July 25, 2021

Posted in Antioxidant, FOXO, Longevity, Resveratrol, SIRT1, SIRT7

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)



(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. 



  • 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)


  • 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


  • 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. 



  • 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






(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.

The Intestine - Axis of Longevity

Aging and health of the intestine appears to be a significant determinant in the lifespan of an organism.  Studies on research animals show that  aging intestine effects on longevity is focused not only in the gut structure and function, but has a systemic effect, modulating aging throughout the body. Aging of the intestine directing correlates to aging of the body. Conclusions reached by researchers is that the intestine is an important target for extreme longevity. (1)


Healthy Intestine Equates to Longevity.

  • Homeostasis. Maintaining functional and healthy intestinal homeostasis is directly correlated with increased lifespan. Loss of homeostasis is due to Inflammation of the intestine, poor stem cell maintenance of epithelial intestinal lining and dysfunction of the intestinal barrier. Homeostasis depends on the constant turnover and regeneration of  healthy new intestinal epithelial cells.  This is the function of intestinal stem cells.(2)
  • Genetic Stability. Genetic mutations accumulate in adult stem cells during the lifespan of an organism. Mutations in the intestine epithelial cells lead to aging of intestine tissue, dysfunction of stem cells and ltumorgenesis. (3)
  • Longevity Signaling.  Expression of Foxo / daf-16 longevity factors in the intestines increases longevity factors throughout the body. By invoking the neuro-endorcrine system, the intestine affects systemic body aging. Furthermore, when brain sensors are activated (for example cold temperatures), this is also relayed to the intestine which triggers longevity factors through neuro-endocrine signaling. In lab animals, activation of the daf-16 longevity factor in the intestine increased lifespan of the organism by 50-60% ! (4,5)


Anti-Aging Support for Intestine

  • Fucoidan - An extract from seaweed, fucoidan is the constituent known as the "Japanese Longevity Secret".
    • Strengthens Intestine Barrier. Tight junctures in the intestine epithelial layer provides protection against toxins and other substances,  while reducing risk of inflammatory bowl disease.(6)
    • SIRT6.  Protector of the Intestine. Fucoidan is an activator of SIRT6, an anti-aging sirtuin. SIRT6 promotes stem cell maintenance. and importantly protects the intestine epithelial cells against injury.(7)
    • SIRT6 suppresses colon cancer proliferation. In contrast, when SIRT6 is depressed, colon cancer cells proliferate.(8, 9)
  • Ursolic Acid | Rosmarinic Acid.  As powerful anti-inflammtory and antioxidant compounds, ursolic and rosmarinic acids offer powerful intestine protection. In animal experimentally induced ulcerative colitis, administration of ursolic acid significantly mitigated the inflammation and tissue destruction. (10) Furthermore, replicated in several animal studies, rosmarinic acid was determined to be a potent inhibitor of colon carcinogensis.(11, 12)
    • Nrf2 Activation. Inhibits intestinal fibrosis. Intestinal fibrosis. which results in a loss of intestinal tissue,  is frequent complication of inflammatory bowl disease. (13).  Both ursolic acid and rosmarinic acid are Nrf2 activators.
    • Nrf2 Supports Intestinal Stem Cell proliferation. In high turnover tissue (e.g. intestine) stem cell regulation is critical for homeostasis. Nrf2 regulates the redox balance in stem cells. Deficient Nrf2 levels  in the stem cells, accelerates aging of the intestinal epithelium . (14)
  • Jujube - Enhances the intestinal barrier, and was shown to mitigate experimentally induced inflammatory bowl disease in lab animals.(15) Further, in research with mice,  indicates that daily administration of jujube to  ameliorate the formation of Aberrant Crypt Formation which is a precursor to colon cancer.(16) 
  • Icariin - Promotes genetic stability, thereby reducing cellular DNA damage. (17) Stem cells which accumulate DNA mutations age the cell, and may promote  tumor formation.
  • Fatty Acid Oxidation - Intestinal Regeneration - Enhancement of intestinal stem cell function, and intestine regeneration, may also be achieved by intermittent (short-term) fasting.  Short-term fasting activates fatty acid oxidation, which promotes stem cell function.(18)


HYPER LONGEVITY (Fucoidan, Ursolic | Rosmarinic, Jujube., Icariin)



(1) Reara M, et al. Organ-specific mediation of lifespan extension: more than a gut feeling?  Ageing Res Rev. 2013 Jan

(2) Santos AJM, et al. The Intestinal Stem Cell Niche: Homeostasis and Adaptations. Trends Cell Biol. 2018 Sep

(3) Blokzij G, et al.Tissue-specific mutation accumulation in human adult stem cells during life. Nature 2016.

(4) Fan X, et al. Intestinal Homeostasis and Longevity: Drosophila Gut Feeling. Adv Exp Med Biol. 2018

(5) Zhang Bi, et al. Brain–gut communications via distinct neuroendocrine signals bidirectionally regulate longevity in C. elegans. Genes Dev. 2018.

(6) Iraha Am et al. Fucoidan enhances intestinal barrier function by upregulating the expression of claudin-1. World J Hastroenterol. 2013 Sep.

(7) Liu F, et al, Sirtuin-6 Preserves R-spondin-1 Expression and Increases Resistance of Intestinal Epithelium to Injury in Mice. Mol Med. 2017.

(8) Tian J, et al. Sirtuin 6 inhibits colon cancer progression by modulating PTEN/AKT signaling.  Biomed Pharmacother. 2018 Oct

(9) Li N, et al. Downregulation of SIRT6 by miR-34c-5p is associated with poor prognosis and promotes colon cancer proliferation through inhibiting apoptosis via the JAK2/STAT3 signaling pathway.

(10) Liu B, et al. Ursolic acid protects against ulcerative colitis via anti-inflammatory and antioxidant effects in mice. Mol Med Rep. 2016 Jun

(11) Venkatachajam K, et al. Biochemical and molecular mechanisms underlying the chemopreventive efficacy of rosmarinic acid in a rat colon cancer. Eur J Pharmocol 2016 Nov 

(12) Furtado RA, et al. Chemopreventive effects of rosmarinic acid on rat colon carcinogenesis.  Eur J Cancer Prev. 2015 Mar

(13) Latella G. Redox Imbalance in Intestinal Fibrosis: Beware of the TGFβ-1, ROS, and Nrf2 Connection. Dig Dis Sci. 2018 Feb;

(14) Hotchmuth CE, et al. Redox regulation by Keap1 and Nrf2 controls intestinal stem cell proliferation in Drosophila. Cell Stem Cell. 2011 Feb

(15) Yue Y, et al. Wild jujube polysaccharides protect against experimental inflammatory bowel disease by enabling enhanced intestinal barrier function. Food Funct. 2015 Aug

(16) Periasamy S, et al. Dietary Ziziphus jujuba Fruit Influence on Aberrant Crypt Formation and Blood Cells in Colitis-Associated Colorectal Cancer in Mice. Asian Pac J Cancer Prev. 2015;

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

(18) Mihaylova MM, et al. Fasting Activates Fatty Acid Oxidation to Enhance Intestinal Stem Cell Function during Homeostasis and Aging. Cell Stem Cell.  2018 May


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.


  • 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.







(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;

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.




Bergamonte® is a registered trademark of HP Ingredients.



(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;

Naked Mole Rats - Clues to their Exceptional Longevity

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) 

  • Proteasomes-  In the cell it is the function of structures called proteasomes, to identify and remove damaged proteins.  Damaged proteins are tagged and then subsequently degraded by the proteasomes. Aging creates an imbalance in protein homeostasis, whereby proteasomes become dysfunctional.
  • Autophagy - Is the quality control in the cell which removes and recycles damaged and non-functional components (organelles and protein) through lysosomal degradation. Animals studies clearly demonstrate that in autophagy deficient mutants, lifespan is significantly reduced. Autophagy works in conjunction with protesomes  to maintain cellular health and extend longevity.
  • Heat Shock Proteins (HSP) - HSP are involved as sentries and chaperons, which monitor the cell for damaged proteins and ensure that they are rapidly degraded and recycled. HSPs work in conjunction with the proteasome system to prevent the accumulation of misfolded and toxic proteins in the cell. HSP identifies damaged misfolded proteins for proteasome degradation. HSP increase longevity, however levels decrease with aging.(10,11)

    FOXO Nrf2 (transcription factors) AND PROTEIN HOMEOSTASIS:

    • FOXO transcription factors are key regulators of cellular quality control including protein homeostasis
    • FOXO is required for the activation of proteasome and autophagy. (5,12)
    • Nrf2 is key for maximal expression of proteasomes for cellular protein homeostasis.(13)
    • Sulforaphane increases both proteasome activity and autophagy.(10) Increased activation of Nrf2 by sulforaphane is an important pathway by which proteasomal activity is increased.(9,11) Also sulforaphane upregulates heat shock proteins (HSP), which further elevates the protein degradation functioning of the proteasomes.(14)
    • Curcumin supports protein homeostasis through enhanced autophagy and HSP (Heat stress proteins)(16, 17)) and Nrf2 activation (13).
    • Resveratrol and Calorie Restriction also increase autophagy and extend lifespan.(15)


      XGEVITY (Glucoraphanin / Sulforaphane)

      AIR VITALITY (Glucoraphanin / Sulforaphane)


      PURPLE LONGEVITY (Resveratrol)



      (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.