Aging and the mucosal immune system in the intestine
Open accessAbstract
Bacterial and viral infections of the gastrointestinal tract are more common in the elderly and represent a major cause of morbidity and mortality. The mucosal immune system provides the first line of defence against pathogens acquired by ingestion and inhalation, but its function is adversely affected in the elderly. This aging-related decline in the immune function is termed immunosenescence and is associated with diminished abilities to generate protective immunity, reduced vaccine efficacy, increased incidence of cancer, inflammation and autoimmunity, and the impaired ability to generate tolerance to harmless antigens. In this review we describe our current understanding of the effects immunosenescence has on the innate and adaptive arms of the mucosal immune system in the intestine. Current estimates suggest that by the year 2050 up to 40% of the UK population will be over 65 years old, bringing with it important health challenges. A thorough understanding of the mechanisms that contribute to the development of immunosenescence is therefore crucial to help identify novel approaches to improve mucosal immunity in the elderly.
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In the aged GI tract, compromised epithelial and mucosal cell turnover, integrity, and function can lead to increased epithelial barrier permeability.
“In the aged GI tract, compromised epithelial and mucosal cell turnover, integrity, and function [32, 36, 76, 83] can lead to increased epithelial barrier permeability [19, 75, 118, 120]”
From Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain (2022) · cites this paper as [76]
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Self-citationCCR6hiCD11cint B cells promote M-cell differentiation in Peyer's patch
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Resistance of Chemokine Receptor 6-Deficient Mice to Yersinia Enterocolitica Infection
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Aging‐Associated Changes in Murine Intestinal Immunoglobulin A and M Secretions
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“In the aged GI tract, compromised epithelial and mucosal cell turnover, integrity, and function [32, 36, 76, 83] can lead to increased epithelial barrier permeability [19, 75, 118, 120], with the increased possibility of luminal microbial and dietary antigens gaining access to the circulation.”
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“The production of antigen-specific immunoglobulin A, which is a key function of the mucosal immune response, decreases in elderly persons [175].”
BackgroundAging, inflammation, immunity and periodontal disease
Ebersole, J. L., Graves, C. L., González, O. A., Dawson, D. R., Morford, L. A., Emecen‐Huja, P., Hartsfield, J. K., Huja, S. S., Pandruvada, S. N. M., & Wallet, S. M. (2016) · Periodontology 2000 · doi:10.1111/prd.12135 · Cited by 308 · see citing works
“To this end, bacterial and viral infections of mucosal surfaces become more prevalent with aging and represent a major cause of morbidity and mortality, potentially through alterations in the molecular components of tight junctions, thus decreasing the innate barrier functions of the intestinal epithelium with aging (…”
The ageing gastrointestinal tract
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Age and Periodontal Health—Immunological View
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The intestinal immune system and gut barrier function in obesity and ageing
Shemtov, S. J., Emani, R., Bielska, O., Covarrubias, A. J., Verdin, E. M., Andersen, J. K., & Winer, D. A. (2022) · FEBS Journal · doi:10.1111/febs.16558 · Cited by 83 · see citing works
Nutrition and Healthy Aging: Prevention and Treatment of Gastrointestinal Diseases
Cristina, N. M., & D’Alba, L. (2021) · Nutrients · doi:10.3390/nu13124337 · Cited by 77 · see citing works
“Aging is associated with “immunosenescence”, which is also a progressive reduction in the mucosal immune response of the intestine, linked to a reduced ability of the aging immune system to provide a tolerance towards antigens and a reduced production of immunoglobulin-specific antigen A, which represents the most imp…”
BackgroundGut microbiota alterations and health status in aging adults: From correlation to causation
Wu, Y., Xu, J., Rong, X., Wang, F., Wang, H., & Zhao, C. (2021) · Aging Medicine · doi:10.1002/agm2.12167 · Cited by 66 · see citing works
Comani, G. B., Panceri, R., Dinelli, M. E., Biondi, A., Mancuso, C., Meneveri, R., & Barisani, D. (2015) · Genes & Nutrition · doi:10.1007/s12263-015-0482-2 · Cited by 57 · see citing works
“There are very few data on the morphological and histological differences in small intestinal architecture at different ages (Ren et al. 2014), and on the development of the immune response in intestine (Mabbott et al. 2015), and no data on miRNA profile that could be different according to age.”
Norovirus in healthcare settings
Iturriza‐Gómara, M., & Lopman, B. A. (2014) · Current Opinion in Infectious Diseases · doi:10.1097/qco.0000000000000094 · Cited by 57 · see citing works
“Immunosenescence may be one contributory factor; this consequence of aging is increasingly recognized as a major risk factor leading to increases in inflammation, autoimmunity, cancer, susceptibility to gastrointestinal infections, and poor response to vaccines, which is particularly acute among the elderly in residen…”
BackgroundUsui, Y., Kimura, Y., Satoh, T., Takemura, N., Ouchi, Y., Hiroko, O., KOBAYASHI, K., Suzuki, H., Satomi, K., Hagiwara, S., et al. (2018) · International Immunology · doi:10.1093/intimm/dxy035 · Cited by 57 · see citing works
Martinis, M. D., Sirufo, M. M., Viscido, A., & Ginaldi, L. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20225580 · Cited by 55 · see citing works
“This mucosal first-line defense mechanism deteriorates with age and orally induced antigen-specific IgA responses weaken [36].”
BackgroundIgA in human health and diseases: Potential regulator of commensal microbiota
Takeuchi, T., & Ohno, H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1024330 · Cited by 53 · see citing works
Sabatino, A. D., Lenti, M. V., Cammalleri, L., Corazza, G. R., & Pilotto, A. (2018) · Digestive and Liver Disease · doi:10.1016/j.dld.2018.03.010 · Cited by 53 · see citing works
Age-Related Differences in the Gut Microbiome of Rhesus Macaques
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“Aging is a multifactorial process characterized by the progressive functional decline of the principal physiological systems, including gastrointestinal/digestive system and the intestinal mucosal immune system (7).”
BackgroundKovacs, E. J., Boe, D. M., Boule, L. A., & Curtis, B. J. (2017) · Clinics in Geriatric Medicine · doi:10.1016/j.cger.2017.06.002 · Cited by 49 · see citing works
Mabbott, N. A. (2015) · Clinical Science · doi:10.1042/cs20150364 · Cited by 39 · see citing works
Self-citationSugahara, H., Okai, S., Odamaki, T., Wong, C. B., Kato, K., Mitsuyama, E., Xiao, J., & Shinkura, R. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.01757 · Cited by 36 · see citing works
“It is known that the gut mucosal immune response is significantly compromised in the elderly, and this decline with aging is associated with diminished antigen-specific antibody titre in the intestinal environment (Mabbott et al., 2015).”
BackgroundThe Aged Intestine: Performance and Rejuvenation
Wang, Q., Qi, Y., Shen, W., Xu, J., Wang, L., Chen, S., Hou, T., & Si, J. (2021) · Aging and Disease · doi:10.14336/ad.2021.0202 · Cited by 35 · see citing works
Liang, D., Wang, L., Liu, S., Li, S., Zhou, X., Xiao, Y., Zhong, P., Chen, Y., Wang, C., Xu, S., et al. (2024) · Nutrients · doi:10.3390/nu16183217 · Cited by 32 · see citing works
“Moreover, age-related changes in gut microbiota composition, known as dysbiosis, compromise mucosal immunity and further heighten the risk of diarrheal diseases [50].”
BackgroundSARS-CoV-2 infection represents a high risk for the elderly: analysis of pathogenesis
Pedreáñez, A. B., Mosquera-Sulbarán, J., & Muñóz, N. (2021) · Archives of Virology · doi:10.1007/s00705-021-05042-w · Cited by 30 · see citing works
Zhu, Q., He, G.-Z., Wang, J., Wang, Y., & Chen, W. (2016) · Scientific Reports · doi:10.1038/srep22044 · Cited by 29 · see citing works
Ageing effects on humoral immune responses in chronic periodontitis
Ebersole, J. L., Al‐Sabbagh, M., González, O. A., & Dawson, D. R. (2018) · Journal Of Clinical Periodontology · doi:10.1111/jcpe.12881 · Cited by 29 · see citing works
Li, L., Feng, X., Tao, M.-T., Paulsen, B. S., Huang, C., Feng, B., Liu, W., Yin, Z., Song, X., Zhao, X., et al. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.992102 · Cited by 28 · see citing works
“The intestine is critical for body immunity and sensitivity to aging progress (41, 42).”
BackgroundImproving intestinal inflammaging to delay aging? A new perspective
Zhang, L., Yan, J., Zhang, C., Feng, S., Zhan, Z., Bao, Y., Zhan, Z., & Chao, G. (2023) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2023.111841 · Cited by 27 · see citing works
Ebersole, J. L., Kirakodu, S. S., Novak, M. J., Orraca, L., González‐Martínez, J., Cunningham, L. L., Thomas, M. V., Stromberg, A. J., Pandruvada, S. N. M., & González, O. A. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00272 · Cited by 26 · see citing works
“4 PD: ↑9; ↑C 1 (2) 0 (1) 0 (2) 4 (3) 2 (1) 3 (1)”
InfluentialEskiocak, O., Gewolb, J., Shah, V., Rouse, J. A., Chowdhury, S., Akyildiz, E. O., Fernández-Maestre, I., Boyer, J. A., Filliol, A. A., Harris, A. S., et al. (2025) · Nature Aging · doi:10.1038/s43587-025-01022-w · Cited by 27 · see citing works
“https://doi.org/10.1038/s43587-025-01022-w”
InfluentialNeurogenic mechanisms in bladder and bowel ageing
Ranson, R. N., & Saffrey, M. J. (2015) · Biogerontology · doi:10.1007/s10522-015-9554-3 · Cited by 25 · see citing works
“Changes in the immune system (Mabbott et al. 2014; Man et al. 2014) and the microbiota (Biagi et al. 2012; Claesson et al. 2012) during ageing have also been described.”
BackgroundA Healthy Gut for a Healthy Brain: Preclinical, Clinical and Regulatory Aspects
Petrella, C., Vecchioli, S. F., Cisale, G. Y., Strimpakos, G., Borg, J.-J., Ceccanti, M., Fiore, M., Monteleone, G., & Nisticò, R. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200730111528 · Cited by 24 · see citing works
“crease in the growth of pathogenic bacteria [66-68].”
BackgroundManchester, A. C., Dogan, B., Guo, Y., & Simpson, K. W. (2020) · Journal of Veterinary Internal Medicine · doi:10.1111/jvim.15995 · Cited by 25 · see citing works
Long-term impacts of tonsillectomy on children's immune functions
Jalali, P., Radman, M., Ferdousi, A., & Khorramdelazad, H. (2020) · Journal of Family Medicine and Primary Care · doi:10.4103/jfmpc.jfmpc_935_19 · Cited by 23 · see citing works
“Journal of Family Medicine and Primary Care 1484 Volume 9 : Issue 3 : March 2020 will not negatively affect the decision for tonsillectomy if there is a valid indication.[8] Progression of tonsillar immunity from childhood may leading severe tonsillar hyperplasia (enlarged tonsils) and further severe functional stenos…”
BackgroundSandionigi, A., Giani, A. D., Tursi, F., Michelotti, A., Cestone, E., Giardina, S., Zampolli, J., & Gennaro, P. D. (2022) · BioMed Research International · doi:10.1155/2022/3860896 · Cited by 24 · see citing works
“Aging is associated with a rise in the incidence of in fl ammation and the susceptibility to gastrointestinal and respiratory infections [50].”
Finnegan, D., Tocmo, R., & Loscher, C. E. (2023) · Nutrients · doi:10.3390/nu15153371 · Cited by 20 · see citing works
“The mucosal immune system of the gastrointestinal tract, which provides the first line of defense against ingested pathogens by deciphering between harmless antigens and generating tolerance towards them or being able to mount a rapid protective immune response against dangerous pathogens, becomes significantly compro…”
BackgroundClose, L. A., Dieterle, M. G., Vendrov, K. C., Bergin, I. L., Rao, K. K., & Young, V. B. (2020) · Infection and Immunity · doi:10.1128/iai.00960-19 · Cited by 17 · see citing works
“Aging is known to cause immune dysfunction and negatively impacts patients in the setting of infectious diseases in the intestine (13).”
BackgroundZhang, K., Bai, P., & Deng, Z. (2021) · Canadian Journal of Diabetes · doi:10.1016/j.jcjd.2021.09.003 · Cited by 17 · see citing works
Reduced IL-37 Production Increases Spontaneous Chemokine Expressions in Colon Epithelial Cells
Günaltay, S., Ghiboub, M., Hultgren, O., & Hörnquist, E. H. (2017) · Digestive Diseases and Sciences · doi:10.1007/s10620-016-4422-9 · Cited by 17 · see citing works
“It has been shown that elderly people can have altered cytokine productions which affects the inflammatory response [reviewed in [52, 53]].”
BackgroundThe role of the immune system in prion infection
Mabbott, N. A., Alibhai, J. D., & Manson, J. C. (2018) · Handbook of clinical neurology · doi:10.1016/b978-0-444-63945-5.00005-2 · Cited by 17 · see citing works
Self-citationKazakevych, J., Stoyanova, E., Liebert, A., & Varga‐Weisz, P. (2019) · Scientific Reports · doi:10.1038/s41598-019-46966-3 · Cited by 16 · see citing works
Glucagon-Like Peptide-2 Improve Intestinal Mucosal Barrier Function in Aged Rats
Ren, W., Wu, J., Li, L., Lu, Y., Shao, Y., Qi, Y., Xu, B., He, Y., & Hu, Y. (2018) · The journal of nutrition health & aging · doi:10.1007/s12603-018-1022-8 · Cited by 16 · see citing works
“A pivotal contributing factor to the geriatric gastrointestinal dysfunction was increased intestinal permeability via age-associated remodeling of intestinal epithelial TJs (26, 27).”
Advanced age exacerbates intestinal epithelial permeability after burn injury in mice
Najarro, K. M., Boe, D. M., Walrath, T., Mullen, J. E., Paul, M. T., Frankel, J. H., Hulsebus, H. J., Idrovo, J., McMahan, R. H., & Kovacs, E. J. (2021) · Experimental Gerontology · doi:10.1016/j.exger.2021.111654 · Cited by 15 · see citing works
Age-related chemokine alterations affect IgA secretion and gut immunity in female mice
Nagafusa, H., & Sayama, K. (2020) · Biogerontology · doi:10.1007/s10522-020-09877-9 · Cited by 15 · see citing works
Older Human B Cells and Antibodies
Dunn‐Walters, D. K., & O’Hare, J. S. (2017) · Springer eBooks · doi:10.1007/978-3-319-64597-1_21-1 · Cited by 14 · see citing works
Yang, X., Da, P., Yang, C., Xia, H., Ligang, Y., Shao-kang, W., & Guiju, S. (2022) · Food & Nutrition Research · doi:10.29219/fnr.v66.5690 · Cited by 14 · see citing works
“The function of the mucosal immune system is impaired in elderly people (9).”
BackgroundResultAging-Related Impairments to M Cells in Peyer’s Patches Coincide With Disturbances to Paneth Cells
Donaldson, D. S., Shih, B. B.-J., & Mabbott, N. A. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.761949 · Cited by 13 · see citing works
“The mucosal immune system is adversely affected by aging and this functional decline is known as immunosenescence (8).”
BackgroundSelf-citationFood anaphylaxis in the elderly: Analysis of allergy vigilance network data from 2002 to 2021
Hanache, H. E., Perennec, T., Beaumont, P., Puillandre, E., Schwender, D., Donguy, F. L., Froidefond, C., Jarlot, S., Petit, N., Nootens, C., et al. (2023) · Clinical & Experimental Allergy · doi:10.1111/cea.14297 · Cited by 13 · see citing works
“Kidney (pork or beef) (16) AlphaGal (8) 8 0 8”
Carcea, M., Turfani, V., Narducci, V., Durazzo, A., Finamore, A., Roselli, M., & Rami, R. (2019) · Foods · doi:10.3390/foods8100510 · Cited by 13 · see citing works
“The immune response was mainly assessed at the intestinal level, since the mucosal immune system, which is known to be also impaired in the older adults [32], represents the first line of contact with ingested antigens and molecules reaching the intestinal lumen.”
BackgroundMethodCompartmentalization of immunosenescence: a deeper look at the mucosa
Martelli, S., Pender, S. L. F., & Larbi, A. (2015) · Biogerontology · doi:10.1007/s10522-015-9628-2 · Cited by 13 · see citing works
Cai, M., Deng, H., Sun, H., Si, W., Li, X., Hu, J., Huang, M., & Fan, W. (2023) · Frontiers in Microbiology · doi:10.3389/fmicb.2023.1052824 · Cited by 12 · see citing works
“Previous studies verified that aging is a multifactorial process and would influence many principal physiological systems, including the gastrointestinal system (Mabbott et al., 2015).”
BackgroundSensor-integrated gut-on-a-chip for monitoring senescence-mediated changes in the intestinal barrier
Brandauer, K., Lorenz, A., Schobesberger, S., Schuller, P., Frauenlob, M., Spitz, S., & Ertl, P. (2025) · Lab on a Chip · doi:10.1039/d4lc00896k · Cited by 11 · see citing works
Gao, J., Li, T., Lu, Z., Wang, X., Zhao, X., & Ma, Y. (2019) · Animals · doi:10.3390/ani9060309 · Cited by 10 · see citing works
“The mucosal immune system is the main site of local non-specific immune function and plays important roles in function of the innate immune system, serving as the first-line of defence against infections [28], which consists of intestinal, respiratory, urogenital mucosa, and the exocrine glands [26].”
BackgroundSenolytic CAR T cells reverse aging-associated defects in intestinal regeneration and fitnessPreprint
Eskiocak, O., Chowdhury, S., Shah, V., Nnuji-John, E., Chung, C., Boyer, J. A., Harris, A. S., Habel, J., Sadelain, M., Beyaz, S., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.03.19.585779 · Cited by 10 · see citing works
Resiliency of the Digestive System During Aging and the Impact of Diet
Sanders, L., Goltz, S. R., & Maki, K. C. (2023) · Nutrition Today · doi:10.1097/nt.0000000000000616 · Cited by 9 · see citing works
The Aging Bowel Dysfunction and Elderly Vulnerability towards COVID-19 Infection
Lerner, A., & McCarty, M. F. (2021) · Life · doi:10.3390/life11020097 · Cited by 9 · see citing works
“The local immunosenescence is expressed by reduced secretion of specific immunoglobulin A [39], mature M cells density in the Peyer’s patches of aged mice is decreased [40], tolerance to naïve antigens is declined [41], Peyer’s M enterocyte transcytosis of luminal antigens is weakened [40], dendritic cells density and…”
BackgroundLee, J., Mohsen, A. S., Banerjee, A., McCullough, L. D., Mizuguchi, K., Shimaoka, M., Kiyono, H., & Park, E. J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073544 · Cited by 9 · see citing works
“Numerous studies have demonstrated the effects of aging on gut morphology and physiology within intestinal tissues [8,10,12].”
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- Authors
- Mabbott, N. A., Kobayashi, A., Sehgal, A., Bradford, B. M., Pattison, M., & Donaldson, D. S.
- Affiliations
- Roslin Institute (GB)
- Tohoku University (JP)
- Corresponding author
- Mabbott, Neil A.
- Venue
- Biogerontology
- Published
- 2014-04-05
- Volume
- 16
- Issue
- 2
- Pages
- 133-145
- ISSN
- 1389-5729 (ISSN-L)
- 1573-6768
- OpenAlex
- W2075174082
- Cited by
- 95
- References
- 117
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 3 · 2023: 8 · 2022: 11 · 2021: 13 · 2020: 10 · 2019: 8 · 2018: 8 · 2017: 7 · 2016: 8 · 2015: 8 · 2014: 1
- FWCI
- 0.75
- Type
- journal article
- Language
- en
- Open access
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Biogerontology (publishedVersion)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (publishedVersion, other-oa)
- Funders
- Biotechnology and Biological Sciences Research Council (BB/M024288/1, BBS/E/D/20231762, BB/J014672/1, BBS/E/D/20231759, BB/K021257/1, BBS/E/D/20251968, BB/L007452/1, BBS/E/D/20251967)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- immunosenescence, intestinal mucosal immunity, aging, gastrointestinal infections, innate immunity, adaptive immunity, vaccine efficacy, autoimmunity, older adults
- MeSH terms
- Immunosenescence, Animals, Humans, Immunity, Innate, Intestinal Mucosa, Cytokines, Models, Immunological
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