1932

Abstract

Aging is a natural process of organismal decay that underpins the development of myriad diseases and disorders. Extensive efforts have been made to understand the biology of aging and its regulation, but most studies focus solely on the host organism. Considering the pivotal role of the microbiota in host health and metabolism, we propose viewing the host and its microbiota as a single biological entity whose aging phenotype is influenced by the complex interplay between host and bacterial genetics. In this review we present how the microbiota changes as the host ages, but also how the intricate relationship between host and indigenous bacteria impacts organismal aging and life span. In addition, we highlight other microbiota-dependent mechanisms that potentially regulate aging, and present experimental animal models for addressing these questions. Importantly, we propose microbiome dysbiosis as an additional hallmark and biomarker of aging.

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2019-12-03
2024-10-10
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Literature Cited

  1. 1. 
    Alavez S, Vantipalli MC, Zucker DJS, Klang IM, Lithgow GJ 2011. Amyloid-binding compounds maintain protein homeostasis during aging and extend lifespan. Nature 472:226–29
    [Google Scholar]
  2. 2. 
    An R, Wilms E, Masclee AAM, Smidt H, Zoetendal EG, Jonkers D 2018. Age-dependent changes in GI physiology and microbiota: time to reconsider?. Gut 67:2213–22
    [Google Scholar]
  3. 3. 
    Andersson SGE, Zomorodipour A, Andersson JO, Sicheritz-Pontén T, Alsmark UCM et al. 1998. The genome sequence of Rickettsia prowazekii and the origin of mitochondria. Nature 396:133–40
    [Google Scholar]
  4. 4. 
    Arnal M-E, Lallès J-P. 2016. Gut epithelial inducible heat-shock proteins and their modulation by diet and the microbiota. Nutr. Rev. 74:181–97
    [Google Scholar]
  5. 5. 
    Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y et al. 2013. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500:232–36
    [Google Scholar]
  6. 6. 
    Ayyaz A, Jasper H. 2013. Intestinal inflammation and stem cell homeostasis in aging Drosophila melanogaster. Front. Cell. Infect. Microbiol 3:98
    [Google Scholar]
  7. 7. 
    Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA 2016. Metformin as a tool to target aging. Cell Metab 23:1060–65
    [Google Scholar]
  8. 8. 
    Berg M, Monnin D, Cho J, Nelson L, Crits-Christoph A, Shapira M 2019. TGFβ/BMP immune signaling affects abundance and function of C. elegans gut commensals. Nat. Commun. 10:604
    [Google Scholar]
  9. 9. 
    Biagi E, Candela M, Fairweather-Tait S, Franceschi C, Brigidi P 2012. Aging of the human metaorganism: the microbial counterpart. Age 34:247–67
    [Google Scholar]
  10. 10. 
    Biagi E, Franceschi C, Rampelli S, Severgnini M, Ostan R et al. 2016. Gut microbiota and extreme longevity. Curr. Biol. 26:1480–85
    [Google Scholar]
  11. 11. 
    Biagi E, Nylund L, Candela M, Ostan R, Bucci L et al. 2010. Through aging, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLOS ONE 5:e10667
    [Google Scholar]
  12. 12. 
    Biagi E, Rampelli S, Turroni S, Quercia S, Candela M, Brigidi P 2017. The gut microbiota of centenarians: signatures of longevity in the gut microbiota profile. Mech. Aging Dev. 165: Part 2 180–84
    [Google Scholar]
  13. 13. 
    Bian G, Gloor GB, Gong A, Jia C, Zhang W et al. 2017. The gut microbiota of healthy aged Chinese is similar to that of the healthy young. mSphere 2:e00327–17
    [Google Scholar]
  14. 14. 
    Biteau B, Hochmuth CE, Jasper H 2011. Maintaining tissue homeostasis: dynamic control of somatic stem cell activity. Cell Stem Cell 9:402–11
    [Google Scholar]
  15. 15. 
    Biteau B, Karpac J, Supoyo S, DeGennaro M, Lehmann R, Jasper H 2010. Lifespan extension by preserving proliferative homeostasis in Drosophila. PLOS Genet 6:e1001159
    [Google Scholar]
  16. 16. 
    Breton J, Tennoune N, Lucas N, Francois M, Legrand R et al. 2016. Gut commensal E. coli proteins activate host satiety pathways following nutrient-induced bacterial growth. Cell Metab 23:324–34
    [Google Scholar]
  17. 17. 
    Brown K, DeCoffe D, Molcan E, Gibson DL 2012. Diet-induced dysbiosis of the intestinal microbiota and the effects on immunity and disease. Nutrients 4:1095–119
    [Google Scholar]
  18. 18. 
    Buchon N, Broderick NA, Lemaitre B 2013. Gut homeostasis in a microbial world: insights from Drosophila melanogaster. Nat. Rev. Microbiol 11:615–26
    [Google Scholar]
  19. 19. 
    Burnett C, Valentini S, Cabreiro F, Goss M, Somogyvári M et al. 2011. Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 477:482–85
    [Google Scholar]
  20. 20. 
    Cabreiro F. 2016. Metformin joins forces with microbes. Cell Host Microbe 19:1–3 https://doi.org/10.1016/j.chom.2015.12.012
    [Crossref] [Google Scholar]
  21. 21. 
    Cabreiro F, Au C, Leung KY, Vergara-Irigaray N, Cochemé HM et al. 2013. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 153:228–39
    [Google Scholar]
  22. 22. 
    Caricilli AM, Saad MJA. 2013. The role of gut microbiota on insulin resistance. Nutrients 5:829–51
    [Google Scholar]
  23. 23. 
    Carvalho BM, Guadagnini D, Tsukumo DML, Schenka AA, Latuf-Filho P et al. 2012. Modulation of gut microbiota by antibiotics improves insulin signalling in high-fat fed mice. Diabetologia 55:2823–34
    [Google Scholar]
  24. 24. 
    Cawthon RM, Smith KR, O'Brien E, Sivatchenko A, Kerber RA 2003. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 361:393–95
    [Google Scholar]
  25. 25. 
    Cho S-Y, Kim J, Lee JH, Sim JH, Cho D-H et al. 2016. Modulation of gut microbiota and delayed immunosenescence as a result of syringaresinol consumption in middle-aged mice. Sci. Rep. 6:39026
    [Google Scholar]
  26. 26. 
    Claesson MJ, Cusack S, O'Sullivan O, Greene-Diniz R, de Weerd H et al. 2011. Composition, variability, and temporal stability of the intestinal microbiota of the elderly. PNAS 108: Suppl. 1 4586–91
    [Google Scholar]
  27. 27. 
    Claesson MJ, Jeffery IB, Conde S, Power SE, O'Connor EM et al. 2012. Gut microbiota composition correlates with diet and health in the elderly. Nature 488:178–84
    [Google Scholar]
  28. 28. 
    Clark RI, Salazar A, Yamada R, Fitz-Gibbon S, Morselli M et al. 2015. Distinct shifts in microbiota composition during Drosophila aging impair intestinal function and drive mortality. Cell Rep 12:1656–67
    [Google Scholar]
  29. 29. 
    Clemente JC, Ursell LK, Parfrey LW, Knight R 2012. The impact of the gut microbiota on human health: an integrative view. Cell 148:1258–70
    [Google Scholar]
  30. 30. 
    Cortese R, Lu L, Yu Y, Ruden D, Claud EC 2016. Epigenome-microbiome crosstalk: a potential new paradigm influencing neonatal susceptibility to disease. Epigenetics 11:205–15
    [Google Scholar]
  31. 31. 
    Cushing K, Alvarado DM, Ciorba MA 2015. Butyrate and mucosal inflammation: New scientific evidence supports clinical observation. Clin. Transl. Gastroenterol. 6:e108
    [Google Scholar]
  32. 32. 
    Dambroise E, Monnier L, Ruisheng L, Aguilaniu H, Joly J-S et al. 2016. Two phases of aging separated by the Smurf transition as a public path to death. Sci. Rep. 6:23523
    [Google Scholar]
  33. 33. 
    Debebe T, Biagi E, Soverini M, Holtze S, Hildebrandt TB et al. 2017. Unraveling the gut microbiome of the long-lived naked mole-rat. Sci. Rep. 7:9590
    [Google Scholar]
  34. 34. 
    Dejea CM, Fathi P, Craig JM, Boleij A, Taddese R et al. 2018. Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria. Science 359:592–97
    [Google Scholar]
  35. 35. 
    Dirksen P, Marsh SA, Braker I, Heitland N, Wagner S et al. 2016. The native microbiome of the nematode Caenorhabditis elegans: gateway to a new host-microbiome model. BMC Biol 14:38
    [Google Scholar]
  36. 36. 
    Donato V, Ayala FR, Cogliati S, Bauman C, Costa JG et al. 2017. Bacillus subtilis biofilm extends Caenorhabditis elegans longevity through downregulation of the insulin-like signalling pathway. Nat. Commun. 8:14332
    [Google Scholar]
  37. 37. 
    Donohoe DR, Garge N, Zhang X, Sun W, O'Connell TM et al. 2011. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon. Cell Metab 13:517–26
    [Google Scholar]
  38. 38. 
    Doonan R, McElwee JJ, Matthijssens F, Walker GA, Houthoofd K et al. 2008. Against the oxidative damage theory of aging: Superoxide dismutases protect against oxidative stress but have little or no effect on life span in Caenorhabditis elegans. Genes Dev 22:3236–41
    [Google Scholar]
  39. 39. 
    Duszka K, Ellero-Simatos S, Ow GS, Defernez M, Paramalingam E et al. 2018. Complementary intestinal mucosa and microbiota responses to caloric restriction. Sci. Rep. 8:11338
    [Google Scholar]
  40. 40. 
    Eisenberg T, Knauer H, Schauer A, Büttner S, Ruckenstuhl C et al. 2009. Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 11:1305–14
    [Google Scholar]
  41. 41. 
    Ermolaeva MA, Segref A, Dakhovnik A, Ou H-L, Schneider JI et al. 2013. DNA damage in germ cells induces an innate immune response that triggers systemic stress resistance. Nature 501:416–20
    [Google Scholar]
  42. 42. 
    Fabbiano S, Suárez-Zamorano N, Chevalier C, Lazarević V, Kieser S et al. 2018. Functional gut microbiota remodeling contributes to the caloric restriction-induced metabolic improvements. Cell Metab 28:907–21.e7
    [Google Scholar]
  43. 43. 
    Finkel T. 2011. Signal transduction by reactive oxygen species. J. Cell Biol. 194:7–15
    [Google Scholar]
  44. 44. 
    Forslund K, Hildebrand F, Nielsen T, Falony G, Le Chatelier E et al. 2015. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528:262–66
    [Google Scholar]
  45. 45. 
    Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M et al. 2000. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci. 908:244–54
    [Google Scholar]
  46. 46. 
    Fransen F, van Beek AA, Borghuis T, Aidy S El, Hugenholtz F et al. 2017. Aged gut microbiota contributes to systemical inflammaging after transfer to germ-free mice. Front. Immunol. 8:1385
    [Google Scholar]
  47. 47. 
    Friedland RP, Chapman MR. 2017. The role of microbial amyloid in neurodegeneration. PLOS Pathog 13:e1006654
    [Google Scholar]
  48. 48. 
    Galkin F, Aliper A, Putin E, Kuznetsov I, Gladyshev VN, Zhavoronkov A 2018. Human microbiome aging clocks based on deep learning and tandem of permutation feature importance and accumulated local effects. bioRxiv 507780. https://doi.org/10.1101/507780
    [Crossref]
  49. 49. 
    García-Calzón S, Zalba G, Ruiz-Canela M, Shivappa N, Hébert JR et al. 2015. Dietary inflammatory index and telomere length in subjects with a high cardiovascular disease risk from the PREDIMED-NAVARRA study: cross-sectional and longitudinal analyses over 5 y. Am. J. Clin. Nutr. 102:897–904
    [Google Scholar]
  50. 50. 
    Garigan D, Hsu A-L, Fraser AG, Kamath RS, Ahringer J, Kenyon C 2002. Genetic analysis of tissue aging in Caenorhabditis elegans: a role for heat-shock factor and bacterial proliferation. Genetics 161:1101–12
    [Google Scholar]
  51. 51. 
    Goubern M, Andriamihaja M, Nübel T, Blachier F, Bouillaud F 2007. Sulfide, the first inorganic substrate for human cells. FASEB J 21:1699–706
    [Google Scholar]
  52. 52. 
    Govindan JA, Jayamani E, Zhang X, Mylonakis E, Ruvkun G 2015. Dialogue between E. coli free radical pathways and the mitochondria of C. elegans. PNAS 112:12456–61
    [Google Scholar]
  53. 53. 
    Guo L, Karpac J, Tran SL, Jasper H 2014. PGRP-SC2 promotes gut immune homeostasis to limit commensal dysbiosis and extend lifespan. Cell 156:109–22
    [Google Scholar]
  54. 54. 
    Gusarov I, Gautier L, Smolentseva O, Shamovsky I, Eremina S et al. 2013. Bacterial nitric oxide extends the lifespan of C. elegans. Cell 152:818–30
    [Google Scholar]
  55. 55. 
    Han B, Sivaramakrishnan P, Lin C-CJ, Neve IAA, He J et al. 2017. Microbial genetic composition tunes host longevity. Cell 169:1249–62.e13
    [Google Scholar]
  56. 56. 
    Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM et al. 2009. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460:392–95
    [Google Scholar]
  57. 57. 
    Heintz C, Mair W. 2014. You are what you host: microbiome modulation of the aging process. Cell 156:408–11
    [Google Scholar]
  58. 58. 
    Hine C, Harputlugil E, Zhang Y, Ruckenstuhl C, Lee BC et al. 2015. Endogenous hydrogen sulfide production is essential for dietary restriction benefits. Cell 160:132–44
    [Google Scholar]
  59. 59. 
    Ho L, Ono K, Tsuji M, Mazzola P, Singh R, Pasinetti GM 2018. Protective roles of intestinal microbiota derived short chain fatty acids in Alzheimer's disease-type beta-amyloid neuropathological mechanisms. Exp. Rev. Neurother. 18:83–90
    [Google Scholar]
  60. 60. 
    Hu S, Wang Y, Lichtenstein L, Tao Y, Musch MW et al. 2010. Regional differences in colonic mucosa-associated microbiota determine the physiological expression of host heat shock proteins. Am. J. Physiol. Liver Physiol. 299:G1266–75
    [Google Scholar]
  61. 61. 
    Hurez V, Dao V, Liu A, Pandeswara S, Gelfond J et al. 2015. Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune-deficient mice. Aging Cell 14:945–56
    [Google Scholar]
  62. 62. 
    Jackson MA, Jeffery IB, Beaumont M, Bell JT, Clark AG et al. 2016. Signatures of early frailty in the gut microbiota. Genome Med 8:8
    [Google Scholar]
  63. 63. 
    Jandhyala SM, Talukdar R, Subramanyam C, Vuyyuru H, Sasikala M, Reddy DN 2015. Role of the normal gut microbiota. World J. Gastroenterol. 21:8836–47
    [Google Scholar]
  64. 64. 
    Jin K. 2010. Modern biological theories of aging. Aging Dis 1:72–74
    [Google Scholar]
  65. 65. 
    Jones RM, Luo L, Ardita CS, Richardson AN, Kwon YM et al. 2013. Symbiotic lactobacilli stimulate gut epithelial proliferation via Nox-mediated generation of reactive oxygen species. EMBO J 32:3017–28
    [Google Scholar]
  66. 66. 
    Jones RM, Mercante JW, Neish AS 2012. Reactive oxygen production induced by the gut microbiota: pharmacotherapeutic implications. Curr. Med. Chem. 19:1519–29
    [Google Scholar]
  67. 67. 
    Jones RM, Neish AS. 2017. Redox signaling mediated by the gut microbiota. Free Radic. Biol. Med. 105:41–47
    [Google Scholar]
  68. 68. 
    Jung M-J, Lee J, Shin N-R, Kim M-S, Hyun D-W et al. 2016. Chronic repression of mTOR complex 2 induces changes in the gut microbiota of diet-induced obese mice. Sci. Rep. 6:30887
    [Google Scholar]
  69. 69. 
    Kaeberlein M, McVey M, Guarente L 1999. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev 13:2570–80
    [Google Scholar]
  70. 70. 
    Kaiko GE, Ryu SH, Koues OI, Collins PL, Solnica-Krezel L et al. 2016. The colonic crypt protects stem cells from microbiota-derived metabolites. Cell 165:1708–20
    [Google Scholar]
  71. 71. 
    Kalisperati P, Spanou E, Pateras IS, Korkolopoulou P, Varvarigou A et al. 2017. Inflammation, DNA damage, Helicobacter pylori and gastric tumorigenesis. Front. Genet. 8:20
    [Google Scholar]
  72. 72. 
    Kibe R, Kurihara S, Sakai Y, Suzuki H, Ooga T et al. 2015. Upregulation of colonic luminal polyamines produced by intestinal microbiota delays senescence in mice. Sci. Rep. 4:4548
    [Google Scholar]
  73. 73. 
    Kim Y, Nam HG, Valenzano DR 2016. The short-lived African turquoise killifish: an emerging experimental model for aging. Dis. Model. Mech. 9:115–29
    [Google Scholar]
  74. 74. 
    Kim YS, Unno T, Kim B-Y, Park M-S 2019. Sex differences in gut microbiota. World J. Mens Health 37:e15
    [Google Scholar]
  75. 75. 
    Koeppel M, Garcia-Alcalde F, Glowinski F, Schlaermann P, Meyer TF 2015. Helicobacter pylori infection causes characteristic DNA damage patterns in human cells. Cell Rep 11:1703–13
    [Google Scholar]
  76. 76. 
    Kong F, Deng F, Li Y, Zhao J 2019. Identification of gut microbiome signatures associated with longevity provides a promising modulation target for healthy aging. Gut Microbes 10:210–15
    [Google Scholar]
  77. 77. 
    Kozik AJ, Nakatsu CH, Chun H, Jones-Hall YL 2017. Age, sex, and TNF associated differences in the gut microbiota of mice and their impact on acute TNBS colitis. Exp. Mol. Pathol. 103:311–19
    [Google Scholar]
  78. 78. 
    Kumar A, Wu H, Collier-Hyams LS, Hansen JM, Li T et al. 2007. Commensal bacteria modulate cullin-dependent signaling via generation of reactive oxygen species. EMBO J 26:4457–66
    [Google Scholar]
  79. 79. 
    Kundu P, Blacher E, Elinav E, Pettersson S 2017. Our gut microbiome: the evolving inner self. Cell 171:1481–93
    [Google Scholar]
  80. 80. 
    Labbadia J, Brielmann RM, Neto MF, Lin Y-F, Haynes CM, Morimoto RI 2017. Mitochondrial stress restores the heat shock response and prevents proteostasis collapse during aging. Cell Rep 21:1481–94
    [Google Scholar]
  81. 81. 
    Langille MG, Meehan CJ, Koenig JE, Dhanani AS, Rose RA et al. 2014. Microbial shifts in the aging mouse gut. Microbiome 2:50
    [Google Scholar]
  82. 82. 
    Larsen PL, Clarke CF. 2002. Extension of life-span in Caenorhabditis elegans by a diet lacking coenzyme Q. Science 295:120–23
    [Google Scholar]
  83. 83. 
    Laserna-Mendieta EJ, Clooney AG, Carretero-Gomez JF, Moran C, Sheehan D et al. 2018. Determinants of reduced genetic capacity for butyrate synthesis by the gut microbiome in Crohn's disease and ulcerative colitis. J. Crohn's Colitis 12:204–16
    [Google Scholar]
  84. 84. 
    Lebreton A, Stavru F, Cossart P 2015. Organelle targeting during bacterial infection: insights from Listeria. Trends Cell Biol 25:330–38
    [Google Scholar]
  85. 85. 
    Lee K-A, Kim S-H, Kim E-K, Ha E-M, You H et al. 2013. Bacterial-derived uracil as a modulator of mucosal immunity and gut-microbe homeostasis in Drosophila. Cell 153:797–811
    [Google Scholar]
  86. 86. 
    Lee S-G, Kaya A, Avanesov AS, Podolskiy DI, Song EJ et al. 2017. Age-associated molecular changes are deleterious and may modulate life span through diet. Sci. Adv. 3:e1601833
    [Google Scholar]
  87. 87. 
    Lemaitre B, Miguel-Aliaga I. 2013. The digestive tract of Drosophila melanogaster. Annu. Rev. Genet 47:377–404
    [Google Scholar]
  88. 88. 
    Leschelle X, Goubern M, Andriamihaja M, Blottière HM, Couplan E et al. 2005. Adaptative metabolic response of human colonic epithelial cells to the adverse effects of the luminal compound sulfide. Biochim. Biophys. Acta Gen. Subj. 1725:201–12
    [Google Scholar]
  89. 89. 
    Li H, Qi Y, Jasper H 2016. Preventing age-related decline of gut compartmentalization limits microbiota dysbiosis and extends lifespan. Cell Host Microbe 19:240–53
    [Google Scholar]
  90. 90. 
    Liu D, Zhang Y, Liu Y, Hou L, Li S et al. 2018. Berberine modulates gut microbiota and reduces insulin resistance via the TLR4 signaling pathway. Exp. Clin. Endocrinol. Diabetes 126:513–20
    [Google Scholar]
  91. 91. 
    Liu H, Dicksved J, Lundh T, Lindberg JE 2014. Heat shock proteins: intestinal gatekeepers that are influenced by dietary components and the gut microbiota. Pathogen 3:187–210
    [Google Scholar]
  92. 92. 
    Liu Y, Samuel BS, Breen PC, Ruvkun G 2014. Caenorhabditis elegans pathways that surveil and defend mitochondria. Nature 508:406–10
    [Google Scholar]
  93. 93. 
    López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G 2013. The hallmarks of aging. Cell 153:1194–217
    [Google Scholar]
  94. 94. 
    López-Otín C, Galluzzi L, Freije JMP, Madeo F, Kroemer G 2016. Metabolic control of longevity. Cell 166:802–21
    [Google Scholar]
  95. 95. 
    Lu M, Wang Z. 2018. Linking gut microbiota to aging process: a new target for anti-aging. Food Sci. Hum. Wellness 7:111–19
    [Google Scholar]
  96. 96. 
    Mariat D, Firmesse O, Levenez F, Guimarăes V, Sokol H et al. 2009. The Firmicutes/Bacteroidetes ratio of the human microbiota changes with age. BMC Microbiol 9:123
    [Google Scholar]
  97. 97. 
    Matsumoto M, Kurihara S, Kibe R, Ashida H, Benno Y 2011. Longevity in mice is promoted by probiotic-induced suppression of colonic senescence dependent on upregulation of gut bacterial polyamine production. PLOS ONE 6:e23652
    [Google Scholar]
  98. 98. 
    McCauley BS, Dang W. 2014. Histone methylation and aging: lessons learned from model systems. Biochim. Biophys. Acta Gene Regul. Mech. 1839:1454–62
    [Google Scholar]
  99. 99. 
    Mesquita A, Weinberger M, Silva A, Sampaio-Marques B, Almeida B et al. 2010. Caloric restriction or catalase inactivation extends yeast chronological lifespan by inducing H2O2 and superoxide dismutase activity. PNAS 107:15123–28
    [Google Scholar]
  100. 100. 
    Mitsuoka T. 2014. Establishment of intestinal bacteriology. Biosci. Microbiota Food Health 33:99–116
    [Google Scholar]
  101. 101. 
    Mizunuma M, Neumann-Haefelin E, Moroz N, Li Y, Blackwell TK 2014. mTORC2-SGK-1 acts in two environmentally responsive pathways with opposing effects on longevity. Aging Cell 13:869–78
    [Google Scholar]
  102. 102. 
    Nagpal R, Mainali R, Ahmadi S, Wang S, Singh R et al. 2018. Gut microbiome and aging: physiological and mechanistic insights. Nutr. Healthy Aging 4:267–85
    [Google Scholar]
  103. 103. 
    Navrotskaya VV, Oxenkrug G, Vorobyova LI, Summergrad P 2012. Berberine prolongs life span and stimulates locomotor activity of Drosophila melanogaster. Am. J. Plant Sci 3:1037–40
    [Google Scholar]
  104. 104. 
    Nguyen TLA, Vieira-Silva S, Liston A, Raes J 2015. How informative is the mouse for human gut microbiota research?. Dis. Model. Mech. 8:1–16
    [Google Scholar]
  105. 105. 
    Noureldein MH, Eid AA. 2018. Gut microbiota and mTOR signaling: insight on a new pathophysiological interaction. Microb. Pathog. 118:98–104
    [Google Scholar]
  106. 106. 
    Odamaki T, Kato K, Sugahara H, Hashikura N, Takahashi S et al. 2016. Age-related changes in gut microbiota composition from newborn to centenarian: a cross-sectional study. BMC Microbiol 16:90
    [Google Scholar]
  107. 107. 
    O'Toole PW, Jeffery IB. 2015. Gut microbiota and aging. Science 350:1214–15
    [Google Scholar]
  108. 108. 
    Papamichael K, Konstantopoulos P, Mantzaris GJ 2014. Helicobacter pylori infection and inflammatory bowel disease: Is there a link?. World J. Gastroenterol. 20:6374
    [Google Scholar]
  109. 109. 
    Peck BCE, Shanahan MT, Singh AP, Sethupathy P 2017. Gut microbial influences on the mammalian intestinal stem cell niche. Stem Cells Int 2017:5604727
    [Google Scholar]
  110. 110. 
    Pedersen HK, Gudmundsdottir V, Nielsen HB, Hyotylainen T, Nielsen T et al. 2016. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature 535:376–81
    [Google Scholar]
  111. 111. 
    Peleg S, Feller C, Ladurner AG, Imhof A 2016. The metabolic impact on histone acetylation and transcription in aging. Trends Biochem. Sci. 41:700–11
    [Google Scholar]
  112. 112. 
    Pérez VI, Van Remmen H, Bokov A, Epstein CJ, Vijg J, Richardson A 2009. The overexpression of major antioxidant enzymes does not extend the lifespan of mice. Aging Cell 8:73–75
    [Google Scholar]
  113. 113. 
    Petrof EO, Kojima K, Ropeleski MJ, Musch MW, Tao Y et al. 2004. Probiotics inhibit nuclear factor-κB and induce heat shock proteins in colonic epithelial cells through proteasome inhibition. Gastroenterology 127:1474–87
    [Google Scholar]
  114. 114. 
    Piper MDW, Blanc E, Leitão-Gonçalves R, Yang M, He X et al. 2014. A holidic medium for Drosophila melanogaster. Nat. Methods 11:100–5
    [Google Scholar]
  115. 115. 
    Pistollato F, Sumalla Cano S, Elio I, Masias Vergara M, Giampieri F, Battino M 2016. Role of gut microbiota and nutrients in amyloid formation and pathogenesis of Alzheimer disease. Nutr. Rev. 74:624–34
    [Google Scholar]
  116. 116. 
    Pryor R, Cabreiro F. 2015. Repurposing metformin: an old drug with new tricks in its binding pockets. Biochem. J. 471:307–22
    [Google Scholar]
  117. 117. 
    Pyo J-O, Yoo S-M, Ahn H-H, Nah J, Hong S-H et al. 2013. Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat. Commun. 4:2300
    [Google Scholar]
  118. 118. 
    Qin Y, Wade PA. 2018. Crosstalk between the microbiome and epigenome: messages from bugs. J. Biochem. 163:105–12
    [Google Scholar]
  119. 119. 
    Rampelli S, Candela M, Turroni S, Biagi E, Collino S et al. 2013. Functional metagenomic profiling of intestinal microbiome in extreme aging. Aging 5:902–12
    [Google Scholar]
  120. 120. 
    Ren C, Webster P, Finkel SE, Tower J 2007. Increased internal and external bacterial load during Drosophila aging without life-span trade-off. Cell Metab 6:144–52
    [Google Scholar]
  121. 121. 
    Renner O, Carnero A. 2009. Mouse models to decipher the PI3K signaling network in human cancer. Curr. Mol. Med. 9:612–25
    [Google Scholar]
  122. 122. 
    Rera M, Clark RI, Walker DW 2012. Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila. PNAS 109:21528–33
    [Google Scholar]
  123. 123. 
    Rinninella E, Raoul P, Cintoni M, Franceschi F, Miggiano GAD et al. 2019. What is the healthy gut microbiota composition? A changing ecosystem across age, environment, diet, and diseases. Microorganisms 7:E14
    [Google Scholar]
  124. 124. 
    Rogina B, Helfand SL. 2004. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. PNAS 101:15998–6003
    [Google Scholar]
  125. 125. 
    Rosenberg E, Zilber-Rosenberg I. 2018. The hologenome concept of evolution after 10 years. Microbiome 6:78
    [Google Scholar]
  126. 126. 
    Ryu D, Mouchiroud L, Andreux PA, Katsyuba E, Moullan N et al. 2016. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat. Med. 22:879–88
    [Google Scholar]
  127. 127. 
    Saint-Georges-Chaumet Y, Edeas M. 2016. Microbiota–mitochondria inter-talk: consequence for microbiota–host interaction. Pathog. Dis. 74:ftv096
    [Google Scholar]
  128. 128. 
    Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG et al. 2016. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease. Cell 167:1469–80.e12
    [Google Scholar]
  129. 129. 
    Saxton RA, Sabatini DM. 2017. mTOR signaling in growth, metabolism, and disease. Cell 168:960–76
    [Google Scholar]
  130. 130. 
    Sebald J, Willi M, Schoberleitner I, Krogsdam A, Orth-Höller D et al. 2016. Impact of the chromatin remodeling factor CHD1 on gut microbiome composition of Drosophila melanogaster. PLOS ONE 11:e0153476
    [Google Scholar]
  131. 131. 
    Segref A, Torres S, Hoppe T 2011. A screenable in vivo assay to study proteostasis networks in Caenorhabditis elegans. Genetics 187:1235–40
    [Google Scholar]
  132. 132. 
    Shen X, Miao J, Wan Q, Wang S, Li M et al. 2018. Possible correlation between gut microbiota and immunity among healthy middle-aged and elderly people in southwest China. Gut Pathog 10:4
    [Google Scholar]
  133. 133. 
    Smith P, Willemsen D, Popkes M, Metge F, Gandiwa E et al. 2017. Regulation of life span by the gut microbiota in the short-lived African turquoise killifish. eLife 6:e27014
    [Google Scholar]
  134. 134. 
    Snyder DL, Pollard M, Wostmann BS, Luckert P 1990. Life span, morphology, and pathology of diet-restricted germ-free and conventional Lobund-Wistar rats. J. Gerontol. 45:B52–58
    [Google Scholar]
  135. 135. 
    Soda K, Dobashi Y, Kano Y, Tsujinaka S, Konishi F 2009. Polyamine-rich food decreases age-associated pathology and mortality in aged mice. Exp. Gerontol. 44:727–32
    [Google Scholar]
  136. 136. 
    Stanfel MN, Shamieh LS, Kaeberlein M, Kennedy BK 2009. The TOR pathway comes of age. Biochim. Biophys. Acta Gen. Subj. 1790:1067–74
    [Google Scholar]
  137. 137. 
    Strozzi GP, Mogna L. 2008. Quantification of folic acid in human feces after administration of Bifidobacterium probiotic strains. J. Clin. Gastroenterol. 42:S179–84
    [Google Scholar]
  138. 138. 
    Tazume S, Umehara K, Matsuzawa H, Yoshida T, Hashimoto K, Sasaki S 1991. Immunological function of food-restricted germfree and specific pathogen-free mice. Jikken Dobutsu 40:523–28
    [Google Scholar]
  139. 139. 
    Thevaranjan N, Puchta A, Schulz C, Naidoo A, Szamosi JC et al. 2017. Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe 21:455–66.e4
    [Google Scholar]
  140. 140. 
    Tissenbaum HA, Guarente L. 2001. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410:227–30
    [Google Scholar]
  141. 141. 
    Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A et al. 2009. A core gut microbiome in obese and lean twins. Nature 457:480–84
    [Google Scholar]
  142. 142. 
    Valdes A, Andrew T, Gardner J, Kimura M, Oelsner E et al. 2005. Obesity, cigarette smoking, and telomere length in women. Lancet 366:662–64
    [Google Scholar]
  143. 143. 
    Valenzano DR, Benayoun BA, Singh PP, Zhang E, Etter PD et al. 2015. The African turquoise killifish genome provides insights into evolution and genetic architecture of lifespan. Cell 163:1539–54
    [Google Scholar]
  144. 144. 
    van Heemst D. 2010. Insulin, IGF-1 and longevity. Aging Dis 1:147–57
    [Google Scholar]
  145. 145. 
    Van Raamsdonk JM, Hekimi S 2009. Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in Caenorhabditis elegans. PLOS Genet 5:e1000361
    [Google Scholar]
  146. 146. 
    Van Remmen H, Ikeno Y, Hamilton M, Pahlavani M, Wolf N et al. 2003. Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiol. Genom. 16:29–37
    [Google Scholar]
  147. 147. 
    Virk B, Correia G, Dixon DP, Feyst I, Jia J et al. 2012. Excessive folate synthesis limits lifespan in the C. elegans: E. coli aging model. BMC Biol 10:67
    [Google Scholar]
  148. 148. 
    Wei Y, Kenyon C. 2016. Roles for ROS and hydrogen sulfide in the longevity response to germline loss in Caenorhabditis elegans. PNAS 113:E2832–41
    [Google Scholar]
  149. 149. 
    Wellman AS, Metukuri MR, Kazgan N, Xu X, Xu Q et al. 2017. Intestinal epithelial Sirtuin 1 regulates intestinal inflammation during aging in mice by altering the intestinal microbiota. Gastroenterology 153:772–86
    [Google Scholar]
  150. 150. 
    Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R et al. 2017. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat. Med. 23:850–58
    [Google Scholar]
  151. 151. 
    Xu M, Pirtskhalava T, Farr JN, Weigand BM, Palmer AK et al. 2018. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24:1246–56
    [Google Scholar]
  152. 152. 
    Yang L, Liu C, Zhao W, He C, Ding J et al. 2018. Impaired autophagy in intestinal epithelial cells alters gut microbiota and host immune responses. Appl. Environ. Microbiol. 84:e00880–18
    [Google Scholar]
  153. 153. 
    Yu T, Guo F, Yu Y, Sun T, Ma D et al. 2017. Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Cell 170:548–63
    [Google Scholar]
  154. 154. 
    Zhang C, Li S, Yang L, Huang P, Li W et al. 2013. Structural modulation of gut microbiota in life-long calorie-restricted mice. Nat. Commun. 4:2163
    [Google Scholar]
  155. 155. 
    Zhang F, Berg M, Dierking K, Félix M-A, Shapira M et al. 2017. Caenorhabditis elegans as a model for microbiome research. Front. Microbiol. 8:485
    [Google Scholar]
  156. 156. 
    Zhang J, Guo Z, Xue Z, Sun Z, Zhang M et al. 2015. A phylo-functional core of gut microbiota in healthy young Chinese cohorts across lifestyles, geography and ethnicities. ISME J 9:1979–90
    [Google Scholar]
  157. 157. 
    Zhang Y, Ikeno Y, Qi W, Chaudhuri A, Li Y et al. 2009. Mice deficient in both Mn superoxide dismutase and glutathione peroxidase-1 have increased oxidative damage and a greater incidence of pathology but no reduction in longevity. J. Gerontol. Ser. A Biol. Sci. Med. Sci. 64:1212–20
    [Google Scholar]
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