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Mechanisms of Age-Related Intestinal Decline and Its Role in Alzheimer's Disease.

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	Mechanisms of Age-Related Intestinal Decline and Its Role in Alzheimer's Disease./
Author:	Wang, Ruixuan.
Description:	1 online resource (248 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 85-11, Section: B.
Contained By:	Dissertations Abstracts International85-11B.
Subject:	Aging. -
Online resource:	click for full text (PQDT)
ISBN:	9798382583440

Mechanisms of Age-Related Intestinal Decline and Its Role in Alzheimer's Disease.
Wang, Ruixuan.

Mechanisms of Age-Related Intestinal Decline and Its Role in Alzheimer's Disease. - 1 online resource (248 pages)

Source: Dissertations Abstracts International, Volume: 85-11, Section: B.

Thesis (Ph.D.)--Albert Einstein College of Medicine, 2024.

Includes bibliographical references

Aging is associated with progressive systemic decline and increased frailty, making it a major underlying risk factor for multiple diseases such as cardiovascular disease, cancer, and Alzheimer's Disease (AD). The dramatic increase in the aging population has placed a significant burden on healthcare, social, and economic systems. Therefore, understanding the mechanisms of aging and its relationship to age-related diseases is crucial to increasing lifespan and healthspan.The gut plays an important role in maintaining homeostasis, and intestinal stem cell (ISC) function declines with age. However, little is known about the extent to which ISC aging is attributable to cell non-autonomous factors. Consistent with recent publications, we observed a notable reduction in ISC function via various assays in mice. Remarkably, this ISC aging phenotype can be transposed from old to young mice through heterochronic parabiosis. We further discovered that strategies aimed at alleviating systemic inflammation could consistently rescue ISC function in old mice. Direct exposure of young organoids to pro-inflammatory factors, including TNFα, was capable of disrupting organoid formation. Direct provision of TNFα to mature organoids impaired de novo crypt budding. A parabiotic rescue model leveraging young intestinal epithelial-specific TNFR1 knockout mice conferred protection against the old environment on ISC function. Mechanistically, we discovered that overnight TNFα treatment to young organoids led to a decrease in a multitude of genes required for mitochondrial function, particularly those required for coordinating fatty acid uptake and oxidation via TNFR1 signaling. Overall, our data suggest TNFα acts as a pro-geronic factor in non-pathogenic, aging gut that impairs ISC function. This study also reveals that ISC aging correlates with at least two hallmarks of aging - inflammation and mitochondrial dysfunction - providing insights into the complex mechanisms of aging and potential interventions to rejuvenate ISC aging.Our second aim focuses on the role of intestinal dysfunction as an underlying factor in Alzheimer's Disease (AD). AD is one of the neurodegenerative diseases where aging is a major contributing factor, although the underlying mechanisms are still being uncovered. The gut-brain axis is increasingly appreciated in brain aging and neurodegenerative conditions, making the intestine a potentially effective target for AD. To better understand the role of the intestine in AD pathogenesis, we employed a robust transgenic amyloid mouse model 5XFAD and fed them with the gut-specific anti-inflammatory agent, 5- aminosalicylate acid (5-ASA), starting at 6 weeks old. 5-ASA acts specifically on the intestine as an anti-inflammatory drug and is poorly absorbed into the circulation at the treatment dosage. We found that 5-ASA-treated mice had ameliorated amyloid burden along with fewer activated microglia, which corresponded to improved anxiety and depressive-like symptoms. While 16S sequencing revealed a distinct flora in 5XFAD female mice versus controls, a matched function PCoA plot suggested 5-ASA restored predicted function to wild type controls. 5-ASA effectively triggered the expression of PPARγ and related genes, though effects were blunted in 5XFAD. Overall, 5-ASA alleviates pathology and symptoms in 5XFAD mice, suggesting that dysregulation and dysbiosis in the gut-brain axis are underlying, but treatable targets for AD.In summary, we have shown that ISC aging can be mediated by aging environment and it is malleable and reversible. TNFα acts as a pro-geronic factor via TNFR1 signaling, impairing ISC function by interrogating fatty acid oxidation, which extends previous understanding of ISC aging. We also showed that 5-ASA, one of the oldest anti-inflammatory agents in use today, could slow the pathology and symptoms of 5XFAD mice effectively. This further sheds light on the potential of gut-specific anti-inflammatory drugs in modulating AD pathology via the gut-brain axis as potentially complementary means of targeting neurodegenerative diseases.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798382583440Subjects--Topical Terms:

559847
Aging.
Subjects--Index Terms:

Alzheimer's DiseaseIndex Terms--Genre/Form:

554714
Electronic books.

Mechanisms of Age-Related Intestinal Decline and Its Role in Alzheimer's Disease.
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