Category Archives: Healthspan/Lifespan

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Polypodium leucotomos Extract Reduces Oxidative DNA Damage and Enhances DNA Repair

Polypodium leucatomos is an epiphytic fern native to tropical and subtropical regions of the Americas.  It’s alternative botanical name is Phlebodium aureum.

The common names for this fern include:

  • golden polypody
  • golden serpent fern
  • cabbage palm fern
  • gold-foot fern
  • hare-foot fern

Other common names in other languages include:

  • calaguala (Spanish language)
  • laua`e haole (Hawaiian)
  • samambaia (Portuguese)
  • hartassbräken (Swedish)

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Figure 1.  Polypodium leucotomos fern

Extracts from the Polypodium leucotomos fern have been used for centuries in South America and Spain, primarily for the treatment of:

  • psoriasis
  • various skin disorders
  • atopic dermatitis
  • vitiligo
  • sun protection from ultraviolet radiation

The phenolic components of Polypodium leucotomos extract include:  1

  • chlorogenic acid
  • coumaric acid
  • vanillic acid
  • caffeic
  • ferulic acid

Multiple Benefits From the Oral Supplementation of Polypodium leucotomos

A number of recent studies have demonstrated through their data that the oral administration of polypodium leucotomos postively effects health and affords the following photoprotective effects:  2

  • activates tumor suppressor p53
  • inhibits UV-induced Cox-2 expression
  • reduces inflammation
  • enhances the removal of UV-induced photoproducts, such as cyclobutane pyrimide dimers (CPDs)
  • reduces oxidative DNA damage and decreased UV-induced mutagenesis
  • reduces the number of 8-hydroxy-2’-deoxyguanosine-positive (8-OH-dG+) cells, which are markers of early DNA damage

Polypodium leucotomos Helps Prevent DNA Damage

Two studies from 2009 and 2010 suggest that Polypodium leucotomos helps prevent DNA damage before and during UV exposure. 3  4 

Oxidative damage of DNA has been implicated as a fundamental cause of the physiologic changes and degenerative diseases associated with aging.  When DNA is impacted by oxidative stress, the chemical 8-Oxo-2′-deoxyguanosine (8-oxo-dG) is produced as a byproduct.

Because 8-oxo-dG is a major product of DNA oxidation, concentrations of 8-oxo-dG within a cell is a ubiquitous marker and measurement of oxidative stress.

8-oxo-dG increases with age in DNA of mammalian tissues.  8-oxo-dG increases in both mitochonndrial DNA and nuclear DNA with age. 5

8-oxo-dG is a pre-mutagenic marker of oxidative damage to DNA and is caused by the UV-induced generation of reactive oxygen species. 8-oxo-dG positive cells were reduced by approximately 59% at 24 hours and by 79% at 48 hours in Polypodium leucotomos-treated animals compared to control animals.

These findings support the concept that Polypodium leucotomos reduces oxidative DNA damage.

Two weeks after UV exposure, mutations in Polypodium leucotomos-fed-mice were approximately 25% less than those from mice treated with UV alone.  6 

A clinical trial from 2010 found that a daily does of 240 mg of polypodium leucotomos by healthy volunteers aged 29 to 54 before UVA exposure decreased levels of a marker of DNA damage.  7 

Among the placebo volunteers a low dose of UV light produced a 217% increase in common DNA deletions.

Among the polypodium leucotomos supplemented volunteers showed a corresponding 84% decrease in common DNA deletions.  8 

When the UV exposure was increased the common DNA deletions increased by 760% for the placebo volunteers, whereas in the polypodium leucotomos volunteers there was only an increase of 61%.  9  

Polypodium Leucotomos Extract: A Photoprotective Anti Aging Oral Supplement

Queen Bee Acid: Facilitates Neurogenesis and Activates AMPK

Royal Jelly

Royal jelly is a honey bee secretion that is used in the nutrition of larvae and adult queen bees.

It is secreted from the glands in the hypopharynx of worker bees, and fed to all larvae in the colony.  The composition of royal jelly includes:

  • water  67%
  • crude protein  12.5%
  • free amino acids
  • simple sugars (monosaccharides)  11%
  • fatty acids  5%
  • trace minerals
  • enzymes
  • antibacterial and antibiotic components
  • pantothenic acid (vitamin B5)
  • pyridoxine (vitamin B6)
  • vitamin C
  • AMP N1-oxide  1 
  • acetylcholine  2 

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Figure 1.  Developing queen larvae surrounded by royal jelly

Royalactin – Protein in Royal Jelly

The queen bee is fed royal jelly exclusively and as a result causes the queen bee to become larger than the worker bees.  It is speculated that a single protein called royalactin is responsible for the unique development and size of the queen bee.

Researchers determined that only royal jelly with an addition of royalactin caused the larvae to become queen bees.  3 

Royalactin plays a central role in this process by switching on the epidermal growth factor (EGF) receptor signaling pathway which ultimately leads to epigenetic changes and a long-lived queen phenotype.

Recently it was shown that royalactin by itself also extends lifespan in Drosophila melanogaster.  4

A study from 2014 demonstrated that royalactin extends lifespan of this nematode and that both EGF (LIN-3) and its receptor (LET-23) are essential to this process. They showed that royalactin enhances locomotion in adult nematodes, implying that royalactin also influences healthspan, suggesting that royalactin is an important lifespan-extending factor in royal jelly and acts by promoting EGF signaling in C. elegans.  5

Specific Fatty Acids in Royal Jelly

Researchers have identified a number of fatty acids contained in royal jelly, including:

  • 10-Hydroxy-2-Decenoic Acid  (10-HDA; about 2 – 3%)
  • 2-Decendioic Acid
  • 10-Hydroxydecanic Acid
  • 10-Hydroxydecenoic Acid
  • P-Hydroxybenzoic Acid
  • 24-Methylenecholesterol
  • 2-Decendioic Acid
  • 10-Hydroxydecanic Acid
  • 10-Hydroxydecenoic Acid
  • P-Hydroxybenzoic Acid
  • Sebacic acid

10-hydroxy-2-decenoic acid (10-HDA) – Queen Bee Acid

The main fatty acid in royal jelly is 10-hydroxy-2-decenoic acid (10-HDA), consisting of about 2 to 3% by volume. 

It is also known as Queen Bee acid.

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Figure 2.  10-hydroxy-2-decenoic acid molecule  (Source)

Royal Jelly’s Pharmacological Activities

Royal jelly as a whole has been reported to possess a variety of pharmacological activities such as:

  • antibacterial  7
  • antitumor  8 
  • anti-allergic  9
  • anti-fatigue  10 
  • anti-inflammatory  11
  • immunomodulatory  12
  • induces neurite outgrowth  13
  • prevents dermatitis  14
  • prevents hypercholesterolemia  15
  • prevents osteoporosis  16
  • stimulates bone formation  17 
  • antioxidant activity  18
  • inhibitory effects on lipid peroxidation  19
  • antihypertensive effects  20

Specific Health Benefits of 10-hydroxy-2-decenoic acid (queen bee acid)

There are two important health benefits of 10-hydroxy-2-decenoic acid (queen bee acid) that has been identified which include:

  • facilitates the differentiation of all types of brain cells (neurons, astrocytes, and oligodendrocytes)
  • activates adenosine monophosphate-activated protein kinase (AMPK)

Facilitates the differentiation of all types of brain cells (neurons, astrocytes, and oligodendrocytes)

The birth of new brain cells (neurogenesis) continues throughout life in the brain, in particular the dentate gyrus region of the hippocampus.

The hippocampus produces roughly 700 new brain cells each day.  This corresponds to an annual turnover of 1.75% of the neurons within the renewing fraction, with a modest decline during aging.

Neurogenesis is generated in two regions of the adult brain:

  • The subventricular zone (SVZ) lining the lateral ventricles
  • The subgranular zone (SGZ), part of the dentate gyrus of hippocampus

Neurogenesis can have tremendous functional significance to the healthy adult brain. In the aging adult, hippocampal function declines with potential memory dysfunction. This may due to the fact that neurogenesis is substantially reduced in the hippocampus in the aging adult.

If neurogenesis in the hippocampus continues throughout life, then one would presume that the size of hippocampus would increase in size. However, this is not the case since the rate of neuron death balances out the proliferation.

Researchers have determined that 10-hydroxy-2-decenoic acid (10-HDA) facilitates the differentiation of all types of brain cells (neurons, astrocytes, and oligodendrocytes).  21

10-hydroxy-2-decenoic acid (10-HDA) significantly increased the percentage in the total cell population of not only neurons immunoreactive for class III beta-tubulin (Tuj1) but also astrocytes immunoreactive for glial fibrillary acidic protein (GFAP), and oligodendrocytes immunoreactive for 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase) generated from NSCs, but decreased that of nestin-positive NSCs.

Resaerchers concluded that 10-hydroxy-2-decenoic acid (10-HDA) facilitates neurogenesis.

Activates adenosine monophosphate-activated protein kinase (AMPK)

AMPK (adenosine monophosphate-activated protein kinase) is an enzyme contained in every cell of the human body that serves as the body’s master regulating switch.

When the AMPK master switch is turned “ON” (by activating AMPK), it inhibits multiple damaging factors of aging and enables cells to become revitalized.  Scientists have found that activated AMPK promotes longevity factors that have been shown to extend life span in numerous organisms.  22 23

There are various studies that show an increase in AMPK supports:

  • Reduced fat storage 24
  • New mitochondria production 25
  • Promotion of healthy blood glucose and lipids already within normal range 26

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Figure 3.  Roles of AMPK in the control of whole-body energy metabolism. Notes: Activation of AMPK (green lines) stimulates the energy-generating pathways in several tissues while inhibiting the energy-consuming pathways (red lines). In skeletal muscle and heart, activation of AMPK increases glucose uptake and fatty acid oxidation. In the liver, AMPK activity inhibits fatty acid and cholesterol synthesis. Lipolysis and lipogenesis in adipose tissue are also reduced by AMPK activation. Activation of AMPK in pancreatic β-cells is associated with decreased insulin secretion. In the hypothalamus, activation of AMPK increases food intake.  Source: AMPK activation: a therapeutic target for type 2 diabetes? Kimberly A Coughlan, Rudy J Valentine, Neil B Ruderman, and Asish K Saha, Diabetes Metab Syndr Obes. 2014; 7: 241–253. Published online 2014 Jun 24. doi: 10.2147/DMSO.S43731

A study from October 2013 determined that queen bee acid activates AMP-activated protein kinase (AMPK) and enhances glucose uptake in skeletal muscle in in vivo testing in mice, and in vitro testing using myotubes.  27 

Researchers treated L6 myotubes with various medium chain fatty acids and showed that 10-hydroxy-2-decenoic acid (10-HDA) administration resulted in a significant increase in phosphorylated AMPKα. 10-hydroxy-2-decenoic acid (10-HDA) activates AMPK independently of insulin and significantly increased glucose uptake into L6 myotubes following translocation of glucose transporter 4 (Glut4) to the plasma membrane (PM). The activation was induced by the upstream kinase Ca²⁺/calmodulin-dependent kinase kinase β, but was independent of changes in AMP:ATP ratio and the liver kinase B1 pathway. 

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

Beta-hydroxybutyrate Extends Lifespan and Protects Against Certain Neurological Diseases

Ketone bodies

Ketone bodies are produced by the liver from fatty acids under the following conditions:

  • low food intake (fasting)
  • low carbohydrate diets (ketogenic diet)
  • starvation
  • prolonged intense exercise

There are three water soluble ketone bodies:

  • acetone
  • acetoacetate
  • beta-hydroxybutyric acid

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Figure 1.  Ketone bodies  (Source)

Ketone bodies are converted to acetyl-CoA in the mitochondria which is then oxidized in the citric acid cycle to produce energy in the form of ATP.

Beta-hydroxybutyrate  (Beta-Hydroxybutyric acid)

Beta-Hydroxybutyric acid is synthesized in the liver from acetoacetate.  Beta-Hydroxybutyric acid is able to cross the blood-brain-barrier into the central nervous system.

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Figure 1.  Beta-hydroxybutyric acid molecule

It has been determined that beta-hydroxybutyric acid has clinical relevance in a number of health related matters:

  • found to act as a histone deacetylase (HDAC) inhibitor.  1 
  • found to increase brain-derived neurotrophic factor (BNDF) levels  2
  • found to increase TrkB signaling in the hippocampus  3 

Beta-Hydroxybutyric acid extends lifespan in C. elegans

A study published in the Journal Aging in August 2014 demonstrated that beta-hydroxybutyric acid (BHB) supplementation extended mean lifespan of the worm C. elegans by approximately 20%.  4

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Figure 3.  Caenorhabditis elegans nimatode (roundworm); C. elegans has been a model organism for research into ageing

What the researchers of this study discovered was that supplementing with BHB had the same effect as caloric restriction.  Caloric restriction has been known to activate longevity genes such as:

  • DAF-16/FOXO
  • SKN-1/Nrf
  • SIR-2.1
  • AMPK

The finding of the researchers in this study was that BHB supplementation also activated these longevity gene pathways.  5

In addition to activating these longevity gene pathways, the researchers found that BHB supplementation also had the following effects:

  • increased worm thermotolerance
  • partially prevented glucose toxicity
  • delayed Alzheimer’s amyloid-beta toxicity
  • decreased Parkinson’s alpha-synuclein aggregation

Alzheimer’s disease

The researchers administered the toxic protein amyloid-beta to the nimatode worms and found that they stopped moving only hours after being given the protein.  However, when the nimatodes were supplemented with BHB, the time to stop moving took longer.

Parkinson’s disease

Alpha-synuclein accumulates in the brains of people suffering from Parkinson’s disease.  Researchers in this study found that BHB supplementation inhibited the accumulation of alpha-synuclein in NL5901 nematodes.

The researchers concluded that:

“Beta-HB (BHB) treatment extended lifespan and protected against metabolic, proteotoxic and thermal stress in Caenorhabditis elegans.  Our data support the hypothesis that beta-HB is a dietary restriction mimetic and that beta-HB treatment will likely be useful in the treatment of many human aging-associated disorders.”  

Resources:

Beta-hydroxybutyric acid is synthesized in the liver under the conditions of low food intake and/or the consumption of a low carbohydrate diet (ketogenic diet). 

However, it is possible to supplement with Beta-hydroxybutyric acid (BHB) which is known as exogenous BHB Ketone salt.  Exogenous BHB is beta-hydroxybutyric acid attached to a mineral salt, such as, sodium, potassium, calcium, or magnesium, in order that the body can adequately metabolize the beta-hydroxybutyric acid.

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