NAD<sup>+</sup> supplementation rejuvenates aged gut adult stem cells

Igarashi, Masaki; Miura, Masaomi; Williams, Eric O.; Jaksch, Frank; Kadowaki, Tomoko; Yamauchi, Toshimasa; Guarente, Leonard

doi:10.1111/acel.12935

Cited by 112 publications

(103 citation statements)

References 31 publications

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“…Both SIRTs have been shown to regulate inflammation in the gut (Akimova et al, 2014;Lo Sasso et al, 2014;Wellman et al, 2017;Zhang et al, 2018). We found that compared with fetal EDMs, aged EDMs expressed less SIRT1 and 6 ( Fig 3B-Left, Middle), consistent with the previous observations of their decline in the aged gut (Liu et al, 2017a;Igarashi et al, 2019). Because age-associated changes in gut microbiome composition is correlated with increases in the pro-inflammatory marker serum monocyte chemoattractant protein (MCP-1) (Conley et al, 2016), which in turn has been implicated in aging-related macrophage dysfunction (Thevaranjan et al, 2017), we analyzed this cytokine in the aged EDMs.…”

Section: Resultssupporting

confidence: 90%

The stress polarity signaling (SPS) pathway serves as a marker and a target in the leaky gut barrier: implications in aging and cancer

et al. 2020

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The gut barrier separates trillions of microbes from the largest immune system in the body; when compromised, a "leaky" gut barrier fuels systemic inflammation, which hastens the progression of chronic diseases. Strategies to detect and repair the leaky gut barrier remain urgent and unmet needs. Recently, a stress-polarity signaling (SPS) pathway has been described in which the metabolic sensor, AMP-kinase acts via its effector, GIV (also known as Girdin) to augment epithelial polarity exclusively under energetic stress and suppresses tumor formation. Using murine and human colon-derived organoids, and enteroid-derived monolayers (EDMs) that are exposed to stressors, we reveal that the SPS-pathway is active in the intestinal epithelium and requires a catalytically active AMP-kinase. Its pharmacologic augmentation resists stress-induced collapse of the epithelium when challenged with microbes or microbial products. In addition, the SPS-pathway is suppressed in the aging gut, and its reactivation in enteroid-derived monolayers reverses aging-associated inflammation and loss of barrier function. It is also silenced during progression of colorectal cancers. These findings reveal the importance of the SPS-pathway in the gut and highlights its therapeutic potential for treating gut barrier dysfunction in aging, cancer, and dysbiosis.

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Section: Resultssupporting

confidence: 90%

The stress polarity signaling (SPS) pathway serves as a marker and a target in the leaky gut barrier: implications in aging and cancer

et al. 2020

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“…Treatment with the NAD + precursor nicotinamide riboside reverses this phenotype and can promote repair of gut damage. Strikingly, this effect is found to be blocked by rapamycin or the SIRT1 inhibitor EX527 (185). These findings obviously contrast with some of the others discussed above, and more work is needed to resolve these controversies.…”

Section: Aging In the Mammalian Intestinementioning

confidence: 71%

Intestinal Stem Cell Aging: Origins and Interventions

Jasper¹

2020

Annu. Rev. Physiol.

127

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Regenerative processes that maintain the function of the gastrointestinal (GI) epithelium are critical for health and survival of multicellular organisms. In insects and vertebrates, intestinal stem cells (ISCs) regenerate the GI epithelium. ISC function is regulated by intrinsic, local, and systemic stimuli to adjust regeneration to tissue demands. These control mechanisms decline with age, resulting in significant perturbation of intestinal homeostasis. Processes that lead to this decline have been explored intensively in Drosophila melanogaster in recent years and are now starting to be characterized in mammalian models. This review presents a model for age-related regenerative decline in the fly intestine and discusses recent findings that start to establish molecular mechanisms of age-related decline of mammalian ISC function. 203 Annu. Rev. Physiol. 2020.82:203-226. Downloaded from www.annualreviews.org Access provided by 44.224.250.200 on 07/08/20. For personal use only.

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“…Recent findings have highlighted age-related changes in the mammalian intestine and have begun to address the role stem cells may play in functional decline. [14][15][16][17] Specifically, ISCs from mouse, and potentially human beings, show a decrease in regenerative capacity as a result of decreased Wnt signaling. 16,17 Our data suggest that human SI and colon crypt cells differ with respect to epigenetic age; however, whether this is physiologically relevant, as determined by functional changes with age, remains to be tested.…”

Section: Discussionmentioning

confidence: 99%

“…In the mouse SI, aging is associated with decreased crypt repair after irradiation, decreasing ISC numbers, slower contribution of Lgr5þ cells to the intestinal epithelium as determined by in vivo fate-mapping experiments, and decreased organoid-forming capacity in vitro. [13][14][15] In addition, decreased Wnt signaling in aged animals impaired the ability of mouse ISCs to maintain homeostasis and contributed to decreased organoid-forming capacity in vitro. 16,17 By contrast, dietary restriction, a lifespan extending intervention, enhanced stem cell numbers and improved regenerative capacity, whereas short-term fasting enhances organoid formation in aged mice.…”

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confidence: 99%

DNA Methylation Analysis Validates Organoids as a Viable Model for Studying Human Intestinal Aging

Lewis

Nachun

Martı́n

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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We found that human intestinal organoids maintain the age of the patient from whom they are derived, as measured by the epigenetic clock. Unexpectedly, we found that crypts and spheroids derived from small intestine showed striking epigenetic age reduction, relative to the colon. BACKGROUND & AIMS:The epithelia of the intestine and colon turn over rapidly and are maintained by adult stem cells at the base of crypts. Although the small intestine and colon have distinct, well-characterized physiological functions, it remains unclear if there are fundamental regional differences in stem cell behavior or region-dependent degenerative changes during aging. Mesenchyme-free organoids provide useful tools for investigating intestinal stem cell biology in vitro and have started to be used for investigating agerelated changes in stem cell function. However, it is unknown whether organoids maintain hallmarks of age in the absence of an aging niche. We tested whether stem cell-enriched organoids preserved the DNA methylationbased aging profiles associated with the tissues and crypts from which they were derived. METHODS:To address this, we used standard human methylation arrays and the human epigenetic clock as a biomarker of age to analyze in vitro-derived, 3-dimensional, stem cell-enriched intestinal organoids. RESULTS:We found that human stem cell-enriched organoids maintained segmental differences in methylation patterns and that age, as measured by the epigenetic clock, also was maintained in vitro. Surprisingly, we found that stem cell-enriched organoids derived from the small intestine showed striking epigenetic age reduction relative to organoids derived from colon. CONCLUSIONS:Our data validate the use of organoids as a model for studying human intestinal aging and introduce methods that can be used when modeling aging or age-onset diseases in vitro. (Cell Mol Gastroenterol Hepatol 2020;9:527-541; https://doi.

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NAD⁺ supplementation rejuvenates aged gut adult stem cells

Cited by 112 publications

References 31 publications

The stress polarity signaling (SPS) pathway serves as a marker and a target in the leaky gut barrier: implications in aging and cancer

The stress polarity signaling (SPS) pathway serves as a marker and a target in the leaky gut barrier: implications in aging and cancer

Intestinal Stem Cell Aging: Origins and Interventions

DNA Methylation Analysis Validates Organoids as a Viable Model for Studying Human Intestinal Aging

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NAD+ supplementation rejuvenates aged gut adult stem cells

Cited by 112 publications

References 31 publications

The stress polarity signaling (SPS) pathway serves as a marker and a target in the leaky gut barrier: implications in aging and cancer

The stress polarity signaling (SPS) pathway serves as a marker and a target in the leaky gut barrier: implications in aging and cancer

Intestinal Stem Cell Aging: Origins and Interventions

DNA Methylation Analysis Validates Organoids as a Viable Model for Studying Human Intestinal Aging

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NAD⁺ supplementation rejuvenates aged gut adult stem cells