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;

Herbal Extracts - Neurogenesis & Recovery of Cognition Impairments

Aging of the brain involves the loss of neurons (hippocapmus shrinkage), loss of synapse integrity between neurons, build-up of toxic amyloid proteins, neuron tangles, defects in blood flow  and chronic inflammation. Under normal age progression, these events do not happen over night and may take years before impairments in cognition become noticed.

Ultimate anti-aging strategies for the brain and memory should target the progressive decline of the brain and promote reversal and recovery of some cognition impairments.

Emerging research in the study of herbal ingredients show their tremendous potential use in mitigating the decline in brain function with age.

• NEUROGENESIS - is the formation of new neurons, specifically in the hippocampus area in the brain.The hippocampus is essential in providing the capacity for memory and learning. Dementia and Alzheimer's disease are associated with brain shrinkage which is correlated to the loss of neurons in the hippocampus. The formation of new neurons may reverse brain shrinkage.

                    Herbs and Extracts

•  Andrographolide - As an extract from Andrographis Paniculata. Lab research has shown stimulation of neurogenesis in the hippocampus by andorgrapholide. Specifically " increased cell proliferation and the density of immature neurons in the dentate gyrus." (1) The dentate gyrus is an area of the hippocampus involved in memory formation.
• Centella asiatica - Acts as a potent memory enhancer, via  increasing hippocampus neurogenesis and support for brain tissue regeneration. (2)
• Baicalin (3)
• Panax Ginseng (4)
  
• Curcumin (5)
• Epimedium (Icariin)  (6)
• Apigenin (7)
  

• BRAIN TISSUE REGENERATION. While in the same theme as neurogenesis, brain tissue regeneration refers to the enhancement and regeneration of critical neuron structures - axons and dendrites. Dendrites transmit signals from the synapse to the body of the neuron. Axons transmit signals away from the body of the neuron and are covered with a myelin sheath which increase speed of the impulse providing rapid impulse transmission. Aging degenerates the structural integrity of dendrites and axon/myelin complex.
  

                     Herbs and Extracts

•  Centella asiatica - Improves structural integrity of axons / myelination and proliferation of dendritic branching and length. Such improvements have been shown to enhance learning and improve memory. (8) Centella asiatica also has been shown to improve learning and memory in normal lab mice.
• Luteolin - Baicalin - promote neuronal survival and neuron differentiation through the outgrowth of neurites  (axons and dendrites) from the neuron.(9.10)
• Rosemary (Carnosic Acid) - Strongly promotes neurite outgrowth as a function of powerful Nrf2 activity. Suppressed Nrf2 activation suppresses neuron differentiation.(11)

• RECOVERY OF COGNITIVE IMPAIRMENT - the  to reversal of certain functional impairments which may improve cognitive function. Many research animal models for cognitive impairment are characteristically similar to Alzheimer's disease (AD). Impairment usually involves cerebral vascular disease, synaptic dysfunction. and more.

          Herbs and Extracts

• Andrographolide - Impairment of synaptic function between neurons plays a significant role in the loss of cognitive function. This is seen in the progression of AD. In research animals with AD-like cognitive disease, the treatment of andrographolide over a 3 month span imporved synaptic function and protected important synaptic proteins.
• Furthermore, andrographolide has been shown to reduce inflammation in the brain and levels of pathological tau protein and beta amyloid in animal models.(12)
• Andrographolide reduces inflammation and dysfunction of the cerebral endothelial cells, which may affect vascular flow to the brain.(13)
• Centella asiactica - in senescence-accelerated lab mice, which had accelerated aging of the brain, administration of centella asiatica significantly improved synaptic plasticity and reduced beta amyloid build-up. Such treated mice showed significant benefits in memory and learning. (14)

• NEUROPROTECTION - AMYLOID & NON-AMYLOID (α-synuclein) TOXICITY | CHRONIC INFLAMMATION - The aging brain is under continual assault and must be protected to prevent cognitive decline and loss of neurons. Key areas of protection include the build-up of amyoid plaques which are toxic to neurons and synapses. Moreover, chronic inflammation in the brain accelerates destruction of the brain and is believed to be the facilitator of degenerative brain diseases.
• Centella asiatica (15)
  
• Epimedium (Icariin)(16,17)
• Apigenin and luteolin (18,19)
  
• Baicalin (20)
  
• Schisandra (21)
• Rosemary (Carnosic Acid)(22)

• REVERSES INSULIN RESISTANCE IN BRAIN NEURONS - Aging brains become increasingly incapable of using glucose as an energy source. Without this energy neurons age faster and die. Reversing the insulin resistance maintains healthy neurons. Brain insulin resistance is associated with Alzheimer's Disease.
• Further reduction in glucose availability is caused by methylglyoxal - a powerful intermediate in the formation of Advanced Glycation End Products (AGEs).
• Curcumin - Improves insulin sensitivity in neurons. (23)
• Sulforaphane - Reverses reduction of glucose uptake by neurons caused by methylglyoxal (a precusor of advanced glycation end products). Sulforaphane also normalizes brain-derived neurotrophic factor (BDNF) signaling, which is critical for maintaining brain function. BDNF pathways are disrupted in Alzheimer's Disease. (24)

YELLOW LONGEVITY

YELLOW NATURALLY

MEMORY ACTION

XGEVITY

LONGEVITY NATURALLY

REFERENCES:

NEUROGENESIS

(1)   Varela-Nallar L, et al. Andrographolide Stimulates Neurogenesis in the Adult Hippocampus. Neural Plast, 2015.

(2)  Sirichoat A, et al. Effects of Asiatic Acid on Spatial Working Memory and Cell Proliferation in the Adult Rat Hippocampus. Nutrients. 2015 Oct 5

(3) Zhang K, et al. Baicalin promotes hippocampal neurogenesis via SGK1- and FKBP5-mediated glucocorticoid receptor phosphorylation in a neuroendocrine mouse model of anxiety/depression. Sci Rep. 2016 Aug 9

(4) Jiang B, et al.  Antidepressant-like effects of ginsenoside Rg1 are due to activation of the BDNF signalling pathway and neurogenesis in the hippocampus. Br J Pharmacol. 2012 Jul;

 (5) Pluta R, et al. Neurogenesis and neuroprotection in postischemic brain neurodegeneration with Alzheimer phenotype: is there a role for curcumin? Folia Neuropathol. 2015

(6) Li F, et al. Icariin decreases both APP and Aβ levels and increases neurogenesis in the brain of Tg2576 mice. Neuroscience. 2015 Sep 24

(7) Taupin P. Apigenin and related compounds stimulate adult neurogenesis. Mars, Inc., the Salk Institute for Biological Studies: WO2008147483. Expert Opin Ther Pat. 2009 Apr

BRAIN TISSUE REGENERATION

(8) Yogeswarin L, et al. Recent Updates in Neuroprotective and Neuroregenerative Potential of Centella asiatica. Malays J Med Sci 2016 Jan.

(9) Chen PY, et al. Up-Regulation of miR-34a Expression in Response to the Luteolin-Induced Neurite Outgrowth of PC12 Cells. J Agric Food Chem. 2015 Apr

(10) Li M, et al. Neuronal differentiation of C17.2 neural stem cells induced by a natural flavonoid, baicalin. Chembiochem. 2011 Feb 11;

(11) Kosaka K, et al. Role of Nrf2 and p62/ZIP in the neurite outgrowth by carnosic acid in PC12h cells. J Biochem. 2010 Jan;

RECOVERING COGNITIVE DYSFUNCTION

(12) Rivera DS, et al. Andrographolide recovers cognitive impairment in a natural model of Alzheimer's disease (Octodon degus). Neurobiol Aging. 2016 Jul 5

(13) Chang CC, et al. Andrographolide, a Novel NF-κB Inhibitor, Inhibits Vascular Smooth Muscle Cell Proliferation and Cerebral Endothelial Cell Inflammation. Acta Cardiol Sin. 2014 Jul;

(14) Xing L, et al. Beneficial effects of asiaticoside on cognitive deficits in senescence-accelerated mice. Fitoterapia. 2013 Jun.

NEUROPROTECTION - AMYLOID TOXICITY AND INFLAMMATION

(15) Gray NE, et al. Centella asiatica Attenuates Amyloid-β-Induced Oxidative Stress and Mitochondrial Dysfunction. J Alzheimers Dis. 2015

(16) Zhang L, et al. Icariin reduces α-synuclein over-expression by promoting α-synuclein degradation. Age (Dondr.) 2015 Aug

(17) Chen YJ, et al. Neuroprotective Effects of Icariin on Brain Metabolism, Mitochondrial Functions, and Cognition in Triple-Transgenic Alzheimer's Disease Mice. CNS Neurosci Ther, 2016 Jan

(18) Dirscherl K, et al. Luteolin triggers global changes in the microglial transcriptome leading to a unique anti-inflammatory and neuroprotective phenotype. J Neuroinflammation 2010 Jan

(19) Rezai-Zedeh K, et al. Apigenin and luteolin modulate microglial activation via inhibition of STAT1-induced CD40 expression. J Neuroinflammation. 2008 Sep

(20) Chen C, et al. Baicalin attenuates alzheimer-like pathological changes and memory deficits induced by amyloid β1-42 protein.  Metab Brain Dis. 2015 Apr

(21) Song F, et al. Schizandrin A Inhibits Microglia-Mediated Neuroninflammation through Inhibiting TRAF6-NF-κB and Jak2-Stat3 Signaling Pathways. PLoS One. 2016 Feb 26;

(22) Habtemariam S. The Therapeutic Potential of Rosemary (Rosmarinus officinalis) Diterpenes for Alzheimer's Disease. Evid Based Complement Alternat Med, 2016

REVERSES BRAIN INSULIN RESISTANCE IN BRAIN NEURONS

(23) Feng HL, et al. Curcumin ameliorates insulin signalling pathway in brain of Alzheimer's disease transgenic mice. Int J Immunopathol. 2016 Jul 27

(24) Angeloni C, et al. Neuroprotective effect of sulforaphane against methylglyoxal cytotoxicity. Chem Res Toxicol, 2015 Jun 15