Monthly Archives: April 2017

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High-mobility group protein 1 (HMG-1): A Marker of Chronic Inflammation

High-mobility group protein 1 (HMG-1) is a protein that in humans is encoded by the HMGB1 gene.

HMGB1 turns on the release of chemical signals called cytokines that generate inflammation in your body.

The molecule HMGB1 is responsible for initiating acute inflammation, which is a helpful reaction when your body is under attack by germs, or following an injury. Unfortunately, when a cell is damaged, its contents of HMGB1 leak out, leading to chronic inflammation.

When HMGB1 leaks out, it acts as a “danger signal” that triggers the release of chemical signaling molecules (called cytokines) that call in more white blood cells, which release still more cytokines, in a vicious cycle.

Inhibiting HMGB1 is a powerful means of slowing and reversing the processes involved in inflammation.

HMGB1 serves as a risk factor for memory impairment, chronic neuro-degeneration, and progression of neuro-inflammation. 1

The Table below lists the recognized and researched substances that may inhibit High-mobility group protein 1 (HMG-1):

Substances that Inhibit HMGB1

HMGB1  
CategoryNutraceuticals/Foods/HerbsReference(s)
Foods
Mung Bean Coat Extract1 2 vitexin, isovitexin
Herbs
Green Tea4 5 6 7
Angelica sinensis (Dong Quai)8
Lipids
Glycyrrhizin (Licorce)9


Resources:

Life Extension Cytokine Suppress with EGCG


 

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  

The Proposed Nine Hallmarks of Aging

Scientist and researchers have attempted to identify and categorize the cellular and molecular hallmarks of aging in a published paper in the research journal Cell on 6th June 2013.  1 

In this paper, researchers proposed nine candidate hallmarks that are generally considered to contribute to the aging process and together determine the aging phenotype.

These nine hallmarks include:

  • altered intercellular communication
  • cellular senescence
  • deregulated nutrient-sensing
  • epigenetic alterations
  • genomic instability
  • loss of proteostasis
  • mitochondrial dysfunction
  • stem cell exhaustion
  • telomere attrition

large Image

The 9 Hallmarks of Aging  (Source: The Hallmarks of Aging)

Researchers set three criteria for each ‘hallmark’:  2

  • it should manifest during normal aging;
  • its experimental aggravation should accelerate aging; and
  • its experimental amelioration should retard the normal aging process and, hence, increase healthy lifespan.

The challenge that the researchers encountered was to show the interconnectedness between the candidate hallmarks and their relative contribution to aging.  The ultimate goal of the research was to “identifying pharmaceutical targets to improve human health during aging with minimal side-effects.”  3

A clear and easy to understand article on the nine Hallmarks of Aging was published by Geroscience.com on 23rd February 2017.  This article, written by Alexandra Bause, PhD, examines each of the nine hallmarks in plain English and provides a better understanding beyond the original publication in the journal Cell.   

Despite the fact that these hallmarks can be complex and complicated and the understanding of them are still limited, there is hope that new medical strategies will emerge that will ameliorate the the normal aging process.

Geroscience.com is the premier site for news, discussion, and scientific insight related to the basic biology of aging and the development of new medicines with the ability to cure or prevent the diseases of aging.

Geroscience.com is committed to bringing its readers the most interesting developments in the science of aging and will: 4

  • Feature a wide range of multimedia content including interviews with experts, looks behind the scenes of everyday lab life, and the latest trends from longevity conferences
  • Capture the perspectives of leading researchers, entrepreneurs, and other experts to act as a platform to share ideas about aging and longevity
  • Cover the emerging biotechnology business of geroscience, including investment coverage, clinical trial data, and insight into the regulatory world
  • Aid collaboration between cross-functional scientific communities, connecting researchers, investors, and industry heads from around the globe

  

Read the article at Geroscience.com:

The hallmarks of aging, in plain English, by Alexandra Bause, PhD at Geroscience.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.

Free E-Book: Enhancing the Growth of New Brain Cells

In 1998, neuroscientists undertook to investigate whether neurogenesis occurs in the adult human brain. They concluded that the human hippocampus retains its ability to generate neurons throughout life. Their results were published in the medical journal Nature Medicine.

While conducting their research, they discovered that the brain contains neural stem cells and progenitor cells which differentiate into brain neurons.

Since DNA ultimately controls the process of neurogenesis, there are specific genes that code for the production of various proteins called neurotrophins. These neurotrophins play a key role in the birth of new brain cells.

The birth of new neurons (neurogenesis) is highly related to neuroplasticity. Neuroplasticity is the ability of a particular part or region of a neuron to change in strength over time. It refers to changes in neural pathways and synapses due to changes in behavior, environment, neural processes, thinking, emotions, as well as changes resulting from bodily injury. Neuroplasticity has replaced the formerly-held position that the brain is a physiologically static organ, and explores how – and in which ways – the brain changes throughout life.

Brain atrophy is a condition in which the brain is in the process of shrinking (or a limited portion of the brain is shrinking) and that little if no neurogenesis is taking place.

If you were to look at neurogenesis as a full spectrum, you would find enhanced and optimal neurogenesis and brain atrophy as polar opposites on this spectrum.

The full spectrum would reveal that in a healthy fully optimized brain there would be enhanced neurogenesis; yet in a compromised brain there would first be neuroinflammation, then at the opposite end, brain atrophy.

The E-book on Neurogenesis will examine the natural substances that can be consumed in the form of Nootropics, Nutraceuticals, Foods, Herbs and Spices to maximize the state of enhanced neurogenesis and to enhance the three (3) main neurotrophins that facilitate neurogenesis.

In addition, the subject of Brain Atrophy will be examined and the recommended substances that can be consumed to prevent and inhibit brain atrophy.

Download Free E-book (PDF):  Enhancing the Growth of New Brain Cells

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.  

Ginkgo biloba Increases Global Cerebral Blood Flow

One of the leading factors of cognitive impairment leading to dementia and eventually Alzheimer’s disease is a condition where there is insufficient blood flow to the brain or an inadequate supply of blood to the brain. 

The condition of reduced blood flow to the brain is called cerebral ischemia or hypoperfusion of the brain.

Hypoperfusion of the brain can severely diminish neurological function and is often the first indication of changes that impact the brain and which precedes structural deterioration of the brain.  1

Researchers published a study in March 2011 that sought to determine if changes in cerebral blood flow could be detected by dynamic susceptibility contrast-enhanced magnetic resonance imaging (DSC-MRI) in elderly human subjects taking an Extract of Ginkgo biloba (EGb).   2

Image result for ginkgo biloba

Ginko biloba leaves

The test subjects were nine healthy men with a mean age of 61±10 years.  They took 60 mg EGb twice daily for 4 weeks.

Cerebral blood flow (CBF) values were computed before and after EGb, and analyzed at three different levels of spatial resolution, using voxel-based statistical parametric mapping (SPM), and regions of interest in different lobes, and all regions combined.

Test results showed a small CBF increase in the left parietal–occipital region. CBF in individual lobar regions did not show any significant change post-EGb, but all regions combined showed a significant increase of non-normalized CBF after EGb (15% in white and 13% in gray matter, respectively, P≤0.0001).

Researchers concluded that a mild increase in CBF is found in the left parietal–occipital WM after EGb, as well as a small but statistically significant increase in global CBF.

Cover Photo credit: Radu Jianu, Brown University