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Yellows - Activating FOXO Longevity Factors and Longevity Pathways

It is known that the activation of FOXO transcription factors promote extreme longevity, which has been demonstrated in research animals as well as in animals such as the multi-cell animal hydra. In  human longevity, those with gene variants which activate higher levels of FOXO are also the longest lived with least amounts of illness and disease.

Despite years of research declaring that antioxidants, such as vitamins C and E, promoted longevity, none have been shown to activate the longevity factors FOXO or Nrf2. Rather, potent longevity factor activation has been shown by many plant based flavonoids. (1) Flavonoids are yellow in nature, and the word is derived from the latin flavus, which means yellow.

 

  • FLAVONOIDS - APGEININ & LUTEOLIN
  • In a comprehensive study comparing flavonoids to antioxidative vitamins, determined that flavonoids are very potent activators of longevity factors, versus antioxidants. Antioxidants, including Vitamin C and E, did not trigger activation of any longevity factors.
  • The flavonoids Apigenin and Luetolin were shown to be the most active longevity triggers of the flavonoids tested.
  • Apigenin and Luteolin highly activate Nrf2, FOXO and PPARγ.
  • EGCG (Green Tea)  - Life extending properties include upregulation of DAF-16 (the longevity factor equivalent to FOXO) and endogenous superoxide dismutase (SOD),
  • ICARIIN (Epimedium) - Inihibits the pathway ISS (Insulin Signaling) which causes an activation of DAF-16 (analogous to FOXO). Also facilitates genome stability by reducing the DNA strand breaks.
  •  MYRICETIN (Bayberry extract) - A longevity enhancing and mitochondrial activating flavonoid. Mitichondria activation improves respiration, endurance and activity levels by increasing the density of mitochondria. Myricetin positively impacts cellular mitochondria through activating PGC-1α and SIRT1. SIRT1 is believed to play a major role in mitochondrial biogenesis and mitophagy (mitichondrial turnover).3

 Other FOXO Activators and Longevity Pathways:

  • TETRAHYDROCURCUMIN - A metabolite of curcumin, tetrahydrocurcumin has unque anti-aging properties including the activation of FOXO. In aging studies using Drosophila melanogaster , tetrahydrocurcumin extended the lifespan, by the involvement of both longevity factors FOXO and Sir2.
  • CURCUMIN -  Increases lifespan in laboratory animals by affecting age-related genes. Enhances gene expression of endogenous antioxidant system, increasing superoxide dismutase (SOD) and reducing lipid peroxidation.

 

YELLOW LONGEVITY

YELLOW NATURALLY

 

 

REFERENCES:

(1) Pallauf K, et al. Flavonoids as Putative Inducers of the Transcription Factors Nrf2, FoxO, and PPARγ. Oxid Med Cell Longev. 2017

(2)  Paredes-Gonzales X, et al. Induction of NRF2-mediated gene expression by dietary phytochemical flavones apigenin and luteolin. Biopharm Drug Dispos.  2015 Oct

(3) Zhang L, et al. Significant longevity-extending effects of EGCG on Caenorhabditis elegans under stress Free Radic Biol Med. February 2009

(4)  Wai-Jiao Cai, et al. Icariin and its Derivative Icariside II Extend Healthspan via Insulin/IGF-1 Pathway in C. elegans. PLoS One, 2011

(5) Zhang SQ, et al. Icariin, a natural flavonol glycoside, extends healthspan in mice. Exp Gerontol. 2015 Sep;

 (6) Jung HY, et al. Myricetin improves endurance capacity and mitochondrial density by activating SIRT1 and PGC-1α. Sci Rep. 2017 Jul 24

(7) Tang BL. Sirt1 and the Mitochondria. Mol Cells. 2016 Feb

(8) Xiang L, et al. Tetrahydrocurcumin extends life span and inhibits the oxidative stress response by regulating the FOXO forkhead transcription factor. Aging (Albany NY) 2011 Nov

(9) Shen LR, et al. Curcumin-supplemented diets increase superoxide dismutase activity and mean lifespan in Drosophila. Age (Dordr) 2013 Aug;

Cardiac Aging - Heart Failure and Limits of Longevity

While we live in an age where people are living longer, an important limiting factor on longevity is the ability of the heart to maintain function.  Known causes of death for the oldest people on record (over 110 years old) were recorded as heart failure. Heart failure is due to the gradual loss of cardiomyocytes (heart muscle cells) and the increase in scarring of the heart muscle. The process may take place due to low grade inflammation of the muscle, which progresses with age, or injury (such as a heart attack) which may cause a more sudden loss of heart function. Inflammation in  the cardiovascular system is common with the aging process, being the result of hypertension, high blood glucose, trigylcerides, or oxidized VDL cholesterol.

Cardiac Aging Characteristics:

  • Increased injury and loss of cardiac muscle due to inflammation and injury,
  • Increased fibrosis and scarring of heart muscle
  • Loss of regenerative ability (cardiomyocytes)
  • Loss of cardiomyocyte homeostasis
  • Reduction in contractile strength of myocytes
  • Increased thickening of muscle (cardiac hypertrophy) - commonly caused by hypertension
  • Diabetes accelerates aging of the heart muscle, and is directly causative of cardiomyopathy - a damaging condition of the heart muscle which leads to heart failure.

Key Conditions of the Aging Heart

  • Atrial Fibrillation
  • Heart Failure (1)
  • Heart failure is primarily the result of insufficient ability to regenerate heart tissue by cardiomyoctes and the replacement of muscle with scar tissue.

 

  • Inhibiting Cardiac Fibrosis and Inflammation supports maintenance of Heart Function with aging.
  • Atrial fibrillation. Changes to the heart through aging, alters the ability of the left atrium to properly conduct the critical electrical impulses, which can cause an abnormal heart beat. Atrial fibrillation results from increased fibrosis in the heart muscle and a remodeling of the heart muscle. Nrf2 activation, which is potently activated by sulforaphane and andrographolide, may reduce fibrosis. 
  • Cardiomyocyte Regeneration and Maintenance (Homeostasis) - Mammal adult heart cells display very poor regenerative ability after incurring inflammation or injury. Instead of regenerating, hearts undergo extensive scarring - reducing functional ability. In order to properly regenerate, there must be a proliferation of cardio myocytes. Hypertension can result in increased cellular death of the cardiomyocytes. An extract of epimedium (icariin) may mitigate the loss of heart muscle due to hypertension.(12) Furthermore, as demonstrated in lab animals, curcumin also may prevent loss of cardiac muscle due to myocardial infarction (heart attack).(16)
  • Cardiomyocyte homeostasis ensures that the heart muscle stays healthy and strong. Cardiac aging leads to a gradual loss of homeostasis, which leads to the death of the cardiomyocyte and eventual heart failure. An important mechanism for maintaining homeostasis is regulated autophagy in the cardiomyocyte. Autophagy eliminates defective proteins and recycles components into new structures.
  • Cardiac scarring is the development of fibrosis in response to an attempt to repair damaged tissue (including inflammation and heart attack). Fibrosis can be reduced by nrf2 activation.
  • Cardiac hypertrophy - is the result of scarring which eventually can lead to cardiac failure. Andrographolide and arjuna have been shown in lab research to inhibit hypertrophy.(2)
  • Contractibility of Cardiomyocytes. Healthy cardiomyocytes have strong contraction capability which may be loss with age and is  factor in heart failure. Luteolin can improve contraction and ameliorate myocardium fibrosis which may improve heart failure.
  • Reducing Myocardial Damage. Carnosic Acid may reduce myocardial damage through properties of anti-inflammatory and antioxidant effects on the heart.(9)
  • Chronic Inflammation - Coronary Artery Disease. Coronary artery disease creates conditions of pervasive inflammation which also affect the heart. Lutein is not only important for vision health, but has potent anti-inflammatory effect in coronary artery patients.(4)
  •  Nrf2 for Oxidative Homeostasis - Aging results in lower levels of nrf2. As a master antioxidant factor, nrf2 is essential to maintain homeostasis of a protective oxidative state for the heart. Increased nrf2 may also protective against cardio fibrosis.

 Natural support for Cardio Anti-aging

  • Terminalia Arjuna (bark extract) - Indian medicine has long recognized arjuna as a cardio tonic and now modern research is supporting this. In young fitness participants, an arjuna extract significantly improved cardiovascular strength and efficiency. Arjuna has also shown potential benefit in heart failure in research animals.(5)
  • Terminalia Arujuna - supports heart function in diabetic rats. Myocardium function improved, as hypothesized by the study researchers, as a result of increased in endogenous antioxidant enzymes.(17)
  • Benefits of Terminalia Arjuna:
    • Improved Diabetic heart function
    • Improved exercise capacity via cardiovascular efficiency
    • Strong improvement of left ventricle output in individuals with cardiovascular ailments.
    • Reduction in mass of cardiac hypertrophy
    • May have beneficial effects on pulmonary hypertension - which is a fatal disease characterized by right ventricular hypertrophy and right heart failure.(20)
    • Protection of cardiac muscle from injury
    • Cardio tonic effect - i.e. positively affecting heart function
  •  Apigenin - Provides supports for hypertrophy and diabetic cardiomyopathy.(2.3)
  •  Luteolin - Supports improved heart muscle contraction in lab animal models of heart failure.(4) Furthermore, in research simulated myocardial infarction (heart attack), luteolin increased autophagy of the heart muscle, increasing mitochondrial biogenesis, thereby lessening subsequent cardiac dysfunction.
  •  Icariin (Epimedium) - helps mitigate hypertension induced cellular death of the   cardiomyocytes.(12)
  •  Lutein - Provides powerful anti-inflammatory action in cardiovascular disease, thereby reducing potential for fibrosis. Lutein is further supportive by acting as an nrf2 activator.  
  • Sulforaphane - Inhibits diabetic cardiomyopathy via the effects as a powerful Nrf2 activator.(13) Experimental research has shown that sulforaphane inhibited cardiomyopathy in both type 1 and type 2 diabetes. In experimental models of cardiac infarctions (heart attack), sulforaphane inhibited changes to the heart muscle, in particular the fibrosis that occurs post-injury.(23)
  • EGCG (Green Tea Extract) - Has an inhibitory effect on myocardial fibrosis.(14)
  • Andrographolide - Nrf2 activator, significantly reducing oxidative stress and potent ant-inflammation agent.(15, 22) Also upregulates glutathione levels in cardiomyocytes, which offers powerful protection against oxygen deprived injury (such as a myocardial infarction). (21) 
  • Curcumin - Regulates autophagy of cardiomyocytes, which supports the degradation and recycling of cardiomyocyte components, such as mis-folded proteins. Autophagy is an essential process in supporting cardiomyocyte homeostasis. When autophagy is dysregulated, the muscle cell dies and may lead to atrophy of the heart and eventually heart failure. In addition to curcumin, resveratrol and berberine also regulate autophagy,(18)

       

      CARDIO VITALITY (Terminalia Arjuna (Rejuna))

      YELLOW LONGEVITY (Curcumin, EGCG, Apigenin, Luteolin, Icariin, Carnosic Acid)*

      YELLOW NATURALLY (Curcumin, EGCG, Apigenin, Luteolin, Icariin, Carnosic Acid)*

      VISION VITALITY MAX (Lutein, Meso Zeaxanthin)

      XGEVITY (Glucoraphanin precursor to Sulforaphane)*

       *Andrographolide is also included

       

      REFERENCES:

      (1) Steenman M, et al. Cardiac aging and heart disease in humans. Biophys Rev. 2017 Apr;

      (2) Zhu ZY, et al. Apigenin ameliorates hypertension-induced cardiac hypertrophy and down-regulates cardiac hypoxia inducible factor-lα in rats. Food Funct. 2016 Apr;7

      (3) Liu HJ, et al. Apigenin alleviates STZ-induced diabetic cardiomyopathy.  Mol Cell Biochem. 2017 Apr

      (4) Hu W, et al. Luteolin improves cardiac dysfunction in heart failure rats by regulating sarcoplasmic reticulum Ca2+-ATPase 2a. Sci Rep. 2017 Jan

      (5) Oberoi L, et al. The aqueous extract, not organic extracts, of Terminalia arjuna bark exerts cardiotonic effect on adult ventricular myocytes. Phytomedicine. 2011 Feb 15

      (6) Parveen A, et al. Terminalia arjuna enhances baroreflex sensitivity and myocardial function in isoproterenol-induced chronic heart failure rats. J Cardiovasc Pharmacol Ther. 2012 Jun

      (7) Kaliq F, et al, Improvement in myocardial function by Terminalia arjuna in streptozotocin-induced diabetic rats: possible mechanisms. J Cardiovasc Pharmacol Ther. 2013 Sept.

      (8) Kumar S, et al. Proteomic analysis of the protective effects of aqueous bark extract of Terminalia arjuna (Roxb.) on isoproterenol-induced cardiac hypertrophy in rats. J Ethnopharmacol. 2017 Feb 23

      (9) Kocak C, et al, Molecular and biochemical evidence on the protective effects of embelin and carnosic acid in isoproterenol-induced acute myocardial injury in rats. Life Sci. 2016 Feb 15

      (10) Chung RWS, et al. Lutein exerts anti-inflammatory effects in patients with coronary artery disease. Atherosclerosis. 2017 May 6;

      (11) Girandola RN, et al. Effect of E-OJ-01 on Cardiac Conditioning in Young Exercising Adults: A Randomized Controlled Trial. Am J Ther. 2017 May

      (12) Qian ZQ, et al. Icariin prevents hypertension-induced cardiomyocyte apoptosis through the mitochondrial apoptotic pathway. Biomed Pharmacother. 2017 Apr.

      (13) Gu J, et al. Metallothionein Is Downstream of Nrf2 and Partially Mediates Sulforaphane Prevention of Diabetic Cardiomyopathy. Diabetes. 2017 Feb;

      (14) Lin CM, et al. Suppressive effect of epigallocatechin-3-O-gallate on endoglin molecular regulation in myocardial fibrosis in vitro and in vivo. J Cell Mol Med. 2016 Nov;

      (15) Tan WS, et al. Is there a future for andrographolide to be an anti-inflammatory drug? Deciphering its major mechanisms of action. Biochem Pharmacol. 2017 Apr 2

      (16) Lv FH, et al. Effects of curcumin on the apoptosis of cardiomyocytes and the expression of NF-κB, PPAR-γ and Bcl-2 in rats with myocardial infarction injury. Exp Ther Med. 2016 Dec

      (17) Khaliq F, et al. Improvement in myocardial function by Terminalia arjuna in streptozotocin-induced diabetic rats: possible mechanisms. J Cardiovasc Pharmacol Ther, 2013 Sep

      (18) Hashemzaei M, et al. Regulation of autophagy by some natural products as a potential therapeutic strategy for cardiovascular disorders. Eur J Pharmacol. 2017 May

      (19) Hu J, et al. Luteolin alleviates post-infarction cardiac dysfunction by up-regulating autophagy through Mst1 inhibition. J Cell Mol Med, 2016 Jan

      (20) Meghwani H, et al. Beneficial effects of aqueous extract of stem bark of Terminalia arjuna (Roxb.), An ayurvedic drug in experimental pulmonary hypertension.  J Ethnopharmocol. 2017 Feb 2

      (21) Woo AY, et al. Andrographolide up-regulates cellular-reduced glutathione level and protects cardiomyocytes against hypoxia/reoxygenation injury. J Pharmacol Exp Ther. 2008 Apr

      (22) Zhang J, et al. Andrographolide Attenuates LPS-Induced Cardiac Malfunctions Through Inhibition of IκB Phosphorylation and Apoptosis in Mice. Cell Physiol Biochem. 2015

      (23) Fernandes RO, et al. Sulforaphane effects on postinfarction cardiac remodeling in rats: modulation of redox-sensitive prosurvival and proapoptotic proteins. J Nutr Biochem. 2016 Aug

       

      Mitophagy - Maintaining Mitochondria & Stem Cell Renewal for Regenerative Longevity

      MITOPHAGY AND  LONGEVITY

      • Cellular homeostasis, which significantly includes mitochondria function, is critical for longevity. Mitochondria are the energy powerhouses of the cell and are essential cellular elements for health and longevity. As part of aging, the mitochondria accumulate damage which decreases cellular vitality while increasing dysfunction. Mitophagy is the ability to clean the cell of damaged mitochondria which, if left to accumulate, would cause irreversible loss of cellular energy. Dysfunctional mitochondria can lead to cellular death, degenerative diseases and shorten the lifespan.
      • Mitophagy is essential for longevity. Higher activity levels of  mitophagy in the cell has been linked to significant increases in longevity in research animals. Improved aging and extended longevity is correlated with a proper balance of mitochondria biogenesis and mitophagy.(1) Age-related decreases in mitophagy result in the accumulation of damaged mitochondria and a decrease in mitochondria biogenesis, 
      • Mitophagy and Autophagy. Mitophagy is the selective degradation of the mitochondria by cellular process known as autophagy. Autophagy is the cellular process used to remove damaged cellular organelles and debris. Increased autophagy is known as a critical component in cellular survival and longevity. Enhanced levels of autophagy is considered a major factor in the  increased longevity in long lived animals.(2)
       

      NRF2 - THE ROLE IN MITOPHAGY AND LONGEVITY  Nrf2 is a latent protein in the cell, which upon activation, regulates the activation of genes which produce antioxidant proteins for cellular protection, reduction of inflammation and reduction of mitochondrial toxins (via glutathione induction).

      • Nrf2 Increases Mitochondria Biogenesis and Mitophagy. .
      • Stem Cells - The basis for extreme longevity. Extreme lifespans are based on the ability to regenerate new cells to replace damaged cells. This is the function of stem cells. Stem cells are undifferentiated cells which, when needed, can differentiate into replacement cells in the body. Examples where stem cells differentiate into new functional cells include cardiomyoctyes (heart cells) and neurons in the brain. Sources of stem cells include a stem cell pool, whereby stem cells undergo a self-renewal (making new stem cell cells) which supply this pool. Additionally there are specific stem cells such as neural stem cells which can produce new neurons in the brain. Aging, and the dysfucntion of stem cell mitochondria, decrease the functional ability of stem cell self renewal and the regeneration ability of stem cells into cells such as neurons.
      • Nrf2 Protects Stem Cells Capacity for Self-Renewal and Differentiation, When levels of Nrf2 are decreased, stem cells and progenitor cells, lose their function for the self renewal and regeneration of cells.. An example of this is seen in neural stem cells in the brain where the ability to stimulate new neuron growth from stem cells  is inhibited when nrf2 levels are low. Researchers believe that nrf2 promotes healthy mitochondria in the stem cells which in turn reverses age related decline in stem cell ability to self-renew and to regenerate new cells. Therefore, nrf2 activation is significant in stem cell self renewal as well as cellular regeneration, including cardiomyocyte regeneration and preserving the function of neural stem cells.(5,6)  
      • SULFORAPHANE is a natural and potent Nrf2 Activator and helps maintain youthful and healthy mitochondria. (4, 7)
      • SULFORAPHANE - BEYOND Nrf2. In addition to providing Nrf2 activation, sulforaphane helps block damage to the mitochondria through non-Nrf2 mechanisms. Sulforaphane supports mitochondria hyperfusion, which is cytoprotective and prevents the formation of pores in the mitochondria.(8)
       
       XGEVITY (Sulforaphane Precursor Glucoraphanin)
       AIR VITALITY (Sulforaphane Precursor Glucoraphanin)

       

       

      REFERENCES:

      (1)  Palikaras K, et al. Mitophagy: In sickness and in health. Mol Cell Oncol. 2015 Jun.

      (2) Palikaras K, et al. Coupling mitogenesis and mitophagy for longevity. Autophagy. 2015.

      (3)  LaPierre L, et al. Transcriptional and epigenetic regulation of autophagy in aging. Autophagy. 2015 Jun

      (4) Greco T, et al. Sulforaphane Inhibits Mitochondrial Permeability Transition and Oxidative Stress. Free Radic Biol Med, 2012 Dec

      (5) Holstrom Kira, et al. The multifaceted role of Nrf2 in mitochondrial function. Curr Opin Toxicol. 2016 Dec

      (6) Wang K, et al. Redox homeostasis: the linchpin in stem cell self-renewal and differentiation. Cell Death Dis. 2013 Mar

      (7) Russo M, et al. Nrf2 targeting by sulforaphane: a potential therapy for cancer treatment. Crit Rev Food Sci Nutr. 2016 Dec 

      (8) O'Mealey GB, et al. Sulforaphane is a Nrf2-independent inhibitor of mitochondrial fission. Redox Biol. 2016 Nov 

      Air Pollution - Ultra-Fine Nanoparticles Major Threat for Brain & Lung and Aging

      Air pollution is a pervasive and often ignored factor in the aging process. Airborne ultra-fine (nanoparticles) pollution particles are microscopic and pose special dangers to health. Researchers agree that ultra-fine air pollution particles are a major threat in negative health consequences in humans. (1)  While being very detrimental to the lungs, long-term exposure to ultra-fine particles also damages the cardiovascular system, contributes to atherosclerosis plaque formation and may lead to degenerative brain diseases - including Alzheimer's disease. These very small particles are able to travel deep into lung tissue and into the blood stream. As a result, there are significant increases in systemic oxidative stress, inflammation with increased DNA damage and mutagenicity. (2-6) Telomere length, which is an indicator of biological aging, becomes shorter in people living in air pollution areas. Shorter telomeres is associated with accelerated aging.(7-8)

      Neuroinflammation. Especially alarming is the effect of ultra-fine particles on the brain. Airborne nano-sized particulate matter migrates through the lungs into the bloodstream and eventually into the brain. Longtime exposure to ultra-fine air pollutants leads to chronic brain inflammation which leads to neurodegenerative diseases. Epidemiological research has linked ultra-fine air particulate matter as a significant environmental  factor involved in Alzheimer's Disease and Parkinson's Disease.(2) 

      Ultra-fine pollutant particles are produced by high heat sources including automobiles, trucks, airplane exhaust and factories and play a significant role in health and longevity. Urban areas, transit routes (highways and roads) and airports are major sources of pollutants but the suburbs are not immune. Such pollutants are so small that most people are unaware that they are inhaling toxic pollutants. Airborne fine particulate matter is a major component of air pollution.

      Sources of ultra-fine particle pollutants:

      (1) City / Urban Areas Particulate Matter. Urban areas create a confluence of major activity which generate ultra-fine air pollution. In studies involving six China urban areas, ultra-fine particulate matter (PM), including polycyclic aromatic hydrocarbon (PAH), were analyzed. The particulate matter was determined as having cytotoxicty to the bronchial cells of the lungs.(9) Substantial sources of outdoor PAHs in particulate pollution include cars and trucks.

      (2) Highways / roadways. high volumes of traffic on highways are significant sources of ultra-fine particulate matter and PAH which is then distributed to surrounding areas and runoff into water ways. People living close to major roadways have increased health risks due increased air pollution exposure. Road paving and asphalt manufacturing are also major sources.

      (3) Indoor sources. Burning of biofuels including coal and wood create dangerous levels of emissions. Also emissions from cigarette smoke.

      (4) Diesel exhaust - classified as a group 1 carcinogen. Shown to cause lung and possibly bladder cancer.Contains nitric oxide and fine particulate matter.

      (5) Airports / Aircraft turbine engines - these aircraft engines produce significant levels of hazardous ultra-fine air pollutants (including benzene and formaldehyde) at both in flight and ground levels. In fact, air quality impacts areas extend far from the airports. The LA times reports that communities as far as 10 miles from LAX airport  are exposed to unsafe levels of air pollutants from aircraft engine exhaust.(10)

       Natural Support:

      SULFORAPHANE -  Sulforaphane is a potent activator of phase 2 detoxification in the body. In a study in high air pollution areas in China, sulforaphane beverages were shown to signifcantly increase metabolism and excretion of hazardous air pollutants benzene and acrolein in participants.(11)  Further studies indicate that through activation of Nrf2, sulforaphane enhances protection against airborne toxin carcinogens and carcinogenesis. (12) Sulforaphane also protects against oxidant effects of diesel emission by invoking an over expression of antioxidant enzymes.(13)

       N-ACETYL-CYSTEINE - Offers  protection against air pollution induced inflammation. Includes specific mitigation against formaldehyde induced lung damage. Formaldehyde is a major emission toxin from airplane exhaust.(14)

       

      XGEVITY  (Glucoraphanin / Sulforaphane and N-Acetyl-Cysteine)

      AIR VITALITY (Glucoraphanin / Sulforaphane and N-Acetyl-Cysteine)

       

      REFERENCES:

      (1) Chen R, et al. Beyond PM2.5: The role of ultrafine particles on adverse health effects of air pollution.  Biochim Biophys Acta. 2016 Dec

      (2)  Heusinkveld HJ, et al. Neurodegenerative and neurological disorders by small inhaled particles. Neurotoxicology. 2016 Sep

      (3)  Valavanidis A, et al. Airborne particulate matter and human health: toxicological assessment and importance of size and composition of particles for oxidative damage and carcinogenic mechanisms. Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2008 Oct-DecBottom of Form

      (4) Pope CA, et al. Exposure to Fine Particulate Air Pollution Is Associated with Endothelial Injury and Systemic Inflammation. Circ Res. 2016 Oct 25

      (5) Bai Y, et al. Fine particulate matter air pollution and atherosclerosis: Mechanistic insights. Biochim Biophys Acta. 2016 Dec

      (6) Risom L, et al. Oxidative stress-induced DNA damage by particulate air pollution. Mutat Res. 2005 Dec 30

      (7) Martens Ds, et al. Air Pollution Stress and the Aging Phenotype: The Telomere Connection.  Curr Environ Health Rep. 2016 Sep

      (8) Ward-Caviness CK, et al. Long-term exposure to air pollution is associated with biological aging. Oncotarget 2016 Oct 25

      (9) Yang L, et al. Pro-inflammatory response and oxidative stress induced by specific components in ambient particulate matter in human bronchial epithelial cells. Environ Toxicol. 2016 Aug

      (10) Ridgeway L. New concerns raised about air pollution at LAX. May 30, 2014

      (11) Egnar PA, et al. Rapid and sustainable detoxication of airborne pollutants by broccoli sprout beverage: results of a randomized clinical trial in China.

      (12) Kensler TW, et al. Keap1-nrf2 signaling: a target for cancer prevention by sulforaphane. Top Curr Chem. 2013.

      (13) Wan J, et al. Antioxidant enzyme induction: a new protective approach against the adverse effects of diesel exhaust particles. Inhal Toxicol 2007.

      (14) Wang M, et al. N-acetylcysteine: A promising drug against formaldehyde-induced damage in lung epithelial cells.  Med Hypotheses. 2014 Nov

      Citrus bergamia risso (Bergamonte®) Bioactives - Promotes Longevity & Cardio Health

      The unique flavonoids in citrus bergamia (Bergamonte®) have been previously shown to have potent cardioprotective properties including effective cholesterol support. Further research indicates that citrus bergamia flavonoids have additional beneficial properties which affect disease progression and longevity.(1)

      • Cardiovascular Health -  Studies show that Bergamonte® decreases triglycerides, plasma blood glucose and dangerous small LDL particles (VLDL), which damage ateries and accelerate atherosclerosis. Furthermore Bergamonte® increases healthy HDL while maintaining essential levels of large LDL.
      • Antioxidant & Anti-Inflammatory - These effects are systemic in nature and are believed responsible for the powerful action of Bergamonte® in supporting cardiovascular health as well as protection against degenerative diseases.
      • Longevity: Activates AMPK - AMP kinase (AMPK) is involved in an important regulator of glucose and fatty acid metabolism. AMPK activation is tightly coupled with longevity, including "energy metabolism, stress resistance, and cellular proteostasis."  AMPK signaling is involved with activation of other longevity activators including FOXO and SIRT1. AMPK activation becomes inhibited with age. (2)  Bergamonte® activates AMPK.

       

      VASCULAR STRENGTH  (Bergamonte®)

       

      Bergamonte® is a registered trademark of HP Ingredients.

       

      REFERENCES:

      (1) HP Ingredients October 2016.

      (2) Salminen A, et al. Age-related changes in AMPK activation: Role for AMPK phosphatases and inhibitory phosphorylation by upstream signaling pathways. Ageing Res Rev. 2016 Jul;

      Brown Adipose Tissue - Support for Obesity Diabetes and Longevity

       In humans, there are two types of adipose tissue. White adipose tissue and brown adipose tissue. White adipose tissue is associated with excessive fat storage, obesity, insulin resistance and diabetes. Whereas, brown adipose tissue has the opposite effect - producing energy, reducing fat storage and obesity, while increasing insulin sensitivity and reducing diabetes. Further, increasing expression of brown adipose tissue (adipocytes) may also be correlated with increases in longevity.

      Newborns have the greatest amount of brown fat, which helps provide a source of heat, but gradually decreases with age. Adults have a predominance of white adipose tissue which correlate with America's obesity epidemic.

      ADIPOCYTES COMPARISON

      • White Adipocytes. Store fat (triglycerides) and is linked to obesity and associated metabolic disorders such as diabetes.
      • Brown and Beige Adipocytes. Energy and thermogenic producing cells. Activation of these cells offer a possible course of treatment for obesity and diabetes.(1)

      BROWN ADIPOSE TISSUE

      • Health benefits. Studies altering white adipocytes, into adipocytes with brown adipose tissue characteristics show dramatic changes. Includes improvement in increased energy expenditure, improved insulin sensitivity, and protection against diet-induced obesity and diabetes. (2)
      • Longevity and UPC1. Aging studies involving animals, showed that increased expression of brown fat increases levels of UCP1 (uncoupling protein 1). UCP1 is contained in the membranes of mitochondria only in brown fat. When UCP1 is activated is provides an enormous source of heat energy.  Increased energy expenditure is recognized as a positive association with longevity.(3) Also UCP1 provides an alternative. less damaging path, for energy generation by the mitochondria. (see below). UCP1 protects the mitochondria from damaging oxidative stress and over a lifetime can have significant effect on lifespan.
      • Mitochondrial Uncoupling -Mitochondrial respiration, the process through which mitochondria produces energy,  also results in damaging end-products which promote cellular damage and death via free radicals - reactive oxygen species (ROS). The free radical theory of aging proposes that the free radicals produced by energy metabolism is linked to the aging process. Mitochondrial uncoupling describes anything which bypasses the normal electron chain which generates ATP energy and high levels of free radicals. Brown adipose tissue produces UCP1 - an important biological protein which enables mitochondrial uncoupling and reduction in damaging ROS generation.(3)

       -------------------------------------------------------------------------------------------

      NUTRITION SUPPLEMENT SUPPORT:

      "Browning" of White Adipocytes.

      Research indicates that fat storing white adipocytes may be altered to take on the characteristics of energy producing brown adipocytes. Such changes to white adipocytes may be an effective strategy for reducing obesity and obesity related disorders (such as insulin resistance and diabetes). Improving insulin sensitivity is a factor not only in diabetes, but also considered significant in longevity.

      • Sulforaphane - In vitro experiments showed an increase in UCP1 expression (the marker for brown adipose tissue activity), in addition to increasing glucose uptake. (4)
      • Curcumin - Curucmin induces browning of white adipocytes as well as inhibition of new fat cell generation. (5)
      • Andrographolide - Enhances brown adipose tissue gene activation attenuating obesity. Improves insulin sensitivity.(6)

      Increase in Mitochondria in Brown Fat during New Cell Formation (Adipogenesis)

      Improvement in number and function of mitochondria during brown fat adipogenesis. This may result in higher energy brown adipose tissue enabling even a stronger thermogenic response

      • Anthocyanins (C3G) - Anthocyanins, and in particular the anthocyanin C3G, has been shown to have beneficial effects towards obesity via brown adipose tissue. The effect is believed to be enhanced through increased mitochondria biogenesis during the formation of brown adipose tissue. (7)

       

      XGEVITY   Glucoraphanin (precursor of Sulforaphane)

      CURCUMIN XTRA-MAX  (includes Andrographolide)

      BLUE NATURALLY   (high anthocyanins and C3G)

       

      REFERENCES:

      (1) Inagaki T, et al. Transcriptional and epigenetic control of brown and beige adipose cell fate and function. Nat Rev Mol Cell Biol. 2016 Jun 2

      (2) Qian SW, et al. BMP4-mediated brown fat-like changes in white adipose tissue alter glucose and energy homeostasis. Proc Natl Acad Sci USA. 2013 Feb

      (3) Mookerjee SA, et al. Mitochondrial Uncoupling and Lifespan. Mech Ageing Dev. 2010 Jul - Aug.

      (4) Zhang HQ, et al. Sulforaphane induces adipocyte browning and promotes glucose and lipid utilization. Mol Nutr Food Res. 2016 May 24

      (5) Lone J, et al. Curcumin induces brown fat-like phenotype in 3T3-L1 and primary white adipocytes. J Nutr Biochem. 2016 Jan

      (6) Ding L, et al. Andrographolide prevents high-fat diet-induced obesity in C57BL/6 mice by suppressing the sterol regulatory element-binding protein pathway. J Pharmacol Exp Ther. 2014 Nov

      (7) You Y, et al. Mulberry and mulberry wine extract increase the number of mitochondria during brown adipogenesis. Food Funct. 2015 Feb

      Short Chain Fatty Acids - Optimizing Metabolic Energy and Longevity

      How and to what extent microbes influence on health is a relatively new area of study. Amazingly,  the influence of gut microbiota on general health and longevity is only now becoming understood. Recent attention is scientific areas concern the importance of intestinal microbes and how they affect not only health of the the gut but also overall health of the body.(1) An area of keen interest is the production of Short Chain Fatty Acids (SCFAs) by microbial fermentation in the gut and how it can significantly improve health.(2)

      Short Chain Fatty Acids (SCFAs - acetic acid, propionic acid and butyric acid) are produced as a fermentation byproduct of soluble fiber (e.g nuts, seeds, certain vegetables) by microbes in the large intestine.

       

      Among the beneficial effects of SCFA's include:

      • IMPROVES HEALTH OF INTESTINES. SCFA's are used as nutrients by the cells in the intestine to improve intestinal health, reducing inflammation and improving  gut barrier dysfunction. Gut barrier dysfunction contributes to chronic low grade inflammation and metabolic endotoxaemia.
      • REDUCING INSULIN RESISTANCE - Insulin Resistance s a major factor in the development and disease progression in diabetes. Furthermore, insulin resistance is significant in aging, and loss of glucose homeostasis accelerates the aging process.(3)
      • IMPROVING TYPE 2 DIABETES METABOLIC CONTROL - SCFA's are now considered as key molecules in mitigating some of the effects of diabetes including reduction in serum levels of glucose, insulin resistance. Furthermore, SCFA's increase the production of Glucogen-like Peptide-1 (GLP-1)  which is protective against diabetic effects. (4)
      • OBESITY - Development of obesity is affected by decreased SCFA production by microbiota in the intestine. Increased gut permeability, inflammation and increased energy are significant contributors to obesity.

         

        THE ROLE OF TAURINE IN SHORT CHAIN FATTY ACID PRODUCTION.

        Furthermore, research indicates that taurine supplementation may significantly improve the intestinal microbiotic environment by increasing the production of SCFAs  and decreasing inflammatory concentrations of serum  lipopolysaccharides (LPS). LPS induced inflammation is a common issue facilitated by the processed western diet.(5)

         

        LONGEVITY NATURALLY (High Taurine Complex)

         

        REFERENCES:

        (1) Andoh A. Physiological Role of Gut Microbiota for Maintaining Human Health. Digestion. 2016 Feb 9

        (2) KeenanMJ, et al. Improving healthspan via changes in gut microbiota and fermentation. Age (Dordr). 2015 Oct.

        (3) Hartl FU. Cellular Homeostasis and Aging. Annu Rev Biochem. 2016 Apr 6.

        (4) Puddu A, et al. Evidence for the gut microbiota short-chain fatty acids as key pathophysiological molecules improving diabetes. Mediators Inflamm. 2014

        (5) Yu H, et al. Effects of taurine on gut microbiota and metabolism in mice. Amino Acids. 2016 Mar 30.