Emerging Interrelationship Between the Gut Microbiome and Cellular Senescence in the Context of Aging and Disease: Perspectives and Therapeutic Opportunities

Sharma, Rohit

doi:10.1007/s12602-021-09903-3

Cited by 39 publications

(26 citation statements)

References 179 publications

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“…Accumulation of senescence has been previously described to occur with ageing, in zebrafish, in a telomerase-dependent manner 55 . The senescence associated secretory phenotype has been described to include matrix metalloproteinases (MMPs), which are potential candidates for tissue destruction and could be involved in affecting gut permeability 106 . Additionally, impaired pathogen clearance may also lead to changes in the microbiome, which has also been implicated in disrupting intestinal permeability 107,108 .…”

Section: Discussionmentioning

confidence: 99%

A subset of gut leukocytes have telomerase-dependent “hyper-long” telomeres and require telomerase for function in zebrafish

Ellis

Martins

Thompson

et al. 2022

Preprint

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Telomerase, the enzyme capable of elongating telomeres, is usually restricted in human somatic cells, which contributes to progressive telomere shortening with cell-division and ageing. Using the zebrafish model, we show that subsets gut immune cells have telomerase-dependent 'hyper-long' telomeres, which we identified as being predominantly macrophages and dendritics (mpeg1.1+ and cd45+mhcII+). Notably, mpeg1.1+ macrophages have much longer telomeres in the gut than in their haematopoietic tissue of origin, suggesting that there is a gut-specific modulation of telomerase in these cells. Moreover, we show that a subset of gut mpeg1.1+ cells express telomerase (tert) in young WT zebrafish, but that the relative proportion of these cells decreases with ageing. Importantly, this is accompanied by telomere shortening and DNA damage responses with ageing and a telomerase-dependent decrease in expression of autophagy and immune activation markers. Finally, these telomerase-dependent molecular alterations are accompanied by impaired phagocytosis of E.coli and increased gut permeability in vivo. Together, our data show that limiting levels of telomerase lead to changes in gut immunity and gut permeability, which, together, are likely contributors to local and systemic tissue degeneration and increased susceptibility to infection with ageing.

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Section: Discussionmentioning

confidence: 99%

A subset of gut leukocytes have telomerase-dependent “hyper-long” telomeres and require telomerase for function in zebrafish

Ellis

Martins

Thompson

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Accumulation of senescence has been previously described to occur with ageing, in zebrafish, in a telomerase-dependent manner [ 55 ]. The senescence associated secretory phenotype has been described to include matrix metalloproteinases (MMPs), which are potential candidates for tissue destruction and could be involved in affecting gut permeability [ 108 ]. Additionally, impaired pathogen clearance may also lead to changes in the microbiome, which has also been implicated in disrupting intestinal permeability [ 109 , 110 ].…”

Section: Discussionmentioning

confidence: 99%

A subset of gut leukocytes has telomerase-dependent “hyper-long” telomeres and require telomerase for function in zebrafish

et al. 2022

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Background Telomerase, the enzyme capable of elongating telomeres, is usually restricted in human somatic cells, which contributes to progressive telomere shortening with cell-division and ageing. T and B-cells cells are somatic cells that can break this rule and can modulate telomerase expression in a homeostatic manner. Whereas it seems intuitive that an immune cell type that depends on regular proliferation outbursts for function may have evolved to modulate telomerase expression it is less obvious why others may also do so, as has been suggested for macrophages and neutrophils in some chronic inflammation disease settings. The gut has been highlighted as a key modulator of systemic ageing and is a key tissue where inflammation must be carefully controlled to prevent dysfunction. How telomerase may play a role in innate immune subtypes in the context of natural ageing in the gut, however, remains to be determined. Results Using the zebrafish model, we show that subsets of gut immune cells have telomerase-dependent”hyper-long” telomeres, which we identified as being predominantly macrophages and dendritics (mpeg1.1+ and cd45+mhcII+). Notably, mpeg1.1+ macrophages have much longer telomeres in the gut than in their haematopoietic tissue of origin, suggesting that there is modulation of telomerase in these cells, in the gut. Moreover, we show that a subset of gut mpeg1.1+ cells express telomerase (tert) in young WT zebrafish, but that the relative proportion of these cells decreases with ageing. Importantly, this is accompanied by telomere shortening and DNA damage responses with ageing and a telomerase-dependent decrease in expression of autophagy and immune activation markers. Finally, these telomerase-dependent molecular alterations are accompanied by impaired phagocytosis of E. coli and increased gut permeability in vivo. Conclusions Our data show that limiting levels of telomerase lead to alterations in gut immunity, impacting on the ability to clear pathogens in vivo. These are accompanied by increased gut permeability, which, together, are likely contributors to local and systemic tissue degeneration and increased susceptibility to infection with ageing. Graphical Abstract

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“…In conclusion, cellular senescence-mediated understanding of aging and age-dependent disorders is rapidly gaining attention as a viable therapeutic target (Soto-Gamez and Demaria, 2017 ). It is increasingly being realized that cellular senescence could be central to developing anti-aging strategies as evidence of its integration with other established age-related phenomena such as immunosenescence and gut dysbiosis is also emerging (Budamagunta et al, 2021 ; Sharma, 2022 ). Besides, the striking presence of cellular senescence in pathophysiologically distinct human disorders renews hope of a single targetable approach to disease management during aging.…”

Section: Secondary Diet Constituents and Cellular Senescencementioning

confidence: 99%

Nutritional components as mitigators of cellular senescence in organismal aging: a comprehensive review

Diwan

Sharma

2022

Food Sci Biotechnol

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The process of cellular senescence is rapidly emerging as a modulator of organismal aging and disease. Targeting the development and removal of senescent cells is considered a viable approach to achieving improved organismal healthspan and lifespan. Nutrition and health are intimately linked and an appropriate dietary regimen can greatly impact organismal response to stress and diseases including during aging. With a renewed focus on cellular senescence, emerging studies demonstrate that both primary and secondary nutritional elements such as carbohydrates, proteins, fatty acids, vitamins, minerals, polyphenols, and probiotics can influence multiple aspects of cellular senescence. The present review describes the recent molecular aspects of cellular senescence-mediated understanding of aging and then studies available evidence of the cellular senescence modulatory attributes of major and minor dietary elements. Underlying pathways and future research directions are deliberated to promote a nutrition-centric approach for targeting cellular senescence and thus improving human health and longevity.

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Emerging Interrelationship Between the Gut Microbiome and Cellular Senescence in the Context of Aging and Disease: Perspectives and Therapeutic Opportunities

Cited by 39 publications

References 179 publications

A subset of gut leukocytes have telomerase-dependent “hyper-long” telomeres and require telomerase for function in zebrafish

A subset of gut leukocytes have telomerase-dependent “hyper-long” telomeres and require telomerase for function in zebrafish

A subset of gut leukocytes has telomerase-dependent “hyper-long” telomeres and require telomerase for function in zebrafish

Nutritional components as mitigators of cellular senescence in organismal aging: a comprehensive review

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