Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain

In the paper

“These changes can adversely affect the host metabolism and immunity [25–27, 40, 64, 86, 110, 112, 118] and are associated with the development of cardiovascular, autoimmune, metabolic, and neurodegenerative disorders [17, 90, 122, 132].”

What the sources say

• Partly supported

  The Abstract links intestinal microbiota alterations to obesity and inflammatory bowel disease, but says the health ramifications of microbiota changes in older people are still being explored. It does not link those aging-related changes to the development of cardiovascular or neurodegenerative disorders, or establish the claimed adverse effects on host metabolism and immunity. (LLM, conf=0.86)

  cites [25] Claesson MJ, Cusack S, ’Sullivan O, O, Greene-Diniz R, De Weerd H, Flannery E, et al. Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc Natl Acad Sci U S A. 2011;108(SUPPL. 1):4586–91. https://doi.org/10.1073/pnas.1000097107. sourceExperimental — accuracy not yet measured
• Partly supported

  The introduction (p. 5) links microbiota changes to inflammatory and metabolic disorders, and the study reports associations between elderly participants’ microbiota and markers of inflammation (p. 3). This supports the immune and metabolic aspects, but the paper does not establish associations with the development of autoimmune or neurodegenerative disorders. It notes a weaker association with blood pressure (p. 9), not cardiovascular disease development. (LLM, conf=0.85)

  cites [26] Claesson MJ, Jeffery IB, Conde S, Power SE, O’connor EM, Cusack S, et al. Gut microbiota composition correlates with diet and health in the elderly. Nature. 2012;488(7410):178–84. https://doi.org/10.1038/nature11319. sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract reports that age-related microbiota changes in Drosophila contribute to immune gene activation, but it does not establish an adverse effect on host metabolism. The opening passage and Discussion link dysbiosis or intestinal barrier dysfunction to cardiovascular, neurological, inflammatory, and metabolic disorders, but do not specifically mention autoimmune disorders. Those human disease links are background associations, not outcomes demonstrated by this fly study. (LLM, conf=0.86)

  cites [27] Clark RI, Salazar A, Yamada R, Fitz-Gibbon S, Morselli M, Alcaraz J, et al. Distinct shifts in microbiota composition during drosophila aging impair intestinal function and drive mortality. Cell Rep. 2015;12(10):1656–67. https://doi.org/10.1016/j.celrep.2015.08.004. sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction says gut microbiota affects host immunity and metabolism, and the Discussion reports that aged-microbiota transfer induced characteristics of immunosenescence in young germ-free mice. The paper also links inflammaging to dementia and cardiovascular disease and discusses metabolic syndrome, but it does not establish that aging-related microbiota changes are associated with development of every listed disorder, particularly autoimmune disorders. (LLM, conf=0.85)

  cites [40] Fransen F, van Beek AA, Borghuis T, El Aidy S, Hugenholtz F, van der Gaast-de Jongh C, et al. Aged gut microbiota contributes to systemical inflammaging after transfer to germ-free mice. Front Immunol. 2017;8(NOV):1385. https://doi.org/10.3389/fimmu.2017.01385. sourceExperimental — accuracy not yet measured
• Partly supported

  The Background links age-related microbiome shifts to likely increased inflammation and describes microbial effects on immune function; the Conclusions suggest possible effects on host vitamin availability and carbohydrate metabolism. The Background also mentions an association between microbiome perturbations and autoimmune disease. Our copy does not support the full list of cardiovascular, metabolic, and neurodegenerative disorders, nor does it establish that the observed aging-related shifts adversely affect host metabolism. (LLM, conf=0.84)

  cites [64] Langille MGII, Meehan CJ, Koenig JE, Dhanani AS, Rose RA, Howlett SE, et al. Microbial shifts in the aging mouse gut. Microbiome. 2014;2(1). https://doi.org/10.1186/s40168-014-0050-9. sourceExperimental — accuracy not yet measured
• Not checked yetcites [86] O’Toole PW, Jeffery IB. Gut microbiota and aging: Science. American Association for the Advancement of Science; 2015. https://doi.org/10.1126/science.aac8469. source
• Supported

  The citation is attached to the first clause, about effects on host metabolism and immunity; the disorder list has a separate citation group. In the Results section on microbial transfer (page unavailable), young- and old-microbiota recipients differed in intestinal defense responses, hyaluronic acid metabolism, and expression of a TOR-pathway gene. The paper links the altered metabolism to inflammation and deregulated immune responses, supporting the hedged claim in its killifish model. (LLM, conf=0.85)

  cites [110] Smith P, Willemsen D, Popkes M, Metge F, Gandiwa E, Reichard M, et al. Regulation of life span by the gut microbiota in the short-lived African turquoise killifish. ELife. 2017;6(August). https://doi.org/10.7554/eLife.27014. source
• Partly supported

  The Introduction says gut microorganisms affect host metabolism and immune responses, and links age-related microbiota changes to immune inflammaging. The Discussion also reports that transfer of an aged microbiome causes systemic inflammation. Our copy does not establish an adverse effect of age-related microbiota changes on host metabolism; the disorder list has a separate citation group in the citing sentence. (LLM, conf=0.84)

  cites [112] Stebegg M, Silva-Cayetano A, Innocentin S, Jenkins TP, Cantacessi C, Gilbert C, et al. Heterochronic faecal transplantation boosts gut germinal centres in aged mice. Nat Commun. 2019;10(1). https://doi.org/10.1038/s41467-019-10430-7. sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction and Discussion report that age-associated gut dysbiosis promotes systemic inflammation and impairs macrophage antibacterial function, supporting the immunity portion. The cited paper does not establish an adverse effect on host metabolism. The disorder associations appear after a separate citation group in the citing sentence, so they are not attributed to this source. (LLM, conf=0.83)

  cites [118] Thevaranjan N, Puchta A, Schulz C, Avee Naidoo JC, Szamosi CP, Verschoor DL, et al. Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe. 2017;21(4):455–466.e4. https://doi.org/10.1016/j.chom.2017.03.002. sourceExperimental — accuracy not yet measured
• Partly supported

  In “The essential role of the gut microbiota in human health” (page not available), the review says changes in the intestinal ecosystem can disrupt host–microbe symbiosis and affect metabolism and immune function. Its Fig. 4 caption links dysbiosis with metabolic disease and increased likelihood of cardiovascular disease. The cited passages do not establish that these are specifically aging-related changes or link them to autoimmune or neurodegenerative disorders. (LLM, conf=0.86)

  cites [17] Boulangé CL, Neves AL, Chilloux J, Nicholson JK, Dumas ME. Impact of the gut microbiota on inflammation, obesity, and metabolic disease. Genome Med. 2016. https://doi.org/10.1186/s13073-016-0303-2. sourceExperimental — accuracy not yet measured

In the paper

“There is some evidence for improved cognition with probiotic use in those with pre-existing cognitive impairment [31]”

What the sources say

• Supported

  The Results (Cognition and mood) state that four probiotic studies reported a positive effect on cognition in participants with pre-existing cognitive impairment. The Discussion describes the evidence as limited and notes study-quality concerns, consistent with the claim’s cautious wording. (LLM, conf=0.94)

  cites [31] Coutts L, Ibrahim K, Tan QY, Lim SER, Cox NJ, Roberts HC. Can probiotics, prebiotics and synbiotics improve functional outcomes for older people: a systematic review. Eur Geriatr Med. 2020. https://doi.org/10.1007/s41999-020-00396-x Springer Science and Business Media Deutschland GmbH. source

In the paper

“Deficiencies in B vitamins are implicated in retinitis pigmentosa and glaucoma, for which improved outcomes can be achieved by dietary supplementation [24, 114].”

What the sources say

• Partly supported

  The Abstract and Discussion report that a nicotinamide-rich diet preserved retinal ganglion cell function and reduced cell loss in a mouse model of glaucoma. This supports improved outcomes with dietary supplementation in that model, but not the broader implication of improved outcomes in people with glaucoma. The paper does not address retinitis pigmentosa. (LLM, conf=0.86)

  cites [24] Chou T-H, Romano GL, Amato R, Porciatti V. Nicotinamide-rich diet in DBA/2J mice preserves retinal ganglion cell metabolic function as assessed by PERG adaptation to flicker. Nutrients. 2020;12(7):1910. https://doi.org/10.3390/nu12071910. sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction identifies nicotinamide as vitamin B3, and the Results (§3.1) report preserved retinal morphology in nicotinamide-treated rats with chemically induced photoreceptor degeneration. But the Methods (§2.3) specify an injection, not dietary supplementation; the study does not show improved outcomes in people with retinitis pigmentosa or glaucoma. The Introduction describes retinitis pigmentosa as genetic rather than linking it to B-vitamin deficiency. (LLM, conf=0.86)

  cites [114] Sugano E, Tabata K, Takezawa T, Shiraiwa R, Muraoka H, Metoki T, et al. N-methyl-N-nitrosourea-induced photoreceptor degeneration is inhibited by nicotinamide via the blockade of upstream events before the phosphorylation of signalling proteins. Biomed Res Int. 2019;2019. https://doi.org/10.1155/2019/3238719. sourceExperimental — accuracy not yet measured

In the paper

“and that FMT modulates resulting metabolic pathway profiles”

• Also stated in: § Background · plain

  “and altered the metabolic potential of the resulting gut microbial composition”

In the paper

“Our cytokine analysis also included IL-12, IL-17, IL-1β, and IL-27, but none of these was above the assay threshold of detection in any group”

In the paper

“The FMT induced significant alterations in the fecal microbiota of recipients (Fig. 5C, D, Figs. S7 and S8, permutational ANOVA on dbRDA F = 55.8, df = 3, P < .01) with experimental time point accounting for 50% of the data variance (R2adj = 50%).”

In the paper

“Transfer of aged donor microbiota into young mice dramatically altered the recipients’ fecal microbiota composition (pairwise PERMANOVA P = .01, after BH correction) and resulted in a microbiota profile resembling that of aged mice at baseline”

In the paper

“In this case, the altered profile was distinct from that of young baseline mice, with the observed shifts following those of young mice transplanted with a young donor microbiota”

In the paper

“The young (3 months) and aged (24 months) groups formed separate clusters in the ordination; however, the old (18 months) group did not form a separate cluster and shared features with both young and aged mice”

In the paper

“The old (18 months) group of animals had significant inter-individual variation in the microbiota composition and did not form a discrete cluster in the ordination”

In the paper

“The most significantly enriched species in aged mice receiving young donor microbiota (Bifidobacterium animalis, Eubacterium sp. 14–2, A. muciniphila, and Clostridium cocleatum) were also enriched in young mice recolonized with young donor microbiota, although others (Parabacteroides distasonis, Lachnospiraceae 28–4, Clostridium ASF356) were only enriched in the aged recipients”

In the paper

“Distance-based redundancy analysis (dbRDA) showed high inter-individual variation with only 24% of variance explained by treatment groupings (4% of variance was explained by cage groupings).”

In the paper

“Young flies fed homogenates from aged flies had significantly decreased lifespan and increased incidence of intestinal barrier dysfunction, compared with flies fed homogenates from young animals [27].”

What the sources say

• Not checked yetcites [27] Clark RI, Salazar A, Yamada R, Fitz-Gibbon S, Morselli M, Alcaraz J, et al. Distinct shifts in microbiota composition during drosophila aging impair intestinal function and drive mortality. Cell Rep. 2015;12(10):1656–67. https://doi.org/10.1016/j.celrep.2015.08.004. source

In the paper

“The altered microbial composition has also been associated with neovascularization and immune cell activation in retinal disease models [4, 50, 99].”

What the sources say

• Not checked yetcites [4] Andriessen EMMAMA, Wilson AM, Mawambo G, Dejda A, Miloudi K, Sennlaub F, et al. Gut microbiota influences pathological angiogenesis in obesity-driven choroidal neovascularization. EMBO Mol Med. 2016;8(12):1366–79. https://doi.org/10.15252/emmm.201606531. source
• Not checked yetcites [50] Horai R, Zárate-Bladés CR, Dillenburg-Pilla P, Chen J, Kielczewski JL, Silver PB, et al. Microbiota-dependent activation of an autoreactive T cell receptor provokes autoimmunity in an immunologically privileged site. Immunity. 2015;43(2):343–53. https://doi.org/10.1016/j.immuni.2015.07.014. source
• Not checked yetcites [99] Rowan S, Jiang S, Korem T, Szymanski J, Chang M-LL, Szelog J, et al. Involvement of a gut–retina axis in protection against dietary glycemia-induced age-related macular degeneration. Proc Natl Acad Sci U S A. 2017;114(22):E4472–81. https://doi.org/10.1073/pnas.1702302114. source

In the paper

“This, together with declining immune cell function and immunosenescence, promotes a state of elevated systemic inflammation termed “inflammaging” [39, 40, 118], contributing to the functional decline in the intestine and CNS in old age [10, 13, 48].”

What the sources say

• Not checked yetcites [39] Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune–metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018. https://doi.org/10.1038/s41574-018-0059-4 Nature Publishing Group. source
• Not checked yetcites [40] Fransen F, van Beek AA, Borghuis T, El Aidy S, Hugenholtz F, van der Gaast-de Jongh C, et al. Aged gut microbiota contributes to systemical inflammaging after transfer to germ-free mice. Front Immunol. 2017;8(NOV):1385. https://doi.org/10.3389/fimmu.2017.01385. source
• Not checked yetcites [118] Thevaranjan N, Puchta A, Schulz C, Avee Naidoo JC, Szamosi CP, Verschoor DL, et al. Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe. 2017;21(4):455–466.e4. https://doi.org/10.1016/j.chom.2017.03.002. source
• Not checked yetcites [10] Becker L, Nguyen L, Gill J, Kulkarni S, Pasricha PJ, Habtezion A. Age-dependent shift in macrophage polarisation causes inflammation-mediated degeneration of enteric nervous system. Gut. 2018;67(5):827–36. https://doi.org/10.1136/gutjnl-2016-312940. source
• Not checked yetcites [13] Bevan-Jones WR, Cope TE, Simon Jones P, Kaalund SS, Passamonti L, Allinson K, et al. Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum. Brain J Neurol. 2020;143(3):1010–26. https://doi.org/10.1093/brain/awaa033. source
• Not checked yetcites [48] Heneka MT. Microglia take Centre stage in neurodegenerative disease. Nat Rev Immunol. 2019;19(2):79–80. https://doi.org/10.1038/s41577-018-0112-5. source

In the paper

“Similar beneficial effects have been reported in aged mice receiving microbiota from young mice to extend life span [8, 61] or halt the functional decline in the mucosal immune system [112].”

What the sources say

• Not checked yetcites [8] Bárcena C, Valdés-Mas R, Mayoral P, Garabaya C, Durand S, Rodríguez F, et al. Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice. Nat Med. 2019;25(8):1234–42. https://doi.org/10.1038/s41591-019-0504-5. source
• Not checked yetcites [61] Kundu P, Lee HU, Garcia-Perez I, Tay EXY, Kim H, Faylon LE, et al. Neurogenesis and prolongevity signaling in young germ-free mice transplanted with the gut microbiota of old mice. Sci Transl Med. 2019;11(518). https://doi.org/10.1126/scitranslmed.aau4760. source
• Not checked yetcites [112] Stebegg M, Silva-Cayetano A, Innocentin S, Jenkins TP, Cantacessi C, Gilbert C, et al. Heterochronic faecal transplantation boosts gut germinal centres in aged mice. Nat Commun. 2019;10(1). https://doi.org/10.1038/s41467-019-10430-7. source

In the paper

“In the short-lived African killifish, the transfer of young donor microbiota to aged individuals ameliorated behavioral decline and extended lifespan [110].”

What the sources say

• Not checked yetcites [110] Smith P, Willemsen D, Popkes M, Metge F, Gandiwa E, Reichard M, et al. Regulation of life span by the gut microbiota in the short-lived African turquoise killifish. ELife. 2017;6(August). https://doi.org/10.7554/eLife.27014. source

In the paper

“Age-related macular degeneration (AMD) is associated with chronic inflammation [29, 65] and altered fecal microbial metabolite profiles [100].”

What the sources say

• Not checked yetcites [29] Combadière C, Feumi C, Raoul W, Keller N, Rodéro M, Pézard A, et al. CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration. J Clin Investig. 2007;117(10):2920–8. https://doi.org/10.1172/JCI31692. source
• Not checked yetcites [65] Langmann T. Microglia activation in retinal degeneration. J Leukoc Biol. 2007;81(6):1345–51. https://doi.org/10.1189/jlb.0207114. source
• Not checked yetcites [100] Rowan S, Taylor A. The role of microbiota in retinal disease. Adv Exp Med Biol. 2018;1074:429–35. https://doi.org/10.1007/978-3-319-75402-4_53. source

In the paper

“We selected all lmm-transformation combinations that had roughly random and normally distributed residuals.”

In the paper

“Together, our data support a causal role for the gut microbiota–retina axis in regulating retinal inflammation and age-related cytokine signaling, along with the expression of a key functional visual protein (RPE65).”

In the paper

“One sample from the aged Pre-Abx group was removed as it clearly represented an outlier in the ordination.”

In the paper

“Animals not achieving 10 s were excluded from the analysis. Similarly, animals not achieving a cumulative 10 s with the familiar object were excluded.”

In the paper

“Together, these data demonstrate that the aged microbiota promotes the breakdown of epithelial barrier integrity, the translocation of bacterial products, and the elevated serum levels of pro-inflammatory cytokines, all of which were reversed by transplantation with young donor microbiota.”

In the paper

“Groups of young (3 months), old (18 months), or aged (24 months) male mice were randomly re-assigned to experimental cages 2 weeks prior to the start of the experiment.”

In the paper

“All experiments were approved by the UEA Animal Welfare and Ethical Review Body”

In the paper

“Chronic inflammation and microglial overactivation in the brain contribute to neurodegenerative pathology, which in turn can lead to cognitive decline”

What the sources say

• Not checked yetcites [48] Heneka MT. Microglia take Centre stage in neurodegenerative disease. Nat Rev Immunol. 2019;19(2):79–80. https://doi.org/10.1038/s41577-018-0112-5. source

In the paper

“To avoid confounding impacts of vendor influences on the microbiota of different age groups, our study used mice of three different ages from the same colony, which were all bred and maintained in the same environment for their entire lifespan.”

• Also stated in: § Experimental model details · plain

  “Male C57BL/6J mice aged 3, 18, or 24 months were used in this study and were all bred and housed in the same room.”

In the paper

“Fecal pellets, blood, and tissue collections and FMT interventions were all performed at the same time of day across all cages to account for circadian rhythm variability in feeding and microbiota/metabolite composition.”

In the paper

“we accounted for potential inter-cage variability, both before FMT by randomizing housing in the weeks prior to the start of the experiment and post-FMT by factoring inter-cage variation into our statistical analyses of the metagenomic data.”

In the paper

“Collectively, these data demonstrate that the intestinal microbiota strongly influences microglia activation and that heterochronic FMT modulates levels of Iba-1+ microglia, increasing the levels in young adult mice transplanted with an aged donor microbiota and reducing them in the CNS of aged animals receiving a young donor microbiota.”

In the paper

“Importantly, we also accounted for any potential cage grouping or housing effects in our analyses.”

In the paper

“the latter in keeping with the increase in proportional abundance of Bifidobacterium spp. in this group”

In the paper

“This adaptation over time however did not limit the impact of the transplanted microbiota on tissues, in which changes in key functional cell types and biomarkers of health were apparent at 18 days post-FMT, the point of tissue collection.”

In the paper

“In mammalian models, altered microglial morphology and function, and elevated expression of microglial activation markers are seen with advancing age [82].”

What the sources say

• Not checked yetcites [82] Mosher KI, Wyss-Coray T. Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem Pharmacol. 2014. https://doi.org/10.1016/j.bcp.2014.01.008. source

In the paper

“Our data support the suggestion that altered gut microbiota in old age contributes to intestinal and systemic inflammation, and so may contribute to driving inflammatory pathologies of aged organs.”

In the paper

“Prevotella species associated with detrimental impacts on intestinal barrier integrity are enriched in IBS patients and in models of intestinal inflammation [52, 113] and may promote inflammatory arthritis [3, 104, 126].”

What the sources say

• Not checked yetcites [52] Iljazovic A, Roy U, Gálvez EJCC, Lesker TR, Zhao B, Gronow A, et al. Perturbation of the gut microbiome by Prevotella spp. enhances host susceptibility to mucosal inflammation. Mucosal Immunol. 2020;May:1–12. https://doi.org/10.1038/s41385-020-0296-4. source
• Not checked yetcites [113] Su T, Liu R, Lee A, Long Y, Lijun D, Lai S, et al. Altered intestinal microbiota with increased abundance of Prevotella is associated with high risk of diarrhea-predominant irritable bowel syndrome. Gastroenterol Res Pract. 2018;2018. https://doi.org/10.1155/2018/6961783. source
• Not checked yetcites [3] Alpizar-Rodriguez D, Lesker TR, Gronow A, Gilbert B, Raemy E, Lamacchia C, et al. Prevotella copri in individuals at risk for rheumatoid arthritis. Ann Rheum Dis. 2019;78(5):590–3. https://doi.org/10.1136/annrheumdis-2018-214514. source
• Not checked yetcites [104] Scher JU, Sczesnak A, Longman RS, Segata N, Ubeda C, Bielski C, et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. ELife. 2013;2013(2):1202. https://doi.org/10.7554/eLife.01202.001. source
• Not checked yetcites [126] Wells PM, Adebayo AS, Bowyer RCE, Freidin MB, Finckh A, Strowig T, et al. Associations between gut microbiota and genetic risk for rheumatoid arthritis in the absence of disease: a cross-sectional study. Lancet Rheumatol. 2020;2(7):e418–27. https://doi.org/10.1016/S2665-9913(20)30064-3. source

In the paper

“In summary, heterochronic FMT resulted in significant shifts in lipid and vitamin metabolism pathways, increasing their proportional abundance in aged mice transplanted with the microbiota of young donors and decreasing their abundance in young mice receiving aged donor microbiota.”

In the paper

“There was also a reduction in methanogenesis suggestive of some impact on gut archaea”

In the paper

“We show that aged donor microbiota transfer to young mice drives inflammation and loss of integrity in the intestinal epithelial barrier elevated systemic and tissue markers of inflammaging, and upregulated inflammation in the retina and brain.”

In the paper

“and are associated with promoting intestinal and extra-intestinal health and healthy aging.”

What the sources say

• Not checked yetcites [38] Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013;110(22):9066–71. https://doi.org/10.1073/pnas.1219451110. source
• Not checked yetcites [73] van der Lugt B, van Beek AA, Aalvink S, Meijer B, Sovran B, Vermeij WP, et al. Akkermansia muciniphila ameliorates the age-related decline in colonic mucus thickness and attenuates immune activation in accelerated aging Ercc1-/Δ7 mice. Immun Ageing. 2019;16:6. https://doi.org/10.1186/s12979-019-0145-z. source
• Not checked yetcites [8] Bárcena C, Valdés-Mas R, Mayoral P, Garabaya C, Durand S, Rodríguez F, et al. Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice. Nat Med. 2019;25(8):1234–42. https://doi.org/10.1038/s41591-019-0504-5. source

In the paper

“metabolites previously associated with beneficial effects in aging [74, 94]”

What the sources say

• Not checked yetcites [74] Ma J, Hong Y, Zheng N, Xie G, Yuanzhi Lyu YG, Xi C, et al. Gut microbiota remodeling reverses aging-associated inflammation and dysregulation of systemic bile acid homeostasis in mice sex-specifically. Gut Microbes. 2020;11(5):1450–74. https://doi.org/10.1080/19490976.2020.1763770. source
• Not checked yetcites [94] Ramos-Molina B, Queipo-Ortuño MI, Lambertos A, Tinahones FJ, Peñafiel R. Dietary and gut microbiota polyamines in obesity- and age-related diseases. Front Nutr. 2019. https://doi.org/10.3389/fnut.2019.00024. source

In the paper

“The transferred aged microbiota and resulting recipient microbiota composition were distinguished by enrichment for Prevotella, Lacnospiraceae, and Facecalibaculum species and depletion of long-chain fatty acid synthesis.”

In the paper

“Furthermore, A. muciniphila is depleted in models of inflammation and metabolic disorders and displays probiotic potential, by regulating mucus production and epithelial barrier integrity and by reducing serum LPS [38].”

What the sources say

• Not checked yetcites [38] Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013;110(22):9066–71. https://doi.org/10.1073/pnas.1219451110. source

In the paper

“Our data show that transplanting an aged donor microbiota into young recipients results in elevated intestinal concentrations of TNF, and elevated surrogate biomarkers of altered epithelial barrier permeability (I-FABP, LBP), supporting a driving role for the age-associated microbiota in the breakdown of barrier integrity and promotion of systemic inflammatory responses.”

In the paper

“Collectively, our results showed that heterochronic FMT resulted in significant alteration of the recipient microbiota structure, enriching for bacterial species distinctive of the donor age group, and that both donor and recipient were influential in the resulting microbiota composition.”

In the paper

“However, some species are currently thought to modulate cholesterol and bile acid metabolism and are considered potential therapeutics [43].”

What the sources say

• Not checked yetcites [43] Ghosh TS, Das M, Jeffery IB, O’Toole PW, O’Toole PW. Adjusting for age improves identification of gut microbiome alterations in multiple diseases. ELife. 2020;9(March). https://doi.org/10.7554/eLife.50240. source

In the paper

“B. animalis, a probiotic species positively associated with longevity in mice [78] and negatively correlated with inflammation and human obesity [81]”

What the sources say

• Not checked yetcites [78] Matsumoto M, Kurihara S, Kibe R, Ashida H, Benno Y. Longevity in mice is promoted by probiotic-induced suppression of colonic senescence dependent on upregulation of gut bacterial polyamine production. PLoS One. 2011;6(8). https://doi.org/10.1371/journal.pone.0023652. source
• Not checked yetcites [81] Million M, Angelakis E, Maraninchi M, Henry M, Giorgi R, Valero R, et al. Correlation between body mass index and gut concentrations of lactobacillus reuteri, Bifidobacterium animalis, Methanobrevibacter smithii and Escherichia coli. Int J Obes. 2013;37(11):1460–6. https://doi.org/10.1038/ijo.2013.20. source

In the paper

“In mouse models of accelerated aging, supplementation with A. muciniphila can also attenuate age-related decline in colon thickness and immune activation [73], and exert beneficial effects on lifespan and healthspan [8].”

What the sources say

• Not checked yetcites [73] van der Lugt B, van Beek AA, Aalvink S, Meijer B, Sovran B, Vermeij WP, et al. Akkermansia muciniphila ameliorates the age-related decline in colonic mucus thickness and attenuates immune activation in accelerated aging Ercc1-/Δ7 mice. Immun Ageing. 2019;16:6. https://doi.org/10.1186/s12979-019-0145-z. source
• Not checked yetcites [8] Bárcena C, Valdés-Mas R, Mayoral P, Garabaya C, Durand S, Rodríguez F, et al. Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice. Nat Med. 2019;25(8):1234–42. https://doi.org/10.1038/s41591-019-0504-5. source

In the paper

“Our procedures were optimized to assess the bacterial fraction of the intestinal microbiota, and as such, we cannot exclude potential contributions from other microbial constituents in the effects we describe.”

In the paper

“This suggests that the aged donor microbiota engraftment was strongest in the young recipients, while the transfer of young donor microbiota was more susceptible to modification by the influence of the FMT procedure, or the recipient intestinal environment, or both.”

In the paper

“In agreement with our findings and interpretation is the observation that the microbiota from aged donors exacerbates paracellular permeability and inflammation in germ-free mice [40, 118].”

What the sources say

• Not checked yetcites [40] Fransen F, van Beek AA, Borghuis T, El Aidy S, Hugenholtz F, van der Gaast-de Jongh C, et al. Aged gut microbiota contributes to systemical inflammaging after transfer to germ-free mice. Front Immunol. 2017;8(NOV):1385. https://doi.org/10.3389/fimmu.2017.01385. source
• Not checked yetcites [118] Thevaranjan N, Puchta A, Schulz C, Avee Naidoo JC, Szamosi CP, Verschoor DL, et al. Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe. 2017;21(4):455–466.e4. https://doi.org/10.1016/j.chom.2017.03.002. source

In the paper

“That these effects are reversed in aged recipients of young donor microbiota supports this hypothesis, suggesting a positive impact of the microbiota of young mice on barrier integrity, or that removal of age-associated microbiota allows for barrier recovery.”

In the paper

“Conversely, transfer of aged mice with young donor microbiota, which was distinguished by enrichment Bifidobacteria, Eubacteria, and Akkermansia species, and enrichment for B vitamin biosynthesis and lipid synthesis pathways reversed inflammatory changes in the aged gut, brain, and retina.”

In the 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”

What the sources say

• Not checked yetcites [8] Bárcena C, Valdés-Mas R, Mayoral P, Garabaya C, Durand S, Rodríguez F, et al. Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice. Nat Med. 2019;25(8):1234–42. https://doi.org/10.1038/s41591-019-0504-5. source
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In the paper

“CNS microglial populations constantly and rapidly remodel [6], making it difficult to discriminate between changes in cell number versus changes in Iba-1 expression in the setting of FMT.”

What the sources say

• Not checked yetcites [6] Askew K, Li K, Olmos-Alonso A, Garcia-Moreno F, Liang Y, Richardson P, et al. Coupled proliferation and apoptosis maintain the rapid turnover of microglia in the adult brain. Cell Rep. 2017;18(2):391–405. https://doi.org/10.1016/j.celrep.2016.12.041. source

In the paper

“Transfer of young donor microbiota results in a decrease in aged mice of cytokines involved in inflammatory immune cell recruitment and pro-inflammatory signaling, including CCL11 (eotaxin), CXCL11, and IL-1β [23, 62, 84], all of which are elevated in aged mouse retinae [108].”

What the sources say

• Not checked yetcites [108] Shinhmar H, Hogg C, Jeffery G. Long wavelength light that improves aged mitochondrial function selectively increases cytokine expression in serum and the retina. BioRxiv. 2021:10.468030. https://doi.org/10.1101/2021.11.10.468030. source

In the paper

“Deficiencies in B vitamins are implicated in retinitis pigmentosa and glaucoma, for which improved outcomes can be achieved by dietary supplementation [24, 114].”

What the sources say

• Not checked yetcites [24] Chou T-H, Romano GL, Amato R, Porciatti V. Nicotinamide-rich diet in DBA/2J mice preserves retinal ganglion cell metabolic function as assessed by PERG adaptation to flicker. Nutrients. 2020;12(7):1910. https://doi.org/10.3390/nu12071910. source
• Not checked yetcites [114] Sugano E, Tabata K, Takezawa T, Shiraiwa R, Muraoka H, Metoki T, et al. N-methyl-N-nitrosourea-induced photoreceptor degeneration is inhibited by nicotinamide via the blockade of upstream events before the phosphorylation of signalling proteins. Biomed Res Int. 2019;2019. https://doi.org/10.1155/2019/3238719. source

In the paper

“Polymorphisms in human complement regulatory factor H (CFH) predispose individuals to AMD [35, 46, 59]”

What the sources say

• Not checked yetcites [35] Edwards AO, Ritter R, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science. 2005;308(5720):421–4. https://doi.org/10.1126/science.1110189. source
• Not checked yetcites [46] Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A. 2005;102(20):7227–32. https://doi.org/10.1073/pnas.0501536102. source
• Not checked yetcites [59] Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308(5720):385–9. https://doi.org/10.1126/science.1109557. source

In the paper

“Loss of intestinal barrier integrity and elevated circulating pro-inflammatory cytokine concentrations are linked with the polarization of CNS microglia toward a pro-inflammatory phenotype [11, 73, 109] and promote neurodegenerative disease [10, 13, 48].”

What the sources say

• Not checked yetcites [11] van Beek AA, Van Bossche J, Mastroberardino PG, de Winther MPJ, Leenen PJM. Metabolic alterations in aging macrophages: ingredients for inflammaging? Trends Immunol. 2019a. https://doi.org/10.1016/j.it.2018.12.007. source
• Not checked yetcites [73] van der Lugt B, van Beek AA, Aalvink S, Meijer B, Sovran B, Vermeij WP, et al. Akkermansia muciniphila ameliorates the age-related decline in colonic mucus thickness and attenuates immune activation in accelerated aging Ercc1-/Δ7 mice. Immun Ageing. 2019;16:6. https://doi.org/10.1186/s12979-019-0145-z. source
• Not checked yetcites [109] Sierra A, Gottfried-Blackmore AC, McEwen BS, Bulloch K. Microglia derived from aging mice exhibit an altered inflammatory profile. Glia. 2007;55(4):412–24. https://doi.org/10.1002/glia.20468. source
• Not checked yetcites [10] Becker L, Nguyen L, Gill J, Kulkarni S, Pasricha PJ, Habtezion A. Age-dependent shift in macrophage polarisation causes inflammation-mediated degeneration of enteric nervous system. Gut. 2018;67(5):827–36. https://doi.org/10.1136/gutjnl-2016-312940. source
• Not checked yetcites [13] Bevan-Jones WR, Cope TE, Simon Jones P, Kaalund SS, Passamonti L, Allinson K, et al. Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum. Brain J Neurol. 2020;143(3):1010–26. https://doi.org/10.1093/brain/awaa033. source
• Not checked yetcites [48] Heneka MT. Microglia take Centre stage in neurodegenerative disease. Nat Rev Immunol. 2019;19(2):79–80. https://doi.org/10.1038/s41577-018-0112-5. source

In the paper

“Upregulation of CXCL11 is seen in RPE cells adjacent to drusen deposits in AMD [62], and its secretion can be triggered by proinflammatory cytokines including TNF and IL-1β.”

What the sources say

• Not checked yetcites [62] Kutty RK, Samuel W, Abay R, Cherukuri A, Nagineni CN, Duncan T, et al. Resveratrol attenuates CXCL11 expression induced by proinflammatory cytokines in retinal pigment epithelial cells. Cytokine. 2015;74(2):335. https://doi.org/10.1016/J.CYTO.2015.03.016. source

In the paper

“Association studies have linked intestinal microbial products with the development and progression of age-related choroidal neovascularization (CNV) and age-related macular degeneration (AMD) [4, 131, 133].”

What the sources say

• Not checked yetcites [4] Andriessen EMMAMA, Wilson AM, Mawambo G, Dejda A, Miloudi K, Sennlaub F, et al. Gut microbiota influences pathological angiogenesis in obesity-driven choroidal neovascularization. EMBO Mol Med. 2016;8(12):1366–79. https://doi.org/10.15252/emmm.201606531. source
• Not checked yetcites [131] Zinkernagel MS, Zysset-Burri DC, Keller I, Berger LE, Leichtle AB, Largiadèr CR, et al. Association of the intestinal microbiome with the development of neovascular age-related macular degeneration. Sci Rep. 2017;7(1):1–9. https://doi.org/10.1038/srep40826. source
• Not checked yetcites [133] Zysset-Burri DC, Keller I, Berger LE, Largiadèr CR, Wittwer M, Wolf S, et al. Associations of the intestinal microbiome with the complement system in neovascular age-related macular degeneration. Npj Genom Med. 2020;5(1):34. https://doi.org/10.1038/s41525-020-00141-0. source

In the paper

“The antibiotics used in this study are, to varying degrees, able to penetrate the blood–brain barrier and cerebrospinal fluid.”

In the paper

“RPE65 is vital for maintaining normal photoceptor function via trans-retinol conversion; mutations or loss of function are associated with retinitis pigmentosa and are implicated in AMD [21].”

What the sources say

• Not checked yetcites [21] Cai X, Conley SM, Naash MI. RPE65: role in the visual cycle, human retinal disease, and gene therapy. Ophthalmic Genet. 2009. https://doi.org/10.1080/13816810802626399 NIH Public Access. source

In the paper

“Upregulation of CXCL11 is seen in RPE cells adjacent to drusen deposits in AMD [62], and its secretion can be triggered by proinflammatory cytokines including TNF and IL-1β.”

What the sources say

• Not checked yetcites [62] Kutty RK, Samuel W, Abay R, Cherukuri A, Nagineni CN, Duncan T, et al. Resveratrol attenuates CXCL11 expression induced by proinflammatory cytokines in retinal pigment epithelial cells. Cytokine. 2015;74(2):335. https://doi.org/10.1016/J.CYTO.2015.03.016. source

In the paper

“Evidence for unsaturated, mono-, and poly-unsaturated fatty acids impacting microglial function comes from both in vitro and in vivo studies [70].”

What the sources say

• Not checked yetcites [70] Leyrolle Q, Layé S, Nadjar A. Direct and indirect effects of lipids on microglia function. Neurosci Lett. 2019. https://doi.org/10.1016/j.neulet.2019.134348 Elsevier Ireland Ltd. source

In the paper

“RPE65 is vital for maintaining normal photoceptor function via trans-retinol conversion; mutations or loss of function are associated with retinitis pigmentosa and are implicated in AMD [21].”

What the sources say

• Not checked yetcites [21] Cai X, Conley SM, Naash MI. RPE65: role in the visual cycle, human retinal disease, and gene therapy. Ophthalmic Genet. 2009. https://doi.org/10.1080/13816810802626399 NIH Public Access. source

In the paper

“CFH deficiency in mice causes retinal abnormalities, including accumulation of complement C3, resulting in significant visual dysfunction [28].”

What the sources say

• Not checked yetcites [28] Coffey PJ, Gias C, McDermott CJ, Lundh P, Pickering MC, Sethi C, et al. Complement factor H deficiency in aged mice causes retinal abnormalities and visual dysfunction. Proc Natl Acad Sci U S A. 2007;104(42):16651–6. https://doi.org/10.1073/pnas.0705079104. source

In the paper

“Retinal degeneration induces upregulation of a cytokine and chemokine production whose expression is coordinated by Müller cells, microglia, and RPE [102].”

What the sources say

• Not checked yetcites [102] Rutar, Matt, Riccardo Natoli, RX Chia, Krisztina Valter, and Jan M Provis. 2015. “Chemokine-mediated inflammation in the degenerating retina is coordinated by Müller cells, activated microglia, and retinal pigment epithelium.” J Neuroinflammation 12 (1): 1–15. https://doi.org/10.1186/S12974-014-0224-1. source

In the paper

“Elevated CCL11 in the plasma and cerebrospinal fluid seen in aging mice and humans are associated with declining neurogenesis, neurodegenerative disease, and cognitive decline and may contribute to driving neovascularisation in AMD via interaction with CCR3 [1, 93, 123].”

What the sources say

• Not checked yetcites [1] Takeda A, Baffi JZ, Kleinman ME, Cho WG, Nozaki M, Yamada K, et al. CCR3 is a target for age-related macular degeneration diagnosis and therapy. Nature. 2009;460(7252):225–30. https://doi.org/10.1038/NATURE08151. source
• Not checked yetcites [93] Leung R, Proitsi P, Simmons A, Lunnon K, Güntert A, Kronenberg D, et al. Inflammatory proteins in plasma are associated with severity of Alzheimer’s disease. PLoS One. 2013;8(6). https://doi.org/10.1371/JOURNAL.PONE.0064971. source
• Not checked yetcites [123] Villeda LJ, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011;477(7362):90–6. https://doi.org/10.1038/nature10357. source

In the paper

“In addition, IL-1β is associated with the progression of retinal pathologies, including AMD [130].”

What the sources say

• Not checked yetcites [130] Zhao BY, Xie W, Shi X, Li F, Yang F, Sun Y, et al. Interleukin-1β level is increased in vitreous of patients with neovascular age-related macular degeneration (NAMD) and polypoidal choroidal vasculopathy (PCV). PLoS One. 2015;10(5). https://doi.org/10.1371/JOURNAL.PONE.0125150. source