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
This research further validates the beneficial life extending benefits of resveratrol.
(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
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 -
BILBERRY ANTHOCYANINS (Blue Color)
GRAPE SEED EXTRACT (GSE) (5-8)
N-ACETYLCYSTEINE (GLUTATHIONE BOOSTER) (9-11)
(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.
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.
Anti-Aging Support for Intestine
(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
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.
Other FOXO Activators and Longevity Pathways:
(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.
(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;
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)
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 (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:
(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.