Category Archives: Immunity

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Probiotic Propionibacterium freudenreichii Extends the Mean Lifespan of Caenorhabditis elegans via Activation of the Innate Immune System

Propionibacterium freudenreichii is a short-chain fatty acid (SCFA)-producing bacterium which ferments lactate to:

  • acetate
  • propionate
  • carbon dioxide

The two short-chain fatty acids, acetate and propionate have been shown to enhance human gut immunity.

A study published in the Journal Scientific Reports in August 2016 evaluated the effects of Propionibacterium freudenreichii on lifespan extension and to elucidate the mechanism of Propionibacterium freudenreichii -dependent lifespan extension in Caenorhabditis elegans.  1 

Caenorhabditis elegans is a small, free-living soil nematode commonly used as a model experimental animal because it is easy to treat, has a short lifespan, can be safely used in the laboratory and propagates through self-fertilization. In particular, C. elegansis frequently used in studies on longevity, immunity, neurodegenerative diseases, fat storage, DNA damage responses and apoptosis.

The results of the study showed that Propionibacterium freudenreichii significantly (p < 0.05) extended the lifespan of C. elegans compared with Escherichia coli OP50, a standard food for the worm.

The MLS of Propionibacterium freudenreichii-fed C. elegans, compared with that of E. coliOP50-fed worms, increased by approximately 13%. The survival rates were similar in both the Propionibacterium freudenreichii- and E. coli OP50-fed C. elegans until day 13.

After day 13, the two groups showed a significant difference in the survival rate.  Analysis of age-related biomarkers showed that Propionibacterium freudenreichii retards ageing.

 

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Figure 1.  The effect of Propionibacterium freudenreichii on the lifespan of C. elegans (N2).  Maturing nematodes were fed E. coli OP50 until the L4 stage, and young adult worms were transferred to a fresh mNGM plate seeded with E. coli OP50 or Propionibacterium freudenreichii . Significant differences shown are relative to E. coli OP50; ***p < 0.001. (Source)

The researchers concluded that Propionibacterium freudenreichii extends the lifespan of C. elegans via the p38 MAPK pathway involved in stress response and the TGF-β pathways associated with anti-inflammation processes in the immune system.  2

Natural Rapalogs that Inhibit the mTOR Pathway

In 1975 scientists discovered the mycelial bacterium Streptomyces hygroscopicus on Rapa Nui, the native name of Easter Island.  From this bacterium they created the molecule named Rapamycin, a pharmaceutical drug which requires a doctor’s prescription.  Also known as Sirolimus, it is an immunosuppressant drug used in orthodox medicine to prevent rejection following organ transplantation.

In addition to its use as an immunosuppressant drug, Rapamycin inhibits the mTOR signalling pathway and studies show it can significantly extend lifespan in mammals, even when taken in later life, with increases in life expectancy for males and females of between 9% and 14% respectively.


 

mTOR Pathway  

“mTOR” or the mechanistic target of rapamycin (mTOR), (formerly mammalian target of rapamycin before it was recognized to be highly conserved among eukaryotes) refers to an enzyme from the serine/threonine protein kinase family encoded by the mTOR gene. It is found in humans as well as worms, mice, flies and yeasts. It regulates the growth, proliferation, motility and survival of cells.

Successfully inhibiting mTOR signalling pathways has been shown to produce increased lifespan in worms, flies, yeasts and even mice if accompanied by calorie restriction and the consumption of adequate protein.

 

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Figure 1.  mTOR Pathway  (Source)

Since Rapamycin is poorly water soluble, which effects its bioavailability, several analogs of Rapamycin have been developed and are termed rapalogs.  Some of these rapalogs have improved pharmacokinetics and include:

  • temsirolimus
  • everolimus
  • ridaforolimus
  • 32-deoxo-rapamycin
  • zotarolimus

The use of these pharamaceutical rapalogs have been generally disappointing in human trials.  One possible explanation for the disappointing results to date is that in human cancer, rapalogs predominately inhibit mTORC1, leading to increased PI3K and AKT signaling by preventing negative feedback through S6K and GRB10.  1 

Recent studies have demonstrated that a number of natural products (or nutraceuticals) isolated from plants (e.g. fruits, vegetables, spices, nuts, legumes, herbs, etc.) also inhibit the mTOR pathway, and exhibit potent anticancer activities. These particular natural products are considered “natural rapalogs”.

The Table below lists the identified natural substances that are considered natural rapalogs or mTOR inhibitors:

Natural Rapalogs (mTOR Inhibitors)

CategorySubstanceReference
Alkaloids
Caffeine1
Amino Acids
NAC2
Herbs
Astragalus3
β-elemene (from the traditional Chinese medicinal herb Rhizoma zedoariae)4
Butein (in the stems of Rhus verniciflua)5
Capsaicin (in chili peppers)6
Celastrol (in the traditional Chinese medicine named “Thunder of God Vine”)7
Cryptotanshinone (Salvia miltiorrhiza Bunge) (Danshen)8
Rhodiola rosea9
Indoles
Indole-3-carbinol and 3,3′-diindolylmethane)10
Mushrooms
Reishi11
Peptides
Carnosine12
Polyphenols
Apigenin13
Curcumin14
Epigallocatechin gallate (EGCG, in green tea)15
Fisetin16
Isoflavones (genistein and deguelin)17
Quercetin18
Resveratrol19
Vitamins
R-Lipoic Acid20
Tocotrienol (Vitamin E)21

The Multiple Health Benefits of Tributyrin, a Triglyceride Form of Butyrate

Short-Chain Fatty Acids

A considerable amount of scientific interest has been focused on short chain fatty acids (SCFAs) for improving colonic and systemic health, and specifically reducing the risk of inflammatory diseases, diabetes, and cardiovascular disease.

Researchers have shown that SCFAs have distinct physiological effects:  1

  • they contribute to shaping the gut environment
  • they influence the physiology of the colon
  • they can be used as energy sources by host cells and the intestinal microbiota 
  • they also participate in different host-signaling mechanisms

Prebiotics, which consist of primarily dietary carbohydrates such as resistant starch and dietary fibers, are the substrates in the large intestine for fermentation that produce SCFAs.  The other source of SCFA, although in smaller amounts than dietary carbohydrates, are amino acids.  Three amino acids:

  • valine
  • leucine
  • isoleucine

obtained from protein breakdown can be converted into isobutyrate, isovalerate, and 2-methyl butyrate, known as branched-chain SCFAs (BSCFAs), which contribute very little (5%) to total SCFA production.  2

There are seven short-chain fatty acids that are produced by the large intestine through the fermentation of dietary fiber and resistant starch.  Of these seven short-chain fatty acids, three of them are the most important and common:

  • acetate
  • propionate
  • butyrate

These three represent about 90–95% of the SCFA present in the colon.  The rate and amount of SCFA production depends on the species and amounts of microflora present in the colon, the substrate source and gut transit time.

Butyrate is the major energy source for colonocytes. Propionate is largely taken up by the liver. Acetate enters the peripheral circulation to be metabolized by peripheral tissues and is the principal SCFA in the colon, and after absorption it has been shown to increase cholesterol synthesis.

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Figure 1.  Fibers, specific oligosaccharides and resistant starch reach the colon intact, where they induce shifts in the composition and function of intestinal bacteria (shifts indicated by different colors). Intestinal bacteria use these compounds as substrates for the production of the short-chain fatty acids acetate, propionate and butyrate. These microbial metabolites are taken up by intestinal epithelial cells called enterocytes. Butyrate mainly feeds the enterocytes, whereas acetate and propionate reach the liver by the portal vein.  (Source:  You are what you eat,  Nature Biotechnology  32, 243–245 (2014) doi:10.1038/nbt.2845)

Butyrate (Butyric Acid)

The most important short-chain fatty acid is butyrate.

Butyrate is a primary energy source for colonic cells.  3 4   Butyrate also has demonstrated anti-inflammatory properties.  5  Butyrate may also have a role in preventing certain types of colitis. A diet low in resistant starch and fiber, which will result in a low production of SCFAs in the colon, may explain the high occurrence of colonic disorders seen in the Western civilization.  6

Studies have demonstrated that butyrate has anti-carcinogenic properties:

  • It inhibits the growth and proliferation of tumor cell lines in vitro.  7
  • It induces differentiation of tumor cells, producing a phenotype similar to that of the normal mature cell.  8
  • It induces apoptosis or programmed cell death of human colorectal cancer cells.  9 10
  • It inhibits angiogenesis by inactivating Sp1 transcription factor activity and down regulating VEGF gene expression. 11

Butyrate has been studied for its role in nourishing the colonic mucosa and in the prevention of cancer of the colon, by promoting cell differentiation, cell-cycle arrest and apoptosis of transformed colonocytes; inhibiting the enzyme histone deacetylase and decreasing the transformation of primary to secondary bile acids as a result of colonic acidification.

Therefore, a greater increase in SCFA production and potentially a greater delivery of SCFA, specifically butyrate, to the distal colon may result in a protective effect.   12

Butyrate is mainly taken up by the colon epithelial cells, only small amounts reach the portal vein and the systemic circulation.  The primary beneficial effects of butyrate occurs at the intestinal level, yet there are additional benefits at the extra intestinal level:

Intestinal effects

  • Is the preferred energy source for the colon epithelial cells
  • Decreases the pH of the colon (which decreases bile salt solubility, increases mineral absorption, decreases ammonia absorption, and inhibits growth of pathogens)
  • Stimulates proliferation of normal colon epithelial cells
  • Prevents proliferation and induces apoptosis of colorectal cancer cells
  • Affects gene expression of colon epithelial cells
  • Plays a protective role against colon cancer and colitis
  • Improves the gut barrier function by stimulation of the formation of mucin, antimicrobial peptides, and tight-junction proteins
  • Interacts with the immune system and regulates immune function
  • Has anti-inflammatory effects
  • Stimulates the absorption of water and sodium
  • Reduces oxidative stress in the colon
  • Assists in ion absorption
  • Assists in proper intestinal motility
  • Induces cell cycle arrest, differentiation, and apoptosis in colon cancer cells

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Figure 2.  The multiple effects of butyrate at the intestinal level.  (Source:  Potential beneficial effects of butyrate in intestinal and extra intestinal diseases)

Extra intestinal effects  13

  • Insulin sensitivity
  • Cholesterol synthesis
  • Energy expenditure
  • Ammonia scavenger
  • Stimulation of β-oxidation of very long chain fatty acids and peroxisome proliferation
  • CFTR function
  • Neurogenesis
  • HbF production

Tributyrin

The major problem with butyrate is achieving high concentrations in the blood. Butyrate is metabolized rapidly as soon as it enters the enteroocytes via its active transport system, and its plasma concentrations are far below those required to exert its antiproliferative/differentiating actions.  14 

An alternative and more advantageous form of butyric acid is the triglycerine form called Tributyrin, also known as glyceryl tributyrate. Tributyrin is a triglyceride containing 3 molecules of butyric acid which are bound by a glycerol molecule. 

Tributyrin is naturally present in butter in trace amounts.  However, it is not recommended to consume butter as a means to obtain therapeutic amounts of tributyrin.  There is no point to recommend consuming butter to someone if the intention is to increase butyric acid consumption.

As an alternative to consuming butter, tributyrin can now be consumed in the form of a supplement or a food additive and can provide considerable amounts of butyrate to the intestine in addition to the endogenous production of SCFAs (butyrate) from the fermentation of dietary fibers.

Tributyrin is known to overcome the pharmacokinetic drawbacks of butyrate.  Because it is rapidly absorbed and chemically stable in plasma, tributyrin diffuses through biological membranes and is metabolized by intracellular lipases, releasing therapeutically effective butyrate over time directly into the cell. 

Ball-and-stick model of the butyrin molecule

Figure 3.  Ball-and-stick model of the tributyrin molecule, the triglyceride of butyric acid.  Source:  By Jynto (talk) – Own workThis chemical image was created with Discovery Studio Visualizer., CC0, https://commons.wikimedia.org/w/index.php?curid=20234384

The technique of attaching butyrate to a glycerol molecule turns the new molecule (tributyrin) into a fat. The attachment of a glycerol molecule to 3 butyric acid molecules is through an ester bond which can only be broken by a specific enzyme called pancreatic lipase.  

Pancreatic lipase is secreted from the pancreas into the small intestine (duodenum) and not in the stomach.  Because of this, tributyrin stays intact in the stomach but once it reaches the small intestine (duodenum), the 3 butyric acid molecules are released by the pancreatic lipase enzyme. 

After the pancreatic lipase action, two free butyric acid molecules and one monobutyrin molecule are formed where they are used in the intestine and taken up by the enterocytes. After transportation through the portal vein they are metabolized in the liver. 

chem formula

Figure 4.  Ester bond of glycerol and 3 butyric acid molecules.  (Source: Bioremediation of Fats and Oils)

The tributyrin form of butyrate ensures high bioavailability of butyrate in all the sections of the small intestine.  Because tributyrin is a delayed release source of butyrate, it achieves more sustained plasma levels. 

According the the U.S. Federal Drug Administration (FDA), tributyrin is a food substance affirmed as Generally Recognized As Safe (GRAS).  15

Multiple Health Benefits of Tributyrin 

Specific studies on tributyrin have demonstrated multiple benefits in a number of disease conditions by releasing therapeutically effective butyrate over time directly into the cell.  The advantage with tributyrin is that it has all the health benefits of butyrate, as evidenced above, as well as its own specific targeted health benefits.

Some of the more important and specific health benefits of tributyrin include:

  • Anticarcinogenic potential
    • Colon cancer
    • Leukemia
    • Melanoma
    • Liver cancer (apoptosis)
  • Alzheimer’s disease and Dementia
  • Antibiotic-associated diarrhea (AAD)
  • Lipopolysaccharide (LPS)-induced liver injury
  • Inflammation

Anticarcinogenic potential

In vitro and in vivo studies have shown that tributyrin acts on multiple anticancer cellular and molecular targets without affecting non-cancerous cells. The mechanisms of action of tributyrin as a anticarcinogenic agent include:  16

  • the induction of apoptosis
  • cell differentiation
  • the modulation of epigenetic mechanisms

Due to the minimum toxicity profile of tributyrin, it is an excellent candidate for combination therapy with other agents for the control of cancer. 

Colon cancer

Tributyrin was shown to be more potent in inhibiting growth and inducing cell differentiation than natural butyrate on growth, differentiation and vitamin D receptor expression in Caco-2 cells, a human colon cancer cell line.  17

Tributyrin provides a useful therapeutic approach in chemoprevention and treatment of colorectal cancer.   

In another in vitro study, tributyrin showed potent antiproliferative, proapoptotic and differentiation-inducing effects in neoplastic cells.  18

Leukemia

In this study monobutyrin (MB) and tributyrin (TB) were studied in vitro for their effects on inducing differentiation of human myeloid leukemia HL60 cells and murine erythroleukemia cells. On a molar basis TB was about 4-fold more potent than either BA or MB for inducing differentiation of HL60 cells. BA, MB, or TB induced erythroid differentiation of murine erythroleukemia cells.  19

Melanoma

A study from February 2011 sought to investigate a possibility to develop tributyrin emulsion as a potent anti-cancer agent against melanoma. Tributyrin emulsion was more potent than butyrate in inhibiting the growth of B16-F10 melanoma cells. Accumulation of cells at sub G(0)/G(1) phase and the DNA fragmentation induced by tributyrin emulsion treatment revealed that tributyrin emulsion inhibited the growth of B16-F10 cells by inducing apoptosis. Treatment with tributyrin emulsion suppressed the colony formation of melanoma cells in a dose-dependent manner.  20

The data from this study suggests that tributyrin emulsion may be developed as a potent anti-cancer agent against melanoma.

Liver cancer

Researchers in this study from November 1999 investigated whether butyrate could induce apoptosis in transformed human liver (Hep G2) cells. Hep G2 cells treated with butyrate displayed acetylated histones, increased DNA fragmentation and morphological features consistent with apoptosis. 

They also investigated whether butyrate present in tributyrin, a triacylglycerol more compatible for inclusion into colloidal lipid structures than butyrate, could also induce apoptosis in Hep G2 cells.

Tributyrin induced DNA fragmentation and morphological features characteristic of apoptotic cells in Hep G2 cells.

These results are a significant advance towards delivering butyrate via colloidal lipid particles to cancerous sites in vivo. This study showed that butyrate and tributyrin are potent apoptotic agents. 21

Alzheimer’s disease and Dementia

Recent research at MIT has determined that, in rodent models of Alzheimer’s dementia, the negative impact of amyloid beta exposure on neuronal function and new memory formation results largely from increased neuronal expression of an enzyme known as HDAC2 (histone deacetylase 2).

A study from March 2004 showed that tributyrin may have the most practical potential to inhibit HDAC by blunting microglial activation. Tributyrin is anti-inflammatory in primary, brain-derived microglial cells.  A blunting of microglial cytokine production might in itself have a favorable impact on progression of Alzheimer’s.  22  23  

Antibiotic-associated diarrhea (AAD)

In a recent study from November 2014, researchers hypothesized that antibiotic-induced changes in gut microbiota reduce butyrate production, varying genes involved with gut barrier integrity and water and electrolyte absorption, lending to AAD, and that simultaneous supplementation with the probiotic Lactobacillus GG  and/or tributyrin would prevent these changes.

Optimizing intestinal health with Lactobacillus GG and/or tributyrin may offer a preventative therapy for AAD.  24  Lipopolysaccharide (LPS)-induced liver injury

In this study from April 2015, researchers elucidated the protective effect of oral administration of tributyrin against LPS-mediated lipid metabolism disorder in rats.  Tributyrin suppresses lipopolysaccharide (LPS)-induced liver injury through attenuating nuclear factor-κB activity with an increased hepatoportal butyrate level.  25

Inflammation

Another study from May 2015 was carried out to investigate the effects of tributyrin (TB) on the growth performance, pro-inflammatory cytokines, intestinal morphology, energy status, disaccharidase activity, and antioxidative capacity of broilers challenged with lipopolysaccharide (LPS).

Taken together, these results suggest that the TB supplementation was able to reduce the release of pro-inflammatory cytokines and improve the energy status and anti-oxidative capacity in the small intestine of LPS-challenged broilers.  26

ELiE Health Solutions

Tributyrin is now available for purchase by consumers and professionals directly from ELiE Health Solutions as a product called BUTYCAPS.

ELiE Health Solutions, based in Sevilla, Spain, was formed through a project based on the science of the microbiota and probiotics.

ELiE Health Solutions is named after Elie Metchnikoff, famed microbiologist and the recipient of the 1908 Nobel Price in Physiology. A century ago he proposed the benefit of acid lactic bacteria to the human host and their role in health and longevity.

David Manrique, a pharmacist with ELiE Health Solutions describes the challenges of finding a more bio-available form of butyric acid:

“The challenge was to find a chemical form of enteric release of butyric acid, and also to ensure microencapsulated as slowly and delayed release possible. It has been a great innovative effort, but we are very satisfied with the results.”  27 

ELiE Health Solutions was successful in developing a delayed release form of butyric acid (tributyrin) using microencapsulation technology in their product BUTYCAPS.  The microencapsulation technology of BUTYCAPS allows a slower and gradual release along the intestine. 

BUTYCAPS contains 900 mg of Tributyrin equivalent to 787 mg of butyric acid in each sachet. Each box contains 30 sachets.  BUTYCAPS are non-chewable granules.

170126_3dbutycaps

Figure 5.  BUTYCAPS product from ELiE Health Solutions

BUTYCAPS can be purchased directly from ELiE Health Solutions. 

Figure 6.  Formulation process of microencapsulated tributyrin. (Source:  ELiE Health Solutions)

Resources:

Purchase BUTYCAPS

Cover photo:  Enterocytes were butyrate is taken up in the intestine (Source)

Delaying the Chronological Aging of the Yeast Saccharomyces cerevisiae by Six Plant Extracts

Researchers from Concordia University in Montreal, Quebec, Canada, in collaboration with the Quebec-based biotech company Idunn Technologies, published a study in the Journal Oncotarget on 29 March 2016, describing their discovery of six plant extracts that increase yeast chronological lifespan to a significantly greater extent than any of the presently known longevity-extending chemical compounds.  1

For the study, the researchers examined many plant extracts that would increase the chronological lifespan of yeast.  They finally found and used 37 plant extracts for this study.  These plant extracts are listed in the Table 1 below:

Table 1: List of plant extracts that have was used in this study

Abbreviated nameBotanical namePlant part used
PE1Echinacea purpureaWhole plant
PE2Astragalus membranaceousRoot
PE3Rhodiola rosea L.Root
PE4Cimicifuga racemosaRoot and rhizome
PE5Valeriana officinalis L.Root
PE6Passiflora incarnate L.Whole plant
PE7Polygonum cuspidatumRoot and rhizome
PE8Ginkgo bilobaLeaf
PE9Zingiber officinale RoscoeRhizome
PE10Theobroma cacao L.Cacao nibs
PE11Camellia sinensis L. KuntzeLeaf
PE12Apium graveolens L.Seed
PE13Scutellaria baicalensisRoot
PE14Euterpe oleraceaFruit
PE15Withania somniferaRoot and leaf
PE16Phyllanthus emblicaFruit
PE17Camellia sinensisLeaf
PE18Pueraria lobataRoot
PE19Silybum marianumSeed
PE20Eleutherococcus senticosusRoot and stem
PE21Salix albaBark
PE22Glycine max L.Bean
PE24Calendula officinalisFlower
PE25Salvia miltiorrhizaRoot
PE27Panax quinquefoliumRoot
PE28Harpagophytum procumbensRoot
PE29Olea europaea L.Leaf
PE30Gentiana luteaRoot
PE31Piper nigrumFruit
PE32Aesculus hippocastanumSeed
PE33Mallus pumila Mill.Fruit
PE34Fragaria spp.Fruit
PE35Ribes nigrumLeaf
PE36Dioscorea oppositaRoot
PE37Cinnamomum verumBark

Table source:  Discovery of plant extracts that greatly delay yeast chronological aging and have different effects on longevity-defining cellular processes

The means by which these six plant extracts (PEs) delays the onset and decreases the rate of yeast chronological aging is by eliciting a hormetic stress response. The budding yeast Saccharomyces cerevisiae is a beneficial model organism for the discovery of genes, signaling pathways and chemical compounds that slow cellular and organismal aging in eukaryotes across phyla.  Yeast was chosen in this study because aging progresses similarly in both yeast and humans.

The six PEs that were identified include:  2

  • Black Cohosh (Cimicifuga racemosa) (PE4)
  • Valerian  (Valeriana officinalis L.)  (PE5)
  • Passion Flower  (Passiflora incarnata L.)  (PE6)
  • Ginko Biloba  (Ginko biloba)  (PE8)
  • Celery Seed  (Apium graveolens L.)  (PE12)
  • White Willow  (Salix alba)  (PE21)

 

The six identified PEs out of the thirty-seven PEs that were examined showed the highest percentage increase of lifespan, (also known as the chronological lifespan (CLS)), in the yeast,   The researchers determined both the mean (average) CLS and the maximum CLS of the six PEs.

Table 2 below list the six PEs and their mean and max. CLS:

Table 2: Percent increase of lifespan of S. cerevisiae by 6 PEs

Plant Extract (PE)Mean CLSMax CLS
PE4 (Black Cohosh)195%100%
PE5 (Valerian)185%87%
PE6 (Passion Flower)180%80%
PE8 (Ginko Biloba)145%104%
PE12 (Celery Seed)160%107%
PE21 (White Willow)475%369%
CLS - Chronological Lifespan

(Source:  Discovery of plant extracts that greatly delay yeast chronological aging and have different effects on longevity-defining cellular processes)

The researchers noted that PE21 appears to be the most potent longevity-extending pharmacological intervention presently known. It increases the mean and maximum CLS of yeast by 475% and 369%, respectively.  PE21 or White Willow bark represents a much greater effect than rapamycin and metformin, the two best drugs known for their anti-aging effects.

These findings by the researchers imply that these extracts slow aging in the following ways:  3

  • PE4 (Black Cohosh) decreases the efficiency with which the pro-aging TORC1 pathway inhibits the anti-aging SNF1 pathway;
  • PE5 (Valerian) mitigates two different branches of the pro-aging PKA pathway;
  • PE6 (Passion Flower) coordinates processes that are not assimilated into the network of presently known signaling pathways/protein kinases;
  • PE8 (Ginko biloba) diminishes the inhibitory action of PKA on SNF1;
  • PE12 (Celery Seed) intensifies the anti-aging protein kinase Rim15; and
  • PE21 (White Willow) inhibits a form of the pro-aging protein kinase Sch9 that is activated by the pro-aging PKH1/2 pathway.

The researchers showed that each of these six PEs decelerates yeast chronological aging and has different effects on several longevity-defining cellular processes, as illustrated in Figure 1.

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Figure 1.  A model for how PE4, PE5, PE6, PE8, PE12 and PE21 delay yeast chronological aging via the longevity-defining network of signaling pathways/protein kinases.  Activation arrows and inhibition bars denote pro-aging processes (displayed in blue color) or anti-aging processes (displayed in red color). Pro-aging or anti-aging signaling pathways and protein kinases are displayed in blue or red color, respectively.  (Source: Discovery of plant extracts that greatly delay yeast chronological aging and have different effects on longevity-defining cellular processes)

Each of the six PEs have different effects on cellular processes that define longevity in organisms across phyla. These effects include the following:

  • increased mitochondrial respiration and membrane potential;
  • augmented or reduced concentrations of reactive oxygen species;
  • decreased oxidative damage to cellular proteins, membrane lipids, and mitochondrial and nuclear genomes;
  • enhanced cell resistance to oxidative and thermal stresses; and
  • accelerated degradation of neutral lipids deposited in lipid droplets.

The researchers also revealed that certain combinations of the six PEs could markedly increase aging-delaying proficiencies of each other.

In conclusion, the study stated that the obvious challenge was to assess whether any of the six PEs can delay the onset and progression of chronic diseases associated with human aging.  Idunn Technologies is collaborating with four other universities for six research programs, to go beyond yeast, and work with an animal model of aging, as well as two cancer models.  4

This study and ongoing research reveals five features of the six PEs as potential interventions for decelerating chronic diseases of old age. These five features include:  5

  • the six PEs are caloric restriction (CR) mimetics that imitate the aging-delaying effects of the CR diet in yeast under non-CR conditions;
  • they are geroprotectors that slow yeast aging by eliciting a hormetic stress response;
  • they extend yeast longevity more efficiently than any lifespan-prolonging chemical compound yet described;
  • they delay aging through signaling pathways and protein kinases implicated in such age-related pathologies as type 2 diabetes, neurodegenerative diseases, cardiac hypertrophy, cardiovascular disease, sarcopenia and cancers; and
  • they extend longevity and delay the onset of age-related diseases in other eukaryotic model organisms.

Probiotics S. salivarius K12 and S. salivarius M18 Strengthen Oral Health

The mouth is colonized by 200 to 300 bacterial species, but only a limited number of these species participate in dental decay (caries) or periodontal disease.   An imbalance of good bacteria and bad bacteria in the mouth is considered dysbiosis in the mouth and is thought to be an important cause of periodontal disease and dental decay.

Dental decay is due to the irreversible solubilization of tooth mineral by acid produced by certain bacteria that adhere to the tooth surface in bacterial communities known as dental plaque.

The main bad bacteria associated with dental decay is Streptococcus mutans.  1 

A number of other types of bacteria, such as Actinomyces viscosus and A. naeslundii, live in the mouth, where they are part of a sticky substance called plaque.

Image result for Streptococcus mutans

Streptococcus mutans strain

Streptococcus mutans is the primary causal agent and the pathogenic species responsible for dental caries (tooth decay or cavities) specifically in the initiation and development stages.  2

Advanced periodontal disease has been linked to many chronic diseases, including:

  • Cardiovascular disease
  • Type 2 diabetes
  • Cognitive decline and Alzheimer’s disease
  • Cancer
  • Autoimmune diseases
  • Chronic kidney disease
  • Osteoporosis

Researchers have investigated the potential of probiotics to restore the good bacterial in the oral cavity.  These particular probiotic strains displace the bad bacteria, thus eliminating dysbiosis and restoring the healthy oral flora.

Certain Probiotics Strengthen Oral Health

A number of research studies have shown that two specific strains of Streptococcus salivarius, that are normally found in the mouth, may improve oral health.  These two strains are:

  • Streptococcus salivarius (S. salivarius) strain M18  (BLIS M18)
  • Streptococcus salivarius (S. salivarius) strain K12  (BLIS K12)

These two strains specifically reduce cariogenic and periodontal pathogen levels in the mouth.  This is accomplished by antimicrobial agents that the strains produce and are termed bactericon-like-inhibitory substances (BLIS), otherwise known as lantibiotics.  There are three types of BLIS that the two strains produce in the oral cavity:

  • Salivaricin A
  • Salivaricin B
  • Salivaricin 9

Streptococcus salivarius (S. salivarius) strain K12 is a potent BLIS producer, specifically Salivaricin A (bacteriostatic) and Salivaricin B (bactericidal). 

Both strains are able to produce BLIS antimicrobials in the mouth, however, BLIS K12 is more targeted to ear, nose, throat and immune health while BLIS M18 primarily supports dental health.

Streptococcus salivarius (S. salivarius) strain M18  (BLIS M18) 

Unfortunately only about two percent of the global population has the Streptococcus salivarius necessary to make the M18 peptides.  This small populace comprise people who rarely experience plaque or tooth decay.

Streptococcus salivarius (S. salivarius) strain M18 (BLIS M18) has the ability to break up plaque and neutralize acid that harms teeth and gums.  BLIS M18 produces two unique enzymes that contribute to support for dental health:

  • Urease – neutralizes that lactic acid that is produced the oral cavity by S. mutans.  3
  • Dextranase –  breaks down plaque biofilms caused by S. mutans and inhibits the development of dextrans or extracellular polysaccharides  4

BLIS M18 also corrects and maintains the oral cavity pH.  A more acidic pH oral cavity can lead to tooth demineralization.

BLIS M18 is a potent producer of BLIS or lantibiotics, which destroy disease causing bacteria in the oral cavity.  5  6

A recent study from January 2015 published in the International Journal of Pharma and Bio Sciences showed that M18 probiotic lozenges were efficacious in reducing both moderate to severe gingivitis and moderate periodontitis.  7 

Twenty eight subjects, of both sexes, were selected and divided into 4 groups (2 test groups and 2 control groups).  All 28 subjects had severe gingivitis and moderate periodontitis.  For 30 days, the Test subjects were given a M18 lozenge and the Control group did not receive a lozenge.  Clinical parameters such as plaque index, gingival index, modified sulcular bleeding index and probing pocket depth were recorded and assessed at baseline, day 15, 30, 45 and day 60.

The Test group showed significant reduction in all parameters when compared to that of Control group. After stopping probiotic administration on day 30, the test group showed a significant increase in all the clinical parameters except probing pocket depth on day 45 and day 60.

The Test subjects saw improvement in three areas:

  • less plaque
  • better gingival health
  • less bleeding on probing

Specifically, for the Test subjects, the results were promising in improving all four of these commonly used assessments of periodontal health:

  • The plaque index score decreased 44% by day 30
  • The gingival index score decreased 42% by day 30
  • The sulcular bleeding index score decreased 53% by day 30
  • The probing pocket depth decreased 20% by day 30

Even after 30 days after stopping the lozenges, the Test subjects showed good scores on the 4 indices.  This indicates that M18 has the ability to colonize the oral cavity after using the lozenges.

Streptococcus salivarius (S. salivarius) strain K12 (BLIS K12)  8

Streptococcus salivarius K12 is a strain isolated from the throat of a New Zealand child (who had evidence of exceptional throat health for several years), and is capable of producing two distinct lantibiotics bacteriocins:  9

  • salivaricin A2
  • salivaricin B

The K12 strain is not only effective against S. pyogenes but also inhibits the growth of pathogens such as:

  • Haemophilus influenzae
  • S. pneumoniae
  • Moraxella catarrhalis

These four pathogens are responsible for almost all bacterial pharyngotonsillitis cases in children and adults.  10 

BLIS K12 is a probiotic primarily used for the oral cavity (mouth) and upper respiratory tract and has now been clinically documented to reduce the incidence of strep throat infections in both adults and children.

Streptococcus salivarius: the probiotic for all ages. Diseases that may be alleviated by Streptococcus salivarius probiotics and the ages at which they generally tend to manifest.  (Source:  Developing Oral Probiotics From Streptococcus salivarius)

BLIS K12 attaches to cells in the oral cavity and colonizes the oral cavity and crowds out the bad bacteria.  This effect equalizes the flora in the oral cavity and allows room for the good bacteria to thrive.

Advantages of BLIS K12:

  • Helps maintain mouth and throat health
  • Helps maintain upper respiratory tract health
  • Naturally supports breath freshness  

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.  

Sarsaparilla (Smilax Glabra Rhizome) Extract Inhibits Cancer Cell Growth by Promoting Apoptosis

Smilax glabra, commonly known as sarsaparilla or Chinaroot, is a plant species in the genus Smilax.  It is native to China, the Himalayas, and Indochina.  The genus Smilax contains about 300–350 species, and are found in temperate zones, tropics and subtropics worldwide. 

Smilax glabra is the Smilax species that is used in Chinese herbology.  The Chinese name of the plant is 土茯苓, and the pinyan name is Tu fu ling.

Smilax_glabraRhizomeDried

Dried Smilax Glabra Rhizome

Smilax glabra is oftentimes confused with two other species of Smilax:

  • Smilax officinalis
  • Smilax aristolochiifolia

Smilax aristolochiifolia is also known as:

  • Gray sarsaparilla
  • Mexican sarsaparilla
  • Sarsaparilla

It is native to Mexico and Central America.  Smilax aristolochiifolia root has a long traditional history of medicinal use.  2  

Smilax glabra contains some interesting active ingredients.  The following Dihydro-flavonol glycosides have been identified in the rhizome of Smilax glabra:   1

  • astilbin
  • neoastilbin
  • isoastilbin
  • neoisoastilbin
  • (2R, 3R)-taxifolin-3′-O-beta-D-pyranoglucoside

The following flavanonol rhamnoside has been identified in the rhizome of Smilax glabra:  

  • smitilbin

Smilax glabra has been studied in vitro and in animal studies (but it has not been studied in clinical trials) as a potent botanical plant in the following areas:

  • anticancer properties  3  4  5 
  • anti-inflammatory  6  7 
  • antioxidant  8  9
  • antiviral  10
  • hepatoprotective  11
  • immunostimulatory  12
  • renoprotective  13 

In a study published in March 2015 in the Journal Cancer Prevention Research, researchers found that Smilax Glabra Rhizome Extract Inhibits Cancer Cell Growth by S Phase Arrest, Apoptosis, and Autophagy via the Redox-Dependent ERK1/2 Pathway.  14

The researchers surmised that Sarsaparilla (Smilax Glabra Rhizome) has growth-inhibitory effects on several cancer cell lines in vitro and in vivo, with little toxicity on normal cells. What was uncertain to the researchers was the underlying functional mechanism of Smilax Glabra Rhizome against several cancer cell lines.

Their study examined the anticancer activity of the supernatant of the water-soluble extract (SW) from sarsaparilla.

Smilax Glabra Rhizome (SW) was shown to markedly inhibit the growth of a broad spectrum of cancer cell lines in the in vitro and in vivo assays. Responsible for SW-induced growth inhibition was any or all of the following:

  • apoptosis
  • autophagy
  • S phase arrest

The researchers concluded:

“Together, our results provide a molecular basis for sarsaparilla as an anticancer agent.”  15


Informational References:

Memorial Sloan Kettering Cancer Center – Smilax glabra


Resources:

Tu fu ling (Chinese smilax rhizome)

SUN TEN – Smilax Tu Fu Ling Concentrated Granules 100g S1870 by Baicao

Tu Fu Ling Liquid Extract, Tu Fu Ling, Glabrous Greenbrier (Smilax Glabra) Root Tincture Supplement 2 oz

 

Cistanche deserticola May Extend Life Span (At Least in Mice)

Cistanche deserticola is a holoparasitic member of the Orobanchaceae family of plants.  It is primarily found in China’s deserts including the provinces of Gansu, Shaanxi, and Qinghai, and the Autonomous Regions of Xinjiang, Ningxia, and Inner Mongolia.

Cistanchedeserticola

Cistanche deserticola

Cistanche deserticola has been widely used in Traditional Chinese Medicine as the herbal medicine called Rou Cong Rong.

In China, it has been used in treating various age-related disorders, including:  1

  • Senile dementia,
  • Impotence
  • Infertility
  • Chronic infection
  • Hematopoietic disorders in the elderly

There are two principal types of compounds isolated as the main active ingredients of Cistanche deserticola:

  • Phenylethanoid glycosides
  • Oligosaccharides

Cistanche deserticola and its extracts have been studied intensively and have been shown to have the following health benefits:

  • Protecting neurons from injury induced by neurotoxins  2
  • Inhibiting carbon tetrachloride induced hepatotoxicity  3
  • Promoting the recovery of bone marrow cells from radiation damage  4
  • Anti-inflammatory, antioxidant, and antiaging effects  5

A group of Chinese researchers published a study on January 9, 2014 which demonstrated that Cistanche deserticola possesses significant effects in extending life span and suggest this is achieved by antagonizing immunosenescence.  6

Immunosenescence refers to the gradual deterioration of the immune system brought on by natural age advancement.  Immunosenescence creates the environment for increased susceptibility in the elderly to:  7

  • Infections
  • Cancer
  • Neurodegenerative diseases
  • Autoimmune diseases

In addition to an reduction in the level of immunity that is evident in aging (Immunosenescence), an increase in chronic inflammation is apparent in aging and manifested as increased levels of proinflammatory cytokines, including IL-6, TNF-α, and IL-1β.  8

The most damaging inflammatory cytokines is IL-6.  IL-6 increases with aging and age-related diseases.  9  10  11  As demonstrated in the study, supplementation with Cistanche deserticola was able to reduce peripheral IL-6 concentrations.  12 

The Chinese researchers took eight-month-old male SAM-P8 mice and treated them with oral administrations of Cistanche deserticola for 4 weeks. The researchers stated that:

“The results showed that dietary supplementation of 150 mg/kg and 450 mg/kg of Cistanche deserticola (ECD) could extend the life span measured by Kaplan-Meier survival analysis in dose-dependent manner. Dietary supplementation of SAM-P8 mice for 4 weeks with 100, 500, and 2500 mg/kg of ECD was shown to result in significant increases in both naive T and natural killer cells in blood and spleen cell populations. In contrast, peripheral memory T cells and proinflammatory cytokine, IL-6 in serum, were substantially decreased in the mice that ingested 100 and 500 mg/kg of ECD daily.”  13

The study revealed that the average life span was significantly increased (by 15.4%) in the Cistanche deserticola supplemented mice:  14

  • Control mice averaged about 325 days
  • Cistanche deserticola supplemented mice averaged about 375 days

601383_fig_001a

601383_fig_001b

Figure 1: The effects of extracts of Cistanche deserticola (ECD) on life span of SAM-P8 mice. Eight-month-old male senescence-accelerated mouse/prone 8 (SAM-P8) mice were randomly divided into 4 groups (in each group, ): 3 treatment groups, and a no treatment control group. The nonsenescent substrain (SAM-R1) of mice was used as an experimental control. The food intake of all of animals was monitored throughout the experiment at 3-day intervals. The 3 treatment groups were fed ad libitum on diets supplemented with low (50 mg/kg), medium (150 mg/kg), and high (450 mg/kg) doses of Cistanche deserticola extract (ECD). The two control animal groups were fed with the same diet without ECD supplementation. (a) Kaplan-Meier survival curves of SAM-P8 mice dieted ECD or vehicle control. The Kaplan-Meier survival analysis was conducted using the Log-rank (Mantel-Cox) and Gehan-Breslow-Wilcoxon tests. (b) Histogram of the average life span of the groups of mice. The error bars show that the standard deviation from the mean and statistical significance was carried out using ANOVA analysis followed by post hoc -test. SAM-P8 versus SAM-R1; high dose treated group versus SAM-P8; medium dose treated group versus SAM-P8 (in each group, ).  (Source:  Extracts of Cistanche deserticola Can Antagonize Immunosenescence and Extend Life Span in Senescence-Accelerated Mouse Prone 8 (SAM-P8) Mice, Evidence-Based Complementary and Alternative Medicine Volume 2014 (2014), Article ID 601383, 14 pages)

The results and conclusion of the study found the following promising health benefits of Cistanche destericola:  15

  • Induced a significant reversal of age-related immunosenescence alterations
  • Reduction in peripheral and spleen cell populations of naive T cells and NK cells
  • Reduction in redundant memory T cells
  • Suppression of necrosis in peripheral lymphocytes
  • Suppression of the proinflammatory cytokine, IL-6
  • Prolonged the life span of senile SAM-P8 mice

Resources:

Life Extension Standardized Cistanche Capsules, 30 Count

Swanson Health Products – Cistanche Tubulosa Extract

Life Extension – Immune Senescence Protection Formula™

Rou Cong Rong


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Dietary Supplements that Show Promise for Cancer Prevention and Adjuvant Treatment*

The link between cancer and diet has been extensively studied.  In fact, major medical institutions recognize diet and nutritional supplements as a means to reduce the risk of cancer.  There are a number of websites that address this important issue:

Cancer is the second most leading cause of death in the United States.  1 

Of all the cancer deaths (at least in the U.S.), there are primarily two causes:  2

  • Genetic defects                        5-10%
  • Environment and lifestyle       90-95%

The lifestyle factors include:  3

  • Alcohol
  • Cigarette smoking
  • Diet (fried foods, red meat)
  • Environmental pollutants
  • Infections
  • Obesity
  • Stress
  • Sun exposure

Evidence suggests that of all the cancer deaths, 30–35% are linked to diet.  4

There are certain natural nutrients and hormones that have been studied for their effective mechanisms of action that may benefit the cancer patient and/or prevent cancer tumor genesis. 

An excellent paper is published on the Life Extension website entitled “Cancer Adjuvant Therapy”.  This paper illustrates an alphabetical list that follows provides quick guidelines for structuring a program, highlighting major nutrients in the prevention and treatment of cancer.

The Table below (from the paper “Cancer Adjuvant Therapy”) list those natural nutrients and hormone that have been researched for their ability to act as promising therapies for the prevention and treatment of certain cancers.  The references for each nutrient and hormone is one of many that exist, and is a starting point for further research.

Basic dietary supplements and suggested doses for cancer prevention and adjuvant treatment

NutrientReferencePreventive DoseCancer Adjuvant Dose
Apigenin110 – 25 mg daily20 – 50 mg daily
Astaxanthin22 – 4 mg daily6 – 12 mg daily
Astragalus3500 mg daily2000 – 4000 mg daily
Blueberry4180 – 450 mg daily900 – 1800 mg daily
Chrysin5500 mg daily1000-2000 mg daily
Curcumin6400 mg daily of a  BCM-95® extract with food800-3600 mg daily of a BCM-95® extract with food
Coenzyme Q107100 mg daily with food200-400 mg daily with food
Green Coffee Extract(standardized to 50% chlorogenic acid)8400 mg three times daily, before meals400 mg three times daily, before meals
EPA-DHA fatty acids92000 – 4000 mg daily of fish oil concentrate supplying 700 – 1400 mg EPA and 500 – 1000mg DHA with food4000 – 8000 mg daily of fish oil concentrate supplying up to 2800 mg EPA and 2000 mg DHA with food
Garlic10600 mg daily with food1200 – 4800 mg daily with food
Gamma Tocopherol11200 – 250 mg daily with food400 – 1000 mg daily with food
GLA (gamma-linolenic acid)12300 mg daily with food700 – 900 mg daily with food
Grape Seed Extract13100 mg daily300 mg daily
Green Tea Extract 14300 – 350 mg daily of EGCGUp to 3000 mg daily of EGCG
Cruciferous vegetable concentrate151 tbsp daily1 – 4 tbsp daily
Indole 3 Carbinol(I3C)1680 – 160 mg daily200 – 600 mg daily
Lignans1725 – 50 mg daily75 – 125 mg daily
Lipoic acid (Sodium R-lipoate)18240 – 480 mg daily on an empty stomach600 – 1200 mg daily on an empty stomach
Lycopene1910 mg daily with food15 – 45 mg daily with food
Melatonin20300 mcg-3 mg before bed10 – 50 mg between 8 – 10pm
Panax ginseng21100 mg daily of standardized to contain 4-7% ginsenosides200 – 600 mg daily of standardized to contain 4-7% ginsenosides
Pomegranate2280 – 120 mg daily of punicalagins280 – 375 mg daily of punicalagins
Proteolytic Enzymes231 – 2 pills daily on an empty stomach of a formula containing pancreatin, papain, trypsin, and chymotrypsin2 – 10 pills, 3 times daily on an empty stomach of a formula containing pancreatin, papain, trypsin, and chymotrypsin
PSK (Coriolusversicolor)24600 – 1200 mg daily of a 40% polysaccharide extract3000 mg daily of a 40% polysaccharide extract
Pterostilbene250.25-3 mg daily1 – 3 mg daily
Quercetin26500 mg daily1000 – 3000 mg daily
Reishi27980 mg daily of standardized to contain 13.5% polysaccharides and 6% triterpenes980 – 3000 mg daily of standardized to contain 13.5% polysaccharides and 6% triterpenes
Selenium28200 mcg daily with food200 – 600 mcg daily with food
Silibinin29225 mg daily225 – 450 mg daily
Sulforaphane30400 – 800 mg daily (broccoli extract)400 – 1600 mg daily (broccoli extract)
Vitamin C311000 – 3000 mg daily4 – 12 g daily
Vitamin D3322000 – 10 000 IU daily with food, based on individual blood testing. Optimal blood levels of vitamin D are 50 – 80 ng/ml.2000 – 10 000 IU daily with food, based on individual blood testing. Optimal blood levels of vitamin D are 50 – 80 ng/ml.
Source: Life Extension Cancer Adjuvant Therapy


*Disclaimer and Safety Information

BioFoundations can assume no responsibility for outcome, apart from a self-assigned duty to stay abreast of the most promising of therapies and to share the data with customers. No warranties (expressed or implied) accompany the material; neither is the information intended to replace medical advice. As always, each reader is urged to consult professional help for medical problems, especially those involving cancer.

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website.

The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the treatments discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.


Resources:

Apigenin

Astaxanthin

Astragalus

Blueberry

Chrysin

Curcumin

Coenzyme Q10

Green Coffee Extract(standardized to 50% chlorogenic acid)

EPA-DHA fatty acids

Garlic

Gamma Tocopherol

GLA (gamma-linolenic acid)

Grape Seed Extract

Green Tea Extract

Cruciferous vegetable concentrate

Indole 3 Carbinol(I3C)

Lignans

Lipoic acid (Sodium R-lipoate)

Lycopene

Melatonin

Panax ginseng

Pomegranate

Proteolytic Enzymes

PSK (Coriolusversicolor)

Pterostilbene

Quercetin

Reishi

Selenium

Silibinin

Sulforaphane

Vitamin C

Vitamin D3


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Tart Cherry Demonstrates Chemoprevention Potential

Tart cherry (Prunus cerasus) is part of the species of Prunus and is native to Europe and southwest Asia.  It is also known as sour cherry or dwarf cherry. 

It is distinct from the sweet cherry (Prunus avium), which is commonly found in grocery stores.  Tart cherries are more acidic than sweet cherries and are typically used in juices and foods, rather than sold as a whole fruit.  The health benefits attributed to cherries are due to the tart cherry and not the sweet cherry.

There are a number of varieties of the tart cherry:

  • Morello cherry  (dark red)
  • Amarelle cherry  (light red)
  • Montmorency cherry (the most popular of the tart cherries)

Figure 1.   Montmorency cherry

Through numerous scientific studies, tart cherry has demonstrated a wide range of health benefits and its ability to counteract some key chronic conditions, including:

  • Reversing cardiovascular risk factors
  • Protection against oxidative stress
  • Inhibiting the early development of diabetes
  • Inhibiting the inflammatory pathway of gout
  • Regulates sleep-wake cycle in humans (due to high melatonin content)
  • Supports muscle recovery after exercise
  • Provides relief from pain associated with exercise exertion 
  • Provides anti-microbial effects 

Tart cherries are rich in anthocyanins, which are water-soluble vacuolar pigments that may appear red, purple, or blue.  They belong to the flavonoids group.  Other fruits and berries contain anthocyanins, but tart cherries are the only berry that contains all six of the key anthocyanins, including:  1

  • Cyanidin
  • Cyanidin 3-glucosylrutinoside (anthocyanin 1)
  • Cyanidin 3-rutinoside (anthocyanin 2)
  • Cyanidin sophoroside
  • Peonidin
  • Peonidin 3-glucoside

The health benefits of tart cherries can be attributed to their rich and broad anthocyanin content.  The anthocyanin content is also responsible to their anticarcinogenic effects.

Research is showing that tart cherries can exert a variety of chemopreventive effects and counteract cancer through various mechanisms by naturally switching off genes that promote cancer.  These genes activate:  2  3  4

  • inflammation
  • cell proliferation
  • angiogenesis (growth of new blood vessels)

The broad range of anthocyanins in tart cherries trigger apoptosis (programmed cell death), which effectively cleans up precancerous cells by having them self-destruct.  5  6 

Tart cherries has been shown to be effective against colon cancer.

A published study from 2003 demonstrated that mice consuming the cherry diet, anthocyanins, or cyanidin had significantly fewer and smaller cecal adenomas than mice consuming the control diet or sulindac.

Anthocyanins and cyanidin also reduced cell growth of human colon cancer cell lines HT 29 and HCT 116. The IC(50) of anthocyanins and cyanidin was 780 and 63 microM for HT 29 cells, respectively and 285 and 85 microM for HCT 116 cells, respectively.

These results suggest that tart cherry anthocyanins and cyanidin may reduce the risk of colon cancer.  7

Tart Cherries Chemoprevention Potential  8

Inhibits Inflammation Pathways

Arrests Cancerous Cell Proliferation

Inhibits Angiogenesis

Promotes and Triggers Apoptosis