PROTEOSTASIS. Defines the ability of the body to maintain the fidelity of biogenesis of protein (non-defective proteins), folding. movement, and removal of old protein aggregates. Especially significant is the removal of old damaged protein aggregates, which are detrimental to the functioning of the cell. Clearing old cellular debris, through a process called autophagy, greatly enhances the youthful functioning of the cell.
CURCUMIN ENHANCES AUTOPHAGY. Lifespan and autophagy are strongly
associated with one another. Calorie restriction, resveratrol and curcumin are known to improve autophagy and increase lifespan. In fact, all life extension mechanisms depend upon the importance of autophagy for clearing cellular damage.(1,2)
Aging affects molecular pathways that influence health and longevity. As a result, there is a reduction of cellular debris clearance (autophagy), decreased the pool of stem cells, increase in inflammation and cellular senescence.
CURCUMIN has been shown to by positively regulate longevity by through important molecular pathways, including IIS, mTOR and FOXO. Curcumin is a powerful activator of the body's antioxidant defense system, as an Nrf2 activator. As an antioxidant, curcumin stabilizes and protects telomeres. Inflammation is also a powerful promoter of aging. Curcumin inhibits the powerful inflammation transcription factor NF-κB and is associated with reduced levels of inflammation.(3) PROTEOSTASIS is impacted by all these aging pathways.(4) Therefore, curcumin supports longevity via aging signaling and proteostasis (autophagy).
Misfolded proteins in the brain are associated with poorly functioning autophagy. Autophagy removes aggregate protein accumulations which is responsible for neurodegeneration. Curcumin, research indicates, may help restore autophagy in the brain, to clear these misfolded proteins. (5) Oleuropein, a component of Olive Oil, in addition to curcumin, is implicated in mitophagy in the brain, removing old and dysfunction mitochondria. (6)
SIRT1 is an enzyme which regulates cellular processes relative to longevity. SIRT1 INCREASES PROTEOSTASIS ,which is an important component of the longevity effect. Natural activators of SIRT1 include Curcumin, Fisetin, Quercetin and Resveratrol.(15)
Cardiac remodeling through failure of autophagy, proteostasis and inflammation are believed to be a root cause of atrial fibrillation. Cardiomyocytes are replaced by non-functional proteins..(12. 13)
With age, cells become replicative scenescent - losing ability to produce new cells. Furthermore, scenescent cells are old cells. Old cells have been shown to lose proteostasis, which further limit the abilty of the cell to respond to external threats and maintain function. Curcumin and pterostilbene(11) helps inhibit cellular scenescence. Fisetin and quercetin are considered senolytics, which are capable of removing scenescent cells. (10) Importantly, recent research also indicates that curcumin also removes scenescent cells.(14)
CURCUMIN PXC® - Incorporates highly bioavailable curcumin Furthermore, Curcumin PXC also includes powerful supplemental ingredients in support of proteostasis.
Aging is a complex consequence of many factors. Cellular age post-translational non-enzymatic protein modifications is considered as critical in this model. Glycation is damaging of protein structures ,via non-enzymatic binding of glucose to protein. Glycation results in damaged proteins which affects functioning inside the cell and outside the cell. Advanced glycation end products (AGEs) are subsequently formed, and trigger oxidative stress and inflammation. Furthermore, inflammation, age-related oxidative stress, as well as decreased levels of NAD+ in the cell all affect proteostasis, a critical factor in longevity.(1,2) An important function of proteostasis is autophagic clearance of damaged and toxic proteins, such as amyloid.
GLYCATION - INTRACELLULAR AGING
With age, there is a buildup of advanced glycation end products (AGEs) in the cell. AGEs create additional oxidative stress and inflammation in the cell. AGEs also reduce cellular proteostasis, which further reduces the cells ability to eliminate AGE complexes through autophagy. The accumulation of AGEs in cardiac and vascular cells, lead to inflammation and fibrosis, causing atherosclerosis and cardiac diseases. (3)
GLYCATION - EXTRACELLULAR AGING
In particular, modifications such as cross-linking of long-lived molecules with slow turnover. In the extracellular matrix (ECM), the cross-linking of molecules such as collagen and elastin, create loss of cellular homeostasis, especially proteostasis. The cross-linking of these long-lived molecules occur through processes such as glycation. Creates an abnormal stiffness and hardening from which cannot be recovered. Stiffness of the ECM contributes to hypertension, rigidity of arteries, atherosclerosis and cancer.(4)
Perhaps most important, these alterations of ECM reduce viability of the cell, reducing longevity. Due to the diminishing amount of functional elastin, it has been suggested that the maximum limit for elastin dependent cardiovascular and respiratory systems is 100-120 years.(5)
ECM aging is also linked to stem-cell aging, and exhaustion of the stem cell supply. (4) Interestingly, older mouse cells transplanted into younger mice, may outlive the maximum lifespan of an organism by three-fold! This exemplifies the importance of the extracellular environment and how stiff ECM affects cellular lifespan.
Further linkage between ECM stiffness and cellular senescence. Which may also be associated with increased fibrosis. FIBROSIS. Is another key aging indicator. Mitochondrial dysfunction also increases in frequency in a aged (stiff) ECM. Skin aging is accelerated by ECM stiffness, which causes increase in breakdown of skin layers.
ATRIAL FIBRILLATION. Advanced glycation endproducts are involved in the pathogenesis of Atrial fibrillation. (6) Suggested modes of treatment include lowering AGE levels and increasing levels of antioxidants.(9)
BOTANICAL EXTRACTS FOR AGING INHIBITION
Apigenin prevents the formation of AGEs by trapping methylglyoxal (MGO), which is a precursor molecule. Through inhibiting MGO, AGEs will not be formed, thereby reducing oxidative stress and inflammation. In turn, this allows for increased proteostasis in the cell.(6)
Sufficient levels of cellular NAD+ are required for anti-aging cellular functions, including proteostasis. (7,8) The principal regular for cellular NAD+ in cells is CD38.
In animal research experiments, berberine reduced glycation levels. (10) In the brain of Alzheimers Disease mice, berberine invoked autophagic clearance of amyloid beta deposits.(11) Also has been shown to reduce the formation of amyloid beta oligomer formation, this is the prior step before amyloid beta fibril formation. (12) When combined with curcumin, there is a synergistic reduction in amyloid beta production.(13)
Research indicates that rosmarinic acid both inhibits glycation and prevents protein aggregation. Both are correlated to aging pathologies.(14).
(1) Baldensperger T, et al. Comprehensive Analysis of Posttranslational Protein Modifications in Aging of Subcellular Compartments. Sci Rep. 2020 May.
(2) Rudzinnska M, et al. Cellular Aging Characteristics and Their Association With Age-Related Disorders. Antioxidants (Basel). 2020 Jan.
(3) Neviere R, et al. Implication of Advanced Glycation End Products (Ages) and Their Receptor (Rage) on Myocardial Contractile and Mitochondrial Functions. Glycoconj J. 2016 Aug.
(4) Fedintsev, A. et al. Stochastic non-enzymatic modification of long-lived macromolecules - A missing hallmark of aging. Ageing Research Reviews. Volume 62. September 2020.
(5) Robert L, et al. Rapid Increase in Human Life Expectancy: Will It Soon Be Limited by the Aging of Elastin? Biogerontology. 2008. Apr.
(6) Zhou, Q. et al. Apigenin and Its Methylglyoxal-Adduct Inhibit Advanced Glycation End Products-Induced Oxidative Stress and Inflammation in Endothelial Cells. Biochem Pharmacol. 2019 Aug.
(7) Griffiths H, et al. Nicotinamide Adenine Dinucleotide (NAD+): Essential Redox Metabolite, Co-Substrate and an Anti-Cancer and Anti-Ageing Therapeutic Target
(8) Ogura Y, et al. CD38 Inhibition by Apigenin Ameliorates Mitochondrial Oxidative Stress Through Restoration of the Intracellular NAD +/NADH Ratio and Sirt3 Activity in Renal Tubular Cells in Diabetic Rats. Aging (Albany NY). 2020 Jun
(9) Prasad K. AGE-RAGE Stress in the Pathophysiology of Atrial Fibrillation and Its Treatment. Int J Angiol. 2020 Jun.
(10) Zych M, et al. Effect of Berberine on Glycation, Aldose Reductase Activity, and Oxidative Stress in the Lenses of Streptozotocin-Induced Diabetic Rats In Vivo-A Preliminary Study. Int J Mol Sci. 2020 Jun.
(11) Huang M, et al. Berberine Improves Cognitive Impairment by Promoting Autophagic Clearance and Inhibiting Production of β-amyloid in APP/tau/PS1 Mouse Model of Alzheimer's Disease. Exp Gerontol, 2017 May.
(12) Fawver J, et al. Probing and Trapping a Sensitive Conformation: Amyloid-β Fibrils, Oligomers, and Dimers. J Alzheimers Dis. 2012.
(13) Lin L, et al. Synergic Effects of Berberine and Curcumin on Improving Cognitive Function in an Alzheimer's Disease Mouse Model. Neurochem Res. 2020 May.
(14) Shamsi A, et al. Rosmarinic Acid Restrains Protein Glycation and Aggregation in Human Serum Albumin: Multi Spectroscopic and Microscopic Insight - Possible Therapeutics Targeting Diseases. Int J Biol Macromol. 2020 Jun.
(15) Lima T, et al. Curcumin, Alone or in Combination With Aminoguanidine, Increases Antioxidant Defenses and Glycation Product Detoxification in Streptozotocin-Diabetic Rats: A Therapeutic Strategy to Mitigate Glycoxidative Stress. Oxid Med Cell Longev. 2020 May.
(16) Lee S, et al. Curcumin Enhances the Production of Major Structural Components of Elastic Fibers, Elastin, and fibrillin-1, in Normal Human Fibroblast Cells. Biosci Biotechnol Biochem. 2015.
(17) Maher P, et al. Fisetin Lowers Methylglyoxal Dependent Protein Glycation and Limits the Complications of Diabetes. PLoS One. 2011.
(18) Lv, L, et al. Stilbene Glucoside From Polygonum Multiflorum Thunb.: A Novel Natural Inhibitor of Advanced Glycation End Product Formation by Trapping of Methylglyoxal. J Agric Food Chem. 2010 Feb.
(19) Liang W, et al. Protective Effects of Rutin on Liver Injury in Type 2 Diabetic db/db Mice. Biomed Pharmacother. 2018 Nov.
Excess body weight is associated with many health concerns, and is rapidly becoming the number one health problem worldwide. among the health risks are diabetes, cardiovascular disease, cancer and premature death. (1) Individuals of the obese classification are especially subject to deleterious health implications. Obesity results in:
Visceral Fat - Obesity results in increases of visceral fat. Visceral fat (also known as belly fat) is the fat that accumulates around organs in the abdominal cavity and is linked to serious diseases, including type 2 diabetes. metabolic syndrome and those affecting organ functioning. Significant levels of inflammatory proteins are generated by visceral fat. In fact, inflammation of the liver which precedes HDLF, is mediated by visceral fat inflammatory proteins.(2)
Nonalcoholic fatty liver disease (NAFLD) - Obesity is a significant risk factor in the development of NAFLD. Most noteworthy, is the excessive buildup of triglycerides in the liver which causes metabolic disturbances throughout the body. As a result, fatty acid metabolism becomes impaired, which may lead to fatty acid intermediates which causes insulin resistance and cardiovascular disease.
Adipose Tissue and Aging - White adipose tissue, associated with obesity, is the most affected tissue in aging. As the adipose tissue ages, there is a significant increase in oxidative stress and the generation of inflammatory proteins resulting in chronic low grade inflammation. In turn, this further damages tissue and accelerates aging. (6)
HYPER LONGEVITY™ (Ursolic Acid | Rosmarinic Acid)
(1) Unamuno Xm et al. Adipokine dysregulation and adipose tissue inflammation in human obesity. Eur J Clin Invest. 2018 Sep
(2) Casagrande BP, et al. Hepatic inflammation precedes steatosis and is mediated by visceral fat accumulation. J Endocrinol. 2020 Mar 1
(3) Conceição G, et al. Fat Quality Matters: Distinct Proteomic Signatures Between Lean and Obese Cardiac Visceral Adipose Tissue Underlie its Differential Myocardial Impact. Cell Physiol Biochem. 2020 Apr 23
(4) Huang N, et al. Novel insight into perirenal adipose tissue: A neglected adipose depot linking cardiovascular and chronic kidney disease. World J Diabetes, 2020 Apr 15
(5) Sreedhar UL, et al. A Systematic Review of Intra-pancreatic Fat Deposition and Pancreatic Carcinogenesis. J Gastrointest Surg. 2019 Nov 20
(6) Yu Q, et al. Sample multiplexing for targeted pathway proteomics in aging mice. Proc Natl Acad Sci USA. 2020 Apr 24
(7) Mangge H, et al. Telomere shortening associates with elevated insulin and nuchal fat accumulation. Sci Rep. 2020 Apr 22
(8) Goldberg EL, et al. How Inflammation Blunts Innate Immunity in Aging. Interdiscip Top Gerontol Geiatr. 2020
(9) Conley SM, et al. Human Obesity Induces Dysfunction and Early Senescence in Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells. Front Cell Dev Biol. 2020 Mar 26
(10) Eckel-Mahan K, et al. Adipose Stromal Cell Expansion and Exhaustion: Mechanisms and Consequences. Cells 2020 Apr 2
(11) Wang Y, et al. Berberine inhibits free fatty acid and LPS-induced inflammation via modulating ER stress response in macrophages and hepatocytes. PLoS One. 2020 May 1
(12) Horvath C, et al. Feeding brown fat: dietary phytochemicals targeting non-shivering thermogenesis to control body weight. Proc Nutr Soc, 2020 Apr
(13) Wang C, et al. Berberine inhibits adipocyte differentiation, proliferation and adiposity through down-regulating galectin-3.
(14) Yu SJ, et al. Berberine alleviates insulin resistance by reducing peripheral branched-chain amino acids. Am J Physiol Endocrinol Metab. 2019 Jan
(15) Su T, et al. Apigenin inhibits STAT3/CD36 signaling axis and reduces visceral obesity. Pharmacol Res. 2020 Feb
(16) Jung UJ, et al. Apigenin Ameliorates Dyslipidemia, Hepatic Steatosis and Insulin Resistance by Modulating Metabolic and Transcriptional Profiles in the Liver of High-Fat Diet-Induced Obese Mice. Nutrients. 2016 May
(16) Yaribeygi H, et al. Antidiabetic potential of saffron and its active constituents. J Cell Physiol, 2019 Jun
(17) Mashmoul M, et al. Protective effects of saffron extract and crocin supplementation on fatty liver tissue of high-fat diet-induced obese rats. BMC Complement Altern Med. 2016 Oct
(18) Al-Saud NBS. Impact of curcumin treatment on diabetic albino rats. Saudi J Biol Sci. 2020 Feb;27
(19) Gaballah HH, et al, Mitigative effects of the bioactive flavonol fisetin on high-fat/high-sucrose induced nonalcoholic fatty liver disease in rats.
(20) Kim M, et al. Lemon Balm and Its Constituent, Rosmarinic Acid, Alleviate Liver Damage in an Animal Model of Nonalcoholic Steatohepatitis. Nutrients. 2020 Apr 22
(21) Rui Y, et al. Rosmarinic acid suppresses adipogenesis, lipolysis in 3T3-L1 adipocytes, lipopolysaccharide-stimulated tumor necrosis factor-α secretion in macrophages, and inflammatory mediators in 3T3-L1 adipocytes. Food Nutr Res. 2017 Jun
(22) Younossi ZM, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology, 2016 Jul;
(23) Milton-Laskibar L, et al. Effects of resveratrol and its derivative pterostilbene on brown adipose tissue thermogenic activation and on white adipose tissue browning process. J Physiol Biochem. 2020 Mar 13
(24) Gomez-Zorita S, et al. Effects of Pterostilbene on Diabetes, Liver Steatosis and Serum Lipids. Curr Med Chem. 2019 Oct 29
(25) Gonzales-Garibay AS, et al, Effect of Ursolic Acid on Insulin Resistance and Hyperinsulinemia in Rats with Diet-Induced Obesity: Role of Adipokines Expression. J Med Food. 2020 Mar;23
Atherosclerosis is a chronic degenerative disease condition which slowly blocks arteries, accelerate aging and is a contributing factor in most age-related deaths.The key event in the initiation and progression of atherosclerosis is injury and inflammation to the arterial lining (endothelial cells).
(1) Tang T, et al. Pterostilbene reduces endothelial cell injury in vascular arterial walls by regulating the Nrf2-mediated AMPK/STAT3 pathway in an atherosclerosis rat model. Exp Ther Med. 2020 Jan
(2) Rath S, et al. Potential TMA-Producing Bacteria Are Ubiquitously Found in Mammalia. Front Microbiol. 2020 Jan
(3) Singh G, et al. High Mobility Group Box 1 Mediates TMAO-Induced Endothelial Dysfunction. Int J Mol Sci 2019 Jul
(4) Koh YC, et al. Prevention of Vascular Inflammation by Pterostilbene via Trimethylamine-N-Oxide Reduction and Mechanism of Microbiota Regulation. Mol Nutr Food Res. 2019 Oct.
(5) Zhang L, et al. Pterostilbene protects vascular endothelial cells against oxidized low-density lipoprotein-induced apoptosis in vitro and in vivo. Apoptosis. 2012 Jan
(6) Kang LL, et al. Pterostilbene Attenuates Fructose-Induced Myocardial Fibrosis by Inhibiting ROS-Driven Pitx2c/miR-15b Pathway. Oxid Med Cell Longev. 2019 Dec
Energy generation from brown adipose tissue (thermogenesis) is important for maintaining longevity, reducing obesity and supporting energy homeostasis. Brown adipose tissue (BAT) is central to physiological energy homeostasis. Enhancing brown adipose tissue reduces obesity, diabetes, insulin resistance and non-alcoholic fatty liver..
BAT dissipates energy in the form of heat through increased theromgenesis.(1) Browning of white adipose tissue, which converts characteristics of white adipose tissue to brown adipose tissue, increases expression of the thermogenic mitochondrial protein UCP-1. The uncoupling protein 1 (UCP-1) is a potent protein which shifts energy from ATP to heat.
Greater amounts of brown adipose tissue and the thermogenic capacity of the tissue are indicative of youth. With age, brown adipose tissue is decreased, while white adipose tissue becomes predominant and accelerates aging via inflammation and insulin resistance. .
GLUCORAPHANIN - Is a precursor of sulforaphane.
In laboratory mice fed a high fat diet, glucoraphanin supplementation promoted increased energy expenditures via an increase in UCP-1 protein expression in adipose deposit areas. Furthermore, results included decreases in weight, increased insulin sensitivity and improved glucose tolerance.(2)
PTEROSTILBENE - Studied in obese rats, pterostilbene increased the thermogenic capability of the BAT through an upregulation of Ucp1 protein expression..(3)
(1) Galmozzi A, et al. ThermoMouse: an in vivo model to identify modulators of UCP1 expression in brown adipose tissue. Cell Rep. 2014. Dec.
(2) Nagata N, et al. Glucoraphanin Ameliorates Obesity and Insulin Resistance Through Adipose Tissue Browning and Reduction of Metabolic Endotoxemia in Mice. Diabetes. 2017 Feb 16.
(3) Aguirre L, et al. Effects of pterostilbene in brown adipose tissue from obese rats. J Physiol Biochem. 2017 Feb 27