What are You Thinking?On
A previous post (‘Blood Bath’) looked at heterochronic parabiosis, which describes the transfusion of blood from young animals to old ones and vice versa. Blood is a rich and highly bioactive soup of mediators, messengers, inhibitors and growth factors, and when drawn from a young ‘un is capable of de-ageing mice and, probably, men.
The process has been shown to rejuvenate murine mitochondria (1, 2), blood vessels (2, 4), skeletal muscle (3), hearts (3) and central nervous systems (4 – 7).
On the basis of pre-clinical findings like these, the US company Alkahest is running clinical trials of young plasma for Alzheimer’s and Parkinson’s diseases (NCT03520998, NCT03713957, NCT03765762), macular degeneration (NCT03558061, NCT03558074), and postoperative recovery following knee or hip replacements (NCT03981419).
Additional trials are administering umbilical cord blood and plasma to treat age-associated frailty in South Korea (NCT02418013), and young plasma to improve neurologic outcomes after acute stroke in China (NCT02913183).
Young blood and plasma is easy to obtain, but it is difficult to guarantee that the red stuff is free of all viruses, prions and phages (8). Your supplier may not have too many miles on the clock, but you don’t know where he (or she) has been. The gerontocrats who run many of our institutions have therefore funded a good deal of research into isolating the key anti-ageing factors, and producing them synthetically.
Much of this pioneering work was done at the Institute of Bioregulation and Gerontology in St Petersburg under the auspices of Col. Professor Vladimir Khavinson, a former champion boxer and track athlete, and a remarkable man by any standards.
From what I’ve been told (an old friend of mine liaises with the Institute, and I have met members of Khavinson’s team), it started with a retinal regeneration project designed to repair retinas damaged by battlefield lasers DARPA was then developing. Khavinson looked for actives in young bovine retina, and found the first of a series of tissue-trophic peptides that encouraged the growth of retina in older animals.
This approach could be dismissed as a modern variant of the age-old (and discredited) Doctrine of Signatures (9), but it works. The results, which I have studied, are breath-taking, and prove beyond all doubt that dead retinal tissue can be reconstructed using simple peptides. But it did not stop there. The St Petersburg team went on to develop over 60 di-, tri- and tetra-peptides which are now being used to regrow / rejuvenate various tissues in adult humans. I have data sheets on 38 of these, and the overall picture is impressive.
Pharmaconutrition is highly effective at reducing the risk of non-communicable degenerative disease, but at a certain point (ie myocardial death after a heart attack or trabecular loss in long bone), it reaches its event horizon.
That is where the St Petersburg approach takes over, and complements and extends our own (ie (11-19). Khavinson’s work worth a post all on its own, but my magpie attention is drawn, today, in a different direction.
Downwards, you might say, and to the subject of heterochronic fecal transfer.
The gut-brain connection is real, and very important. It has been known for a decade or so that germ-free rodents have specific cognitive deficits (ie 20). It is also known that the gut microbiome changes with age (ie 21, 22), becoming less diverse (23) and probably leaving the owner less able to resist nutritional and environmental stresses (24). And as time passes, the ageing rodent’s memory and other cognitive functions start to falter; much like our own.
Might these changes be related, and if so, how? Does the faltering brain affect microbiomal change, or does the ageing microbiome drive brain ageing? It certainly contributes to many other aspects of the ageing process, and to age-related pathologies including the neurodegenerative diseases (ie 25).
In 2020 a Chinese team showed that fecal transplants from old to young rats caused cognitive decline and created the kinds of micro-anatomical changes in neuronal structure normally found in aged animals (26). The following year, an Irish group working with mice demonstrated that fecal transplants from young to old rats had the opposite effect (27), leading to improvements in working memory.
The old mice learned to solve mazes more rapidly, and were better at remembering the maze layout on subsequent attempts. Their hippocampi started to rejuvenate, becoming more physically and chemically similar to the brains of younger animals (27).
This fits rather well with a 2021 clinical study which found that older humans who have more diverse microbiomes (and who are thought to have eaten a more varied and plant-based diet) age more successfully (28).
In this American study, health and life expectancy was significantly reduced in those whose microbiome was characterised by high levels of Bacteroides species. These gram-negative microbes occur in most anaerobic infections and are associated with significant mortality (29). Being gram negative they are also associated with increased inflammatory stress in the gut, and endotoxaemia (29, 30).
Adding prebiotic fibers to the diet of mice raises numbers of probiotic, gram-positive species such as lactobacilli and bifidobacterial. These drive down the numbers of Bacteroides, thus stopping the chronic inflammation and the endotoxaemia (30). Prebiotic fibers work in exactly the same way in humans (31). This neatly explains why humans with better diets and who consume more dietary fibers have less Bacteroides, and live longer (28).
To recap …
Many of the links between an ageing microbiome and age-related pathologies in humans involve the modern, ultra-processed diet.
Our high-fat, low-fiber diet drives a shift from predominantly gram-positive fiber-utilising probiotic species to gram-negative proteolytic species, with a consequent reduction in anti-inflammatory post-biotics such as butyrate (32, 33) and increased chronic inflammatory stress in the gut. Increased numbers of gram-negative bacteria plus chronic inflammation equals ‘leaky gut’ and endotoxaemia (34-37).
Endotoxaemia causes chronic inflammation everywhere (38, 39). It is a known contributor to NAFLD (39), unsurprisingly considering that venous drainage from the gut flows directly into the liver. It accelerates the ageing process everywhere else (41, 42). And, all these problems can be stopped at source, by eating more fiber.
The foundations of this idea were laid half a century ago by the redoubtable British surgeon and researcher Dennis Burkett, and his colleague Hubert Trowell (43), and substantiated more recently by major epidemiological and other research programs (ie 44, 45). So there you have it. And here, if you want, is how to have it better.
By adding a mix of prebiotic fibers to your diet and maintaining a more youthful and less inflammatory microbiome you will have less inflammation, less endotoxaemia and less inflammageing. You will therefore live healthier and longer.
Given colonic length, transit time and the different fermentation rates of different prebiotic fibers, it would be logical to use an appropriately blended mix of different prebiotic fibers.
Next week: The Spice / Time Continuum. How the spice routes ebb and flow through our tissues, how they affect DNA and RNA, and how they rejuvenate our cells.
- Gonzalez-Armenta JL, Li N, Lee RL, Lu B, Molina AJA. Heterochronic Parabiosis: Old Blood Induces Changes in Mitochondrial Structure and Function of Young Mice. J Gerontol A Biol Sci Med Sci. 2021 Feb 25;76(3):434-439.
- Kiss T, Tarantini S, Csipo T, Balasubramanian P, Nyúl-Tóth Á, Yabluchanskiy A, Wren JD, Garman L, Huffman DM, Csiszar A, Ungvari Z. Circulating anti-geronic factors from heterochonic parabionts promote vascular rejuvenation in aged mice: transcriptional footprint of mitochondrial protection, attenuation of oxidative stress, and rescue of endothelial function by young blood. Geroscience. 2020 Apr;42(2):727-748.
- Sinha I, Sinha-Hikim AP, Wagers AJ, Sinha-Hikim I. Testosterone is essential for skeletal muscle growth in aged mice in a heterochronic parabiosis model. Cell Tissue Res. 2014 Sep;357(3):815-21. doi: 10.1007/s00441-014-1900-2.
- Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, Chen JW, Lee RT, Wagers AJ, Rubin LL. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science. 2014;344:630–634.
- Fan X, Wheatley EG, Villeda SA. Mechanisms of hippocampal aging and the potential for rejuvenation. Annu Rev Neurosci. 2017;40:251–272.
- Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, Smith LK, Bieri G, Lin K, Berdnik D, Wabl R, Udeochu J, Wheatley EG, Zou B, Simmons DA, Xie XS, Longo FM, Wyss-Coray T. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med. 2014;20:659–663.
- Castellano JM, Palner M, Li SB, Freeman GM, Jr, Nguyen A, Shen B, Stan T, Mosher KI, Chin FT, de Lecea L, Luo J, Wyss-Coray T. In vivo assessment of behavioral recovery and circulatory exchange in the peritoneal parabiosis model. Sci Rep. 2016;6:29015.
- Tetz G, Tetz V. Bacteriophages as New Human Viral Pathogens. Microorganisms. 2018 Jun 16;6(2):54.
- Wells C. Poppy juice and willow bark: Advances in their use for the 21st Century; 2006.
- Anisimov VN, Khavinson VKh, Morozov VG. Effect of synthetic dipeptide Thymogen (Glu-Trp) on life span and spontaneous tumor incidence in rats. The Gerontologist. 1998;38:7–8.
- Khavinson VKh, Malinin VV. Gerontological aspects of genome peptide regulation. Basel (Switzerland): Karger AG. 2005
- Khavinson V, Goncharova N, Lapin B. Synthetic tetrapeptide epitalon restores disturbed neuroendocrine regulation in senescent monkeys. Neuroendocrinol Lett. 2001;22:251–54.
- Khavinson VKh, Lezhava TA, Monaselidze JR, Jokhadze TA, Dvalishvili NA, Bablishvili NK, Trofimova SV. Peptide Epitalon activates chromatin at the old age. Neuroendocrinol Lett. 2003;24:329–33.
- Khavinson VKh. Peptide regulation of ageing. SPb.: Humanistica. 2008
- Korkushko OV, Khavinson VKh, Shatilo VB, Antonyk-Sheglova I.A. Peptide Geroprotector from the Pineal Gland Inhibits Rapid Aging of Elderly People: Results of 15-Year Follow-Up. Bull Exp Biol Med. 2011;151:366–69.
- Vanyushin BF, Khavinson VKh. Short Biologically Active Peptides as Epigenetic Modulators of Gene Activity. Eds. W. Doerfler, P. Böhm. Epigenetics. A Different Way of Looking at Genetics. 2016:69–90.
- Khavinson V, Popovich I. Short Peptides Regulate Gene Expression, Protein Synthesis and Enhance Life Span. Ed. A.M. Vaiserman. Anti-aging Drugs: From Basic Research to Clinical Practice. 2017;57:496–513.
- Khavinson VK, Linkova NS, Diatlova AS, Gutop EO, Orlova OA. Short peptides: regulation of skin function during aging. ]. Adv Gerontol. 2020;33(1):46-54. Russian.
- Gareau MG, Wine E, Rodrigues DM, Cho JH, Whary MT, Philpott DJ, Macqueen G, Sherman PM. Bacterial infection causes stress-induced memory dysfunction in mice. Gut. 2011; 60:307–17.
- Claesson MJ, Cusack S, O’Sullivan O, Greene-Diniz R, de Weerd H, Flannery E, Marchesi JR, Falush D, Dinan T, Fitzgerald G, Stanton C, van Sinderen D, O’Connor M, Harnedy N, O’Connor K, Henry C, O’Mahony D, Fitzgerald AP, Shanahan F, Twomey C, Hill C, Ross RP, O’Toole PW. Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc Natl Acad Sci USA. 2011. (Suppl 1); 108:4586–91.
- Hopkins MJ, Macfarlane GT. Changes in predominant bacterial populations in human faeces with age and with Clostridium difficile infection. J Med Microbiol. 2002; 51:448–54.
- Claesson MJ, Jeffery IB, Conde S, Power SE, O’Connor EM, Cusack S, Harris HM, Coakley M, Lakshminarayanan B, O’Sullivan O, Fitzgerald GF, Deane J, O’Connor M, et al. Gut microbiota composition correlates with diet and health in the elderly. Nature. 2012; 488:178–84.
- Yachi S, Loreau M. Biodiversity and ecosystem productivity in a fluctuating environment: the insurance hypothesis. Proc Natl Acad Sci USA. 1999; 96:1463–68.
- Kim M, Benayoun BA. The microbiome: an emerging key player in aging and longevity. Transl Med Aging. 2020;4:103-116.
- Li Y, Ning L, Yin Y, Wang R, Zhang Z, Hao L, Wang B, Zhao X, Yang X, Yin L, Wu S, Guo D, Zhang C. Age-related shifts in gut microbiota contribute to cognitive decline in aged rats. Aging (Albany NY). 2020 May 1;12(9):7801-7817.
- Boehme M, Guzzetta KE, Bastiaanssen TFS and 22 others. Microbiota from young mice counteracts selective age-associated behavioral deficits. Nat Aging 1, 666–676 (2021). https://doi.org/10.1038/s43587-021-00093-9
- Wilmanski T, Diener C, Rappaport N, Patwardhan S, Wiedrick J, Lapidus J, Earls JC, Zimmer A, Glusman G, Robinson M, Yurkovich JT, Kado DM, Cauley JA, Zmuda J, Lane NE, Magis AT, Lovejoy JC, Hood L, Gibbons SM, Orwoll ES, Price ND. Gut microbiome pattern reflects healthy ageing and predicts survival in humans. Nat Metab. 2021 Feb;3(2):274-286.
- Wexler H. Bacteroides: the Good, the Bad and the Ugly. Clin Microbiol Rev. 2007 Oct; 20(4): 593–621.
- Li LL, Wang YT, Zhu LM, Liu ZY, Ye CQ, Qin S. Inulin with different degrees of polymerization protects against diet-induced endotoxemia and inflammation in association with gut microbiota regulation in mice. Sci Rep. 2020 Jan 22;10(1):978.
- Looijer-van Langen MA, Dieleman LA. Prebiotics in chronic intestinal inflammation. Inflamm Bowel Dis. 2009 Mar;15(3):454-62.
- Woodmansey EJ. Intestinal bacteria and ageing. J Appl Microbiol. 2007;102(5):1178–1186.
- Salazar N, Arboleya S, Fernández-Navarro T, de Los Reyes-Gavilán CG, Gonzalez S, Gueimonde M. Age-associated changes in gut microbiota and dietary components related with the immune system in adulthood and old age: a cross-sectional study. Nutrients. 2019;11(8).
- Rohr M.W, Narasimhulu C.A, Rudeski-Rohr TA, Parthasarathy S. Negative effects of a high-fat diet on intestinal permeability: a review. Adv Nutr. 2020;11(1):77–91.
- Nagpal R, Newman TM, Wang S, Jain S, Lovato JF, Yadav H. Obesity-linked gut microbiome dysbiosis associated with derangements in gut permeability and intestinal cellular homeostasis independent of diet. J Diabetes Res. 2018;2018
- Moreira A.P, Texeira TF, Ferreira AB, Peluzio Mdo C, Alfenas Rde C. Influence of a high-fat diet on gut microbiota, intestinal permeability and metabolic endotoxemia. Br. J. Nutr. 2012;108(5):801–809.
- Ragonnaud E, Biragyn A. Gut microbiota as the key controllers of “healthy” aging of elderly people. Immun Ageing. 2021 Jan 5;18(1):2.
- Patterson E, Ryan PM, Cryan JF, Dinan TG, Ross RP, Fitzgerald GF, Stanton C. Gut microbiota, obesity and diabetes. Postgrad Med J. 2016 May;92(1087):286-300.
- Netto Candido TL, Bressan J, Alfenas RCG. Dysbiosis and metabolic endotoxemia induced by high-fat diet. Nutr Hosp. 2018 Dec 3;35(6):1432-1440.
- Pang J, Xu W, Zhang X, Wong GL, Chan AW, Chan HY, Tse CH, Shu SS, Choi PC, Chan HL, Yu J, Wong VW. Significant positive association of endotoxemia with histological severity in 237 patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2017 Jul;46(2):175-182.
- Kim KA, Jeong JJ, Yoo SY, Kim DH. Gut microbiota lipopolysaccharide accelerates inflammaging in mice. BMC Microbiol. 2016 Jan 16;16:9.
- Fransen F, van Beek AA, Borghuis T, Aidy SE, Hugenholtz F, van der Gaast-de Jongh C, Savelkoul HFJ, De Jonge MI, Boekschoten MV, Smidt H, Faas MM, de Vos P. Aged Gut Microbiota Contributes to Systemical Inflammaging after Transfer to Germ-Free Mice. Front Immunol. 2017 Nov 2;8:1385.
- Refined Carbohydrate Foods and Disease – Some Implications of Dietary Fibre. Eds Burkitt DP, Trowell HC. Academic Press Inc (London) Ltd, 1975
- Reynolds A, Mann J, Cummings J, Winter N, Mete E, Te Morenga L. Carbohydrate quality and human health: a series of systematic reviews and meta-analyses. Lancet 2019; 393: 434–5.
- O’Keefe SJ. The association between dietary fibre deficiency and high-income lifestyle-associated diseases: Burkitt’s hypothesis revisited. Lancet Gastroenterol Hepatol. 2019 Dec;4(12):984-996.