Abstract
The human oral and gut microbiomes influence health via competition for a distinct niche in the body with pathogens, via metabolic capabilities that increase host digestive capacity and generate compounds engaged in signaling pathways and modulation of immune system functions. Old age alters our metabolic and regenerative capacity. Following recruitment of 65 human subjects in the age range of 70 to 82, we discerned healthy aging (HA) and non-healthy aging (NHA) cohorts discordant in the occurrence of one or more major diseases: (1) cancer, (2) acute or chronic cardiovascular diseases, (3) acute or chronic pulmonary diseases, (4) diabetes, and (5) stroke or neurodegenerative disorders. We analyzed these cohorts’ oral microbiomes (saliva) and gut microbiomes (stool) to assess diversity and identify microbial biomarkers for HA. In contrast to the gut microbiome where no change was observed, we found that the saliva microbiome had higher α-diversity in the HA compared with the NHA group. We observed the genus Akkermansia to be significantly more abundant in the gut microbiota of the HA group. Akkermansia muciniphila is a colonic mucin-degrading bacterium believed to have beneficial effects on gastrointestinal health, particularly in the context of diabetes and obesity. Erysipelotrichaceae UCG-003 was a taxon increased in abundance in the HA cohort. Streptococcus was the only genus observed to be significantly decreased in abundance in both the gut and oral microbiomes of the HA cohort compared with the NHA cohort. Our data support the notion that these microbes are potential probiotics to decrease the risks of non-healthy aging.
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Aas JA, Paster BJ, Stokes LN, Olsen I, Dewhirst FE (2005) Defining the normal bacterial flora of the oral cavity. J Clin Microbiol 43:5721–5732. https://doi.org/10.1128/JCM.43.11.5721-5732.2005
Ames BN, Shigenaga MK, Hagen TM (1993) Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci U S A 90:7915–7922
Arumugam M, Raes J, Pelletier E, le Paslier D, Yamada T, Mende DR, Fernandes GR, Tap J, Bruls T, Batto JM, Bertalan M, Borruel N, Casellas F, Fernandez L, Gautier L, Hansen T, Hattori M, Hayashi T, Kleerebezem M, Kurokawa K, Leclerc M, Levenez F, Manichanh C, Nielsen HB, Nielsen T, Pons N, Poulain J, Qin J, Sicheritz-Ponten T, Tims S, Torrents D, Ugarte E, Zoetendal EG, Wang J, Guarner F, Pedersen O, de Vos WM, Brunak S, Doré J, MetaHIT Consortium, Antolín M, Artiguenave F, Blottiere HM, Almeida M, Brechot C, Cara C, Chervaux C, Cultrone A, Delorme C, Denariaz G, Dervyn R, Foerstner KU, Friss C, van de Guchte M, Guedon E, Haimet F, Huber W, van Hylckama-Vlieg J, Jamet A, Juste C, Kaci G, Knol J, Lakhdari O, Layec S, le Roux K, Maguin E, Mérieux A, Melo Minardi R, M'rini C, Muller J, Oozeer R, Parkhill J, Renault P, Rescigno M, Sanchez N, Sunagawa S, Torrejon A, Turner K, Vandemeulebrouck G, Varela E, Winogradsky Y, Zeller G, Weissenbach J, Ehrlich SD, Bork P (2011) Enterotypes of the human gut microbiome. Nature 473:174–180. https://doi.org/10.1038/nature09944
Belzer C, de Vos WM (2012) Microbes inside-from diversity to function: the case of Akkermansia. ISME J 6:1449–1458. https://doi.org/10.1038/ismej.2012.6
Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol 57:289–300. https://doi.org/10.2307/2346101
Bratic A, Larsson NG (2013) The role of mitochondria in aging. J Clin Invest 123:951–957. https://doi.org/10.1172/JCI64125
Bray JR, Curtis JT (1957) An ordination of the upland forest communities of southern Wisconsin. Ecol Monogr 27:326–349. https://doi.org/10.2307/1942268
Cabreiro F, Au C, Leung KY, Vergara-Irigaray N, Cochemé HM, Noori T, Weinkove D, Schuster E, Greene NDE, Gems D (2013) Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 153:228–239. https://doi.org/10.1016/j.cell.2013.02.035
Carmona-Gutierrez D, Hughes AL, Madeo F, Ruckenstuhl C (2016) The crucial impact of lysosomes in aging and longevity. Ageing Res Rev 32:2–12. https://doi.org/10.1016/j.arr.2016.04.009
Chen W, Liu F, Ling Z, Tong X, Xiang C (2012) Human intestinal lumen and mucosa-associated microbiota in patients with colorectal cancer. PLoS One 7:e39743. https://doi.org/10.1371/journal.pone.0039743
Chen Y, Fu LL, Wen X, Wang XY, Liu J, Cheng Y, Huang J (2014) Sirtuin-3 (SIRT3), a therapeutic target with oncogenic and tumor-suppressive function in cancer. Cell Death Dis 5:e1047. https://doi.org/10.1038/cddis.2014.14
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 (2011) Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc Natl Acad Sci U S A 108(Suppl 1):4586–4591. https://doi.org/10.1073/pnas.1000097107
Claesson MJ, Jeffery IB, Conde S, Power SE, O’Connor EM, Cusack S, Harris HMB, Coakley M, Lakshminarayanan B, O’Sullivan O, Fitzgerald GF, Deane J, O’Connor M, Harnedy N, O’Connor K, O’Mahony D, van Sinderen D, Wallace M, Brennan L, Stanton C, Marchesi JR, Fitzgerald AP, Shanahan F, Hill C, Ross RP, O’Toole PW (2012) Gut microbiota composition correlates with diet and health in the elderly. Nature 488:178–184. https://doi.org/10.1038/nature11319
Collado MC, Derrien M, Isolauri E, de Vos WM, Salminen S (2007) Intestinal integrity and Akkermansia muciniphila, a mucin-degrading member of the intestinal microbiota present in infants, adults, and the elderly. Appl Environ Microbiol 73:7767–7770. https://doi.org/10.1128/AEM.01477-07
Dao MC, Everard A, Aron-Wisnewsky J, Sokolovska N, Prifti E, Verger EO, Kayser BD, Levenez F, Chilloux J, Hoyles L, MICRO-Obes Consortium, Dumas ME, Rizkalla SW, Doré J, Cani PD, Clément K (2016) Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut 65:426–436. https://doi.org/10.1136/gutjnl-2014-308778
Derrien M, Collado MC, Ben-Amor K, Salminen S, de Vos WM (2008) The Mucin degrader Akkermansia muciniphila is an abundant resident of the human intestinal tract. Appl Environ Microbiol 74:1646–1648. https://doi.org/10.1128/AEM.01226-07
Desai MS, Seekatz AM, Koropatkin NM, Kamada N, Hickey CA, Wolter M, Pudlo NA, Kitamoto S, Terrapon N, Muller A, Young VB, Henrissat B, Wilmes P, Stappenbeck TS, Núñez G, Martens EC (2016) A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell 167:1339–1353 e1321. https://doi.org/10.1016/j.cell.2016.10.043
Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA (2005) Diversity of the human intestinal microbial flora. Science 308:1635–1638. https://doi.org/10.1126/science.1110591
Edgar RC (2013) UPARSE: highly accurate OTU sequences from microbial amplicon reads. Nat Methods 10:996–998. https://doi.org/10.1038/nmeth.2604
Franceschi C, Campisi J (2014) Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 69(Suppl 1):S4–S9. https://doi.org/10.1093/gerona/glu057
Fulop T, Larbi A, Dupuis G, le Page A, Frost EH, Cohen AA, Witkowski JM, Franceschi C (2017) Immunosenescence and inflamm-aging as two sides of the same coin: friends or foes? Front Immunol 8:1960. https://doi.org/10.3389/fimmu.2017.01960
Gans KM, Ross E, Barner CW, Wylie-Rosett J, McMurray J, Eaton C (2003) REAP and WAVE: new tools to rapidly assess/discuss nutrition with patients. J Nutr 133:556S–562S. https://doi.org/10.1093/jn/133.2.556S
Gill SR, Pop M, DeBoy RT, Eckburg PB, Turnbaugh PJ, Samuel BS, Gordon JI, Relman DA, Fraser-Liggett CM, Nelson KE (2006) Metagenomic analysis of the human distal gut microbiome. Science 312:1355–1359. https://doi.org/10.1126/science.1124234
Gomez A, Espinoza JL, Harkins DM, Leong P, Saffery R, Bockmann M, Torralba M, Kuelbs C, Kodukula R, Inman J, Hughes T, Craig JM, Highlander SK, Jones MB, Dupont CL, Nelson KE (2017) Host genetic control of the oral microbiome in health and disease. Cell Host Microbe 22:269–278 e263. https://doi.org/10.1016/j.chom.2017.08.013
Greer RL, Dong X, Moraes ACF, Zielke RA, Fernandes GR, Peremyslova E, Vasquez-Perez S, Schoenborn AA, Gomes EP, Pereira AC, Ferreira SRG, Yao M, Fuss IJ, Strober W, Sikora AE, Taylor GA, Gulati AS, Morgun A, Shulzhenko N (2016) Akkermansia muciniphila mediates negative effects of IFNgamma on glucose metabolism. Nat Commun 7:13329. https://doi.org/10.1038/ncomms13329
Gruver AL, Hudson LL, Sempowski GD (2007) Immunosenescence of ageing. J Pathol 211:144–156. https://doi.org/10.1002/path.2104
Harman D (1972) The biologic clock: the mitochondria? J Am Geriatr Soc 20:145–147
Heintz C, Mair W (2014) You are what you host: microbiome modulation of the aging process. Cell 156:408–411. https://doi.org/10.1016/j.cell.2014.01.025
Human Microbiome Project C (2012) Structure, function and diversity of the healthy human microbiome. Nature 486:207–214. https://doi.org/10.1038/nature11234
Jiang Q, Liu J, Chen L, Gan N, Yang D (2018) The oral microbiome in the elderly with dental caries and health. Front Cell Infect Microbiol 8:442. https://doi.org/10.3389/fcimb.2018.00442
Kaakoush NO (2015) Insights into the role of Erysipelotrichaceae in the human host. Front Cell Infect Microbiol 5:84. https://doi.org/10.3389/fcimb.2015.00084
Kau AL, Ahern PP, Griffin NW, Goodman AL, Gordon JI (2011) Human nutrition, the gut microbiome and the immune system. Nature 474:327–336. https://doi.org/10.1038/nature10213
Kilian M, Riley DR, Jensen A, Bruggemann H, Tettelin H (2014) Parallel evolution of Streptococcus pneumoniae and Streptococcus mitis to pathogenic and mutualistic lifestyles. MBio 5:e01490–e01414. https://doi.org/10.1128/mBio.01490-14
Kong X, Wang R, Xue Y, Liu X, Zhang H, Chen Y, Fang F, Chang Y (2010) Sirtuin 3, a new target of PGC-1alpha, plays an important role in the suppression of ROS and mitochondrial biogenesis. PLoS One 5:e11707. https://doi.org/10.1371/journal.pone.0011707
Krajmalnik-Brown R, Ilhan ZE, Kang DW, DiBaise JK (2012) Effects of gut microbes on nutrient absorption and energy regulation. Nutr Clin Pract 27:201–214. https://doi.org/10.1177/0884533611436116
Kumar M, Babaei P, Ji B, Nielsen J (2016) Human gut microbiota and healthy aging: recent developments and future prospective. Nutr Health Aging 4:3–16. https://doi.org/10.3233/NHA-150002
Leishman SJ, Do HL, Ford PJ (2010) Cardiovascular disease and the role of oral bacteria. J Oral Microbiol 2. https://doi.org/10.3402/jom.v2i0.5781
Lin K, Dorman JB, Rodan A, Kenyon C (1997) daf-16: an HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science 278:1319–1322
Liu G, Tang CM, Exley RM (2015) Non-pathogenic Neisseria: members of an abundant, multi-habitat, diverse genus. Microbiology 161:1297–1312. https://doi.org/10.1099/mic.0.000086
Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15:550. https://doi.org/10.1186/s13059-014-0550-8
McMurdie PJ, Holmes S (2013) Phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data. PLoS One 8:e61217. https://doi.org/10.1371/journal.pone.0061217
McMurdie PJ, Holmes S (2014) Waste not, want not: why rarefying microbiome data is inadmissible. PLoS Comput Biol 10:e1003531–e1003531. https://doi.org/10.1371/journal.pcbi.1003531
Meyer JN, Leung MC, Rooney JP, Sendoel A, Hengartner MO, Kisby GE, Bess AS (2013) Mitochondria as a target of environmental toxicants. Toxicol Sci 134:1–17. https://doi.org/10.1093/toxsci/kft102
Parmentier-Decrucq E, Duhamel A, Ernst O, Fermont C, Louvet A, Vernier-Massouille G, Cortot A, Colombel JF, Desreumaux P, Peyrin-Biroulet L (2009) Effects of infliximab therapy on abdominal fat and metabolic profile in patients with Crohn’s disease. Inflamm Bowel Dis 15:1476–1484. https://doi.org/10.1002/ibd.20931
Quast C, Pruesse E, Yilmaz P, Gerken J, Schweer T, Yarza P, Peplies J, Glöckner FO (2013) The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res 41:D590–D596. https://doi.org/10.1093/nar/gks1219
Rajagopala SV, Yooseph S, Harkins DM, Moncera KJ, Zabokrtsky KB, Torralba MG, Tovchigrechko A, Highlander SK, Pieper R, Sender L, Nelson KE (2016) Gastrointestinal microbial populations can distinguish pediatric and adolescent Acute Lymphoblastic Leukemia (ALL) at the time of disease diagnosis. BMC Genomics 17:635. https://doi.org/10.1186/s12864-016-2965-y
Rajaram S, Oono Y (2010) NeatMap--non-clustering heat map alternatives in R. BMC Bioinformatics 11:45. https://doi.org/10.1186/1471-2105-11-45
Reichardt N, Duncan SH, Young P, Belenguer A, McWilliam Leitch C, Scott KP, Flint HJ, Louis P (2014) Phylogenetic distribution of three pathways for propionate production within the human gut microbiota. ISME J 8:1323–1335. https://doi.org/10.1038/ismej.2014.14
Reunanen J, Kainulainen V, Huuskonen L, Ottman N, Belzer C, Huhtinen H, de Vos WM, Satokari R (2015) Akkermansia muciniphila adheres to enterocytes and strengthens the integrity of the epithelial cell layer. Appl Environ Microbiol 81:3655–3662. https://doi.org/10.1128/AEM.04050-14
Rios-Covian D, Ruas-Madiedo P, Margolles A, Gueimonde M, de Los Reyes-Gavilan CG, Salazar N (2016) Intestinal short chain fatty acids and their link with diet and human health. Front Microbiol 7:185. https://doi.org/10.3389/fmicb.2016.00185
Rose G, Dato S, Altomare K, Bellizzi D, Garasto S, Greco V, Passarino G, Feraco E, Mari V, Barbi C, BonaFe M, Franceschi C, Tan Q, Boiko S, Yashin AI, de Benedictis G (2003) Variability of the SIRT3 gene, human silent information regulator Sir2 homologue, and survivorship in the elderly. Exp Gerontol 38:1065–1070
Round JL, Mazmanian SK (2009) The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 9:313–323. https://doi.org/10.1038/nri2515
Salminen A, Kaarniranta K (2010) Insulin/IGF-1 paradox of aging: regulation via AKT/IKK/NF-kappaB signaling. Cell Signal 22:573–577. https://doi.org/10.1016/j.cellsig.2009.10.006
Schaubeck M, Clavel T, Calasan J, Lagkouvardos I, Haange SB, Jehmlich N, Basic M, Dupont A, Hornef M, Bergen M, Bleich A, Haller D (2016) Dysbiotic gut microbiota causes transmissible Crohn’s disease-like ileitis independent of failure in antimicrobial defence. Gut 65:225–237. https://doi.org/10.1136/gutjnl-2015-309333
Schippa S, Conte MP (2014) Dysbiotic events in gut microbiota: impact on human health. Nutrients 6:5786–5805. https://doi.org/10.3390/nu6125786
Schloss PD, Westcott SL, Ryabin T, Hall JR, Hartmann M, Hollister EB, Lesniewski RA, Oakley BB, Parks DH, Robinson CJ, Sahl JW, Stres B, Thallinger GG, van Horn DJ, Weber CF (2009) Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities. Appl Environ Microbiol 75:7537–7541. https://doi.org/10.1128/AEM.01541-09
Schneeberger M, Everard A, Gómez-Valadés AG, Matamoros S, Ramírez S, Delzenne NM, Gomis R, Claret M, Cani PD (2015) Akkermansia muciniphila inversely correlates with the onset of inflammation, altered adipose tissue metabolism and metabolic disorders during obesity in mice. Sci Rep 5:16643. https://doi.org/10.1038/srep16643
Sebastiani P et al (2010) Genetic signatures of exceptional longevity in humans. Science. https://doi.org/10.1126/science.1190532
Sebastiani P, Solovieff N, DeWan AT, Walsh KM, Puca A, Hartley SW, Melista E, Andersen S, Dworkis DA, Wilk JB, Myers RH, Steinberg MH, Montano M, Baldwin CT, Hoh J, Perls TT (2012) Genetic signatures of exceptional longevity in humans. PLoS One 7:e29848. https://doi.org/10.1371/journal.pone.0029848
Shang FM, Liu HL (2018) Fusobacterium nucleatum and colorectal cancer: a review. World J Gastrointest Oncol 10:71–81. https://doi.org/10.4251/wjgo.v10.i3.71
Shen EZ, Song CQ, Lin Y, Zhang WH, Su PF, Liu WY, Zhang P, Xu J, Lin N, Zhan C, Wang X, Shyr Y, Cheng H, Dong MQ (2014) Mitoflash frequency in early adulthood predicts lifespan in Caenorhabditis elegans. Nature 508:128–132. https://doi.org/10.1038/nature13012
Sun J, Kato I (2016) Gut microbiota, inflammation and colorectal cancer. Genes Dis 3:130–143. https://doi.org/10.1016/j.gendis.2016.03.004
Tan J, McKenzie C, Potamitis M, Thorburn AN, Mackay CR, Macia L (2014) The role of short-chain fatty acids in health and disease. Adv Immunol 121:91–119. https://doi.org/10.1016/B978-0-12-800100-4.00003-9
Team RC (2015) R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna
Tissenbaum HA, Guarente L (2001) Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410:227–230. https://doi.org/10.1038/35065638
Tsuzukibashi O, Uchibori S, Kobayashi T, Umezawa K, Mashimo C, Nambu T, Saito M, Hashizume-Takizawa T, Ochiai T (2017) Isolation and identification methods of Rothia species in oral cavities. J Microbiol Methods 134:21–26. https://doi.org/10.1016/j.mimet.2017.01.005
Unger MM, Spiegel J, Dillmann KU, Grundmann D, Philippeit H, Bürmann J, Faßbender K, Schwiertz A, Schäfer KH (2016) Short chain fatty acids and gut microbiota differ between patients with Parkinson’s disease and age-matched controls. Parkinsonism Relat Disord 32:66–72. https://doi.org/10.1016/j.parkreldis.2016.08.019
van den Bogert B, Erkus O, Boekhorst J, de Goffau M, Smid EJ, Zoetendal EG, Kleerebezem M (2013) Diversity of human small intestinal Streptococcus and Veillonella populations. FEMS Microbiol Ecol 85:376–388. https://doi.org/10.1111/1574-6941.12127
Velarde MC (2014) Mitochondrial and sex steroid hormone crosstalk during aging. Longev Healthspan 3:2. https://doi.org/10.1186/2046-2395-3-2
Wexler HM (2007) Bacteroides: the good, the bad, and the nitty-gritty. Clin Microbiol Rev 20:593–621. https://doi.org/10.1128/CMR.00008-07
Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD (2008) FOXO3A genotype is strongly associated with human longevity. Proc Natl Acad Sci U S A 105:13987–13992. https://doi.org/10.1073/pnas.0801030105
Woods JA, Wilund KR, Martin SA, Kistler BM (2012) Exercise, inflammation and aging. Aging Dis 3:130–140
Yamamura K, Baba Y, Nakagawa S, Mima K, Miyake K, Nakamura K, Sawayama H, Kinoshita K, Ishimoto T, Iwatsuki M, Sakamoto Y, Yamashita Y, Yoshida N, Watanabe M, Baba H (2016) Human microbiome Fusobacterium nucleatum in esophageal cancer tissue is associated with prognosis. Clin Cancer Res 22:5574–5581. https://doi.org/10.1158/1078-0432.CCR-16-1786
Yang L, Lu X, Nossa CW, Francois F, Peek RM, Pei Z (2009) Inflammation and intestinal metaplasia of the distal esophagus are associated with alterations in the microbiome. Gastroenterology 137:588–597. https://doi.org/10.1053/j.gastro.2009.04.046
Acknowledgments
We thank Mr. Zachary Gortler (Danbury Hospital) and Mrs. Tamara Tsitrin (J. Craig Venter Institute) for their contributions to coordinate specimen collection, shipment, cataloging samples, and generating aliquots for laboratory analysis.
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This work was generously funded by the Ruggles Family Foundation, Moline, IL, and Mr. and Mrs. Rudy Ruggles.
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Harinder Singh: microbiome data analysis and interpretation, manuscript writing; Manolito G Torralba, led DNA library preparation work; K. Moncera, generated DNA libraries; Joann Petrini, directed human subject enrolment, questionnaires on medical history, sample collections, and human subject protocols; Lauren DiLello, coordinated human subject enrolment; Karen E. Nelson, project conception and design and manuscript review; Rembert Pieper, project conception, directed the study over all, wrote manuscript, and interpreted data.
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Singh, H., Torralba, M.G., Moncera, K.J. et al. Gastro-intestinal and oral microbiome signatures associated with healthy aging. GeroScience 41, 907–921 (2019). https://doi.org/10.1007/s11357-019-00098-8
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DOI: https://doi.org/10.1007/s11357-019-00098-8