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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)

REFERENCES:

(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

Fucoidan - Brown Seaweed Extract to Reverse Aging

Exceptional longevity in the population of Okinawa Japan is believed to be dietary, and most significantly due to their high consumption of brown seaweed. The anti-aging component in seaweed has been identified as fucoidan. Fucoidan is a sulfated molecule which has been studied extensively for health and anti-aging benefits.

• Stem Cell Mobilization -
  Fucoidan supports mobilization of stem cells from bone marrow into blood stream, via increased expression of CXCR4, and may enhance healing throughout body, including vascular and heart.(1)
• SIRT6 Activation - SIRT6 is a longevity promoting sirtuin protein, similar to the better known SIRT1. Fucoidan is an SIRT6 activator.(2) Among the anti-aging benefits, SIRT6 is a key regular of genome and telomere stability, DNA repair, controlling NF-Kappa (inflammation pathway)(3) and supports maintenance of beta cells in the pancreas in type 2 diabetes (5)
• SIRT6 Expression Affects Longevity. Increases in SIRT6 expression is associated with increased longevity. (3) Deficits in SIRT6 are associated with premature aging.(4)
  
• Attenuates Amyloid-beta Accumulation. In experimental aninmal, c. elegans, fucoidan signicantly reduced the accumulation of amyloid-beta, a signifcant factor in Alzheimer's Disease,(6)
• Stimulates Immune Response.  Fucoidans enhance immune reponse which may be beneficial in inhibiting cancer. (7)
• Healthy Intestinal Wall Barrier. The source of much inflammation in the intestine and in the body occurs when the intestine barrier breaks down due to injury or illness. Fucoidan supports the integrity of the intestine wall barrier by increasing levels of claudin-1, an important component of the intestine wall. In experimental studies, fucoidan was shown to repair injured intestines and even gradually restore villi.(8)  Furthermore, authors of another study indicated that by improving the intestinal wall barrier, fucoidan may offer a potential area of treatment for inflammatory bowl diseases whereby the intestinal barrier is impaired.(10)
• Healthy Microbiotic Diversity in Intestine. Fucoidan promotes healthy microbiotic content, including the increase in anti-inflammtory short chain fatty acid producers (e.g. Coprococcus, Rikenella, and Butyricicoccus)(8-9)
  

HYPER LONGEVITY (Fucoidan - Brown Seaweed Extract)

REFERENCES:

(1) Irhimeh MR, et al. Fucoidan ingestion increases the expression of CXCR4 on human CD34+ cells. Exp Hematol. 2007 Jun

(2) Rahnasto-Rilla MK, et al. The Identification of a SIRT6 Activator from Brown Algae Fucus distichus. Mar Drugs. 2017 Jun 

(3) Hirvonen K, et al. SIRT6 polymorphism rs117385980 is associated with longevity and healthy aging in Finnish men. BMC Med Genet. 2017 Apr

(4) Peshti V, et al. Characterization of physiological defects in adult SIRT6-/- mice. PLoS One. 2017 Apr

(5) Qin K, et al. SIRT6-mediated transcriptional suppression of Txnip is critical for pancreatic beta cell function and survival in mice. Diabetologia. 2018 Jan 10

(6) Wang X, et al. Fucoidan inhibits amyloid-β-induced toxicity in transgenic Caenorhabditis elegans by reducing the accumulation of amyloid-β and decreasing the production of reactive oxygen species.  Food Funct. 2018 Jan

(7) Vetvicka V, et al. Fucoidans Stimulate Immune Reaction and Suppress Cancer Growth. Anticancer Res. 2017 Nov

(8) Xue M, et al. The effect of fucoidan on intestinal flora and intestinal barrier function in rats with breast cancer. Food Funct. 2018 Jan 31

(9) Shi H, et al. Dietary fucoidan of Acaudina molpadioides alters gut microbiota and mitigates intestinal mucosal injury induced by cyclophosphamide. Food Funct. 2017 Sep 

 (10) Iraha A, et al. Fucoidan enhances intestinal barrier function by upregulating the expression of claudin-1. World J Gastroenterol. 2013 Sep