Prolongevity: New Evidence of Anti-Aging Effect of Resveratrol

For years, it has been known that resveratrol is one of the most effective anti-aging compounds studied. Beneficial effects on lifespan have been demonstrated across many research organisms, including worms and flies. In 2003, resveratrol was identified as a molecule which could activate SIRT1, mimicking the life extending benefits shown by calorie restriction. Furthermore, resveratrol also activates the anti-aging Nrf2 pathway, and AMPK which enhances NAD+ availability. (1) Cellular NAD+ levels are linked to longevity. 

In a new study, the silkworm was used to further illustrate the life extending effects of resveratrol via significant improvement of antioxidant activity.. Oxidation is a key factor is anti-aging and shortening of the lifespan.(2)

Resveratrol was shown to activate antioxidant function in the silkworm via increased activity of the GST enzyme, key in the antioxidant enzyme system.

RESVERATROL ACTIVATES the GST Antioxidant System via

• SIRT7 (activation) ---> activates FOXO --> activates GST (antioxidant) 

This research further validates the beneficial life extending benefits of resveratrol.

PURPLE LONGEVITY (Resveratrol : Pterostilbene)

REFERENCES:

(1) Li Z, et al. Aging and age‐related diseases: from mechanisms to therapeutic strategies. Biogerontology. 2021 Jan 

(2) Song J, et al.  Resveratrol elongates the lifespan and improves antioxidant activity in the silkworm Bombyx mori. J Pharm Anal. 2021 Jun

PURPLE LONGEVITY® - Rich purple Anthocyanins, Activating Longevity Genes Autophagy and Increasing Glutathione

Boosting longevity is a function of many different attributes. Key among these are activating longevity genes (SIRT1 and FOXO) and decreasing levels of oxidative stress. 

ACTIVATING LONGEVITY GENES -

• Resveratrol and Pterostilbene  - Act as antiaging gene activators, including SIRT1 gene activator.(1)
• Resveratrol and Pterostilbene are correlated with longevity.
• Lingonberry (Lowbush Cranberry) contains powerful anthocyanins which activate FOXO longevity genes. (2)
• Lingonberry may have beneficial effects on obesity health issues, including high fat diet cholesterol, glucose and inflammation.(3)

BILBERRY ANTHOCYANINS (Blue Color)

• Significant increases antioxidant capacity and induction of autophagy (4)
• AUTOPHAGY promotes health and longevity.
• AUTOPHAGY - invoked through increased AMPK and reduced mTOR
• AUTOPHAGY further enhanced intestinal epithelial barrier

 GRAPE SEED EXTRACT (GSE) (5-8)

• GSE grape seeds are anti-oxidative, anti-inflammatory and anti-tumor
• Vascular protective. Including blood pressure-lowering effect in hypertensive research animals. 
• Cardio protective properties, especially against cardiac dysfunction after myocardial infarction.
• Offers protection against ischemic stroke, by reducing oxidative stress levels.
• Is a natural aromatase inhibitor, an enzyme involved with converting androgens (testosterone) to estrogen. 

N-ACETYLCYSTEINE (GLUTATHIONE BOOSTER) (9-11)

• Is a precursor to glutathione. Decreases in glutathione are correlated with aging. Levels of cellular glutathione are predictive of longevity. 
• Improved experimental organisms health and longevity. Increased longevity corresponds to Increased levels of antioxidant enzymes (Catalase and Glutathione)
• Supports restoration of intestinal barrier.
• May be effective against cardiovascular events by increasing intracellular glutathione levels. Glutathione reduces  inflammatory IL-1β, which can can promote atherogenesis

 PURPLE LONGEVITY®  

=> (RESVERATROL | PTEROSTILBENE | LINGONBERRY)

REFERENCES:

(1) Li Y, et al. Effect of resveratrol and pterostilbene on aging and longevity. Biofactors. 2018 Jan.

(2) Scerbak C, et al. Lowbush cranberry acts through DAF-16/FOXO signaling to promote increased lifespan and axon branching in aging posterior touch receptor neurons. Geroscience. 2018 Apr.

(3) Ryyti R, et al. Beneficial effects of lingonberry (Vaccinium vitis-idaea L.) supplementation on metabolic and inflammatory adverse effects induced by high-fat diet in a mouse model of obesity. PLoS One. 2020 May.

(4) Li J, et al. Reduction of Aging-Induced Oxidative Stress and Activation of Autophagy by Bilberry Anthocyanin Supplementation via the AMPK-mTOR Signaling Pathway in Aged Female Rats.  J Agric Food Chem. 2019 Jul.

(5) Mas-Capdevila A, et al. Changes in arterial blood pressure caused by long-term administration of grape seed proanthocyanidins in rats with established hypertension. Food Funct. 2020 Oct.

(6) Ruan Y, et al. Grape Seed Proanthocyanidin Extract Ameliorates Cardiac Remodelling After Myocardial Infarction Through PI3K/AKT Pathway in Mice. Front Pharmacol. 2020 Dec. 

(7) Kadri S, et al. Protective effect of grape seed extract and orlistat co-treatment against stroke: Effect on oxidative stress and energy failure. Biomed Pharmacother. 2021  Apr.

(8) Kijima K, et al. Grape seed extract is an aromatase inhibitor and a suppressor of aromatase expression. Cancer Res. 2006 Jun.

(9) Niraula P, et al. N-Acetylcysteine extends lifespan of Drosophila via modulating ROS scavenger gene expression. Biogerontology. 2019 Aug.

(10) McCarty M, et al. Perspective: Prospects for Nutraceutical Support of Intestinal Barrier Function. Adv Nutr. 2021 Mar.

(11) DiNicolantonio J, et al. Supplemental N-acetylcysteine and other measures that boost intracellular glutathione can downregulate interleukin-1β signalling: a potential strategy for preventing cardiovascular events? Open Heart. 2017 Jul.

Fisetin - Potent for Anti-Aging Senolytics and Homeostasis

In the field of anti-aging, the flavonoid fisetin is emerging as a potent longevity compound. Fisetin affects the aging process in experimental animals through multiple pathways, including senolytics (removing senescent cells)m SIRT1 activation, calorie restriction mimic and homeostasis.

SENOLYTICS

• Senolytics- the rejuvenation of the cellular environment, by eliminating senescent cells. Aging is characterized by the accumulation of senescent cells. These are cells which are irreversibly unable to grow and function and are resistant to normal cellular clearance. Senescent cells not only interfere with normal tissue functioning, but may also be toxic to neighboring cells. Fisetin, has been shown to be a potent senolytic, with the ability to eliminate senescent cells. (1)

• Scenescent Cells Accelerate Aging. Scenescent cells promote inflammation, stem cell dysfunction, chronic disease, and cellular aging.(2)
• Improve Healthy Lifespan. The elimination of specific age accelerating senescent cell populations is a potential strategy in improving health and longevity.(3)
• Fisetin - was the most potent and selective senolytic among flavonoids tested. Most importantly. fisetin administered to late-life laboratory animals, restored all markers of tissue homeostasis,  and amazingly extended median and maximum lifespans.(4)

REDOX HOMEOSTASIS / IONIC HOMEOSTASIS

• Fisetin Improves Redox Homeostasis. Plasma membranes are affected by increased levels of oxidation and reduced antioxidants in cellular membranes. Fisetin signifcantly increases antioxidants in membranes and activates the redox protection system. (5)
• Fisetin Improves Ionic Homeostasis. Aging affects the plasma membrane of cells, and the membrane transporters. Impairment of the membranes transport function is related to age progression and disease. Specifically, membrane transporters are responsible for ionic homeostasis between intracellular and extracellular environments. Fisetin reverses these aging declines.(6)

SIRTUIN ACTIVATION (SIRT1)

• Fisetin is an SIRT1 activator. Sirtuin activation plays a significant role in longevity. Among the anti-aging benefits include inhibition of cellular senescense, reduced telomere reductions, and enhanced DNA repair. Sirtuins interact with the major longevity pathways, among which is FOXO.(7)

PLURIPOTENT STEM CELLS (Induction)

• Stem cells are the regenerative cells of the body, and represent a primary mechanism for longevity. Fisetin has the unique capablity of converting adult cells (somatic)into pluripotent stem cells. A process known as induced pluripotent stem cells (iPSC). Pluripotent stem cells revert to any specialized cells for tissue repair, organ repair, and  other anti-aging regeneration.(8) Fisetn as a sirtuin activator, enhances the generation of cellular reprogramming.

NRF2 ACTIVATION

• Nrf2 is a powerful antioxidant pathway with strong correlation to longevity.(9)
• Fisetin is a potent activator of Nrf2 and is responsible for the cellular antioxidant activity of fisten.(10)

PROTEOSTASIS - ABNORMAL PROTEIN ACCUMULATION / AUTOPHAGY

• Proteostasis is the homeostasis of protein generation, folding and degradation of proteins. The dysregulation of this process results in aging and disease. Alzheimers Disease (AD) is example of the accumulation of toxic proteins in the brain.
• Fisetn supports reduction in abnormal accumulation and alterations of amyloid and tau in the brain. Fisetin has both antiamyloidogenic and fibril-destabilization activity,(11)
• Alzheimers Disease is characterized by amyoid beta and phosphoryated tau fibrils. FIsetin, through increased Nrf2 activation, enhanced the autophagic removal of phosphorylated tau.(12)

CURCUMIN PXC  (contains Fisetin)

REFERENCES:

(1) Glossmann HH, et al, Metformin and Aging: A Review. Gerontology. 2019. Sept.

(2) Kirkland JL, et al. Cellular Scenescence. A Translational Perspective. EBioMedicine, 2017 

(3) van Deursen JM. The role of Scenescent Cells in Ageing. Nature 2014.

(4) Yousefzadeh MJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine, 2018

(5) Singh S, et al. Fisetin, a potential calorie restriction mimetic, attenuates senescence biomarkers in rat erythrocytes.  Biochem Cell Biol. 2019 Aug

(6) Singh S, et al. Fisetin, a potential calorie restriction mimetic,modulates ionic homeostasis in senescence induced and naturally aged rats.  Biochem Cell Biol. 2019 Sept.

(7) Shin-Hae Lee, et al. Sirtuin signaling in cellular senescence and aging. BMB Rep. 2019 Jan

(8) Chen T, et al. Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells. Aging Cell. 2011.

 (9) Bai, et al. Small Molecules as SIRT Modulators.  Mini Rev Med Chem. 2018.

(10) Zhang H, et al. Nrf2⁻ARE Signaling Acts as Master Pathway for the Cellular Antioxidant Activity of Fisetin. Molecules. 2019 Feb.

(10) Zheng W, et al. Fisetin inhibits IL-1β-induced inflammatory response in human osteoarthritis chondrocytes through activating SIRT1 and attenuates the progression of osteoarthritis in mice. Int Immunopharmacol. 2017 Apr

(11) Simunkova M, et al. Management of oxidative stress and other pathologies in Alzheimer's disease. Arch Toxicol. 2019 Aug

(12) Sunhyo K, et al. Fisetin stimulates autophagic degradation of phosphorylated tau via the activation of TFEB and Nrf2 transcription factors Sci Rep. 2016.

Two times Power of Anti-Aging Resveratrol - Ursolic Acid and Rosmarinic Acid

Resveratrol has long been known as an natural anti-aging gene activator. The target of this activation is SIRT1. Research now indicates that another extract  (ursolic acid) is even more powerful than resveratrol in the activation SIRT1. Furthermore, the extracts ursolic acid and rosmarinic acid promote anti-aging in other ways,, including preservation of the functioning of the hypothalamus (implicated as playing a significant role in the aging process), inhibiting fibrosis (amyloid and tau) and inhibiting NOX2 and NOX4.

URSOLIC ACID

• SIRT1 Activator - Ursolic acid is a powerful activator of anti-aging protein SIRT1. In fact, when compared to resveratol, ursolic acid is double the power of activating SIRT1 versus resveratol.(1)

• Hypothalamus Anti-Aging - Recent research indicates that the hypothalamus is an important determinant in longevity, Dysregulation of the hypothalamus during aging affects the neuroendocrine system, and contributes to the exhaustion of stem cells, and the loss of proteostasis.(2) Ursolic acid beneficially supports health of the hypothalamus by enhancing levels of anti-aging SIRT1, SIRT6, PGC-1β and α-Klotho.(3)

• Nrf2 Preservation - Nrf2 is the master protein activator of the endogenous antioxidant system in the body, and is related to increased longevity. Ursolic acid is a potent inhibitor of the degradation of Nrf2, which supports increased level of Nrf2. (4)

ROSMARINIC ACID

• Longevity Extender -  In experimental studies with c. elegans, rosmarinic acid significantly extended lifespan by increasing anti-aging gene expression of daf-16 and other proteins.(5) 

• NOX2 and NOX4 (NADPH oxidases) Inhibitor - NOX2 and NOX4 play critical roles in aging.
• NOX2 - involved in hypertension, atherosclerosis, cardiac hypertrophy, diabetes and aging. The inhibition of NOX-2 is proposed for maintaining cardiovascular homeostasis.(6)
• NOX4 - involved in cellular senescence. The inhibition of NOX-4 may support anti-aging in body, which is expressed in many organs in the body.(7)
• Both NOXs are viewed as potential therapeutic targets to block.
• Rosmarinic acid inhibits both NOX2 and NOX4.(7)

• Amyoid Aggregation Inhibitor  -  An important hallmark of aging, both in the brain (Alzheimers Disease) and throughout the body, is the formation of amyloid fibril aggregates.
• While resveratrol has been shown to be inactive in the inhibition of aggregate formation,  rosmarinic acid, is shown as a powerful inhibitor.(8)
• Tau Aggregation Inhibitor - Insoluble tau protein is another protein abnormality (in conjunction with amyloid) associated with Alzheimer's Disease in the brain. Aging and chronic stress may induce tau aggregation. In lab animals, rosmarinic acid was shown to reduce tau protein aggregation. (9)

• Glycation Inhibitor - Supports Elastic Arteries and Skin. Glycation is the damaging of protein structure, accelerating aging of all protein structures in the body. Includes loss of elasticity of skin and arterial function.
• Glycation results in stiffness of the skin (and old appearance) and arteries. All indicators of significant aging. Rosmarinic acid was shown to improve the parameters of skin and arterial elasticity in human test subjects.(10)

• Insulin Resistance - AMPK. Rosmarinic acid significantly reduced skeletal muscle insulin resistance in insulin resistant lab animals. Rosmarinic acid activated AMPK in the muscle, which resulted in increased mitochondrial biogenesis,(11)

HYPER LONGEVITY  (Ursolic Acid | Rosmarinic Acid)

REFERENCES:

(1) Bakhtian N, et al. Mounting evidence validates Ursolic Acid directly activates SIRT1: A powerful STAC which mimic endogenous activator of SIRT1. Arch Biochem Biophys. 2018 Jul

(2) Kim K, et al. Role of hypothalamus in aging and its underlying cellular mechanisms. Mech. Ageing Dev. 2018. May.

(3) Bahrami SA, et al Ursolic acid regulates aging process through enhancing of metabolic sensor proteins level. Biomed Pharmacother, 2016 Aug

(4) Kamble SM, et al. In silico Evidence for Binding of Pentacyclic Triterpenoids to Keap1-Nrf2 Protein-Protein Binding Site. Comb Chem High Throughput Screen. 2017

(5) Wang F, et al. The Molecular Mechanism of Rosmarinic Acid Extending the Lifespan of Caenorhabditis elegans. Applied Mechanics and Materilals. 2011.

(6) Forte M, et al. The Pathophysiological Role of NOX2 in Hypertension and Organ Damage. High Blood Press. Cardiovasc Prev. 2016 Dec

(7) Revoltella S, et al. Identification of the NADPH Oxidase 4 Inhibiting Principle of Lycopus europaeus. Molecules. 2018 Mar.

(8) Ramazzotti M, et al, Mechanism for the inhibition of amyloid aggregation by small ligands.Biosci Rep. 2016 Sept.

(9) Shan Y, et al. Aging as a Precipitating Factor in Chronic Restraint Stress-Induced Tau Aggregation Pathology, and the Protective Effects of Rosmarinic Acid.  J Alzheimers Dis. 2016

(10) Yui S, et al. Beneficial Effects of Lemon Balm Leaf Extract on In Vitro Glycation of Proteins, Arterial Stiffness, and Skin Elasticity in Healthy Adults. J Nutr Sci Vitaminol (Tokyo) 2017

(11) Jayanthy G, et al, Rosmarinic Acid Mediates Mitochondrial Biogenesis in Insulin Resistant Skeletal Muscle Through Activation of AMPK. J Cell Biochem. 2017 Jul

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;