Abstract:The biology of aging is focused on the identification of novel pathways that regulate the underlying processes of aging to develop interventions aimed at delaying the onset and progression of chronic diseases to extend lifespan. However, the research on the aging field has been conducted mainly in animal models, yeast, Caenorhabditis elegans, and cell cultures. Thus, it is unclear to what extent this knowledge is transferable to humans since they might not reflect the complexity of aging in people. An organoid… Show more
“…These challenges lead researchers to study senescent cells in vitro ( González-Gualda et al, 2021 ) however, as discussed above, 2D cell cultures do not reflect the true representation of human aging. Very recently, researchers have been focused on more advanced methods to study senescence and one of the most promising techniques to study CS is proposed as 3D organoid cultures ( Torrens-Mas et al, 2021 ). Organoid systems are simplified organs developed to model many human tissues and diseases ( Hu et al, 2018 ), reconstructing physiological 3D tissue structure and cellular composition in vitro ( Simian and Bissell, 2017 ).…”
Section: The Tools Of Cellular Senescence Researchmentioning
confidence: 99%
“…Since organoids have the ability to histologically recapitulate human tissues in vivo , this technology holds the potential to test potential longevity drugs that target the hallmarks of aging including CS, while paving the way to personalized interventions. However, organoid cultures also lack some physiological features of the organisms such as vascularization and further developments are needed to better represent the physiology of human aging ( Torrens-Mas et al, 2021 ).…”
Section: The Tools Of Cellular Senescence Researchmentioning
Increasing chronological age is the greatest risk factor for human diseases. Cellular senescence (CS), which is characterized by permanent cell-cycle arrest, has recently emerged as a fundamental mechanism in developing aging-related pathologies. During the aging process, senescent cell accumulation results in senescence-associated secretory phenotype (SASP) which plays an essential role in tissue dysfunction. Although discovered very recently, senotherapeutic drugs have been already involved in clinical studies. This review gives a summary of the molecular mechanisms of CS and its role particularly in the development of cardiovascular diseases (CVD) as the leading cause of death. In addition, it addresses alternative research tools including the nonhuman and human models as well as computational techniques for the discovery of novel therapies. Finally, senotherapeutic approaches that are mainly classified as senolytics and senomorphics are discussed.
“…These challenges lead researchers to study senescent cells in vitro ( González-Gualda et al, 2021 ) however, as discussed above, 2D cell cultures do not reflect the true representation of human aging. Very recently, researchers have been focused on more advanced methods to study senescence and one of the most promising techniques to study CS is proposed as 3D organoid cultures ( Torrens-Mas et al, 2021 ). Organoid systems are simplified organs developed to model many human tissues and diseases ( Hu et al, 2018 ), reconstructing physiological 3D tissue structure and cellular composition in vitro ( Simian and Bissell, 2017 ).…”
Section: The Tools Of Cellular Senescence Researchmentioning
confidence: 99%
“…Since organoids have the ability to histologically recapitulate human tissues in vivo , this technology holds the potential to test potential longevity drugs that target the hallmarks of aging including CS, while paving the way to personalized interventions. However, organoid cultures also lack some physiological features of the organisms such as vascularization and further developments are needed to better represent the physiology of human aging ( Torrens-Mas et al, 2021 ).…”
Section: The Tools Of Cellular Senescence Researchmentioning
Increasing chronological age is the greatest risk factor for human diseases. Cellular senescence (CS), which is characterized by permanent cell-cycle arrest, has recently emerged as a fundamental mechanism in developing aging-related pathologies. During the aging process, senescent cell accumulation results in senescence-associated secretory phenotype (SASP) which plays an essential role in tissue dysfunction. Although discovered very recently, senotherapeutic drugs have been already involved in clinical studies. This review gives a summary of the molecular mechanisms of CS and its role particularly in the development of cardiovascular diseases (CVD) as the leading cause of death. In addition, it addresses alternative research tools including the nonhuman and human models as well as computational techniques for the discovery of novel therapies. Finally, senotherapeutic approaches that are mainly classified as senolytics and senomorphics are discussed.
“…Telomere shortening is also a hallmark of the aged intestine and predisposes to age-related intestinal disease. While studies in organoids derived from the elderly have shown reduced formation efficiency 85 , indicative of a stem cell compromise, the effect of telomere shortening on differentiation and function of the intestine is not known. In particular, a region-specific analysis would be important, as heterogeneity in telomere length is observed in the intestine, including shorter telomeres in neoblastic adenomas that are invariably characterized by inflammation 86 .…”
Intestinal epithelium dysfunction causes barrier defects, malabsorption and dysbiosis, predicting local and systemic disease, morbidity and mortality in humans. However, the underlying causes are not well understood. Here we show that telomere shortening is a host intrinsic factor that impairs enterocyte differentiation. The presence of such undifferentiated enterocytes is associated with barrier disruption and malabsorption of nutrients such as fructose. A fructose-rich diet causes increased fructose spillover to the colon and induces colitis in a microbiome-dependent manner. The microbiome uses fructose to synthesize essential metabolites, including NAD precursors, that complement the host s low NAD pool in the inflamed colon. Thus, telomere shortening drives enterocyte dysfunction and predisposes to diet-induced colitis through barrier disruption, increased nutrient flux to the colon and modulation of the microbiome. This differerentiation defect expands the canonical stem cell failure-centered view of how telomere shortening impacts the intestine and predisposes to intestinal disease in conditions associated with short telomeres.
“…However, brain organoids resemble the prenatal brain, which limits the ability of these organoids to model the mature brain ( 143 ). Therefore, developing reliable strategies to age brain organoids will be crucial for studying ageing-related disorders such as AD and PD ( 144 , 145 ).…”
Microglia, the macrophages of the brain, are vital for brain homeostasis and have been implicated in a broad range of brain disorders. Neuroinflammation has gained traction as a possible therapeutic target for neurodegeneration, however, the precise function of microglia in specific neurodegenerative disorders is an ongoing area of research. Genetic studies offer valuable insights into understanding causality, rather than merely observing a correlation. Genome-wide association studies (GWAS) have identified many genetic loci that are linked to susceptibility to neurodegenerative disorders. (Post)-GWAS studies have determined that microglia likely play an important role in the development of Alzheimer’s disease (AD) and Parkinson’s disease (PD). The process of understanding how individual GWAS risk loci affect microglia function and mediate susceptibility is complex. A rapidly growing number of publications with genomic datasets and computational tools have formulated new hypotheses that guide the biological interpretation of AD and PD genetic risk. In this review, we discuss the key concepts and challenges in the post-GWAS interpretation of AD and PD GWAS risk alleles. Post-GWAS challenges include the identification of target cell (sub)type(s), causal variants, and target genes. Crucially, the prediction of GWAS-identified disease-risk cell types, variants and genes require validation and functional testing to understand the biological consequences within the pathology of the disorders. Many AD and PD risk genes are highly pleiotropic and perform multiple important functions that might not be equally relevant for the mechanisms by which GWAS risk alleles exert their effect(s). Ultimately, many GWAS risk alleles exert their effect by changing microglia function, thereby altering the pathophysiology of these disorders, and hence, we believe that modelling this context is crucial for a deepened understanding of these disorders.
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