Naked Mole Rats (NMR), native to parts of East Africa, are extremely long lived rodents, living up to 8x's longer than comparably sized mice. This is equivalent to a humans living to be 800 years! Better yet, the NMR maintain their vitality and health to almost the end of their lives, including brains which are resistant to degeneration. So, what is behind such extreme longevity?
The key is enhanced cellular protein homeostasis. (1-3) Key regulators of the aging process is the ability to maintain cellular quality including the removal of defective, damaged and toxic proteins. In the cell, proteasomes, the cellular machinery which removes damaged protein in conjunction with lysosomal autophagy are involved in the removal of damaged protein and cellular components. NMR maintain a very high level of protein homeostasis by enhanced activity of proteasomes and maintaining high active levels of autophagy.
Increased proteasome and autophagy activity extends lifespans in animal experiments. However, dysfunction of protein homeostasis increases with age, and leads to cellular accumulation of damaged protein, and the onset of disease and aging. In Alzheimer's Disease, for example, damaged proteins (amyloid and tau proteins) begin to aggregate, and eventually kill the surrounding neurons. Normal protein homeostasis is disrupted in Alzheimer's Disease, and most notably impairment of autophagy.(4)
PROTEIN HOMEOSTASIS is essential for extreme longevity. The two primary molecular mechanisms for maintaining health cell quality control and protein are: Proteasomes and Autophagy. "Aging is considered to be the loss of physiological integrity accompanied by a cumulative dysfunction in securing cellular homeostasis, resulting in the accumulation of damage and a progressive decline of cellular function over time." (7)
FOXO Nrf2 (transcription factors) AND PROTEIN HOMEOSTASIS:
XGEVITY (Glucoraphanin / Sulforaphane)
AIR VITALITY (Glucoraphanin / Sulforaphane)
PURPLE LONGEVITY (Resveratrol)
REFERENCES:
(1) Triplett JC, et al. Age-related changes in the proteostasis network in the brain of the nakedmole-rat. Implications promoting healthy longevity. BiochimBiophys Acta. 2015 Oct.
(2) Triplett JC, et al. Metabolic clues to salubrious longevity in the brain of the longest-lived rodent: the naked mole-rat. J Neurochem. 2015 Aug.
(3) Pride H, et al. Long-lived species have improved proteostasis compared to phylogenetically-related shorter lived species. Biochem Biophys Res. Commun. 2015 Feb.
(4) Chondrogianni N, et al. 20S proteasome activation promotes life span extension and resistance to proteotoxicity in Caenorhabditis elegans. FASEB J. 2015 Feb
(5) Chondrogianni N, et al. Enhanced proteasome degradation extends Caenorhabditis elegans lifespan and alleviates aggregation-related pathologies. Free Radic Biol Med. 2014 Oct.
(6) Salminen A, et al. Impaired autophagy and APP processing in Alzheimer's disease: The potential role of Beclin 1 interactome. Prog. Neurobiol. 2013 Jul-Aug;
(7) Grimmel M, et al. WIPI-Mediated Autophagy and Longevity. Cells. 2015 May.
(8) Liu Y, et al. Sulforaphane enhances proteasomal and autophagic activities in mice and is a potential therapeutic reagent for Huntington's disease. J Neurochem 2014 May
(9) Chapple SJ, et al. Crosstalk between Nrf2 and the proteasome: therapeutic potential of Nrf2 inducers in vascular disease and aging. Int J Biochem Cell Biol. 2012 Aug
(10) Murshid A, et al. Stress proteins in aging and life span. Int J Hyperthermia. 2013 Aug.
(11) Calderwood SK, et al. The shock of aging: molecular chaperones and the heat shock response in longevity and aging--a mini-review. Gerontology. 2009.
(12) Webb AE, et al. FOXO transcription factors: key regulators of cellular quality control. Trends Biochem Sci. 2014 Apr.
(13) Pickering AM, et al. Nrf2-dependent induction of proteasome and Pa28αβ regulator are required for adaptation to oxidative stress. J Biol Chem. 2012 Mar.
(14) Gan N, et al. Sulforaphane activates heat shock response and enhances proteasome activity through up-regulation of Hsp27. J Biol Chem. 2010 Nov.
(15) Testa G, et al. Calorie restriction and dietary restriction mimetics: a strategy for improving healthy aging and longevity. Curr. Pharm Des. 2014
(16) Petrovski G, et al. Does autophagy take a front seat in lifespan extension? J Cell Mol Med. 2010 Nov
(17) Alavez S, et al. Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan. Nature. 2011 Apr.
ATRIAL FIBRILLATION (AF) is the most common arrhythmia of the heart and is caused when the atrial contraction becomes out of sync with the ventricle due to dysfunctional electrical signaling. The result is the ineffective movement of blood through the body. Atrial fibrillation may result in a fast fluttering heartbeat, which is a common characteristic. Because the blood is not being pumped through the body properly, atrial fibrillation increases risk of heart failure and the pooling of blood in the heart, which increases chances of blood clot formation. Blood clots which travel to the brain may cause a stroke.
Risk of atrial fibrillation increases with age which coincides with increased oxidative stress, where excessive free radicals exceed the body’s ability to protect against them. Oxidative stress activates inflammatory pathways and chronic inflammation. Mitochondrial production of free radicals is a major source of oxidative stress in the atrial cells. Onset of atrial fibrillation includes changes to the atrial myocardium which includes inflammation and fibrosis which effects changes to the electrical properties and loss of synchronization. Therefore, research suggests two important factors may play a role in the alteration of the atrial cells and electrical impulse: Oxidative stress and inflammation.
AGING AND ENDURANCE EXERCISE
• AGING: A prominent risk factor for atrial fibrillation is aging. Aging is correlated with increased levels of systemic oxidative stress and inflammation.
• ENDURANCE EXERCISE: AF has an increased occurrence in athletes, in particular those involved in endurance exercise (e.g. long distance running). The frequency of AF in endurance athletes is most notable in veteran endurance athletes (from ages 45 and higher). (1,2)
• During endurance exercise, versus moderate exercise, repeated strenuous overloads of the atria result in microtears and consequently inflammation and fibrosis.(2)
NATURAL SUPPORT:
Inhibition of oxidative stress and inflammation of the artrial myocardial tissue, which reduces potential for fibrosis in the atria, are key in reducing the risk for atrial fibrillation. Beneficial steps:
• INCREASING NRF2 – Nrf2 is a transcription factor which regulates the expression of proteins involved with cellular protection. Deficiency of Nrf2 reduces levels of protective proteins and facilitates the pathogenesis of structural changes to the atrial tissue, including fibrosis.(3-6) The condition of AF continues the cycle of oxidative stress, further altering the atrial tissue.
• INHIBITION OF INFLAMMATION. TNF-alpha and NK-BKappa are signaling proteins which are central to the inflammatory pathway activation. TNF-alpha plays an important role in the pathogenesis of atrial structural changes and atrial fibrillation.(6)
• ROLE OF NRF2 ACTIVATORS such as sulforaphane (and precursor glucoraphanin), supports the reduction of the tissue oxidative state while concurrently reducing the activation of the formation of fibrotic atrial tissue.(3-6) The Nrf2 activators, as powerful cell protectors, also support inflammation reduction and decrease expression of proinflammatory TNF-Alpha and NF-KappaB,
• RESVERATROL may also have direct effects on cardiac function and the pathways that affect the structural changes to the atria. Recent research indicates that resveratrol may inhibit changes to the atria with decreased atrial fibrosis formation.(7-8)
XGEVITY (Glucoraphanin / Sulforaphane plus other Nrf2 activators)
PURPLE LONGEVITY (Resveratrol plus Nrf2 activators)
REFERENCES:
(1) Laszio R, et al. Atrial fibrillation and physical activity: An overview. Herz. 2015 Sept.
(2) Redpath CJ, et al. Atrial fibrillation and the athletic heart. Curr Opin Cardiol. 2015 Jan.
(3) Hecker L, et al. Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Sci Transl Med. 2014 Apr
(4) Wolke C, et al. Redox control of cardiac remodeling in atrial fibrillation. Biochim Biophys Acta. 2015 Aug;
(5) Yeh YH, et al. Rosuvastatin suppresses atrial tachycardia-induced cellular remodeling via Akt/Nrf2/heme oxygenase-1 pathway. J Mol Cell Cardiol. 2015 May.
(6) Ren M, et al. Role of tumor necrosis factor alpha in the pathogenesis of atrial fibrillation: A novel potential therapeutic target? Ann Med. 2015 Jun
(7) Baczkó I, et al. Resveratrol and derivatives for the treatment of atrial fibrillation. Ann N Y Acad Sci. 2015 Aug
(8) Chong E, et al. Resveratrol, a red wine antioxidant, reduces atrial fibrillation susceptibility in the failing heart by PI3K/AKT/eNOS signaling pathway activation. Heart Rhythm. 2015 May
POWERFUL YELLOWS AND AGING. Apigenin and Luteolin. Many changes occur during the aging process, with the most profound being inflammation. Inflammation contradicts good health and becomes increasingly unregulated with age. Since inflammation is key in accelerating aging, it is important to modulate these effects, especially in the brain.
The gradual destruction of neurons by chronic inflammation (neuroinflammation) leads to brain deterioration and pathologies. In the arteries, inflammation facilitates the initiation and rapid onset of arteriosclerosis. It also is responsible for creating immune system dysfunction and autoimmune disease. Another affliction of the aging process is cancer, which is tightly associated with inflammation and cellular dysregulation. Apigenin and luteolin have both shown promise in supporting health aging including ensuring a healthy inflammatory response.
Longevity NAD+.
Nrf2 Activation.
Inflammation
Cardiovascular Artery Inflammation
Brain Degeneration / Neuroinflammation
Immune System
Anti-Cancer
Anti-Diabetic Activity
Skin Rejuvenation
Hypertension
YELLOW LONGEVITY (15 mg Apigenin plus 15mg Luteolin)
YELLOW NATURALLY (10 mg Apigenin plus 10 mg Luteolin)
LONGEVITY NATURALLY (10 mg Apigenin plus 10 mg Luteolin)
CARTILAGE MAX (15 mg Apigenin plus 15 mg Luteolin)
REFERENCES:
1. Escande C, et al. Flavonoid Apigenin Is an Inhibitor of the NAD(+)ase CD38. Diabetes. 2013 Apr.
2. Braidy N, et al. Mapping NAD(+) metabolism in the brain of ageing Wistar rats: potential targets for influencing brain senescence. Biogerontology. 2014 Apr;
3. Blackwell TK, et al. SKN-1/Nrf, stress responses, and aging in Caenorhabditis elegans. Free Radic Biol Med. 2015 Aug.
4. Paredes-Gonzalez X, et al. Induction of NRF2-mediated gene expression by dietary phytochemical flavones apigenin and luteolin. Biopharm Drug Dispos. 2015 Apr
5. Wang Q, et al. Inhibition of autophagy ameliorates atherogenic inflammation by augmenting apigenin-induced macrophage apoptosis. Int Immunopharmacol. 2015 Jul;
6. Zeng P, et al. Apigenin Attenuates Atherogenesis through Inducing Macrophage Apoptosis via Inhibition of AKT Ser473 Phosphorylation and Downregulation of Plasminogen Activator Inhibitor-2. Oxid Med Cell Longev. 2015
7. Yuan Y, et al. Anti-inflammatory effects of Edaravone and Scutellarin in activated microglia in experimentally induced ischemia injury in rats and in BV-2 microglia. BMC Neurosci. 2014 Nov
8. Wang S, et al. Neuroprotection of Scutellarin is mediated by inhibition of microglial inflammatory activation. Neuroscience. 2011 Jun
9. Theoharides TC, et al. Brain "fog," inflammation and obesity: key aspects of neuropsychiatric disorders improved by luteolin. Front Neurosci. 2015 Jul
10. Huang F, et al. The inhibitory effect of luteolin on inflammation in LPS-induced microglia. Zhong Yao Cai. 2011 Nov
11. Taupin P. Neurogenic drugs and compounds. Recent Pat CNS Drug Discov. 2010 Nov
12. Li R, et al. The effects of apigenin on lipopolysaccharide-induced depressive-like behavior in mice. Neurosci Lett. 2015 May
13. Liu R, et al. The flavonoid apigenin protects brain neurovascular coupling against amyloid-β₂₅₋₃₅-induced toxicity in mice. J Alzheimers Dis. 2011
14. Kritas SK, et al. Luteolin inhibits mast cell-mediated allergic inflammation. J Biol Regul Homeost Agents. 2013 Oct-Dec
17. Banerjee K, et al. Oxidative stress triggered by naturally occurring flavone apigenin results in senescence and chemotherapeutic effect in human colorectal cancer cells. Redox Biol. 2015 Apr
18. Tang AQ, et al. Apigenin inhibits the self-renewal capacity of human ovarian cancer SKOV3‑derived sphere-forming cells. Mol Med Rep. 2015 Mar.
19. Liu J, et al. Apigenin inhibits HeLa sphere-forming cells through inactivation of casein kinase 2α. Mol Med Rep. 2015 Jan
21. Ma L, et al. Luteolin exerts an anticancer effect on NCI-H460 human non-small cell lung cancer cells through the induction of Sirt1-mediated apoptosis. Mol Med Rep. 2015 Sep
22. Davies AH, et al. Inhibition of RSK with the novel small-molecule inhibitor LJI308 overcomes chemoresistance by eliminating cancer stem cells. Oncotarget. 2015 Aug
23. Bumke-Vogt C, et al. The flavones apigenin and luteolin induce FOXO1 translocation but inhibit gluconeogenic and lipogenic gene expression in human cells. PLoS One. 2014 Aug
24 Zhang Y, et al. Apigenin induces dermal collagen synthesis via smad2/3 signaling pathway. Eur J Histochem. 2015 Apr
25. Chen X, et al. Scutellarin attenuates hypertension-induced expression of brain Toll-like receptor 4/nuclear factor kappa B. Mediators Inflamm. 2013
Ideal Natural Cardiovascular Support. If there were an ideal natural support ingredient for cardiovascular health it would include the following:
Contrary to the opinions of many doctors, cholesterol is essential for health and life! Furthermore, the larger sized LDL may not have a significant effect on cardiovascular health (with balanced HDL levels). In fact, larger LDL is essential for the function of the body, including cell membranes, synaptic junctions in the brain, and production of Vitamin D and sex hormones and should not be significantly reduced. VLDL, however is dangerous. It is a carrier of both triglycerides and cholesterol and easily infiltrates and damages the lining of the artery and accelerates atherosclerosis. High levels of VLDL are correlated with high triglycerides and coronary artery disease.
Nearly perfect. Bergamonte® is the proprietary extract of Bergamot and virtually meets all the criteria for an ideal supplement for cardiovascular health.
At a dose of 500mg per day (preferably before meals), in several major clinical studies involving patients with hyperlipemia, hypercholesterol or metabolic syndrome, Bergamonte® was shown to have the following affects:
REFERENCES:
(1) HP Ingredients research 2015
Bergamonte® is a registered trademark of HP Ingredients
In a study from Japan, higher levels of dietary taurine was identified as the main factor attributing to the longer lifespan of the of the Japanese people.(1) Since then research has validated that taurine plays a major role in not only longevity, but quality longevity. Taurine plays a crucial role in most every system in the body and is considered an essential supplement for healthy aging.
Normal dietary intake of taurine is quite low, normally ranging between 40mg - 400mg. Clinical studies indicate the need for up to 3,000mg (or more) to make significant health improvements and promote longevity.
LONGEVITY NATURALLY (3000 mg of Taurine per serving)
VISION VITALITY (800 mg of Taurine per serving)
VASCULAR STRENGTH (500 mg of Taurine per serving)
REFERENCES
(1) Yamori Y, et al. Taurine as the nutritional factor for the longevity of the Japanese revealed by a world-wide epidemiological survey. Adv Exp Med Biol. 2009
(2) Ito T, et al. Tissue depletion of taurine accelerates skeletal muscle senescence and leads to early death in mice. PLoS One. 2014 Sep 17
(3) Ito T, et al. Potential Anti-aging Role of Taurine via Proper Protein Folding: A Study from Taurine Transporter Knockout Mouse. Adv Exp Med Biol. 2015
(4) Labbadia J, et al. Proteostasis and longevity: when does aging really begin? F1000Prime Rep. 2014 Feb
(5) Yang J, et al. Taurine increases testicular function in aged rats by inhibiting oxidative stress and apoptosis. Amino Acids. 2015 Aug.
(6) Gebara E, et al. Taurine increases hippocampal neurogenesis in aging mice. Stem Cell Res. 2015 May
(7) Sergeeva OA, et al. aurine-induced long-lasting enhancement of synaptic transmission in mice: role of transporters. J Physiol. 2003 Aug
(8) Hansen SH, et al. Taurine and regulation of mitochondrial metabolism. Adv Exp Med Biol. 2015;
(9) Jong CJ, et al. The ubiquitin-proteasome system and autophagy are defective in the taurine-deficient heart. Amino Acids 2015 Jul 21.
(10) Schaffer SW, et al. Does taurine prolong lifespan by improving heart function? Adv Exp Med Biol. 2015;
(11) Murakami S. Taurine and atherosclerosis. Amino Acids. 2014.
(12) Sirdah MM. Protective and therapeutic effectiveness of taurine in diabetes mellitus: a rationale for antioxidant supplementation. Diabetes Metab Syndr 2015 Jan-Mar;
(13) Dantos-Silva JC, et al. Taurine supplementation ameliorates glucose homeostasis, prevents insulin and glucogon hypersecretion, and controls Beta, alpha and gamma masses in genetic obese mice. Amino Acids. 2015 Aug;
(14) Moloney MA, et al. Two weeks taurine supplementation reverses endothelial dysfunction in young male type 1 diabetics. Diab Vasc Dis Res. 2010 Oct
(15) Ramila KC, et al. Role of protein phosphorylation in excitation-contraction coupling in taurine deficient hearts. Am J Physiol Heart Circ Physiol. 2015 Feb
(16) Heller-Stilb B, et al. Disruption of the taurine transporter gene (taut) leads to retinal degeneration in mice. FASEB J. 2002 Feb
(17) Froger N, et al. Taurine: the comeback of a neutraceutical in the prevention of retinal degenerations. Prog Retin Eye Res. 2014 Jul.
(18) Froger N, et al. Taurine is a crucial factor to preserve retinal ganglion cell survival. Adv Exp Med Biol. 2013.
(19) Gaucher D, et al. Taurine deficiency damages retinal neurones: cone photoreceptors and retinal ganglion cells. Amino Acids. 2012.
(20) Spriet LL, et al. Taurine and skeletal muscle function. Curr Opin Clin Nutr Metab Care. 2015 Jan;
(21) Goodman CA, Horvath D, Stathis C, et al. Taurine supplementation increases skeletal muscle force production and protects muscle function during and after high-frequency in vitro stimulation.J Appl Physiol.2009 Jul.
(22) Zhang M, et al. Role of taurine supplementation to prevent exercise-induced oxidative stress in healthy young men. Amino Acids, 2004.
(23) Manabe S, et al. Decreased blood levels of lactic acid and urinary excretion of 3-methylhistidine after exercise by chronic taurinetreatment in rats
(24) Yatabe Y, et al. Effects of taurine administration on exercise. Adv Exp Med Biol. 2009;
(25) Kato T, et al. The effects of taurine administration against inflammation in heavily exercised skeletal muscle of rats. Adv Exp Med Biol. 2015.
New research suggests that miRNA (microRNA) is a new target in the war against prostate cancer. MiRNA are short segments of RNA but are not involved with the coding of protein. However, miRNA does play a role in gene expression, frequently to silence the expression of a gene. In the case of prostate cancer, miRNA silences the expression of a tumor suppression protein, thereby allowing growth of the prostate cancer. Resveratrol and pterostilbene increases expression of the tumor suppression protein by decreasing levels of miRNA, thereby suppressing prostate cancer growth. Authors of the new research suggest that both stilbenes (resveratrol and pterostilbene) as candidates for chemopreventive and therapeutic use in prostate cancer.
REFERENCES:
(1) Dhar S, et al. Resveratrol and pterostilbene epigenetically restore PTEN expression by targeting oncomiRs of the miR-17 family in prostate cancer. Oncotarget. 2015 Aug 6
Longevity requires the continued optimal functioning of organs in the body, including heart, lungs, liver and pancreas. Injury and inflammation causes damage to organs, and the body attempts repair by laying down fibrotic tissue (scar tissue) to heal the damage. This process of fibrosis results in non-functional scar tissue being applied to a critical organ. In younger people, the scar tissue is eventually replaced with functional tissue. However, with age, this recovery process becomes compromised, and scar tissue remains, disrupting the ability of the organ to function. Over time scar tissue can accumulate and further inhibits the normal function of the organ.
Scar tissue which accumulates in the heart, lungs, kidneys or liver can result in devastating effects and even lead to death. Pulmonary fibrosis, for example, resulting from smoking or environmental factors progressively scar the lung until the person can no longer breath, and the disease is fatal. Aging of the heart is associated with fibrotic scars, which can lead to atrial fibrillation and decreased capacity of the heart to function.Cirrhosis of the liver is scarring of the liver, from chronic inflammation, which leads to liver failure.
Natural Nrf2 activators include sulforaphane (derived from glucoraphanin), curcumin, andrographolide, n-acetyl-cysteine, anthocyanins, C3G (anthocyanin), rosemary (carnosic acid), resveratrol, pterostilbene, baicalin, apigenin, luteolin
XGEVITY
AIR VITALITY
PURPLE LONGEVITY
BLUE NATURALLY
CURCUMIN XTRA-MAX / YELLOW LONGEVITY
REFERENCES:
(1) Hecker L, et al. Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Sci Transl Med. 2014 Apr.
(2) Zhao YY, et al. Metabolomics analysis reveals the association between lipid abnormalities and oxidative stress, inflammation, fibrosis, and Nrf2 dysfunction in aristolochic acid-induced nephropathy. Sci Rep. 2015 Aug 7
(3) Ni S, et al. Bone marrow mesenchymal stem cells protect against bleomycin-induced pulmonary fibrosis in rat by activating Nrf2 signaling. Int J Clin Exp Pathol. 2015 Jul 1
(4) Zhang Z, et al. Sulforaphane prevents the development of cardiomyopathy in type 2 diabetic mice probably by reversing oxidative stress-induced inhibition of LKB1/AMPK pathway.
(5) Dzeshka MS, et al. Cardiac Fibrosis in Patients With Atrial Fibrillation: Mechanisms and Clinical Implications. J Am Coll Cardiol. 2015 Aug 25
(6) Lee TY, et al. Modulation of thioacetamide-induced hepatic inflammations, angiogenesis and fibrosis by andrographolide in mice. J Ethnopharmacol. 2014 Dec 2
(7) Aboonabi A, et al. Chemopreventive role of anthocyanins in atherosclerosis via activation of Nrf2-ARE as an indicator and modulator of redox. Biomed Pharmacother. 2015 May
(8) Speciale A, et al. Cyanidin-3-O-glucoside (C3G) counters the response to TNF-alpha of endothelial cells by activating Nrf2 pathway. Mol Nutr Food Res. 2013 Nov.
(9) Paredes-Gonzalez X, et al. Induction of NRF2-mediated gene expression by dietary phytochemical flavones apigenin and luteolin. Biopharm Drug Dispos. 2015 Apr 22.