The Grim Reaper – land of the young – the thread of life

ReverseFX® is a revolutionary formulation that targets very specific genes to enhance the body’s ability to regenerate for eternal health and youth through reduction of oxidative stress, NRF2 activation, and support of stem cell rejuvenation!

It accomplishes this by targeting:

  • NANOG – in Irish mythology, means Land of the Young. It helps embryonic stem cells maintain pluripotency.
  • GRIM REAPER – DAF-2/IGF1R also known as “the grim reaper gene” was discovered to regulate the rate of aging, reproductive development, resistance to oxidative stress, thermotolerance, resistance to hypoxia, and resistance to bacterial pathogens.
  • KLOTHO – the name of the gene comes from Klotho or Clotho, one of the Moirai, or Fates, in Greek mythology. They controlled the mother thread of life of every mortal from birth to death. Klotho provides some control over the sensitivity of the organism to insulin and appears to be involved in aging. Overexpression of Klotho in mice might extend their average life span between 19% and 31% compared to normal mice. 

NANOG – Land of the Young

ESCs (embryonic stem cells) are pluripotent cells that have two distinctive properties: an unlimited capacity for self-renewal and pluripotency.

Pluripotent is something that has no fixed developmental potential, as in being able to differentiate into different cell types in the case of pluripotent stem cells.

The capability for self-renewal and the pluripotency of ESCs seem to be under the control of multiple transcriptional factors, most common among them being Nanog (Nanog homeobox), Oct4 (Octamer Binding Transcription Factor-4), and SOX2 [SRY (Sex Determining Region-Y) Box-2].[1]

https://www.thermofisher.com/us/en/home/life-science/antibodies/antibodies-learning-center/antibodies-resource-library/cell-signaling-pathways/nanog-mammalian-esc-pluripotency/jcr:content/MainParsys/image_1b0c.img.320.low.jpg/1499003273836.jpg

Land of the Young

Tír na nÓg, in Irish mythology, means Land of the Young or Tír na hÓige (Land of Youth) and refers to the Celtic Otherworld.[2]

The name NANOG derives from Tír na nÓg (Irish for “Land of the Young”), a name given to the Celtic Otherworld in Irish and Scottish mythology.

Residents of Tír na nÓg are described as having eternal health and youth, hence the connection to the NANOG protein.

NANOG is a transcription factor in embryonic stem cells (ESCs) and is thought to be a key factor in maintaining pluripotency.[3]

These cells have the ability to become virtually any cell of any of the three germ layers (endoderm, ectoderm, and mesoderm). It is for this reason that understanding the mechanisms that maintain a cell’s pluripotency is critical for researchers to understand how stem cells work and may lead to future advances in treating degenerative diseases.

Pathways

NANOG also is intimately involved with the Innate Immune System[4], Cytokine Signaling in Immune system[5], Developmental Biology[6], Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways[7], Wnt / Hedgehog / Notch signaling pathways[8], and the NRF2 pathway through KEAP1[9].

NANOG is in part regulated by SALL4[10], a transcription factor with a key role in the maintenance and self-renewal of embryonic and hematopoietic stem cells.

ReverseFX® in part targets the NANOG gene and its networks to enhance the body’s ability to regenerate thus gaining access to the Tír na nÓg (Land of the Young).

The science behind the Ingredients for NANOG expression.

NANOG

Chondroitin sulfate is required to maintain the pluripotency of ESCs.[11]

Nattokinase enhances wound healing through NANOG.[12]

N-acetylglucosamine (NAG) impacts neurodevelopmental timing and metabolism.[13]

Mannose metabolism is involved with NANOG expression.[14]

Bladderwrack helps coordinate stem-cell signaling and maintenance in cells.[15]

Beta-glucans enhance hematopoietic stem cell mobilization[16].

Choline ameliorates disease phenotypes in human induced pluripotent stem cells (iPSC) models.[17]

Prunella vulgaris (self-heal) inhibits HMGB1[18], which associates and coordinates with NANOG[19]. HMGB1 is a critical member of the transcriptional regulatory network which regulates hematopoietic stem cell (HSC) multipotency and self-renewal.

Resveratrol enhances the pluripotency of embryonic stem cells. Several studies have reported the effects of resveratrol on mESC differentiation, pluripotency, and cell reprogramming.[20]

Pomegranate extract impacts NRF2 expression and cross talks with NANOG for smell cell regulation.[21]

Dan Shen maintains stem cell pluripotency via leukemia-induced factor (LIF) replacement for maintaining embryonic stem cells (ESCs).[22]

Kudzu root, consisting of the bioactive compounds of daidzein, impacts DNA methylation through TET1 which is required for the maintenance of demethylation of NANOG in embryonic stem cells.[23]

Ginger (Zingiber officinale) can be considered as a potential alternative non-toxic substance for the induction of neuronal cells and can be used for the induction of Bone marrow stromal cells (BMSCs) to neuron-like cells[24]. Shogaol (6-shogaol), a constituent of ginger, targets cancer stem cells.[25]

Ashwagandha, which contains Withaferin-A, has pleiotropic mechanisms of action and impacts the expression of NANOG. Withaferin-A resulted in a cell line-specific alteration in the mRNA expression of stem cell markers[26]. Withaferin A is accompanied by in vivo suppression of self-renewal of cancer stem cells.[27]

Medium-chain fatty acids (MCTs), found in Coconut derivatives, are selective Peroxisome Proliferator-Activated Receptor (PPAR) agonists[28], which help in the maintenance of hematopoietic stem cells (HSCs) and pluripotent stem cell (PSC).[29]-[30]

Caffeic Acid Phenethyl Ester (CAPE) derived from Propolis impacts the HA/CD44-mediated NANOG signaling pathways for regulation of embryonic stem cells and pluripotent stem cells.[31]

Consumption of Sea Buckthorn mobilizes stem cell types involved in regenerative and reparative functions.[32]

Glabridin, a chemical compound that is found in the root extract of Licorice (Glycyrrhiza), enhances the self-renewal capacity of Mesenchymal stem cells (MSCs).[33]

Chinese Skullcap impacts LincRNA regulator of reprogramming (lincRNA-ROR), a major regulator of stem cell pluripotency, which is highly expressed in pluripotent cells. LincRNA-ROR participates in the self-renewal of human embryonic stem cells via modulating NANOG.[34]

Vinpocetine attenuates NE-4C neural stem cells (NSCs)[35]. Vinpocetine also impacts Adipose-derived mesenchymal stem cells (ADSCs) through PDE1C inhibition and JMJD6 Jumonji C domain-containing protein 6.[36]

Shilajit stimulates osteoblastic differentiation of mesenchymal stem cells[37]. Fulvic acid, found in Shilajit, helps in the absorption of iron into the body, making it bioavailable to bone marrow stem cells for blood formation.[38]

GRIM REAPER

Biologists identify pathways that extend lifespan by 500%.[39]

“The increase in lifespan would be the equivalent of a human living for 400 or 500 years, according to one of the scientists. The new research uses a double mutant in which the insulin signaling (IIS) and TOR pathways have been genetically altered. Because alteration of the IIS pathways yields a 100 percent increase in lifespan and alteration of the TOR pathway yields a 30 percent increase, the double mutant would be expected to live 130 percent longer. But instead, its lifespan was amplified by 500 percent.”

The goal of aging research is to extend healthy, active life. DAF-2/IGF1 impacts the expression of DAF-16 which is responsible for up-regulating transcription of about 100 genes that code for cell-protecting products such as heat shock proteins and antioxidants. Genetic analysis reveals that the presence of functioning DAF-16 is required to produce the extended lifespan observed in DAF-2 knock-downs.[40]

Moreover, the IGF-1-pathway is associated with extreme longevity in humans and its function has not only been correlated with longer life, but also maintaining more youthful characteristics, such as active movement, neuronal function, and memory, indicating an extension of healthspan as well as lifespan.[41]

Aging is an inevitable process, commonly accompanied by the risks of many human age-related diseases such as neurodegenerative disorders, cardiovascular diseases, type 2 diabetes, and various cancers.[42]

DAF-16 is for longevity, as it up-regulates genes involved in lifespan extensions such as stress response genes and down-regulates specific life-shortening genes[43]. It has been proven that telomeres have an implication in the aging process, and in C. elegans the lifespan-extending effect of long telomeres is dependent on DAF-16.[44]

The insulin and insulin-like growth factor (IGF) signaling (IIS) pathway play a major role in the control of longevity.[45]

Pathways

Nanog in Mammalian ESC Pluripotency[46], Oocyte meiosis[47], Signaling pathways regulating pluripotency of stem cells[48], Embryonic and Induced Pluripotent Stem Cell Differentiation Pathways and Lineage-specific Markers[49], Neural Stem Cell Differentiation Pathways and Lineage-specific Markers[50]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572328/bin/fphar-08-00548-g0001.jpg

The science behind the Ingredients for GRIM REAPER

Mannose is used to generate mannose-6-phosphate (M6PR)[51]. Mannose impacts the insulin-like growth factor II/mannose 6-phosphate (IGF-II/M6P) receptor pathway. The IGF-II/M6P receptor is distributed widely in the central nervous system, has additional roles in mediating neurotransmitter release and memory enhancement/consolidation and plays a role in the development of neurodegenerative diseases[52]. IGF2/M6P receptors are involved in organ development and growth[53]. Alterations in IGF-II/M6P receptor levels/distribution are possibly associated with the altered functioning of the lysosomal enzymes and/or loss of neurons[54]. Mannose receptors also crosstalk with Growth Hormone (GH) via the pituitary gland[55]. GH produced by the anterior pituitary regulates the biosynthesis and release of IGF-1 by the liver and peripheral tissues to control mammalian growth.[56]

N-acetylglucosamine (NAG) is a key sensor of nutrient status and has been genetically linked to the regulation of insulin signaling[57]. O-linked-N-acetylglucosamine (O-GlcNAc) attachment and detachment (cycling) is mediated, in part, by O-GlcNAc transferase (OGT). OGT and O-GlcNAc are important for the regulation of the insulin-like pathway and embryonic stem cells[58]. O-GlcNAc-marked promoters are biased toward genes associated with insulin-like signaling, metabolism, aging, stress, and pathogen-response pathways thus have important implications for human diseases of aging, including diabetes and neurodegeneration[59]. GlcN extends life span in evolutionary distinct species by mimicking a low-carbohydrate diet.[60]

Fucoidan (Bladderwrack) downregulates the insulin-like growth factor-I receptor[61].

Chondroitin Sulfate reduces DAF-2[62]. Insulin-like growth factor 1 (IGF-1) stimulates cartilage repair and HB-IGF-1 (heparin-binding) is specifically retained in cartilage through its high abundance of Chondroitin Sulfate.[63]

Beta-glucan reduces intestinal fat deposition and improved healthspan in C. elegans through a mechanism involving the DAF-2 gene.[64]

Phosphatidylcholine extends lifespan via DAF16 and reduces amyloid-beta-induced toxicity in C. elegans.[65]

Prunella vulgaris contains Oleanolic Acid, Ursolic acid, and Rosmarinic acid[66]. Oleanolic acid activates DAF-16 to increase lifespan in C. elegans[67]. Ursolic acid modulates dietary restriction mediated longevity and ameliorates toxic protein aggregation in C. elegans, and considerably affects life span and health span (increase ~31.3% in the mean life span of wild-type (WT) N2 worms)[68]. Rosmarinic acid increases C. elegans stress resistance and longevity in a DAF-16.[69]

Resveratrol protection of neuronal function in a DAF-16/FOXO-dependent manner[70]. Piceatannol, an analog of resveratrol, extends the lifespan of C. elegans via DAF‐16[71].

Pomegranate extract extended lifespan and reduced intestinal fat deposition in C. elegans via DAF-16[72]. Pomegranate could be used as a supplement to enhance longevity, fertility and growth rate for the other living organisms and human beings.[73]

Salvia miltiorrhiza (Dan Shen) has significant anti-aging activity with Tanshinones isolated from the plant including cryptotanshione, tanshinone I, and tanshinone IIa, which are the active components[74]. Tanshinone I induces mitochondrial protection through an Nrf2-dependent mechanism[75]. Tanshinone IIA attenuates Insulin-Like Growth Factor 1.[76]

Kudzu root contains isoflavones, including puerarin (about 60% of the total isoflavones), daidzein, daidzin (structurally related to genistein), inhibits Insulin-Like Growth Factors signaling.[77]-[78]

Ginger root, containing the active compound of 6-gingerol, showed potent longevity-promoting activity and elevated the survival rate of C. elegans against stressful environment including thermal, osmotic, and oxidative conditions[79]. [6]-Gingerol, from Zingiber officinale, potentiates GLP-1 mediated glucose-stimulated insulin secretion pathway.[80]

Ashwagandha (Withania somnifera) extends lifespan of C. elegans[81]. Withania somnifera, in part, modulates DAF-16 and orchestrates the process of stress adaptation (including aging or disease pathology)[82]. Withanolide A improves healthspan, delays age-associated physiological changes and also extends lifespan of C. elegans.[83]

Medium-chain fatty acids (MCTs), found in Coconut derivatives, are selective Peroxisome Proliferator Activated Receptor (PPAR) agonists[84], to which converge on DAF-16 and insulin signaling pathways[85]. Myricetin, which may be found in Coconut derivatives[86] prolongs the mean adult lifespan of C. elegans by 32.9%.[87]

Propolis showed a 9.0% increase in mean lifespan of C. elegans and regulating DAF-16[88]. Caffeic Acid Phenethylester (CAPE) is an active constituent of propolis and is a known activator of the redox-active Nrf2 signaling pathway. The increase of reactive oxygen species induced by thermal stress was diminished by about 50%. CAPE caused nuclear translocation of DAF-16. CAPE increased stress resistance of the nematode against thermal stress and finally a prolongation of the median and maximum lifespan by 9 and 17%, respectively.[89]

Sea buckthorn partially prevents UV-induced ROS generation and enhances the level of non-enzymatic antioxidants such as glutathione (GSH), thioredoxin (Trx) and vitamin E and A. Moreover, it stimulates the activity of Nrf2 leading to enhanced antioxidant enzyme activity[90]-[91]. Sea buckthorn also contains the complex lipids which accelerate skin regeneration and cell renewal and slows the aging process[92]. Sea buckthorn ameliorates adiposity, hepatic steatosis, insulin resistance, and inflammation in diet-induced obesity[93]. Emodin, which is present in Sea buckthorn, extends lifespan of C. elegans through insulin/IGF-1 signaling pathway depending on DAF-16 and SIR-2.1.[94]

Bacillus subtilis natto B-12 is isolated from Nattokinase[95]. Bacillus subtilis biofilm extends C. elegans longevity through DAF-2/DAF-16/HSF-1 signalling axis and the downregulation of the insulin-like signalling (ILS) pathway.[96]

Isoliquiritigenin, derived from Chinese licorice root (Glycyrrhiza), exerts antioxidant activity in C. elegans via insulin-like signaling pathway and SKN-1. Chinese licorice root (Glycyrrhiza) exerts its effect by activating the transcription factors DAF-16/FOXO and SKN-1/Nrf2 which regulate many genes.[97]

Chinese skullcap (Baicalein) has been demonstrated to be an activator of the transcription factor NRF2 and prolongs the life span of C. elegans[98]. Baicalein increases the lifespan and stress resistance of C. elegans.[99]

Endogenous cGMP (cyclic guanosine monophosphate) regulates adult longevity via the insulin signaling pathway in C. elegans. Inhibition of PDE activity by Vinpocetine regulates cGMP activity[100]. Cyclic GMP-dependent protein kinase EGL-4 controls body size and lifespan in C. elegans.[101]

Shilajit, which contains Humic acid, extends the lifespan C elegans by means of regulatory and stress response pathways[102]-[103]. Collagen genes are upregulated by Humic acid which increases lifespan through insulin/IGF-1-signaling[104]. Shilajit is a rejuvenator (‘Rasayana’).[105]

KLOTHO

The name of the gene comes from Klotho or Clotho, one of the Moirai, or Fates, in Greek mythology.[106]-[107]

Clotho is one of the Three Fates or Moirai who spin the thread of Life. She also made major decisions, such as when a person was born, thus in effect controlling people’s lives. This power enabled her not only to choose who was born, but also to decide when gods or mortals were to be saved or put to death.[108]

Reduced production of this protein has been observed in patients with chronic renal failure (CRF), and this may be one of the factors underlying the degenerative processes (e.g., arteriosclerosis, osteoporosis, and skin atrophy) seen in CRF. Also, the malfunctioning with this protein has been associated with ageing, bone loss and alcohol consumption.[109]-[110]

Transgenic mice that overexpress Klotho live longer than wild-type mice.[111]

Genetic variants in KLOTHO have been associated with human aging.[112]-[113]

Klotho protein has been shown to be a circulating factor detectable in serum that declines with age.[114]

Klotho-deficient mice manifest a syndrome resembling accelerated human aging and display extensive and accelerated arteriosclerosis. Additionally, they exhibit impaired endothelium-dependent vasodilation and impaired angiogenesis, suggesting that Klotho protein may protect the cardiovascular system through endothelium-derived NO production.

It was demonstrated that overexpression of Klotho in mice might extend their average life span between 19% and 31% compared to normal mice.[115]

https://www.klotho.com/wp-content/uploads/2017/09/Amount-of-Klotho.jpg

In addition, variations in the Klotho gene are associated with both life extension and increased cognition in human populations.[116]

Klotho changes cellular calcium homeostasis, by both increasing the expression and activity of TRPV5, which may manifest as hyperparathyroidism, and bone loss[117], and decreasing that of TRPC6[118] associated with depression and anxiety.[119]

Additionally, klotho increases membrane expression of the inward rectifier channel ROMK[120], which is known to play a critical role in cardioprotection against ischemic-reperfusion injury in the heart[121], as well as in the protection against hypoxia-induced brain injury from stroke or other ischemic attacks[122]. ROMK also has a role in hypokalemia and magnesium deficiency.[123]

Klotho-deficient mice show increased production of vitamin D, and altered mineral-ion homeostasis is suggested to be a cause of premature aging‑like phenotypes, because the lowering of vitamin D activity by dietary restriction reverses the premature aging‑like phenotypes and prolongs survival in these mutants. These results suggest that aging‑like phenotypes were due to klotho-associated vitamin D metabolic abnormalities (hypervitaminosis).[124]-[125]-[126]-[127]

Pathways

Cytokine Signaling in Immune system[128], HIV Life Cycle[129], Innate Immune System[130], Longevity regulating pathway.[131]

https://ars.els-cdn.com/content/image/1-s2.0-S0085253815524605-gr2.jpg

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5816951/bin/nihms941402u1.jpg

Science behind the Ingredients for KLOTHO

Mannose and N-acetylglucosamine residues are involved in N-linked glycosylation[132]. N-linked glycosylation is an essential modification that regulates protein structure and function[133]. N-linked glycans, which involve mannose and N-acetylglucosamine, impact Ca2+ channel TRPV5, thereby impacting Klotho[134]. Individual N-glycan branches are initiated by N-acetylglucosamine addition to mannose residues.[135]

https://www.researchgate.net/profile/Orson_Moe/publication/50868894/figure/fig3/AS:277568415649798@1443188875657/Model-for-regulation-of-TRPV5-by-Klotho-a-Structure-of-the-typical-complex-type.png

Klotho is a novel β-Glucuronidase, which catalyze the breakdown of complex carbohydrates[136]. Brown seaweed, such as Bladderwrack, are polysaccharides that contain a monosaccharide called L-fucose as their principal component which modify the N-glycan of Npt2b involved with Klotho in chronic renal failure[137]. Klotho displays significant similarity to family 1 β-glycosidases. Glycosidases are the enzymes that hydrolyze the glycosidic bond between two carbohydrates or between carbohydrate and non-carbohydrate moieties. β-glycosidases participate in essential steps of synthesis and degradation of oligosaccharides and polysaccharides, which are involved in pathogen defense systems, detoxification, control of signal transduction, and modification of hormone among others[138]. L-fucose also modifies airway cells in lungs through α1,6-fucosyltransferase (Fut8), thereby decreasing emphysema by mechanisms involved with Klotho.[139]

Beta glucan has been shown to modulate Klotho-Related Protein Glucosylceramidase Beta 3 (GBA3) which is able to hydrolyze galactosylceramide/GalCer, glucosylsphingosine/GlcSph and galactosylsphingosine/GalSph. This Klotho-Related Protein can also hydrolyze a broad variety of dietary glycosides including phytoestrogens, flavonols, flavones, flavanones and cyanogens in vitro and could therefore play a role in the metabolism of xenobiotics.[140] Glucosylceramidase beta provides instructions for making an enzyme called beta-glucocerebrosidase. This enzyme is active in lysosomes, which are structures inside cells that act as recycling centers. Lysosomes use digestive enzymes to break down toxic substances, digest bacteria that invade the cell, and recycle worn-out cell components. Based on these functions, enzymes in the lysosome are sometimes called housekeeping enzymes. Beta-glucocerebrosidase is a housekeeping enzyme that helps break down a large molecule called glucocerebroside into a sugar (glucose) and a simpler fat molecule (ceramide). Glucocerebroside is a component of the membrane that surrounds cells. It gets broken down by beta-glucocerebrosidase when cells die, and the components are reused as new cells are formed.[141]

Anti-aging gene Klotho is upregulated by Chondroitin Sulfate and N-acetylglucosamine (NAG)[142]. The Klotho proteins, αKlotho and βKlotho, are essential components of endocrine fibroblast growth factor (FGF) receptor complexes, as they are required for the high-affinity binding of FGF19, FGF21 and FGF23 to their cognate FGF receptors (FGFRs). Collectively, these proteins form a unique endocrine system that governs multiple metabolic processes in mammals. The FGF-Klotho endocrine system also has a crucial role in the pathophysiology of ageing-related disorders, including diabetes, cancer, arteriosclerosis and chronic kidney disease. Therefore, targeting the FGF-Klotho endocrine axes might have therapeutic benefit in multiple systems[143]. Chondroitin Sulfate stimulates bone healing[144]. Chondroitin Sulfates are required for Fibroblast Growth Factor-2-dependent proliferation and maintenance in Neural Stem Cells[145]

α-Klotho (α-Kl) and its homolog, β-Klotho (β-Kl) are key regulators of mineral homeostasis and bile acid/cholesterol metabolism, respectively. FGF15/ human FGF19, FGF21, and FGF23, members of the FGF19 subfamily, are believed to act as circulating metabolic regulators. Overproduction of 1,25(OH)2D and altered mineral-ion homeostasis are a major cause of premature aging-like phenotypes observed in α-kl−/− mice [146]. FGF19 is a post-prandial enterokine and a cornerstone of BA synthesis control, also regulating carbohydrate, lipid and energy homeostasis. The landmark discovery of the FXR-FGF19 axis in the regulation of the BA homeostasis core opened new avenues for intestinal-specific therapeutic management of chronic diseases of the gut-liver axis. Bile acids in absence of phosphatidylcholine are cytotoxic[147]. Therefore, tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms require Phosphatidylcholine (PC) to maintain proper balance of bile acid within the gut-liver axis[148].

Prunella vulgaris impacts the Nrf2/HO-1/eNOS pathways which cross talks with Klotho in the PI3K/AKT/eNOS/NO pathways thus impacting Nitric Oxide signaling in Atherosclerosis. Klotho ameliorates oxidized low density lipoprotein (ox-LDL)-induced oxidative stress via regulating LOX-1 and PI3K/Akt/eNOS pathways[149]. Oleanolic acid (OA), found in Prunella vulgaris, is an activator of NF-E2-related factor 2 (Nrf2) and restores the expression of Nrf2 and Klotho[150]. Ursolic Acid (UA) is found in Prunella Vulgaris and in regard to the key role of α-Klotho in aging, our data indicate that UA may be on the horizon to forestall diseases of aging[151]. Ursolic Acidthrough increasing of SIRT1 up-regulation ameliorate reverse cholesterol transport, fatty acid use and oxidative stress defense. In addition, it seems that UA by enhancing of SIRT6 expression promotes cholesterol homeostasisthrough repressing SREBP1 and SREBP2. Reciprocally, UA might be involved in VLDL synthesis and exportation through PGC-1β up-regulation. Finally, UA might be as key regulators of mineral homeostasis and bile acid/cholesterol metabolism, by inducing Klotho overexpression[152]. Oleanolic Acid and Ursolic Acid improve bone properties and calcium balance and modulate Vitamin D metabolism[153]. Oleanolic acid (OA) has been shown to impact Endoplasmic Reticulum Stress (ERS). The ER performs a variety of cellular functions, including the regulation of protein biosynthesis, folding trafficking and modification. ER function can change in response to environmental stimuli, such as ischemia, glucose deprivation, or oxidative stress, as well as to genetic mutations, which can result in abnormal protein folding. Accumulation of misfolded proteins in the ER lumen induces a range of ER dysfunctions, collectively referred to as ERS associated with the Unfolded Protein Response (UPR)[154]. Ursolic Acid shows antioxidant and anti-inflammatory mechanisms of neuroprotection addressing brain injury, cerebral Ischemia, cognition deficit, anxiety, and depression in a Klotho co-dependent way[155]. Rosmarinic acid impacts the FGF21/FGFR1/b-klotho complex and enhances angiogenesis and wound healing of human brain microvascular endothelial cells and has benefits for the treatment of human brain injury[156]. Rosmarinic acid can activate the Nrf2 pathway.[157]

Resveratrol increases anti-aging Klotho gene expression via the activating transcription factor 3/c-Jun complex-mediated signaling pathway[158]. Stilbene, which is found in Resveratrol[159], extends mouse life span via upregulating neural klotho and downregulating neural insulin or insulin-like growth factor 1[160]. Klotho has numerous physiological functions, such as regulating calcium and phosphorus levels, delaying senescence, improving cognition, reducing oxidative stress, and protecting vascular endothelial cells. Stilbene, a small molecule with anti-aging effects, regulates the expression and physiological effects of klotho[161].

Pomegranate enhances a healthy lifespan in drosophila melanogaster[162]. Pomegranate attenuates glucocorticoid-induced bone loss and hypercalciuria associated with TRPV5 in correlation with klotho[163]. Pomegranate extract (PE) play a strong role on removal of free oxygen radicals and prevention of oxidative stress. Pomegranate extract is rich in antioxidants of the polyphenolic class that includes tannins and anthocyanins. These antioxidants are more potent, on a molar basis than many other antioxidants, including Vitamins C and E, coenzyme Q-10, and lipoic acid. The antioxidant levels in PE were found higher than levels in other natural juices, such as blueberry, cranberry, and orange, as well as in red wine[164].

Klotho acts as a regulator of fibroblast growth factor signaling[165]-[166]. Salvia miltiorrhiza (Dan Shen) accelerates the healing of burn wounds through fibroblast growth factor signaling[167]. Cryptotanshinone inhibits angiogenesis, a physiological process of new blood vessel formation by endothelial cells, through Basic fibroblast growth factor (bFGF) signaling[168]. Salvia Miltiorrhiza induces human umbilical cord blood mesenchymal stem Cells into nerve-like cells[169]. Salvia miltiorrhiza (Dan Shen) increases the activities of catalase, manganese superoxide dismutase, glutathione peroxidase, and coupled endothelial nitric oxide synthase. In addition, SM reduces the impact of ischemia/reperfusion injury, prevents cardiac fibrosis after myocardial infarction, preserves cardiac function in coronary disease, maintains the integrity of the blood-brain barrier, and promotes self-renewal and proliferation of neural stem/progenitor cells in stroke[170]. Salvia Miltiorrhiza (Dan Shen) reduces blood pressure through inhibition of vascular remodeling and oxidative stress[171]. Salvia miltiorrhiza has therapeutic actions of suppressing tumor angiogenesis by targeting VEGF/VEGFRs pathway in relation to basic fibroblast growth factor (bFGF)[172]. Increased basic fibroblast growth factor-2 (FGF2) and reduced Klotho have both been reported to be closely associated with renal fibrosis.[173]

Kudzu root, which contains compounds similar to Genistein, exhibits impressive anti-renal fibrosis activities by recovering epigenetic loss of Klotho, a kidney-enriched anti-aging and fibrosis-suppressing protein. Genistein demethylates Klotho promoter by inhibiting aberrant DNMT1/3a expression[174]. HDAC inhibition prevents Klotho loss and attenuates the CKD-associated bone complication in a mouse model of CKD-MBD via Genistein.[175]

Ginger upregulates Klotho through the suppression of NFκB. The inflammatory cytokines TWEAK and TNFα reduce renal klotho expression through NFκB[176]-[177]. Zingerone, a major component found in ginger root, has been known as anti-mutagenic and anti-carcinogenic activities that are often associated with its anti-oxidative and anti-inflammatory activities. Zingerone had not only the antioxidant effect by constitutive suppression of ROS, but also anti-inflammatory effects by suppression of nuclear factor (NF)-kappaB activation. Zingerone treatment suppressed gene activation of pro-inflammatory enzymes, COX-2 and iNOS, which were upregulated with aging through NF-kappaB activation and IKK/MAPK signaling pathway. Zingerone treatment may provide some preventive measure against chronic inflammatory conditions that underlie many age-related inflammatory diseases, such as metabolic syndrome, cardiovascular disease, dementia, arthritis, diabetes, osteoporosis, and cancers.[178]

Withaferin A, found in Ashwagandha, impacts the Klotho/fibroblast growth factor 23 (FGF23) axis through NFκB inhibition. Protein kinase C (PKC) is crucial for most cellular responses including the regulation of gene expression, cell migration, proliferation, differentiation, and apoptosis. Moreover, PKC is implicated in the pathophysiology of frequent disorders such as heart failure, diabetes, Alzheimer and Parkinson’s disease, as well as inflammatory and immune disorders. According to this experiment with NFκB inhibitor withaferin A, the PKC effect on FGF23 was, at least partly, dependent on NFκB pointing to the decisive role of this pro-inflammatory transcription factor complex in the regulation of FGF23. Moreover, PKC activation induced the expression of pro-inflammatory cytokines TNFα and IL-6 which are themselves stimulators of FGF23 production[179]. Fibroblast growth factor (FGF23) plasma levels are elevated in cardiac and renal failure and correlate with poor clinical prognosis of those disorders. Both disorders are associated with inflammation and activation of the inflammatory transcription factor NFκB. An excessive FGF23 level is further observed in Klotho-deficient mice. The present study explored a putative sensitivity of FGF23 expression to transcription factor NFκB, which is known to upregulate Orai1, the Ca(2+) channel accomplishing store-operated Ca(2+) entry (SOCE)[180].

In Greek mythology, the ‘Orai’ are the keepers of the gates of heaven: Eunomia (order or harmony), Dike (justice) and Eirene (peace)[181]. Fgf23 transcription is decreased by Orai inhibitors and Orai1 silencing. Fgf23 transcription is lowered by NFκB inhibitors[182]. Withaferin A is also an Orai1 inhibitor.[183]

Medium-chain fatty acids (MTCs), found in Coconut derivatives, are selective Peroxisome Proliferator-Activated Receptor (PPAR) agonists[184]. Activation of peroxisome proliferator-activated receptor γ inhibits vascular calcification by upregulating Klotho. Treatment with PPARγ agonists inhibited the calcification and enhanced the expression of Klotho in vascular smooth muscle cells (VSMCs) associated with cardiovascular diseases and chronic kidney disease[185]. Klotho is a target gene of PPAR-gamma. PPAR-gamma agonists increased both klotho mRNA.[186]

Propolis alleviates oxidized low-density lipoprotein-induced endothelial cells injury[187]. Klotho ameliorates oxidized low-density lipoprotein (ox-LDL)-induced oxidative stress via regulating LOX-1 and PI3K/Akt/eNOS pathways[188]. Caffeic Acid Phenethyl Ester, found in Propolis, is an NF‐kB inhibitor rescues Klotho reduction[189]. Caffeic acid phenethyl ester promotes wound healing of mice pressure ulcers affecting NF-κB, NOS2 and NRF2 expression[190]. CAPE could potentially be considered as a promising neuroprotective agent against progressive neurodegenerative diseases such as AD by upregulating the Nrf2/HO-1 pathway[191]. Hmgb1 inhibits Klotho expression. Hmgb1 was agonized by NF-κB inhibitor CAPE which upregulates Klotho.[192]

Sea Buckthorns unique unsaturated fatty acids, such as palmitooleic acid (omega-7) and gamma-linolenic acid (omega-6), give sea-buckthorn skin regeneration and repair properties. Sea-buckthorn also improves blood circulation, facilitates oxygenation of the skin, removes excess toxins from the body and easily penetrates through the epidermis. Because inside the skin the gamma-linolenic acid is converted to prostaglandins, sea-buckthorn protects against infections, prevents allergies, eliminates inflammation and inhibits the aging process. With close to 200 properties, sea-buckthorn is a valuable addition to health and beauty products[193]. Palmitoleic acid, found in Sea Buckthorn, stimulated the uptake of glucose and impaired the lipogenesis in the liver by activation of AMPk and FGF-21, dependent on PPAR-α. All these effects are essential to control insulin resistance and to reduce the ectopic deposition of lipids in the liver[194]. Expression of Fibroblast Growth Factor 21 and β-Klotho regulates hepatic fibrosis[195]. Sea buckthorn oil partially prevents UV-induced ROS generation and enhances the level of non-enzymatic antioxidants such as glutathione (GSH), thioredoxin (Trx) and vitamin E and A. Moreover, it stimulates the activity of Nrf2 leading to enhanced antioxidant enzyme activity. As a result, decreases in lipid peroxidation products (4-hydroxynonenal, 8-isoprostaglandin) and increases in the endocannabinoid receptor levels were observed.[196]

Klotho deficiency has been observed in kidneys, parathyroid glands, and other organs during the course of CKD. In arterial wall, decreased klotho expressions potentiate the development of arterial calcification. Nattokinase, rich in Vitamin K, attenuates for arterial calcification associated with klotho deficiency[197].

Klotho protein inhibits IS (Indoxyl Sulphate )-induced upregulation of Nox2 and Nox4 and NADPH related genes[198]. Nox4 is a novel target of the inhibition of ROS generation for the treatment of heart failure. Glycyrrhizic acid, found in Chinese licorice root, can inhibit the NOX4 expression[199], thus upregulating Klotho. Klotho, a beta-glucuronidase, hydrolyzes extracellular sugar residues on TRPV5, entrapping the channel in the plasma membrane[200]. Glycyrrhiza, found in Chinese licorice root, is an inhibitor of beta-glucuronidase which displays hepatoprotective activity[201]. Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1, which impacts klotho expressions. Ghrelin treatment prolongs survival in klotho-deficient mice[202]-[203]. Isoliquiritigenin might increase the reactivity of an orexigenic hormone ghrelin and ameliorate aging‐associated anorexia. Isoliquiritigenin is a potent inhibitor of NLRP3 inflammasome activation and diet‐induced adipose tissue inflammation[204]. Klotho controls the NLRP3 Inflammasome. Klotho may control the production of inflammatory mediators and the entry of immune cells by suppressing local 1,25-VD3 production and downstream inflammasome activation by TXNIP.[205]

Oroxylin A, a natural flavonoid isolated from Scutellaria baicalensis (Chinese skullcap), has been reported to have anti-inflammatory and antioxidant effects. Oroxylin A significantly reduced the levels of intracellular calcium and reactive oxygen species and increased the levels of CAT and Mn/SOD. Oroxylin A also inhibited the activation of caspase-3. Oroxylin A inhibits also H2O2-induced oxidative stress[206]. H2O2 significantly suppresses Klotho expression. Klotho ameliorates hydrogen peroxide-induced oxidative injury. Increasing Klotho expression plays a protective role against oxidative stress[207]. Therefore, Scutellaria baicalensis upregulates klotho expressionsthrough inhibition of H2O2-induced oxidative stress. Scutellaria baicalensis effectively inhibited airway inflammation by regulating the expression of inflammatory cytokines by blocking MIP2 and CXCL-1 secretion. Therefore, S. baicalensis may be a potential therapeutic agent for COPD[208]. Klotho reduction in alveolar macrophages contributes to cigarette smoke extract-induced inflammation in chronic obstructive pulmonary disease (COPD)[209]. Baicalin protects neonatal rat brains against hypoxic-ischemic injury[210]. Baicalin ameliorates neuroinflammation-induced depressive-like behavior through inhibition of toll-like receptor 4 expressions via the PI3K/AKT/FoxO1 pathway[211]. FGF21 promotes functional recovery after hypoxic-ischemic brain injury in neonatal rats by activating the PI3K/Akt signaling pathway via FGFR1/β-klotho.[212]

Vinpocetine improves oxidative stress through the reduction of MDA serum level and elevation of SOD improving oxidative stress and pro-inflammatory mediators[213].

Pathological cardiac remodeling, characterized by cardiac hypertrophy and fibrosis, is a pathological feature of many cardiac disorders that leads to heart failure and cardiac arrest. Vinpocetine, a derivative of the alkaloid vincamine, has been used for enhancing cerebral blood flow to treat cognitive impairment and is an Angiotensin II Receptor Inhibitor[214]. Therefore, Vinpocetine increases klotho expressions by enhancing klotho and decreasing oxidative stress levels[215]. Vinpocetine has been used for the treatment of Tumoral calcinosis (TC), a calcifying disease associated with Klotho and Fibroblast growth factor 23 (FGF23) genes[216]. Vinpocetine attenuates for DNA Damage and Vascular Aging through Klotho gene expression.[217]

Humic acid, found in Shilajit, has been used as a wound healing and anti-inflammatory agent in folk medicine.Humic acid promotes wound healing in rats via accelerated wound contraction and increased hydroxyproline content. More importantly, these wound-healing effects of Humic acid might be mediated through the TGF-β/Smad signaling pathway associated with fibroblast signaling. Control wound tissue showed small numbers of inflammatory cells with increased numbers of fibroblasts forming the epidermal layer[218]. Klotho is a regulator of fibroblast growth factor signaling[219]. Shilajit can be used in wound healing and in related inflammatory disease states[220]. Shilajit increases human bone marrow mesenchymal stem cells (hMSCs). Shilajit is an inhibitor of osteoclastogenesis and a potent stimulator of osteoblastic differentiation of mesenchymal stem cells. In addition to osteoblasts, fibroblasts are also capable of synthesizing extracellular matrix and collagens. Therefore, enhancing the activities of fibroblasts such as proliferation and ECM secretion is also an approach to treat connective tissue diseases and wound healing with Shilajit[221]. Shilajit is a traditional medicine used in Asian countries for bone/cartilage repair and regeneration. Shilajit stimulates connective tissue repair and fulvic acid may inhibit bacteria associated with biofilm bacterium of Streptococcus mutans, and on gingival fibroblast cells, which mediate connective tissue in repair/regeneration in periodontal disease.[222]

Disclaimer: This is intended for education, research, and data collection. These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease. The information provided on this site is for informational purposes only and is not intended as a substitute for advice from your physician or other health care professional or any information contained on or in any product label or packaging. You should not use the information on this site for diagnosis or treatment of any health problem or for prescription of any medication or other treatment. You should consult with a healthcare professional before starting any diet, exercise or supplementation program, before taking any medication, or if you have or suspect you might have a health problem. You are solely responsible for doing your own research on any information provided. This should not substitute professional advice. Individual results may vary. Database references herein are not all-inclusive. Getting well from reading or using the information contained herein is purely coincidental. Any and all products or services may be subject to change.

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