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Longevity in Mice Is Promoted by Probiotic-Induced Suppression of Colonic Senescence Dependent on Upregulation of Gut Bacterial Polyamine Production
Open accessAbstract
BACKGROUND: Chronic low-grade inflammation is recognized as an important factor contributing to senescence and age-related diseases. In mammals, levels of polyamines (PAs) decrease during the ageing process; PAs are known to decrease systemic inflammation by inhibiting inflammatory cytokine synthesis in macrophages. Reductions in intestinal luminal PAs levels have been associated with intestinal barrier dysfunction. The probiotic strain Bifidobacterium animalis subsp. lactis LKM512 is known to increase intestinal luminal PA concentrations. METHODOLOGY/PRINCIPAL FINDINGS: We supplemented the diet of 10-month-old Crj:CD-1 female mice with LKM512 for 11 months, while the controls received no supplementation. Survival rates were compared using Kaplan-Meier survival curves. LKM512-treated mice survived significantly longer than controls (P<0.001); moreover, skin ulcers and tumors were more common in the control mice. We then analyzed inflammatory and intestinal conditions by measuring several markers using HPLC, ELISA, reverse transcription-quantitative PCR, and histological slices. LKM512 mice showed altered 16S rRNA gene expression of several predominant intestinal bacterial groups. The fecal concentrations of PAs, but not of short-chain fatty acids, were significantly higher in LKM512-treated mice (P<0.05). Colonic mucosal function was also better in LKM512 mice, with increased mucus secretion and better maintenance of tight junctions. Changes in gene expression levels were evaluated using the NimbleGen mouse DNA microarray. LKM512 administration also downregulated the expression of ageing-associated and inflammation-associated genes and gene expression levels in 21-month-old LKM512-treated mice resembled those in 10-month-old untreated (younger) mice. CONCLUSION/SIGNIFICANCE: Our study demonstrated increased longevity in mice following probiotic treatment with LKM512, possibly due to the suppression of chronic low-grade inflammation in the colon induced by higher PA levels. This indicates that ingestion of specific probiotics may be an easy approach for improving intestinal health and increasing lifespan. Further studies are required to clarify its effectiveness in humans.
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“Similarly, nutrient supplementation with polyamine preparations containing spermidine or provision of a polyamine-producing gut flora increases longevity in mice (Matsumoto et al., 2011; Soda et al., 2009).”
From The Hallmarks of Aging (2013) · cites this paper as Matsumoto et al., 2011
In the citing paper
“Members of the Bifidobacteriaceae, Akkermansiaceae, and Eubacteriaceae families that are associated with beneficial effects on intestinal and extra-intestinal health in both mice and humans”
From Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain (2022) · cites this paper as [78]
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“B. animalis, a probiotic species positively associated with longevity in mice [78] and negatively correlated with inflammation and human obesity [81]”
From Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain (2022) · cites this paper as [78]
In the citing paper
“Polyamines exhibit numerous beneficial effects including increased longevity, recovery of injured mucosa, as well as favorable effects on cognitive function.122, 123, 124”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [124]
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“As shown in other organisms, such as mice, maintaining a healthy gastrointestinal tract via increased levels of gut microbes significantly lengthens the life of the organism [51].”
BackgroundAn Integrated Outlook on the Metagenome and Metabolome of Intestinal Diseases
Aw, W., & Fukuda, S. (2015) · Diseases · doi:10.3390/diseases3040341 · Cited by 15
“host tissues but polyamine synthesis can also occur in the gut microbiota [77–79].”
Backgroundvan Beek, A. A., Hoogerland, J. A., Belzer, C., de Vos, P., de Vos, W. M., Savelkoul, H. F. J., & Leenen, P. J. M. (2015) · Beneficial Microbes · doi:10.3920/bm2015.0094 · Cited by 12
“lactis LKM512 extended lifespan and improved quality of life in mice (Matsumoto et al., 2011).”
BackgroundNatural products as geroprotectors: An autophagy perspective
Raj, S. D., Fann, D. Y., Wong, E. S. P., & Kennedy, B. K. (2021) · Medicinal Research Reviews · doi:10.1002/med.21815 · Cited by 12
Salmonella Typhimurium exploits host polyamines for assembly of the type 3 secretion machinery
Miki, T., Uemura, T., Kinoshita, M., Ami, Y., Ito, M., Okada, N., Furuchi, T., Kurihara, S., Haneda, T., Minamino, T., et al. (2024) · PLoS Biology · doi:10.1371/journal.pbio.3002731 · Cited by 11
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“Interestingly, administration of probiotics was shown to modulate and increase the PAproducing colonic microbiota [15].”
BackgroundDynamic change of fecal microbiota and metabolomics in a polymicrobial murine sepsis model
Muratsu, A., Ikeda, M., Shimizu, K., Kameoka, S., Motooka, D., Nakamura, S., Matsumoto, H., Ogura, H., & Shimazu, T. (2022) · Acute Medicine & Surgery · doi:10.1002/ams2.770 · Cited by 12
Zhao, L., Zhao, D., Xiao, S., Zhang, A., Deng, Y., Dai, X., Zhou, Z., Ji, Z., & Cao, Q. (2022) · Molecules · doi:10.3390/molecules27248939 · Cited by 11
“For example, putrescine, an organic cation, is required for cell growth, cell differentiation, and DNA synthesis [33].”
BackgroundShimokawa, H., Sakanaka, M., Fujisawa, Y., Ohta, H., Sugiyama, Y., & Kurihara, S. (2023) · Biomedicines · doi:10.3390/biomedicines11041123 · Cited by 14
“In 2011, it was reported that the administration of Bifidobacterium to mice increased spermidine levels in the intestinal tract and decreased haptoglobin levels, an inflammatory signal, in the urine, resulting in an extension of the lifespan [4].”
BackgroundSelf-citationSoft TCPTP Agonism—Novel Target to Rescue Airway Epithelial Integrity by Exogenous Spermidine
Ghisalberti, C. A., Borzı̀, R. M., Cetrullo, S., Flamigni, F., & Cairo, G. (2016) · Frontiers in Pharmacology · doi:10.3389/fphar.2016.00147 · Cited by 11
“…anti-“inflammaging” action and barrier reinforcement triggered by TCPTP agonism (or autophagy, see below) may account for the positive effects of enhanced spermidine/PA production in the luminal tracts on longevity (Matsumoto et al., 2011; Kibe et al., 2014) and tumorigenesis (Soda et al., 2013).”
BackgroundSakanaka, M., Sugiyama, Y., Nara, M., Kitakata, A., & Kurihara, S. (2018) · FEMS Microbiology Letters · doi:10.1093/femsle/fny003 · Cited by 11
“Polyamines are one of the major metabolites produced by gut microbes; they are believed to exert both beneficial and harmful effects onhost health (Upp et al. 1988;Matsumoto et al. 2011; Kibe et al. 2014).”
BackgroundSelf-citationPotential benefits of L. acidophilus in dyslipidemic rats
Reamtong, O., Thiangtrongjit, T., Kosoltanapiwat, N., Panbangred, W., & Prangthip, P. (2021) · Scientific Reports · doi:10.1038/s41598-021-85427-8 · Cited by 11
de Celis, M. F. R., & Bonner‐Weir, S. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1217729 · Cited by 11
Harnessing gut microbiota for longevity: Insights into mechanisms and genetic manipulation
Shi, P., Xu, S., Yang, Z., Wang, L., Wu, Y., Li, Y., & Zhu, Z. (2024) · iMetaOmics. · doi:10.1002/imo2.36 · Cited by 11
“In addition, the Bifidobaceterium lactis strain LKM512, a known probiotic, has been proven to suppress chronic inflammation, maintain intestinal barrier integrity, and extend the lifespan of mammals by increasing the concentrations of intestinal polyamines (PAs) [12].”
A Cellular Senescence-Centric Integrated Approach to Understanding Organismal Aging
Sharma, R., & Diwan, B. (2022) · Current Aging Science · doi:10.2174/1874609815666220914104548 · Cited by 9
Shirasawa, H., Nishiyama, C., Hirano, R., KOYANAGI, T., Okuda, S., Takagi, H., & Kurihara, S. (2022) · Bioscience of Microbiota Food and Health · doi:10.12938/bmfh.2022-011 · Cited by 10
“For example, polyamines have been reported to reduce the risk of cardiovascular disease [12], to inhibit inflammation in blood vessels [13–17], to increase life span [14, 18, 19], to improve brain function [20, 21], and to enhance the intestinal barrier [22].”
BackgroundSelf-citationIdentification and enzymatic properties of arginine decarboxylase from Aspergillus oryzae
Murakami, Y., Ikuta, S., Fukuda, W., Akasaka, N., Maruyama, J., Shinma, S., Fukusaki, E., & Fujiwara, S. (2024) · Applied and Environmental Microbiology · doi:10.1128/aem.00294-24 · Cited by 9
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Structural characteristics of gut microbiota in longevity from Changshou town, Hubei, China
Ai, X., Liu, Y., Shi, J., Xie, X., Li, L., Duan, R., Lv, Y., Xiong, K., Miao, Y., & Zhang, Y. (2024) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-024-13140-3 · Cited by 9
“The finding has also been validated in mouse models (Matsumoto et al. 2011).”
Miki, T., Kurihara, S., Uemura, T., Ami, Y., Ito, M., Haneda, T., Furuchi, T., Okada, N., Minamino, T., & Kim, Y. (2025) · mBio · doi:10.1128/mbio.01786-25 · Cited by 8
“Previous studies showed that the gut microbiota ‒ dependent production of polyamines is an intricate process that relies on numerous commensal bacteria (21–30), contributing to healthy and diseased states (31–35).”
Self-citationLiang, J., Chen, X., Chu, Y., & Leng, Y. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1664233 · Cited by 9
Singh, B. R., & Singh, R. K. (2014) · Probiotics and Antimicrobial Proteins · doi:10.1007/s12602-014-9160-8 · Cited by 8
“The better body weight in Axone group might be due to growth enhancing effect of Axone due to its probiotic value as reported earlier with Axone and with other probiotic containing foods/probiotics given to pigs, mice and other experimental animals [2, 3, 6, 7, 12, 14].”
BackgroundBoahen, A., Chew, S. Y., Neela, V. K., & Than, L. T. L. (2023) · Probiotics and Antimicrobial Proteins · doi:10.1007/s12602-023-10050-0 · Cited by 10
Heterochronic Fecal Microbiota Transfer Reverses Hallmarks of the Aging Murine Gut, Eye and BrainPreprint
Parker, A., Romano, S., Ansorge, R., Aboelnoer, A., Gall, G. L., Savva, G. M., Telatin, A., Jones, E. J., Baker, D., Rudder, S. J., et al. (2021) · SSRN Electronic Journal · doi:10.2139/ssrn.3811833 · Cited by 8
The Interplay of Aging and Cancer: Mechanisms, Implications, and Therapeutic Strategies
Wang, L., Luo, Y., Chen, X., Wang, Y., & Zhang, Y. (2025) · MedComm – Oncology · doi:10.1002/mog2.70041 · Cited by 8
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“For example, Bifidobacterium lactis strain LKM512 can extend the lifespan of mammals by increasing the concentration of polyamines (PAs) in the gut, inhibiting chronic inflammation, and maintaining the integrity of the intestinal barrier [7].”
Feng, C., He, Q., Kwok, L., & Sun, Z. (2026) · Trends in Food Science & Technology · doi:10.1016/j.tifs.2026.105818 · Cited by 7
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“Consistent with these results, polyamines have life-extending effects when supplemented to aged animals [37,50,51].”
Hsu, C., Marx, F. R., Guldenpfennig, R., & de Godoy, M. R. C. (2024) · Scientific Reports · doi:10.1038/s41598-024-80176-w · Cited by 6
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Kuroda, A., Jaisue, J., Isobe, N., & Nii, T. (2025) · Poultry Science · doi:10.1016/j.psj.2025.106241 · Cited by 6
“…inflammation in the intestine has been reported to develop with aging, and such inflammation leads to symptoms including tissue damage and atrophy (Matsumoto et al., 2011; Sovran et al., 2019) However, in this study, no tissue damage, atrophy, or mucosal inflammation was observed in the ileum or…”
Yang, Y., Du, H., Pan, Y., Gong, P., Yang, Y. M., Wu, F., Pan, D., Xie, W., Fu, Z., & Ni, Y. (2023) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b23-00406 · Cited by 6
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Advances in pharmacological interventions of aging in mice
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“Probiotics have the potential to stimulate innate immune responses without inducing inflammation; initiate responses mediated by interacting with follicle-associated epithelial cells, macrophages, T- and B-lymphocytes and dendritic cells (DCs) (Matsumoto et al. 2011).”
BackgroundXu, W., Grindler, S., Kenéz, Á., Dänicke, S., Frahm, J., & Huber, K. (2022) · Journal of Animal Science and Biotechnology/Journal of animal science and biotechnology · doi:10.1186/s40104-022-00741-z · Cited by 6
“Polyamines were suggested to increase longevity by decreasing low-grade inflammation in the gut and other organs [41].”
Background
Metadata
- Authors
- Matsumoto, M., Kurihara, S., Kibe, R., Ashida, H., & Benno, Y.
- Affiliations
- RIKEN (JP)
- Kyoto University (JP)
- Corresponding author
- Matsumoto, Mitsuharu
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-08-16
- Volume
- 6
- Issue
- 8
- Pages
- e23652
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3156754
- OpenAlex
- W2164188362
- Cited by
- 290
- References
- 60
- Citations by year
- 2026: 10 · 2025: 30 · 2024: 19 · 2023: 27 · 2022: 29 · 2021: 38 · 2020: 15 · 2019: 25 · 2018: 23 · 2017: 16 · 2016: 10 · 2015: 8 · 2014: 18 · 2013: 14 · 2012: 8
- FWCI
- 18.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Topics
- Life Sciences › Agricultural and Biological Sciences › Food Science › Probiotics and Fermented Foods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- probiotics, polyamines, longevity, lifespan extension, low-grade inflammation, gut microbiota, intestinal barrier function, mucus secretion, tight junctions, skin ulcers
- MeSH terms
- Animals, Bacteria, Bifidobacterium, Colon, Feces, Female, Longevity, Mice, Inbred ICR, Mucus, Neoplasms, Polyamines, RNA, Ribosomal, 16S, Skin Ulcer, Spermine, Gene Expression Regulation, Bacterial, Cellular Senescence, Tight Junctions, Probiotics, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Mice, Kaplan-Meier Estimate
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