Category Archives: Antioxidants

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F2-Isoprostanes: A Major Aging Marker of Lipid Peroxidation and Risk Marker for Developing Coronary Heart Disease

Arachidonic acid

Arachidonic acid (AA) is a polyunsaturated omega-6 fatty acid (20:4(ω-6)) and is converted from linoleic acid, which is an essential fatty acid, known as omega-6 fatty acid.

In the body, arachidonic acid is present in the phospholipids of cell membranes and mostly abundant in the:

  • brain
  • muscles (accounting for roughly 10-20% of the phospholipid fatty acid content on average)
  • liver

Only animals and not plants can convert linoleic acid to arachidonic acid.  Arachidonic acid can also be obtained endogenously from the diet by consuming primarily animal foods, such as:

  • meat
  • poultry
  • eggs

Physiologically, the body requires a certain level of AA.  However, when that level is outside the accepted reference range, this can progress into a pro-inflammatory environment.  AA is actually considered to produce various pro-inflammatory eicosanoids. 

Image result for Arachidonic acid

Figure 1.  Arachidonic Acid cascade  (Source)

One measure of cellular inflammation is the AA:EPA Ratio.  The AA: EPA ratio provides a more specific indicator of the balance between omega-6 and omega-3 fatty acids in circulation. When this ratio is higher, there is preferred incorporation of AA into cell membranes over EPA, leading to a pro-inflammatory environment.

While both of these fatty acids are essential to human health, the optimal ratio of AA:EPA is around 1.7.  1 

Isoprostanes

Isoprostanes are prostaglandin-like compounds formed in the body from the free radical-catalyzed peroxidation of arachidonic acid.  Isoprostanes acts as inflammatory mediators and possess potent biological activity.  They are accurate markers of lipid peroxidation of oxidative stress.  2

Image result for lipid peroxidation

Figure 2.  Harmful Effects of Lipid Peroxidation  (Source)

Lipid peroxidation occurs in the cell membrane when free radicals oxidize or degrades the lipids contain the the cell membranes.  This ultimately results in cell damage.  Polyunsaturated fatty acids (mostly AA) are particularly vulnerable to lipid peroxidation due to the numerous double bonds in their structure.

F2-Isoprostanes

F2-Isoprostanes are produced by the reaction of free radicals with arachidonic acid.

Image result for F2-Isoprostanes

Figure 3.  Metabolism of F2-Isoprostanes  (Source)

The damage done by F2-Isoprostanes can be widespread, since they can generally cause:

  • blood vessels to constrict
  • blood pressure to raise
  • promotion of blood clots
  • promotion of the clumping of platelets

Numerous studies carried out over the past decade have shown that these compounds are extremely accurate measures of lipid peroxidation and have illuminated the role of oxidant injury in a number of human diseases including atherosclerosis, Alzheimer’s disease and pulmonary disorders.  3

Measuring and Testing for F2-isoprostanes

The F2-isoprostanes test is considered the gold standard for oxidative stress and is measured in a urine specimen. 

Elevated F2-isoprostanes levels are at a more than 30-fold risk for developing coronary heart disease compared with those with normally low levels.  4

According to the Cleveland HeartLab, Inc., your F2-isoprostanes risk is low when your level is less than 0.86 ng/mg; at or above that level places you at high risk.  5

 

Cleveland HeartLab, Inc.

Reference Range for F2-isoprostanes

Age                                                                ng/mg creatinine

All Ages                                                                  <0.86

 

 

Informational References:

Cleveland HeartLab, Inc. offers the F2-isoprostanes Test through the Know Your Risk Program®

Cleveland HeartLab, Inc. F2-isoprostanes Handout

Video:  Marc Penn – Trials and Tribulations of Assessing CVD Risk in 2013 (Cleveland HeartLab)

 

Puerarin, a Potent Bioactive Ingredient from Kudzu, Shows Promise as a Neuroprotective Agent

Kudzu, also called Japanese arrowroot, is a group of plants in the genus Pueraria, in the pea family Fabaceae.  It is native to Asia and the Pacific Islands.  The name is derived from the Japanese name for the plants, kuzu (クズ or 葛?).  It tends to be a very invasive plant and grows as a vine.

Image result for Kudzu root

Figure 1.  Kudzu root  (Source)

 

Figure 2.  Flowers of Pueraria montana var. lobata  (Source)

The Chinese derived the traditional medicine called Gegen (Ge Gen) from Pueraria lobata (Willd.) Ohwi, a specieis of Pueraria.

Image result for puerarin

Figure 3.  Puerarin molecule  (Source)

One of the major bioactive ingredients of Kudzu is puerarin and is its is most abundant secondary metabolite.  Since its isolation in the 1950’s, puerarin has been extensively investigated for its pharmacological properties.  It has been widely used in the treatment of:

  • cardiovascular and cerebrovascular diseases
  • diabetes and diabetic complications
  • osteonecrosis
  • Parkinson’s disease
  • Alzheimer’s disease
  • endometriosis
  • cancer

The beneficial effects of puerarin on the various medicinal purposes may be due to its wide spectrum of pharmacological properties such as:

  • vasodilation
  • cardioprotection
  • neuroprotection
  • antioxidant
  • anticancer
  • antiinflammation
  • alleviating pain
  • promoting bone formation
  • inhibiting alcohol intake
  • attenuating insulin resistance

Recent studies have revealed that puerarin can be neuroprotective in the following areas:

  • learning and memory impairment induced by D-galactose  1
  • protected neurons against apoptosis in the cortex and hippocampus of Alzheimer’s diseased rats caused by Aβ25–35 through downregulating Aβ1–40 and Bax expression in brain tissues, therefore alleviating the spatial learning and memory impairment of diseased animals.  2 
  • ischemic brain injury.  Puerarin could improve the learning-memory ability after global cerebral ischemia and reperfusion in rats. The protective mechanism might be related to the effect of inhibiting or delaying the cell apoptosis through up-regulating the expression of Bcl-2 after ischemia and reperfusion.  3 

The anti-Alzheimer’s disease effects of puerarin were also suggested to be related to its abilities in decreasing the lipid peroxidase levels and increasing superoxide dismutase levels in brain tissues, enhancing cerebral blood flow, and improving brain microcirculation   4  

Freezing Broccoli Sprouts Increases Sulforaphane Yield

Three-day old broccoli sprouts are concentrated sources of glucoraphanin, which is the precursor to sulforaphane.  Fresh broccoli sprouts contain 10 to 100 times more glucoraphanin by weight than mature broccoli plants. 1  Fresh broccoli sprouts can contain at least 73 mg of glucoraphanin (also called sulforaphane glucosinolate) per 1-oz serving.

A study from 2015 published in the journal RSC Advances by researchers from the College of Food Science and Technology, Nanjing Agricultural University, Nanjing, People’s Republic of China and the College of Food Science and Engineering, Qingdao Agricultural University, Qingdao, People’s Republic of China, investigated whether freezing broccoli sprouts would have an effect on glucoraphanin and ascorbic acid content, myrosinase activity, sulforaphane and sulforaphane nitrile formation.  2

The researchers froze broccoli sprouts at −20 °C (DF-20), −40 °C (DF-40) and −80 °C (DF-80) or stored at −20 °C (LN-20), −40 °C (LN-40) and −80 °C (LN-80) after being frozen in liquid nitrogen for 5 min or always frozen in liquid nitrogen (LN).

The results showed the following:

  • glucoraphanin content was not significantly affected by freezing
  • myrosinase activity was enhanced
  • sulforaphane yield  was increased by 1.54–2.11 fold
  • sulforaphane nitrile formation decreased
  • ascorbic acid content was decreased

By freezing fresh broccoli sprouts, sulforaphane can be increased by on average 1.825 times its original value when fresh and not frozen. 

Eating frozen broccoli sprouts may not be very appetizing.  Instead it is recommended to use the frozen broccoli sprouts in a smoothie.  Make sure you use the broccoli sprouts straight from the freezer and do not allow them to thaw.  

Increasing Nrf2: A Master Regulator of the Aging Process

Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or Nrf2, is a transcription factor. The Nrf2 pathway is “the primary cellular defense against the cytotoxic effects of oxidative stress.”

Activation of Nrf2 results in the induction of many cytoprotective proteins. These include, but are not limited to, the following:

  • NAD(P)H quinone oxidoreductase 1 (Nqo1)
  • Glutamate-cysteine ligase, catalytic (Gclc) and glutamate-cysteine ligase, modifier (GCLM)
  • Heme oxygenase-1 (HMOX1, HO-1)
  • The glutathione S-transferase (GST) family
  • The UDP-glucuronosyltransferase (UGT) family
  • Multidrug resistance-associated proteins (Mrps)

A wide variety of dietary components have been shown in vitro or cell culture to activate Nrf2 and directly increase activity of phase II enzymes; these include:

  • epigallocatechin gallate (EGCG)
  • resveratrol
  • curcumin and its metabolite tetrahydrocurcumin, which has greater phase II activity
  • cinnamaldehyde
  • caffeic acid phenyethyl ester
  • alpha lipoic acid
  • alpha tocopherol
  • lycopene
  • apple polyphenols (chlorogenic acid and phloridzin)
  • gingko biloba
  • chalcone
  • capsaicin
  • hydroxytyrosol from olives
  • allyl sulfides from garlic
  • chlorophyllin
  • xanthohumols from hops

The beneficial effects of these phytochemicals have been demonstrated in numerous animal and human studies, particularly their chemopreventative and antioxidant abilities; these effects may be explained by their indirect stimulation of antioxidant enzyme production and phase II detoxification through Nrf2 signaling. (Source: Life Extension)


References:

Yuan JH, Li YQ, Yang XY. Inhibition of epigallocatechin gallate on or- thotopic colon cancer by upregulating the Nrf2-UGT1A signal path- way in nude mice. Pharmacology 2007; 80: 269 – 78

Hsieh TC, Lu X, Wang Z, Wu JM. Induction of quinone reductase NQO1 by resveratrol in human K562 cells involves the antioxidant response element ARE and is accompanied by nuclear translocation of tran-scription factor Nrf2. Med Chem 2006; 2: 275 – 85

Nayak S and Sashidhar RB. Metabolic intervention of aflatoxin B1 toxicity by curcumin. J Ethnopharmacol 2010;127 (3) : 641-4

Osawa T. Nephroprotective and hepatoprotective effects of curcuminoids. Adv Exp Med Biol 2007;595 : 407-23

Liao BC, Hsieh CW, Liu YC, Tzeng TT, Sun YW, Wung BS. Cinnamaldehyde inhibits the tumor necrosis factor-alpha-induced expression of cell adhesion molecules in endothelial cells by suppressing NF-kap- paB activation: Effects upon IkappaB and Nrf2. Toxicol Appl Pharmacol 2008; 229: 161 – 71

Lii CK, Liu KL, Cheng YP et al. Sulforaphane and alpha-lipoic acid upregulate the expression of the pi class of glutathione S-transferase through c-jun and Nrf2 activation. J Nutrition 2010;140 (5) : 885-92

Feng Z, Liu Z, Li X, et al. α-Tocopherol is an effective Phase II enzyme inducer: protective effects on acrolein-induced oxidative stress and mitochondrial dysfunction in human retinal pigment epithelial cells. J Nutr Biochem 2010;21 (12) : 1222-31

Wang H and Leung LK. The carotenoid lycopene differentially regulates phase I and II enzymes in dimethylbenz[a]anthracene-induced MCF-7 cells. Nutrition 2010;26 (11-12) : 1181-7

Veeriah S, Miene C, Habermann N et al. Apple polyphenols modulate expression of selected genes related to toxicological defence and stress response in human colon adenoma cells. Int J Cancer 2008;122 (12) : 2647-55

Liu XP, Goldring CE, Wang HY, Copple IM, Kitteringham NR, Park BK. Extract of Ginkgo biloba induces glutathione-S-transferase subunit-P1 in vitro. Phytomedicine 2009; 16(5):451–455

Liu YC, Hsieh CW, Wu CC, Wung BS. Chalcone inhibits the activation of NF-kappaB and STAT3 in endothelial cells via endogenous electrophile. Life Sci 2007; 80: 1420 – 30

Joung EJ, Li MH, Lee HG, Somparn N, Jung YS, Na HK et al. Capsaicin in- duces heme oxygenase-1 expression in HepG2 cells via activation of PI3K-Nrf2 signaling: NAD(P)H:quinone oxidoreductase as a potential target. Antioxid Redox Signal 2007; 9: 2087 – 98

Zhu L, Liu Z, Feng Z et al. Hydroxytyrosol protects against oxidative damage by simultaneous activation of mitochondrial biogenesis and phase II detoxifying enzyme systems in retinal pigment epithelial cells. J Nutr Biochem 2010;21 (11) : 1089-98

Gong P, Hu B, Cederbaum AI. Diallyl sulfide induces heme oxygenase-1 through MAPK pathway. Arch Biochem Biophys 2004; 432: 252 – 60

Zhang Y, Guan L, Wang X, Wen T, Xing J, Zhao J. Protection of chloro- phyllin against oxidative damage by inducing HO-1 and NQO1 ex- pression mediated by PI3K/Akt and Nrf2. Free Radic Res 2008; 42: 362–71

Dietz BM, Kang YH, Liu G et al. Xanthohumol isolated from Humulus lupulus Inhibits menadione-induced DNA damage through induction of quinone reductase. Chem Res Toxicol 2005;18 (8) : 1296-305

Surh YJ, Kundu JK, Na HK. Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. Planta Med 2008;74 (13) : 1526-39


Informational Reference:

Nrf2.com  

Inhibiting the Destructive Effects of arNOX (ENOX3)

The Aging-Related Cell Surface NADH Oxidase (arNOX) enzyme is one in a class of newly-identified ECTO-NOX (external NADH oxidase or ENOX (Ectos is Greek for outside) ) proteins that are located on external cell membranes.  arNOX is also known as ENOX3.

As the cells mitochondria age and produce less energy, arNOX becomes increasingly active.  arNOX is present in all cells tested, and in particular in the serum and saliva as well as the dermis and epidermis of the skin. 

ArNOX activity increases with age between 30 and 50–65 years and generates the destructive superoxide free radical.  arNOX transmits cell surface oxidative changes to surrounding cells and circulating lipoproteins. 

arNOX promotes tissue aging, especially in the vascular walls and the skin and the structural components of the skin’s extracellular matrix, such as collagen and elastin. arNOX is shed from the cell surface and is found in saliva, urine, perspiration, and interstitial fluids that surround the collagen and elastin matrix underlying dermis.

There is a strong correlation with the level of arNOX in the blood or saliva and a persons age.  The older one looks, apparently the more arNOX is in the blood and saliva.  arNOX is inactive in youth and can vary among individuals after age 30.  arNOX activity correlates with age and reaches a maximum at about age 65 in males and 55 in females.

Inhibiting arNOX by exogenous (dietary) natural substances is the only way to lessen and mitigate the destrucitve effects of arNOX.

Inhibiting arNOX activity

There are a number of natural substances that have been shown to inhibit arNOX activity and reduce oxidative damage caused by the superoxide free radical.  The following natural substances are able to inhibit arNOX:

Co-enzyme Q10 (CoQ10)

Co-enzyme Q, especially CoQ10 is capable of inhibiting arNOX.  1  The generation of superoxide by arNOX proteins is inhibited by Coenzyme Q10 as one basis for an anti-aging benefit of CoQ10 supplementation in human subjects.  arNOX activity was reduced between 25 and 30% by a 3 x 60 mg daily dose Coenzyme Q10 supplementation. Inhibition was the result of Coenzyme Q10 presence. 2

Tyrosol and Hydroxytyrosol

Tyrosol and Hydroxytyrosol are capable of inhibit arNOX activity.  3

Herbes de Provence

Based on the scientific research of James and Dorothy M. Morré, they demonstrated that natural compounds from French culinary seasonings – “Herbes de Provence” inhibit arNOX activity.  4

Herbes de Provence typically comprise:

  • basil (Ocimum basilicum)
  • fennel seed (Foeniculum vulgare)
  • marjoram (Origanum majorana)
  • oregano (Oreganum vulgare)
  • rosemary (Rosmarinus officinalis)
  • sage (Salvia officinalis)
  • summer savory (Satureja hortensis)
  • tarragon (or estragon, dragon’s-wort, Artemisia dracunculus)
  • thyme (Thymus vulgaris)

The ratio of these herbs that make up Herbes de Provence vary with personal or regional choice.

Of the herbs listed, the following are particularly active as arNOX inhibitors:

  • basil
  • tarragon (especially French tarragon)
  • rosemary
  • marjoram
  • sage
  • savory (especially summer savory)

Figure 1.  Summer Savory

Summer savory was the herb that had the highest arNOX activity inhibition at 89%.

Figure 2:  arNOX activity % inhibition.  (Source:  U.S. Patent 20120207862 A1)

According to U.S. Patent 20120207862 A1 entitled ORAL INHIBITORS OF AGE-RELATED NADH OXIDASE (arNOX), COMPOSITIONS AND NATURAL SOURCES, by the inventors, D. James Morré, Dorothy M. Morré, Thomas Shelton, components can be incorporated in the following proportions:

  • basil, 0-95%
  • thyme, 0-50%
  • oregano, 0-90%
  • tarragon, 0-95%
  • rosemary, 0-95%
  • lavender, 0-50%
  • sage, 0-95%
  • savory, 0-95%
  • marjoram, 0-95%

The U.S. Patent recommends the following dosages.  By formulating the herbal preparations as sustained-release preparations, 24 h of protection were attained with just two 400-mg capsules/day (one in the morning and one before bedtime) A preferred total daily dose is from about 200 mg to about 600 mg of a combination of herbs and/or natural products as described herein.

Free E-Book: The Health and Medicinal Benefits of Ashitaba

Ashitaba, which is the common name used in Japan, is botanically known as Angelica keiskei or Angelica Keiskei Koidzumi. The English translation of the Japanese word “Ashitaba” (アシタバ or 明日葉) is “Tomorrow’s Leaf”. Ashita means ‘tomorrow and ba means ‘leaf.’ The name stems from the plant’s ability to quickly regenerate new leaves after taking cuttings. This give an indication of its potential for longevity of life.

asitab_5

Ashitaba plant

There are two separate substances (products) that are derived from the Ashitaba plant.

The first is the hot-air dried powder of Ashitaba from the leaves and stems. The color of this powder is bright green. The leaves of the Ashitaba plant contain approximately 0.25% to 0.35% chalcones.

The second is the powder made from the unique yellow sap which is collected from the Ashitaba’s stem. It is commonly called Ashitaba Chalcone Powder which consists up to 8% chalcones. The color of Ashitaba Chalcone Powder is bright yellow and is a fat-soluble substance.

Although the green Ashitaba powder from the leaves and stems provide nutritional and health benefits, it is the Ashitaba Chalcone Powder (bright yellow powder from the sap of the stem) that is the Chalconoids are natural phenols related to chalcone. They form the central core for a variety of important biological compounds.

997422_orig

Chalcone sap from Ashitaba stem

Chalcones are the active factors in Angelica Keiskei Koidzumi. At least 20 chalcones have been identified in Angelica Keiskei.

Ashitaba contains a thick, sticky yellow sap, which is not found in other celery plants, and are unique to this strain of angelica. This yellowish element in Ashitaba contain the chalconoids.

 

Download the Free E-Book (PDF): The Health and Medicinal Benefits of Ashitaba

Left-click to download into new window, then right-click (in new window) to save as PDF file.

Astaxanthin and Other Natural Substances Increase the Activity of the FOXO3 Longevity Gene

The gene FOXO3a codes for a human protein called Forkhead box O3, also known as FOXO3.

FOXO3 belongs to the family of transcription factors which are characterized by a distinct fork head DNA-binding domain. There are three other FoxO family members in humans:

  • FOXO1
  • FOXO4
  • FOXO6

Protein FOXO3 PDB 2K86.png

Structure of protein FOXO3. Based on PyMOL rendering of PDB 2K86  (Source: Pleiotrope – Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=15989699)

This important protein has many vital functions in the human body and is primarily associated with human longevity, which is why it is often referred to as the “longevity gene”.  1  2 

Among the many functions and roles that this protein plays in the human body, the most important have been identified:

  • functions as a trigger for apoptosis through upregulation of genes necessary for cell death  3
  • upregulates antioxidants such as catalase and MnSOD  4
  • suppresses tumorgenesis in cancer  5
  • functions in DNA repair mechanisms  6  7
  • promotes resistance to oxidative stress  8

These important functions of the FOXO3 protein will only happen when the FOXO3 gene is activated and increased to encode the protein. 

Researchers have identified certain natural substances that activate and increase the FOXO3 gene:  These natural substances include:

  • Astaxanthin 9
  • Baicalein (from the Scutellaria baicalensis root or Baikal skullcap)  10
  • Butyrate (as Calcium Magnesium Butyrate) 11
  • R-Lipoic Acid 12
  • Selenium 13
  • Vitamin D  14

A Closer Look at Astaxanthin

Astaxanthin is a keto-carotenoid which belongs to a larger class of chemical compounds known as terpenes.  Astaxanthin is usually classified as a xanthophyll.

Astaxanthin can be found in:

  • microalgae
  • yeast
  • salmon
  • trout
  • krill
  • shrimp
  • crayfish
  • crustaceans
  • feathers of some birds (e.g., flamingos)

A recent study published in 2017 and co-authored by the The University of Hawaii John A. Burns School of Medicine (“JABSOM”) and Cardax, Inc. (“Cardax”), a Honolulu based life sciences company, demonstrated that the Astaxanthin compound (CDX-085 (developed by Cardax)) is able to switch on the FOX03 ‘longevity gene’ in mice.  15

Researchers of the study stated that all humans have the FOXO3 gene, which protects against aging in humans, but about one in three persons carry a version of the FOXO3 gene that is associated with longevity. By activating the FOXO3 gene common in all humans, researchers stated that they can make it act like the “longevity” version. This important study has shown that Astaxanthin “activates” the FOXO3 gene.

The study used mice which were fed either normal food or food containing a low or high dose of the Astaxanthin compound CDX-085 provided by Cardax. They witnessed a significant increase in the activation of the FOXO3 gene in the heart tissue of those mice that were fed the higher amount of the Astaxanthin compound.  In fact, they found a nearly 90% increase in the activation of the FOXO3 gene in the mice fed the higher dose of the Astaxanthin compound CDX-085. 

The researchers concluded that their hope is that these findings will lead to a highly effective anti-aging therapy that extends the lifespan of human beings.  

7,8-dihydroxyflavone (7,8-DHF): An Flavone With Remarkable Health Benefits

7,8-Dihydroxyflavone (7,8-DHF) is a naturally-occurring flavone found in:

  • Godmania aesculifolia
  • Tridax procumbens
  • Primula tree leaves

Flavones are a class of flavonoids which are a class of plant secondary metabolites.

Natural flavones include:

  • Apigenin (4′,5,7-trihydroxyflavone)
  • Luteolin (3′,4′,5,7-tetrahydroxyflavone)
  • Tangeritin (4′,5,6,7,8-pentamethoxyflavone)
  • Chrysin (5,7-hydroxyflavone)
  • 6-hydroxyflavone
  • Baicalein (5,6,7-trihydroxyflavone)
  • Scutellarein (5,6,7,4′-tetrahydroxyflavone)
  • Wogonin (5,7-dihydroxy-8-methoxyflavone)

Synthetic flavones include:

  • Diosmin
  • Flavoxate
  • 7,8-dihydroxyflavone (7,8-DHF)

7,8-Dihydroxyflavone (7,8-DHF) has been determined and studied to be a potent and selective agonist of the TrkB receptor, which is the main signaling receptor of brain-derived neurotrophic factor (BDNF). It is able to penetrate the blood-brain-barrier after oral consumption.

7,8-DHF has been very therapeutically efficient in various central nervous system disorders including:

  • Depression [1]
  • Alzheimer’s disease [2]
  • Schizophrenia [3]
  • Parkinson’s disease [4]
  • Huntington’s disease [5]
  • Amyotrophic lateral sclerosis [6]
  • Traumatic brain injury [7]
  • Cerebral ischemia [8]

7,8-DHF has also been found to be a potent antioxidant [9] and provides neuroprotection against glutamate-induced excitotoxicity.

The authors of the study concluded that:

Our data demonstrate that 7,8-DHF protects against hydrogen peroxide and menadione-induced cell death, suggesting that 7,8-DHF has an antioxidant effect. In summary, although 7,8-DHF is considered as a selective TrkB agonist, our results demonstrate that 7,8-DHF can still confer neuroprotection against glutamate-induced toxicity in HT-22 cells via its antioxidant activity.” [10]


References:

[1] Liu X, Chan CB, Jang SW, Pradoldej S, Huang J, He K et al. (2010). “A synthetic 7,8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent antidepressant effect”. J. Med. Chem. 53 (23): 8274–86. doi:10.1021/jm101206p. PMC 3150605. PMID 21073191

[2] Castello NA, Nguyen MH, Tran JD, Cheng D, Green KN, LaFerla FM (2014). “7,8-Dihydroxyflavone, a small molecule TrkB agonist, improves spatial memory and increases thin spine density in a mouse model of Alzheimer disease-like neuronal loss”. PLoS ONE 9 (3): e91453. doi:10.1371/journal.pone.0091453. PMC 3948846. PMID 24614170.

Chen C, Li XH, Zhang S, Tu Y, Wang YM, Sun HT (2014). “7,8-dihydroxyflavone ameliorates scopolamine-induced Alzheimer-like pathologic dysfunction”. Rejuvenation Res 17 (3): 249–54. doi:10.1089/rej.2013.1519. PMID 24325271.

Zhang Z, Liu X, Schroeder JP, Chan CB, Song M, Yu SP et al. (2014). “7,8-dihydroxyflavone prevents synaptic loss and memory deficits in a mouse model of Alzheimer’s disease”. Neuropsychopharmacology 39 (3): 638–50. doi:10.1038/npp.2013.243. PMID 24022672.

[3] Yang YJ, Li YK, Wang W, Wan JG, Yu B, Wang MZ et al. (2014). “Small-molecule TrkB agonist 7,8-dihydroxyflavone reverses cognitive and synaptic plasticity deficits in a rat model of schizophrenia”. Pharmacol. Biochem. Behav. 122: 30–6. doi:10.1016/j.pbb.2014.03.013. PMID 24662915.

[4] Jang SW, Liu X, Yepes M, Shepherd KR, Miller GW, Liu Y et al. (2010). “A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone”. Proc. Natl. Acad. Sci. U.S.A. 107 (6): 2687–92. doi:10.1073/pnas.0913572107. PMC 2823863. PMID 20133810.

[5] Jiang M, Peng Q, Liu X, Jin J, Hou Z, Zhang J et al. (2013). “Small-molecule TrkB receptor agonists improve motor function and extend survival in a mouse model of Huntington’s disease”. Hum. Mol. Genet. 22 (12): 2462–70. doi:10.1093/hmg/ddt098. PMC 3658168. PMID 23446639.

[6] Korkmaz OT, Aytan N, Carreras I, Choi JK, Kowall NW, Jenkins BG et al. (2014). “7,8-Dihydroxyflavone improves motor performance and enhances lower motor neuronal survival in a mouse model of amyotrophic lateral sclerosis”. Neurosci. Lett. 566: 286–91. doi:10.1016/j.neulet.2014.02.058. PMID 24637017

[7] Wu CH, Hung TH, Chen CC, Ke CH, Lee CY, Wang PY et al. (2014). “Post-injury treatment with 7,8-dihydroxyflavone, a TrkB receptor agonist, protects against experimental traumatic brain injury via PI3K/Akt signaling”. PLoS ONE 9 (11): e113397. doi:10.1371/journal.pone.0113397. PMC 4240709. PMID 25415296.

[8] Wang B, Wu N, Liang F, Zhang S, Ni W, Cao Y et al. (2014). “7,8-dihydroxyflavone, a small-molecule tropomyosin-related kinase B (TrkB) agonist, attenuates cerebral ischemia and reperfusion injury in rats”. J. Mol. Histol. 45 (2): 129–40. doi:10.1007/s10735-013-9539-y. PMID 24045895.Uluc K, Kendigelen P, Fidan E, Zhang L, Chanana V, Kintner D et al. (2013). “TrkB receptor agonist 7, 8 dihydroxyflavone triggers profound gender- dependent neuroprotection in mice after perinatal hypoxia and ischemia”. CNS Neurol Disord Drug Targets 12 (3): 360–70. PMC 3674109. PMID 23469848.

[9] Flavonoids, Coumarins, and Cinnamic Acids as Antioxidants in a Micellar System. Structure−Activity Relationship†

[10] Antioxidant activity of 7,8-dihydroxyflavone provides neuroprotection against glutamate-induced toxicity.  

In Search of Geroprotectors: The Final Four Have Been Identified

A geroprotector is one of the five different types of senotherapeutic strategies that aims to affect the root cause of aging and age-related diseases, and thus prolong the life span of animals.  Geroprotectors utilize agents and strategies which prevent or reverse the senescent state by preventing triggers of cellular senescence, including:

  • DNA damage
  • Oxidative stress
  • Proteotoxic stress
  • Telomere shortening

Senotherapeutics refers to therapeutic agents and strategies that specifically target cellular senescence and include any of the following therapies:

  • Gene therapy
  • Geroprotectors
  • Immune clearance of senescent cells
  • SASP inhibitors
  • Senolytics  (compounds capable of identifying and eliminating senescent cells)

Senescent cells enter a stage in which they no longer properly divide and function and become dysfunctional, which utlimately leads to organ failure.  Senescent cells also generate pro-inflammatory compounds which potentially damage healthy tissues.

Senolytics and geroprotectors eliminate aging and senescent cells from the tissues which then makes room for newer more active cells.

Life Extension® has partnered with Insilico Medicine to identify nutrient cocktails that function as geroprotectors by employing artificial intelligence biomedical algorithms.  These strategic uses of high-speed computer programs accelerates the research into potential geroprotectors. 

In a study published on April 23, 2016 in the Journal Aging, the authors, including Life Extension® and Insilico Medicine, among others, used GeroScope to develop a list of geroprotectors. 1

GeroScope is a computational tool that can aid prediction of novel geroprotectors from existing human gene expression data. GeroScope maps expression differences between samples from young and old subjects to aging-related signaling pathways, then profiles pathway activation strength (PAS) for each condition.

Known substances are then screened and ranked for those most likely to target differential pathways and mimic the young signalome. 

The study identified and shortlisted ten substances, all of which have lifespan-extending effects in animal models.  These ten substances include:

  • 7-Cyclopentyl-5-(4-phenoxy)phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine
  • Epigallocatechin gallate (EGCG)
  • Fasudil (HA-1077)
  • HA-1004
  • Myricetin
  • N-acetyl-L-cysteine (NAC)
  • Nordihydroguaiaretic acid (NDGA)
  • PD-98059
  • Staurosporine
  • Ursolic acid
Drug Code Model Organism Lifespan (LS) Parameter % Increase Ref.
Nordihydroguaiaretic acid A D. melanogaster Median LS 23 [47]
Mus Musculus Median LS 12 [48]
Myricetin B C. elegans Mean LS 32.9 [48,49]
HA-1004 C D. melanogaster Mean LS 18 [50]
7-Cyclopentyl-5-(4-phenoxy)phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine D C. elegans Mean LS 11 [51]
Staurosporine E D. Melanogaster Mean LS 34.8 [50]
Ursolic acid F C. elegans Mean LS 39 [52]
N-acetyl-L-cysteine G Mice Max LS 40 [53]
Fasudil (HA-1077) H D. melanogaster Mean LS 14.5 [50]
PD-98059 I D. melanogaster Mean LS 27 [50]
Epigallocatechin gallate J C. elegans Mean LS 10.1 [54]
Rattus norvegicus Median LS 13.5 [55]

Table 3. Previously reported lifespan effects of test substances in animal models (compiled from geroprotectors.org [15].)  Source:  In search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state

The researchers narrowed down the list of ten substances to the final four compounds, which include:

  • Gamma tocotrienol (Vitamin E)
  • Epigallocatechin gallate (EGCG) (found in Green tea)
  • N-acetyl-L-cysteine (NAC)
  • Myricetin

These final four compounds combat numerous aging factors throughout the body by working together by influencing key anti-aging pathways. 

The researchers concluded that these four compounds reduced cellular aging and protect against the development of senescent cells by modulating a group of signaling pathways.

For a breakdown of the various pathways modulated by the final four compounds, read and review the April 2017 article from Life Extension®.

Life Extension® has combined these final four compounds into a new supplement product called GEROPROTECT™ Ageless Cell™.  Supplementing with this product may reduce the body’s burden of senescent cells.  

Sangre de Grado: A Powerful Antioxidant

Sangre de Grado (Peruvian Spanish) or Sangre de Drago (Ecuadorian Spanish) is known by its botantical name as Croton lechleri and  is a species of flowering plant that is native to northwestern South America.  It translates to “Dragon’s Blood”.  The dragon’s blood refers to the trees thick red latex.

imagen_sangre_drago_01

Red sap (latex) of Sangre de Grado tree bark

Sangre de Grado includes a number of biologically active chemical substances:

  • Alpha-Calacorene
  • Alpha-Copaene
  • Alpha-Pinene
  • Alpha-Thujene
  • Beta-Caryophyllene
  • Beta-Elemene
  • Betaine
  • Beta-Pinene
  • Borneol
  • Calamenene
  • Camphene
  • Cuparophenol
  • Dimethylcedrusine
  • Dipentene
  • Eugenol
  • Euparophenol
  • Gamma-Terpinene
  • Gamma-Terpineol
  • Lignin
  • Limonene
  • Linalool
  • Methylthymol
  • Oligomeric Proanthocyanidins (OPC)
  • P-Cymene
  • Tannins
  • Taspine
  • Terpinen-4-ol
  • Vanillin

Purported Uses of Sangre de Grado

Taspine is an alkaloid which acts as a potent acetylcholinesterase inhibitor. [1] Taspine has also been found to be a dual topoisomerase inhibitor effective in cells overexpressing drug efflux transporters and induces wide-spread apoptosis in multicellular spheroids. [2]

Taspine promotes early phases of wound healing in a dose-dependent manner with no substantial modification due to its mechanism of action related to its chemotactic properties on fibroblasts. [3]

Taspine has also shown anti-inflammatory potential. [4]

Dimethylcedrusine, another biologically active substance in Sangre de Grado, was shown to inhibit thymidine incorporation, while protecting cells against degradation in a starvation medium. [5]

Sangre de grado exerts anti-viral effects against influenza viruses, parainfluenza viruses, herpes simplex viruses types I and II, hepatitis A virus and hepatitis B virus. [6]

Sangre de grado may also present a complementary and alternative medicine approach for the treatment of fluid loss in watery diarrhea. [7]

Sangre de grado has also been found to induce apoptosis in human gastrointestinal cancer cells. [8]

Antioxidant Activity of Sangre de Grado

Another important health benefit to Sangre de Grado is its potential as a powerful antioxidant herb.

An article published in the Nutrition Journal in 2010 entitled The total antioxidant content of more than 3100 foods, beverages, spices, herbs and supplements used worldwide, by Monica H Carlsen, Bente L Halvorsen, Kari Holte, Siv K Bøhn, Steinar Dragland, Laura Sampson, Carol Willey, Haruki Senoo, Yuko Umezono, Chiho Sanada, Ingrid Barikmo, Nega Berhe, Walter C Willett, Katherine M Phillips, David R Jacobs, Jr, and Rune Blomhoff, found that Sange de Grado had the highest antioxidant content of the 59 herbal products tested in the database.

Sange de Grado tested at 2897.1 mmol/100 g, much higher than the next highest herb formula Triphala at 706.25 mmol/100 g.

Other antioxidant rich products are Triphala, Amalaki and Arjuna from India and Goshuyu-tou, a traditional kampo medicine from Japan, with antioxidant values in the range of 132.6 to 706.3 mmol/100 g. [9]


References:

[1] Rollinger, JM; Schuster, D; Baier, E; Ellmerer, EP; Langer, T; Stuppner, H (2006). “Taspine: Bioactivity-guided isolation and molecular ligand-target insight of a potent acetylcholinesterase inhibitor from Magnolia x soulangiana”. Journal of Natural Products 69 (9): 1341–1346. doi:10.1021/np060268p. PMC 3526713. PMID 16989531

[2] Identification of a Novel Topoisomerase Inhibitor Effective in Cells Overexpressing Drug Efflux Transporters

[3] Porras-Reyes, B. H., et al. Enhancement of wound healing by the alkaloid taspine defining mechanism of action. Proc Soc Exp Biol Med. 203(1):18-25, 1993.

[4] Perdue, G. P., et al. South American plants II: taspine isolation and anti-inflammatory activity. J Pharm Sci. 68(1):124-126, 1979

[5] Isolation of a dihydrobenzofuran lignan from South American dragon’s blood (Croton spp.) as an inhibitor of cell proliferation

[6] Williams, J. E. Review of antiviral and immunomodulating properties of plants of the Peruvian rainforest with a particular emphasis on una de gato and sangre de grado. Alternative Medicine Review. 6(6):567-579, 2001

[7] Fischer, H., et al. A novel extract SB-300 from the stem bark latex of Croton lechleri inhibits CFTR-mediated chloride secretion in human colonic epithelial cells. Journal of Ethnopharmacology. 93(2-3):351-357, 2004.

[8] Sangre de grado Croton palanostigma induces apoptosis in human gastrointestinal cancer cells

[9] The total antioxidant content of more than 3100 foods, beverages, spices, herbs and supplements used worldwide; Nutr J. 2010; 9: 3. Published online 2010 Jan 22. doi: 10.1186/1475-2891-9-3


Informational References:

The Antioxidant Food Table, Carlsen et al. 2010 (PDF)

Memorial Sloan Kettering Cancer Center

Note: PDF files require a viewer such as the free Adobe Reader


Resources:

Herb Pharm Dragon’s Blood (Sangre de Drago) Liquid Tree Sap for Digestive Support – 1 Ounce