Intestinal Stem Cell Aging: Origins and Interventions

Abstract

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.

Tissue Adaptation to Environmental Cues by Symmetric and Asymmetric Division Modes of Intestinal Stem Cells

“…In both mammals and insects, aging of the intestine involves microbial dysbiosis, barrier dysfunction, and inflammation. However, whereas studies in mice, though still conflictual, suggest that ISC proliferate less with age [68][69][70][71], studies in Drosophila have clearly shown that ISC accelerate their proliferation rate [69,[72][73][74][75]. In old mice, a reduced capacity of the Lgr5+ ISC to proliferate is a consequence of increased mTORC1 signaling, which triggers the decline of Wnt/Wg signaling through the production of the extracellular Wnt inhibitor Notum [68,70] (Table 1).…”

“…However, whereas studies in mice, though still conflictual, suggest that ISC proliferate less with age [68][69][70][71], studies in Drosophila have clearly shown that ISC accelerate their proliferation rate [69,[72][73][74][75]. In old mice, a reduced capacity of the Lgr5+ ISC to proliferate is a consequence of increased mTORC1 signaling, which triggers the decline of Wnt/Wg signaling through the production of the extracellular Wnt inhibitor Notum [68,70] (Table 1). In aged Drosophila, loss of acidity in the lumen, induced by metaplasia in the acidic region of the midgut, and immuno-senescence provoke dysbiosis, which in turn triggers chronic elevation of ROS (reactive oxygen species) level in a DUOX-and Keap1/Nrf2-dependent manner [72,[74][75][76][77].…”

“…In addition, JNK in ISC induces the alignment of mitotic spindles in the planar plane, which makes ISC symmetric division a hallmark of aging contributing to the loss of tissue homeostasis in old animals. consequence of increased mTORC1 signaling, which triggers the decline of Wnt/Wg signaling through the production of the extracellular Wnt inhibitor Notum [68,70] (Table 1). In aged Drosophila, loss of acidity in the lumen, induced by metaplasia in the acidic region of the midgut, and immunosenescence provoke dysbiosis, which in turn triggers chronic elevation of ROS (reactive oxygen species) level in a DUOX-and Keap1/Nrf2-dependent manner [72,[74][75][76][77].…”

Impact des bioinsecticides à base de Bacillus thuringiensis sur le développement de cancers de l’intestin

“…En effet, lors du vieillissement, apparait une perte de diversité du microbiote, notamment de bactéries bénéfiques, ce qui provoque un déséquilibre (dysbiose) en faveur de bactéries pro-inflammatoires. Cette dysbiose entraine une activation chronique de plusieurs voies de signalisation inflammatoires, notamment les voies NF-κB (nuclear factor-kappa B) et JNK [9]. Ainsi, bactéries, inflammation, dysplasie et cancer sont étroitement liés, mettant en lumière l'importance de l'équilibre cellulaire et physiologique des cellules intestinales.…”

A Non-stop identity complex (NIC) supervises enterocyte identity and protects from pre-mature aging

“…Aging affects the entire midgut, and is associated with loss of EC identity, mis-differentiation of progenitors, pathological activation of the immune system, and loss of the physiological properties of the gut and its integrity. It also results in loss of intestinal compartmentalization, and microbiota-dysbiosis, all leading to reduced lifespan (Biteau et al 2010; Rera et al 2012; Bonnay et al 2013; Ferrandon, 2013; Chen et al 2014; Li, et al 2020; Rodriguez-Fernandezet al 2020; Jasper H. 2020). During aging, the protein levels of identity supervisors such as Hey and LamC decline, resulting in inability to maintain EC-gene programs and ectopic expression of previous- and non-relevant gene programs (Neves et al 2015; Takeda et al 2018; Flint-Brodsly et al 2019).…”