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Bifidobacterium adolescentis regulates catalase activity and host metabolism and improves healthspan and lifespan in multiple species

Nature Aging volume 1, pages 991–1001 (2021)Cite this article

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Abstract

To identify candidate bacteria associated with aging, we performed fecal microbiota sequencing in young, middle-aged and older adults, and found lower Bifidobacterium adolescentis abundance in older individuals aged ≥60 years. Dietary supplementation of B. adolescentis improved osteoporosis and neurodegeneration in a mouse model of premature aging (Terc−/−) and increased healthspan and lifespan in Drosophila melanogaster and Caenorhabditis elegans. B. adolescentis supplementation increased the activity of the catalase (CAT) enzyme in skeletal muscle and brain tissue from Terc−/− mice, and suppressed cellular senescence in mouse embryonic fibroblasts. Transgenic deletion of catalase (ctl-2) in C. elegans abolished the effects of B. adolescentis on the lifespan and healthspan. B. adolescentis feeding also led to changes in oxidative stress-associated metabolites in Terc−/− mouse feces. These results suggest a role for B. adolescentis in improving the healthspan and lifespan through the regulation of CAT activity and host metabolism.

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Fig. 1: Alteration of gut microbiota diversity and B. adolescentis abundance with human aging.
Fig. 2: B. adolescentis feeding suppresses premature aging in Terc−/− mice.
Fig. 3: B. adolescentis supplementation induces lifespan extension and healthspan improvement in D. melanogaster and C. elegans.
Fig. 4: CAT is essential for lifespan and healthspan regulation by B. adolescentis in C. elegans and Terc−/− mice.

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Data availability

All data supporting the findings of the present study are available within this article and the Supplementary Information files. Source data are provided with this paper. Raw 16S rRNA-sequencing data files are available in the Sequence Read Archive database under accession no. PRJNA625181 (http://www.ncbi.nlm.nih.gov/bioproject/625181).

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Acknowledgements

We thank X. Wang and W. Liu (Zhejiang Academy of Agricultural Sciences) for sharing the anaerobic operating system and guidance on bacteria culture, Z. Song (Zhejiang University) for kindly providing Terc+/− G0 mice, F. Xu and Y. Wang (Zhejiang University) for helpful discussions, and L. Wang (University of Miami) and U. AI-Sheikh (Zhejiang University) for language editing. This project was supported by the National Foundation of Natural Science of China awarded to Liangjing W. (grant no. 82072623), X.Y. (grant no. 31900736) and L.K. (grant no. 31771113), and the National Key R&D Program of China awarded to Liangjing W. (grant no. 2016YFC1303200). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author information

Author notes

  1. These authors contributed equally: Shujie Chen, Luyi Chen, Yadong Qi.

  2. These authors jointly supervised this work: Liangjing Wang, Lijun Kang, Jianmin Si.

Authors and Affiliations

  1. Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang, China

    Shujie Chen, Luyi Chen, Yadong Qi, Jilei Xu, Yawen Zhang, Lan Wang, Tongyao Hou & Jianmin Si

  2. Prevention and Treatment Research Center for Senescent Disease, Zhejiang University School of Medicine, Zhejiang, China

    Shujie Chen, Luyi Chen, Yadong Qi, Jilei Xu, Qiwei Ge, Yawen Zhang, Lan Wang, Tongyao Hou, Jianmin Si & Liangjing Wang

  3. Department of Gastroenterology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China

    Qiwei Ge & Liangjing Wang

  4. Department of Neurobiology and Department of Neurosurgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China

    Yuedan Fan, Du Chen & Lijun Kang

  5. NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain–Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Zhejiang, China

    Yuedan Fan, Du Chen & Lijun Kang

  6. Institute of Genetics and Department of Genetics, Division of Human Reproduction and Developmental Genetics of the Women’s Hospital, Zhejiang University, Zhejiang, China

    Xiaohang Yang & Yongmei Xi

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  1. Shujie Chen
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Contributions

S.C., Liangjing W., L.K., J.S., X.Y. and Y.X. conceived the research idea and designed the study. S.C., L.C., Y.Q. and J.X. carried out the experiments. L.C., Lan W. and Y.Z. collected clinical samples. S.C., L.C., Y.Q., J.X., Q.G., Y.F., D.C. and T.H. performed data analysis. S.C. and L.C. wrote the manuscript with input from the coauthors. All authors critically revised and approved the final version of the manuscript.

Corresponding authors

Correspondence to Jianmin Si, Lijun Kang or Liangjing Wang.

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The authors declare no competing interests.

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Peer review information Nature Aging thanks Sven Pettersson and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Pathways predicted active in different age groups according to KEGG pathway analysis.

Red columns represented pathways more active in 20–40 yrs group, blue columns represented pathways more active in 40–60 yrs group, green columns represented pathways more active in 60+ yrs group. KEGG, Kyoto Encyclopedia of Genes and Genome. 20–40 yrs, n=46; 40–60 yrs, n=77; 60+ yrs, n=43.

Source data

Extended Data Fig. 2 Alteration of B. adolescentis abundance with aging in mice.

(a) Comparison of B. adolescentis abundance by quantitative real-time PCR between 3-month-old (n=16) and 10-month-old (n=11) mice, Wilcoxon rank sum test was performed, p<0.0001. (b) Comparison of B. adolescentis abundance by quantitative real-time PCR between 7-month-old wild-type mice (WT, n=5) and Terc-/- G3 mice (G3, n=7), two-sided Student’s t-test was performed, p=0.0017. Data were shown as mean ± SEM. **p<0.01; ****p<0.0001. n=3 biological independent replicates.

Source data

Extended Data Fig. 3 B. adolescentis induced locomotion ability improvement in C. elegans.

(a and b) Number of sine waves (≥1 mm) that N2 worms crawled out in 30s on day 2 (baseline) and on day 8 (a) and day16 (b) when fed on E. coli OP50, 1:1 or 1:2 mixture of E. coli OP50 and B. adolescentis, respectively. n=50 worms each group. Bounds of box show the 25th and 75th percentiles, the central lines in the box plots represent the median value and whiskers show minima and maxima. Wilcoxon rank sum test was performed. **p<0.01; ****p<0.0001; n.s., not significant. n=3 biological independent replicates.

Source data

Extended Data Fig. 4 Relative mRNA expression of aging-associated genes in Drosophila strain w1118 and C. elegans.

(a) Heatmap for relative mRNA expression of aging-associated genes in Drosophila strain w1118 supplemented with B. adolescentis (B.a) or 2.5% sucrose solution (NC) on day 40. (b) Venn plot showed the intersection of D. melanogaster and C. elegans relative mRNA expression results. (c) Relative mRNA expression of sod-3 and Cat in Drosophila supplemented with B. adolescentis (B.a) or 2.5% sucrose solution (NC) on day 40. n=3 biological independent replicates each group. Data were shown as mean ± SEM and two-sided Student’s t-test was performed. *p<0.05; **p<0.01; ****p<0.0001; n.s., not significant.

Source data

Extended Data Fig. 5 B. adolescentis supplement improves aging-related phenotypes in Terc-/- mice, suppressed cellular senescence in MEFs and regulates the activity of CAT.

(a) Relative mRNA expression of Cat in the muscle tissue of 7-month-old mice among three groups by quantitative real-time PCR. n=10 (WT+PBS), n=6 (G3+PBS), n=9 (G3+B.a). (b) Representative images of immunohistochemistry staining of p53 in the hippocampal DG region among three groups, scale bar, 200 μm. The black boxes indicate the area magnified in the down panels, scale bar, 50 μm. (c) Representative images of immunohistochemistry staining of CAT in brain region including hippocampal CA3, DG region and cortex. Scale bar, 50 μm. (d and e) Representative images of senescence-associated β-galactosidase (SA-β-gal) staining of replicative senescent MEFs supplemented with PBS (NC) or B. adolescentis (B.a) at passage 4 (P4) and passage 12 (P12) (d) and corresponding percentage evaluation of SA-β-gal-positive cells (e). Scale bar, 100 μm. (f and g) Representative images of SA-β-gal staining of wild-type MEFs supplemented with PBS (NC), DOX-induced senescent MEFs supplemented with PBS (D-sen) or B. adolescentis (D-sen+B.a) (f) and corresponding percentage evaluation of SA-β-gal-positive cells (g). Scale bar, 100 μm. (h) Quantitative real-time PCR of Cat expression in replicative senescent MEFs at P4 and P12. (i) Quantitative real-time PCR of Cat expression in DOX-induced senescent MEFs supplemented with PBS (D-sen) or B. adolescentis (D-sen+B.a). (j) Expression levels of CAT in replicative and DOX-induced senescent MEFs supplemented with PBS (D-sen) or B. adolescentis (D-sen+B.a). For a, e and g-i, data were shown as mean ± SEM. For a, Wilcoxon rank sum test was performed; for e and g-i, Student’ t-test was performed. *p<0.05; **p<0.01; ***p<0.001; n.s., not significant. For a and d-j, n=3 biological independent replicates. DOX, doxorubicin. WT + PBS, wild-type C57BL/6 mice gavaged with PBS; G3 + PBS, Terc-/- G3 mice gavaged with PBS; G3 + B.a, Terc-/- G3 mice gavaged with B. adolescentis.

Source data

Extended Data Fig. 6 B. adolescentis regulated oxidative stress-associated metabolites in Terc-/- mice.

(a) The volcano plot of the gut metabolites analysis of 7-month-old Terc-/- G3 mice gavage with PBS (n=7, 3 males, 4 females) or B. adolescentis (n=9, 6 males, 3 females). The labeled data points show the abundance of metabolites with two-fold or more difference. Red boxes represent the enrichment of metabolites in the feces of mice gavage with B. adolescentis, blue box represents the enrichment of metabolites in the feces of mice gavage with PBS. (b) Heatmap of hierarchical clustering analysis. The blue or red boxes indicate the fold change of metabolites abundance less or more than the mean. G3+PBS, Terc-/- G3 mice gavage with PBS, n=7; G3+B.a, Terc-/- G3 mice gavage with B. adolescentis, n=9. (c) Total ion chromatography (TIC) diagrams in positive (up) and negative (down) ion mode of quality control (QC) sample. 1, Ginsenoside Ia; 2, Cholic acid; 3, Hypoxanthine; 4, 4-Trimethylammoniobutanoic acid; 5, Enterodiol; 6, Apiin; 7, 3-Dehydroxycarnitine; 8, Erucic acid; 9, 9,10-DHOME; 10, Cosmosiin; 11, Daidzin; 12, 2-Hydroxycinnamic acid; 13, L-Malic acid. Metabolites in red were found in higher concentrations in Terc-/- G3 mice gavage with B. adolescentis; metabolites in blue were found in higher concentrations in Terc-/- G3 mice gavage with PBS.

Source data

Supplementary information

Supplementary Information

Supplementary Information, Fig. 1 and Tables 1–5.

Reporting Summary

Source data

Source Data Fig. 1

Statistical source data.

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Chen, S., Chen, L., Qi, Y. et al. Bifidobacterium adolescentis regulates catalase activity and host metabolism and improves healthspan and lifespan in multiple species. Nat Aging 1, 991–1001 (2021). https://doi.org/10.1038/s43587-021-00129-0

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