Aging is a physiological and immunological process involving the deterioration of human health, characterised by the progressive alteration of organs and their functions. The speed and extent of such decline are dependent on lifestyle, environment, and genetic factors. Moreover, with advancing age, humans become progressively more fragile and prone to acute and chronic diseases. Although the intestinal microbiota is predisposed to perturbations that accompany aging and frailty, it is generally accepted that the gut microbiota engages in multiple interactions that affect host health throughout the host life span. In the current study, an exhaustive in silico investigation of gut-associated bifidobacteria in healthy individuals from birth to old age revealed that Bifidobacterium longum subsp. longum is the most prevalent member, especially during infancy and in centenarians. Moreover, B. longum subsp. longum genome reconstruction and strain tracing among human gut microbiomes allowed the identification of prototypes of this taxon in the human gut microbiota of healthy elderly individuals. Such analyses guided culturomics attempts to isolate B. longum subsp. longum strains that matched the genomic content of B. longum subsp. longum prototypes from healthy elderly individuals. The molecular effects of selected B. longum subsp. longum strains on the human host were further investigated using in vitro microbe-host interactions, revealing differences in the host immune system transcriptome, with a reduction in gene expression of inflammation-related cytokines. These intriguing findings support the potential anti-aging effects of elderly associated prototypes of B. longum subsp. longum.
Purchase
Buy instant access (PDF download and unlimited online access):
Institutional Login
Log in with Open Athens, Shibboleth, or your institutional credentials
Personal login
Log in with your brill.com account
Alessandri, G., Fontana, F., Tarracchini, C., Rizzo, S.M., Bianchi, M.G., Taurino, G., Chiu, M., Lugli, G.A., Mancabelli, L., Argentini, C., Longhi, G., Anzalone, R., Viappiani, A., Milani, C., Turroni, F., Bussolati, O., van Sinderen, D. and Ventura, M., 2023. Identification of a prototype human gut Bifidobacterium longum subsp. longum strain based on comparative and functional genomic approaches. Frontiers in Microbiology 14: 1130592. https://doi.org/10.3389/fmicb.2023.1130592
Arboleya, S., Watkins, C., Stanton, C. and Ross, R.P., 2016. Gut bifidobacteria populations in human health and aging. Frontiers in Microbiology 7: 1204. https://doi.org/10.3389/fmicb.2016.01204
Argentini, C., Mancabelli, L., Alessandri, G., Tarracchini, C., Barbetti, M., Carnevali, L., Longhi, G., Viappiani, A., Anzalone, R., Milani, C., Sgoifo, A., van Sinderen, D., Ventura, M. and Turroni, F., 2022. Exploring the ecological effects of naturally antibiotic-insensitive bifidobacteria in the recovery of the resilience of the gut microbiota during and after antibiotic treatment. Applied and Environmental Microbiology 88: e0052222. https://doi.org/10.1128/aem.00522-22
Bankevich, A., Nurk, S., Antipov, D., Gurevich, A.A., Dvorkin, M., Kulikov, A.S., Lesin, V.M., Nikolenko, S.I., Pham, S., Prjibelski, A.D., Pyshkin, A.V., Sirotkin, A.V., Vyahhi, N., Tesler, G., Alekseyev, M.A. and Pevzner, P.A., 2012. SPAdes: a new genome assembly algorithm and its applications to single-cell sequencing. Journal of Computational Biology 19: 455-477. https://doi.org/10.1089/cmb.2012.0021
Biagi, E., Franceschi, C., Rampelli, S., Severgnini, M., Ostan, R., Turroni, S., Consolandi, C., Quercia, S., Scurti, M., Monti, D., Capri, M., Brigidi, P. and Candela, M., 2016. Gut microbiota and extreme longevity. Current Biology 26: 1480-1485. https://doi.org/10.1016/j.cub.2016.04.016
Biagi, E., Nylund, L., Candela, M., Ostan, R., Bucci, L., Pini, E., Nikkila, J., Monti, D., Satokari, R., Franceschi, C., Brigidi, P. and De Vos, W., 2010. Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLoS ONE 5: e10667. https://doi.org/10.1371/journal.pone.0010667
Bianchi, M.G., Chiu, M., Taurino, G., Brighenti, F., Del Rio, D., Mena, P. and Bussolati, O., 2019. Catechin and procyanidin B(2) modulate the expression of tight junction proteins but do not protect from inflammation-induced changes in permeability in human intestinal cell monolayers. Nutrients 11: 2271. https://doi.org/10.3390/nu11102271
Blagosklonny, M.V., 2008. Aging: ROS or TOR. Cell Cycle 7: 3344-3354. https://doi.org/10.4161/cc.7.21.6965
Bustin, S.A., Benes, V., Nolan, T. and Pfaffl, M.W., 2005. Quantitative real-time RT-PCR – a perspective. Journal of Molecular Endocrinology 34: 597-601. https://doi.org/10.1677/jme.1.01755
Calder, P.C., Bosco, N., Bourdet-Sicard, R., Capuron, L., Delzenne, N., Dore, J., Franceschi, C., Lehtinen, M.J., Recker, T., Salvioli, S. and Visioli, F., 2017. Health relevance of the modification of low grade inflammation in ageing (inflammageing) and the role of nutrition. Ageing Research Reviews 40: 95-119. https://doi.org/10.1016/j.arr.2017.09.001
Chen, Y., Ye, W., Zhang, Y. and Xu, Y., 2015. High speed BLASTN: an accelerated MegaBLAST search tool. Nucleic Acids Research 43: 7762-7768. https://doi.org/10.1093/nar/gkv784
Cipollone, F., Iezzi, A., Fazia, M., Zucchelli, M., Pini, B., Cuccurullo, C., De Cesare, D., De Blasis, G., Muraro, R., Bei, R., Chiarelli, F., Schmidt, A.M., Cuccurullo, F. and Mezzetti, A., 2003. The receptor RAGE as a progression factor amplifying arachidonate-dependent inflammatory and proteolytic response in human atherosclerotic plaques: role of glycemic control. Circulation 108: 1070-1077. https://doi.org/10.1161/01.CIR.0000086014.80477.0D
Clarke, G., Ting, K.N., Wiart, C. and Fry, J., 2013. High Correlation of 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, ferric reducing activity potential and total phenolics content indicates redundancy in use of all three assays to screen for antioxidant activity of extracts of plants from the malaysian rainforest. Antioxidants 2: 1. https://doi.org/10.3390/antiox2010001
Engle, M.J., Goetz, G.S. and Alpers, D.H., 1998. Caco-2 cells express a combination of colonocyte and enterocyte phenotypes. Journal of Cell Physiology 174: 362-369. https://doi.org/10.1002/(SICI)1097-4652(199803)174:3<362::AID-JCP10>3.0.CO;2-B
Faith, J.J., Guruge, J.L., Charbonneau, M., Subramanian, S., Seedorf, H., Goodman, A.L., Clemente, J.C., Knight, R., Heath, A.C., Leibel, R.L., Rosenbaum, M. and Gordon, J.I., 2013. The long-term stability of the human gut microbiota. Science 341: 1237439. https://doi.org/10.1126/science.1237439
Finamore, A., Roselli, M., Donini, L., Brasili, D.E., Rami, R., Carnevali, P., Mistura, L., Pinto, A., Giusti, A. and Mengheri, E., 2019. Supplementation with Bifidobacterium longum Bar33 and Lactobacillus helveticus Bar13 mixture improves immunity in elderly humans (over 75 years) and aged mice. Nutrition 63-64: 184-192. https://doi.org/10.1016/j.nut.2019.02.005
Fontana, F., Alessandri, G., Tarracchini, C., Bianchi, M.G., Rizzo, S.M., Mancabelli, L., Lugli, G.A., Argentini, C., Vergna, L.M., Anzalone, R., Longhi, G., Viappiani, A., Taurino, G., Chiu, M., Turroni, F., Bussolati, O., van Sinderen, D., Milani, C. and Ventura, M., 2022. Designation of optimal reference strains representing the infant gut bifidobacterial species through a comprehensive multi-omics approach. Environmental Microbiology 24: 5825-5839. https://doi.org/10.1111/1462-2920.16205
Fraga, C.G., Shigenaga, M.K., Park, J.W., Degan, P. and Ames, B.N., 1990. Oxidative damage to DNA during aging: 8-hydroxy-2’-deoxyguanosine in rat organ DNA and urine. Proceedings of the National Academy of Sciences of the USA 87: 4533-4537. https://doi.org/10.1073/pnas.87.12.4533
Fulop, T., Dupuis, G., Witkowski, J.M. and Larbi, A., 2016. The role of immunosenescence in the development of age-related diseases. Revista de Investigación Clı́nica 68: 84-91.
Fulop, T., Larbi, A., Dupuis, G., Le Page, A., Frost, E.H., Cohen, A.A., Witkowski, J.M. and Franceschi, C., 2017. Immunosenescence and inflamm-aging as two sides of the same coin: friends or foes? Frontiers in Immunology 8: 1960. https://doi.org/10.3389/fimmu.2017.01960
Fulop, T., McElhaney, J., Pawelec, G., Cohen, A.A., Morais, J.A., Dupuis, G., Baehl, S., Camous, X., Witkowski, J.M. and Larbi, A., 2015. Frailty, inflammation and immunosenescence. Interdisciplinary Topics in Gerontology and Geriatrics 41: 26-40. https://doi.org/10.1159/000381134
Geissmann, F., Manz, M.G., Jung, S., Sieweke, M.H., Merad, M. and Ley, K., 2010. Development of monocytes, macrophages, and dendritic cells. Science 327: 656-661. https://doi.org/10.1126/science.1178331
Hyatt, D., Chen, G.L., Locascio, P.F., Land, M.L., Larimer, F.W. and Hauser, L.J., 2010. Prodigal: prokaryotic gene recognition and translation initiation site identification. BMC Bioinformatics 11: 119. https://doi.org/10.1186/1471-2105-11-119
Jain, C., Rodriguez, R.L., Phillippy, A.M., Konstantinidis, K.T. and Aluru, S., 2018. High throughput ANI analysis of 90 K prokaryotic genomes reveals clear species boundaries. Nature Communications 9: 5114. https://doi.org/10.1038/s41467-018-07641-9
Lin, W.Y., Lin, J.H., Kuo, Y.W., Chiang, P.R. and Ho, H.H., 2022. Probiotics and their metabolites reduce oxidative stress in middle-aged mice. Current Microbiology 79: 104. https://doi.org/10.1007/s00284-022-02783-y
Longhi, G., van Sinderen, D., Ventura, M. and Turroni, F., 2020. Microbiota and cancer: the emerging beneficial role of bifidobacteria in cancer immunotherapy. Frontiers in Microbiology 11: 575072. https://doi.org/10.3389/fmicb.2020.575072
Lopez-Otin, C., Blasco, M.A., Partridge, L., Serrano, M. and Kroemer, G., 2013. The hallmarks of aging. Cell 153: 1194-1217. https://doi.org/10.1016/j.cell.2013.05.039
Lugli, G.A., Fontana, F., Tarracchini, C., Milani, C., Mancabelli, L., Turroni, F. and Ventura, M., 2023a. MEGAnnotator2: a pipeline for the assembly and annotation of microbial genomes. Microbiome Research Reports 2: 15. https://doi.org/10.20517/mrr.2022.21
Lugli, G.A., Mancabelli, L., Milani, C., Fontana, F., Tarracchini, C., Alessandri, G., van Sinderen, D., Turroni, F. and Ventura, M., 2023b. Comprehensive insights from composition to functional microbe-based biodiversity of the infant human gut microbiota. NPJ Biofilms Microbiomes 9: 25. https://doi.org/10.1038/s41522-023-00392-6
Lugli, G.A., Milani, C., Mancabelli, L., van Sinderen, D. and Ventura, M., 2016. MEGAnnotator: a user-friendly pipeline for microbial genomes assembly and annotation. FEMS Microbiology Letters 363: fnw049. https://doi.org/10.1093/femsle/fnw049
Lugli, G.A. and Ventura, M., 2022. A breath of fresh air in microbiome science: shallow shotgun metagenomics for a reliable disentangling of microbial ecosystems. Microbiome Research Reports 1: 8. https://doi.org/10.20517/mrr.2021.07
Mancabelli, L., Mancino, W., Lugli, G.A., Argentini, C., Longhi, G., Milani, C., Viappiani, A., Anzalone, R., Bernasconi, S., van Sinderen, D., Ventura, M. and Turroni, F., 2021. Amoxicillin-clavulanic acid resistance in the genus Bifidobacterium. Applied and Environmental Microbiology 87: e03137-20. https://doi.org/10.1128/AEM.03137-20
Mariat, D., Firmesse, O., Levenez, F., Guimaraes, V., Sokol, H., Dore, J., Corthier, G. and Furet, J.P., 2009. The Firmicutes/Bacteroidetes ratio of the human microbiota changes with age. BMC Microbiology 9: 123. https://doi.org/10.1186/1471-2180-9-123
Milani, C., Casey, E., Lugli, G.A., Moore, R., Kaczorowska, J., Feehily, C., Mangifesta, M., Mancabelli, L., Duranti, S., Turroni, F., Bottacini, F., Mahony, J., Cotter, P.D., McAuliffe, F.M., van Sinderen, D. and Ventura, M., 2018. Tracing mother-infant transmission of bacteriophages by means of a novel analytical tool for shotgun metagenomic datasets: METAnnotatorX. Microbiome 6: 145. https://doi.org/10.1186/s40168-018-0527-z
Milani, C., Duranti, S., Bottacini, F., Casey, E., Turroni, F., Mahony, J., Belzer, C., Delgado Palacio, S., Arboleya Montes, S., Mancabelli, L., Lugli, G.A., Rodriguez, J.M., Bode, L., de Vos, W., Gueimonde, M., Margolles, A., van Sinderen, D. and Ventura, M., 2017. The first microbial colonizers of the human gut: composition, activities, and health implications of the infant gut microbiota. Microbiology and Molecular Biology Reviews 81: e00036-17. https://doi.org/10.1128/MMBR.00036-17
Milani, C., Lugli, G.A., Fontana, F., Mancabelli, L., Alessandri, G., Longhi, G., Anzalone, R., Viappiani, A., Turroni, F., van Sinderen, D. and Ventura, M., 2021. METAnnotatorX2: a comprehensive tool for deep and shallow metagenomic data set analyses. mSystems 6: e0058321. https://doi.org/10.1128/mSystems.00583-21
Morshedi, M., Hashemi, R., Moazzen, S., Sahebkar, A. and Hosseinifard, E.S., 2019. Immunomodulatory and anti-inflammatory effects of probiotics in multiple sclerosis: a systematic review. Journal of Neuroinflammation 16: 231. https://doi.org/10.1186/s12974-019-1611-4
Odamaki, T., Bottacini, F., Kato, K., Mitsuyama, E., Yoshida, K., Horigome, A., Xiao, J.Z. and van Sinderen, D., 2018. Genomic diversity and distribution of Bifidobacterium longum subsp. longum across the human lifespan. Science Reports 8: 85. https://doi.org/10.1038/s41598-017-18391-x
Pang, S., Chen, X., Lu, Z., Meng, L., Huang, Y., Yu, X., Huang, L., Ye, P., Chen, X., Liang, J., Peng, T., Luo, W. and Wang, S., 2023. Longevity of centenarians is reflected by the gut microbiome with youth-associated signatures. Nature Aging 3: 436-449. https://doi.org/10.1038/s43587-023-00389-y
Parks, D.H., Imelfort, M., Skennerton, C.T., Hugenholtz, P. and Tyson, G.W., 2015. CheckM: assessing the quality of microbial genomes recovered from isolates, single cells, and metagenomes. Genome Research 25: 1043-1055. https://doi.org/10.1101/gr.186072.114
Pawelec, G., Larbi, A. and Derhovanessian, E., 2010. Senescence of the human immune system. Journal of Computational Pathology 142(Suppl 1): S39-S44. https://doi.org/10.1016/j.jcpa.2009.09.005
Popovic, M., Kaurinovic, B., Trivic, S., Mimica-Dukic, N. and Bursac, M., 2006. Effect of celery (Apium graveolens) extracts on some biochemical parameters of oxidative stress in mice treated with carbon tetrachloride. Phytotherapy Research 20: 531-537. https://doi.org/10.1002/ptr.1871
Rizzo, S.M., Vergna, L.M., Alessandri, G., Lee, C., Fontana, F., Lugli, G.A., Carnevali, L., Bianchi, M.G., Barbetti, M., Taurino, G., Sgoifo, A., Bussolati, O., Turroni, F., van Sinderen, D. and Ventura, M., 2024. GH136-encoding gene (perB) is involved in gut colonization and persistence by Bifidobacterium bifidum PRL2010. Microbial Biotechnology 17: e14406. https://doi.org/10.1111/1751-7915.14406
Ross, R., 1999. Atherosclerosis – an inflammatory disease. New England Journal of Medicine 340: 115-126. https://doi.org/10.1056/NEJM199901143400207
Salazar, N., Valdes-Varela, L., Gonzalez, S., Gueimonde, M. and de Los Reyes-Gavilan, C.G., 2017. Nutrition and the gut microbiome in the elderly. Gut Microbes 8: 82-97. https://doi.org/10.1080/19490976.2016.1256525
Schulthess, B., Bloemberg, G.V., Zbinden, R., Böttger, E.C. and Hombach, M., 2014. Evaluation of the Bruker MALDI Biotyper for identification of Gram-positive rods: development of a diagnostic algorithm for the clinical laboratory. Journal of Clinical Microbiology 52: 1089-1097. https://doi.org/10.1128/JCM.02399-13
Sela, D.A., Chapman, J., Adeuya, A., Kim, J.H., Chen, F., Whitehead, T.R., Lapidus, A., Rokhsar, D.S., Lebrilla, C.B., German, J.B., Price, N.P., Richardson, P.M. and Mills, D.A., 2008. The genome sequence of Bifidobacterium longum subsp. infantis reveals adaptations for milk utilization within the infant microbiome. Proceedings of the National Academy of Sciences of the USA 105: 18964-18969. https://doi.org/10.1073/pnas.0809584105
Tarracchini, C., Alessandri, G., Fontana, F., Rizzo, S.M., Lugli, G.A., Bianchi, M.G., Mancabelli, L., Longhi, G., Argentini, C., Vergna, L.M., Anzalone, R., Viappiani, A., Turroni, F., Taurino, G., Chiu, M., Arboleya, S., Gueimonde, M., Bussolati, O., van Sinderen, D., Milani, C. and Ventura, M., 2023. Genetic strategies for sex-biased persistence of gut microbes across human life. Nature Communications 14: 4220. https://doi.org/10.1038/s41467-023-39931-2
Tarracchini, C., Milani, C., Lugli, G.A., Mancabelli, L., Fontana, F., Alessandri, G., Longhi, G., Anzalone, R., Viappiani, A., Turroni, F., van Sinderen, D. and Ventura, M., 2021. Phylogenomic disentangling of the Bifidobacterium longum subsp. infantis taxon. Microbial Genomics 7: 000609. https://doi.org/10.1099/mgen.0.000609
Turroni, F., Bottacini, F., Foroni, E., Mulder, I., Kim, J.H., Zomer, A., Sanchez, B., Bidossi, A., Ferrarini, A., Giubellini, V., Delledonne, M., Henrissat, B., Coutinho, P., Oggioni, M., Fitzgerald, G.F., Mills, D., Margolles, A., Kelly, D., van Sinderen, D. and Ventura, M., 2010. Genome analysis of Bifidobacterium bifidum PRL2010 reveals metabolic pathways for host-derived glycan foraging. Proceedings of the National Academy of Sciences of the USA 107: 19514-19519. https://doi.org/10.1073/pnas.1011100107
Turroni, F., Serafini, F., Foroni, E., Duranti, S., O’Connell Motherway, M., Taverniti, V., Mangifesta, M., Milani, C., Viappiani, A., Roversi, T., Sanchez, B., Santoni, A., Gioiosa, L., Ferrarini, A., Delledonne, M., Margolles, A., Piazza, L., Palanza, P., Bolchi, A., Guglielmetti, S., van Sinderen, D. and Ventura, M., 2013. Role of sortase-dependent pili of Bifidobacterium bifidum PRL2010 in modulating bacterium-host interactions. Proceedings of the National Academy of Sciences of the USA 110: 11151-11156. https://doi.org/10.1073/pnas.1303897110
Turroni, F., Taverniti, V., Ruas-Madiedo, P., Duranti, S., Guglielmetti, S., Lugli, G.A., Gioiosa, L., Palanza, P., Margolles, A., van Sinderen, D. and Ventura, M., 2014. Bifidobacterium bifidum PRL2010 modulates the host innate immune response. Applied and Environmental Microbiology 80: 730-740. https://doi.org/10.1128/AEM.03313-13
Vaiserman, A.M., Koliada, A.K. and Marotta, F., 2017. Gut microbiota: A player in aging and a target for anti-aging intervention. Ageing Research Reviews 35: 36-45. https://doi.org/10.1016/j.arr.2017.01.001
Van Dijk, L.R., Walker, B.J., Straub, T.J., Worby, C.J., Grote, A., Schreiber, H.L.T., Anyansi, C., Pickering, A.J., Hultgren, S.J., Manson, A.L., Abeel, T. and Earl, A.M., 2022. StrainGE: a toolkit to track and characterize low-abundance strains in complex microbial communities. Genome Biology 23: 74. https://doi.org/10.1186/s13059-022-02630-0
Van Tongeren, S.P., Slaets, J.P., Harmsen, H.J. and Welling, G.W., 2005. Fecal microbiota composition and frailty. Applied and Environmental Microbiology 71: 6438-6442. https://doi.org/10.1128/AEM.71.10.6438-6442.2005
Vemuri, R., Gundamaraju, R., Shastri, M.D., Shukla, S.D., Kalpurath, K., Ball, M., Tristram, S., Shankar, E.M., Ahuja, K. and Eri, R., 2018. Gut microbial changes, interactions, and their implications on human lifecycle: an ageing perspective. Biomed Research International 2018: 4178607. https://doi.org/10.1155/2018/4178607
Werner, G., Fleige, C., Fessler, A.T., Timke, M., Kostrzewa, M., Zischka, M., Peters, T., Kaspar, H. and Schwarz, S., 2012. Improved identification including MALDI-TOF mass spectrometry analysis of group D streptococci from bovine mastitis and subsequent molecular characterization of corresponding Enterococcus faecalis and Enterococcus faecium isolates. Veterinary Microbiology 160: 162-169. https://doi.org/10.1016/j.vetmic.2012.05.019
Xiao, Y., Yang, C., Yu, L., Tian, F., Wu, Y., Zhao, J., Zhang, H., Yang, R., Chen, W., Hill, C., Cui, Y. and Zhai, Q., 2021. Human gut-derived B. longum subsp. longum strains protect against aging in a D-galactose-induced aging mouse model. Microbiome 9: 180. https://doi.org/10.1186/s40168-021-01108-8
Aging is a physiological and immunological process involving the deterioration of human health, characterised by the progressive alteration of organs and their functions. The speed and extent of such decline are dependent on lifestyle, environment, and genetic factors. Moreover, with advancing age, humans become progressively more fragile and prone to acute and chronic diseases. Although the intestinal microbiota is predisposed to perturbations that accompany aging and frailty, it is generally accepted that the gut microbiota engages in multiple interactions that affect host health throughout the host life span. In the current study, an exhaustive in silico investigation of gut-associated bifidobacteria in healthy individuals from birth to old age revealed that Bifidobacterium longum subsp. longum is the most prevalent member, especially during infancy and in centenarians. Moreover, B. longum subsp. longum genome reconstruction and strain tracing among human gut microbiomes allowed the identification of prototypes of this taxon in the human gut microbiota of healthy elderly individuals. Such analyses guided culturomics attempts to isolate B. longum subsp. longum strains that matched the genomic content of B. longum subsp. longum prototypes from healthy elderly individuals. The molecular effects of selected B. longum subsp. longum strains on the human host were further investigated using in vitro microbe-host interactions, revealing differences in the host immune system transcriptome, with a reduction in gene expression of inflammation-related cytokines. These intriguing findings support the potential anti-aging effects of elderly associated prototypes of B. longum subsp. longum.