nrf2 activator, fisetin supports increased autophagic activity, and therefore clearance of toxic proteins.(3) Fisten supports decreased levels pf tau and amyloid beta, and increased expression of neprilysin, an amyloid beta remover.(4) Further, fisetin is a potent neuroprotective against amyloid beta toxicity(5) and brain aging.(6)
• Fisetin when provided to late in life mice, restored tissue homeostasis and increased median and maximum lifespans.(8)
• CURCUMIN - Increases autophagic activity by increasing biogenesis of lysosomes,which will degrade misfolded and damaged proteins. Furthermore, curcumin facilitates loading of the proteins into the lysosomes by increasing HSP70.(12)
• SENOLYTICS - both Fistein and Curcumin are considered senolytics, having the ability to remove senescent cells. Both are considered significant senolytics, however fisetin is considered most powerful.(8.12)

AGING - LOSS OF PROTEOSTASIS (TOXIC PROTEINS)

• AMYLOID. Amyloid is the resulting end-product of defective protein homeostasis. The ability of an organism to bind and autophagically remove toxic amyloid, supports health of the brain and life extension. Specifically, extracellular amyloid beta plaques in the brain are associated withAlzheimer's Disease.(2) 

• TAU Fibrils. Tau hyperphosphorylation results in toxic fibrils which is integral in the pathogenesis of Alzheimers Disease. Tau fibrils are typically present with amyloid beta in Alzheimers patients. The tau pathology in the brain represents detrimental structural changes, and is present in all adults over 70 years of age.(7)

• LIPOFUSICIN - The brown-yellow age pigment which accumulates in cells, and is considered a hallmark of aging. Intra-neuronal accumulation of lipofuscin is observed in all aged brains. Eventually, lipofusin accumulation will lead to neuron cell death.  Lipofuscin accumulation is also associated with dysfunction autophagic lysosomal functioning. Fisetin, Curcumin, Rosmarinic acid (9), Carnosic acid and Myricetin (11) are active in the removal of cellular lipofuscin. Reductions in lipofsucin are correlated with increased lifespan. Lipofuscin accumulation is also a significant factor in macular degeneration. Lipofuscin is a precursor molecule of amyloid.(10)

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

Fisetin - Potent for Anti-Aging Senolytics and Homeostasis

In the field of anti-aging, the flavonoid fisetin is emerging as a potent longevity compound. Fisetin affects the aging process in experimental animals through multiple pathways, including senolytics (removing senescent cells)m SIRT1 activation, calorie restriction mimic and homeostasis.

SENOLYTICS

• Senolytics- the rejuvenation of the cellular environment, by eliminating senescent cells. Aging is characterized by the accumulation of senescent cells. These are cells which are irreversibly unable to grow and function and are resistant to normal cellular clearance. Senescent cells not only interfere with normal tissue functioning, but may also be toxic to neighboring cells. Fisetin, has been shown to be a potent senolytic, with the ability to eliminate senescent cells. (1)

• Scenescent Cells Accelerate Aging. Scenescent cells promote inflammation, stem cell dysfunction, chronic disease, and cellular aging.(2)
• Improve Healthy Lifespan. The elimination of specific age accelerating senescent cell populations is a potential strategy in improving health and longevity.(3)
• Fisetin - was the most potent and selective senolytic among flavonoids tested. Most importantly. fisetin administered to late-life laboratory animals, restored all markers of tissue homeostasis,  and amazingly extended median and maximum lifespans.(4)

REDOX HOMEOSTASIS / IONIC HOMEOSTASIS

• Fisetin Improves Redox Homeostasis. Plasma membranes are affected by increased levels of oxidation and reduced antioxidants in cellular membranes. Fisetin signifcantly increases antioxidants in membranes and activates the redox protection system. (5)
• Fisetin Improves Ionic Homeostasis. Aging affects the plasma membrane of cells, and the membrane transporters. Impairment of the membranes transport function is related to age progression and disease. Specifically, membrane transporters are responsible for ionic homeostasis between intracellular and extracellular environments. Fisetin reverses these aging declines.(6)

SIRTUIN ACTIVATION (SIRT1)

• Fisetin is an SIRT1 activator. Sirtuin activation plays a significant role in longevity. Among the anti-aging benefits include inhibition of cellular senescense, reduced telomere reductions, and enhanced DNA repair. Sirtuins interact with the major longevity pathways, among which is FOXO.(7)

PLURIPOTENT STEM CELLS (Induction)

• Stem cells are the regenerative cells of the body, and represent a primary mechanism for longevity. Fisetin has the unique capablity of converting adult cells (somatic)into pluripotent stem cells. A process known as induced pluripotent stem cells (iPSC). Pluripotent stem cells revert to any specialized cells for tissue repair, organ repair, and  other anti-aging regeneration.(8) Fisetn as a sirtuin activator, enhances the generation of cellular reprogramming.

NRF2 ACTIVATION

• Nrf2 is a powerful antioxidant pathway with strong correlation to longevity.(9)
• Fisetin is a potent activator of Nrf2 and is responsible for the cellular antioxidant activity of fisten.(10)

PROTEOSTASIS - ABNORMAL PROTEIN ACCUMULATION / AUTOPHAGY

• Proteostasis is the homeostasis of protein generation, folding and degradation of proteins. The dysregulation of this process results in aging and disease. Alzheimers Disease (AD) is example of the accumulation of toxic proteins in the brain.
• Fisetn supports reduction in abnormal accumulation and alterations of amyloid and tau in the brain. Fisetin has both antiamyloidogenic and fibril-destabilization activity,(11)
• Alzheimers Disease is characterized by amyoid beta and phosphoryated tau fibrils. FIsetin, through increased Nrf2 activation, enhanced the autophagic removal of phosphorylated tau.(12)

CURCUMIN PXC  (contains Fisetin)

REFERENCES:

(1) Glossmann HH, et al, Metformin and Aging: A Review. Gerontology. 2019. Sept.

(2) Kirkland JL, et al. Cellular Scenescence. A Translational Perspective. EBioMedicine, 2017 

(3) van Deursen JM. The role of Scenescent Cells in Ageing. Nature 2014.

(4) Yousefzadeh MJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine, 2018

(5) Singh S, et al. Fisetin, a potential calorie restriction mimetic, attenuates senescence biomarkers in rat erythrocytes.  Biochem Cell Biol. 2019 Aug

(6) Singh S, et al. Fisetin, a potential calorie restriction mimetic,modulates ionic homeostasis in senescence induced and naturally aged rats.  Biochem Cell Biol. 2019 Sept.

(7) Shin-Hae Lee, et al. Sirtuin signaling in cellular senescence and aging. BMB Rep. 2019 Jan

(8) Chen T, et al. Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells. Aging Cell. 2011.

 (9) Bai, et al. Small Molecules as SIRT Modulators.  Mini Rev Med Chem. 2018.

(10) Zhang H, et al. Nrf2⁻ARE Signaling Acts as Master Pathway for the Cellular Antioxidant Activity of Fisetin. Molecules. 2019 Feb.

(10) Zheng W, et al. Fisetin inhibits IL-1β-induced inflammatory response in human osteoarthritis chondrocytes through activating SIRT1 and attenuates the progression of osteoarthritis in mice. Int Immunopharmacol. 2017 Apr

(11) Simunkova M, et al. Management of oxidative stress and other pathologies in Alzheimer's disease. Arch Toxicol. 2019 Aug

(12) Sunhyo K, et al. Fisetin stimulates autophagic degradation of phosphorylated tau via the activation of TFEB and Nrf2 transcription factors Sci Rep. 2016.

Carnosic Acid - Protects Retina and Supports Healthy Cartilage

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

          RETINA - MITIGATING AGING EYE DETERIORATION

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

           CARTILAGE - BENEFICIAL EFFECTS FOR OSTEOARTHRITIS

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

 VISION VITALITY™    (with CARNOSIC ACID)

REFERENCES:

(1) Rezaie T, et al. Protective effect of carnosic acid, a pro-electrophilic compound, in models of oxidative stress and light-induced retinal degeneration. Invest, Ophthalmol Vis Sci, 2012 Nov

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

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

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

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

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

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

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

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

NEUROTREX™ - DIetary Supplement for Longterm Brain Support

Neurotrex™ is a premier memory and brain support formula, with emphasis on botanical extracts shown to benefit brain health. More Information

NEUROTREX is a trademark of Geres Dengle

The Intestine - Axis of Longevity

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

Healthy Intestine Equates to Longevity.

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

Anti-Aging Support for Intestine

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

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

REFERENCES:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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