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Journal of Cellular and Molecular... Sep 2023We are facing a growing aging population, along with increasing pressure on health systems, caused by the impact of chronic co-morbidities (i.e. cancer, cardiovascular... (Review)
Review
We are facing a growing aging population, along with increasing pressure on health systems, caused by the impact of chronic co-morbidities (i.e. cancer, cardiovascular and neurodegenerative diseases) and functional disabilities as people age. Relatively simple preventive lifestyle interventions, such as dietary restriction and physical exercise, are important contributors to active and healthy aging in the general population. However, as shown in model organisms or in 'in vitro' conditions, lifestyle-independent interventions may have additional health benefits and can even be conceived as possible reversers of the aging process. Thus, pharmaceutical laboratories, research institutes, and universities are putting more and more effort into finding new molecular pathways and druggable targets to develop gerotherapeutics. One approach is to target the driving mechanisms of aging, some of which, like cellular senescence and impaired autophagy, we discussed in an update on the biology of aging at AgingFit 2023 in Lille, France. We underline the importance of carefully and extensively testing senotherapeutics, given the pleiotropism and heterogeneity of targeted senescent cells within different organs, at different time frames. Other druggable targets emerging from new putative mechanisms, like those based on transcriptome imbalance, nucleophagy, protein phosphatase depletion, glutamine metabolism, or seno-antigenicity, have been evidenced by recent preclinical studies in classical models of aging but need to be validated in humans. Finally, we highlight several approaches in the discovery of biomarkers of healthy aging, as well as for the prediction of neurodegenerative diseases and the evaluation of rejuvenation strategies.
Topics: Humans; Aged; Longevity; Aging; Medicine; Biomedical Research; Cellular Senescence
PubMed: 37610311
DOI: 10.1111/jcmm.17912 -
EMBO Molecular Medicine Dec 2019Organismal ageing is a complex process driving progressive impairment of functionality and regenerative potential of tissues. Cellular senescence is a state of stable... (Review)
Review
Organismal ageing is a complex process driving progressive impairment of functionality and regenerative potential of tissues. Cellular senescence is a state of stable cell cycle arrest occurring in response to damage and stress and is considered a hallmark of ageing. Senescent cells accumulate in multiple organs during ageing, contribute to tissue dysfunction and give rise to pathological manifestations. Senescence is therefore a defining feature of a variety of human age-related disorders, including cancer, and targeted elimination of these cells has recently emerged as a promising therapeutic approach to ameliorate tissue damage and promote repair and regeneration. In addition, in vivo identification of senescent cells has significant potential for early diagnosis of multiple pathologies. Here, we review existing senolytics, small molecules and drug delivery tools used in preclinical therapeutic strategies involving cellular senescence, as well as probes to trace senescent cells. We also review the clinical research landscape in senescence and discuss how identifying and targeting cellular senescence might positively affect pathological and ageing processes.
Topics: Aging; Animals; Cellular Senescence; Humans; Translational Research, Biomedical
PubMed: 31746100
DOI: 10.15252/emmm.201810234 -
Experimental Eye Research Jun 2022Ageing has been defined as a specific individual plasticity and remodeling capacity to the environment' insults and stimuli. The precise physiology of aging is not... (Review)
Review
Ageing has been defined as a specific individual plasticity and remodeling capacity to the environment' insults and stimuli. The precise physiology of aging is not entirely understood. Several theories have been proposed and included programmed cell death, genetic mutations, the epigenetic clock, wear-and-tear and free radicals. Ocular surface represents a complex morpho-functional unit composed of different tissues that strictly interact to preserve homeostasis and function. Ageing severely disrupts this system by means of inflammaging and immunosenescence, leading to ocular surface failure in older population.
Topics: Aged; Aging; Apoptosis; Humans; Immunosenescence; Inflammation
PubMed: 35307396
DOI: 10.1016/j.exer.2022.109035 -
Molecular Oncology Sep 2022Advancing age is a major risk factor for malignant transformation and the development of cancer. As such, over 50% of neoplasms occur in individuals over the age of 70.... (Review)
Review
Advancing age is a major risk factor for malignant transformation and the development of cancer. As such, over 50% of neoplasms occur in individuals over the age of 70. The pathologies of both ageing and cancer have been characterized by respective groups of molecular hallmarks, and while some features are divergent between the two pathologies, several are shared. Perturbed mitochondrial function is one such common hallmark, and this observation therefore suggests that mitochondrial alterations may be of significance in age-related cancer development. There is now considerable evidence documenting the accumulation of somatic mitochondrial DNA (mtDNA) mutations in ageing human postmitotic and replicative tissues. Similarly, mutations of the mitochondrial genome have been reported in human cancers for decades. The plethora of functions in which mitochondria partake, such as oxidative phosphorylation, redox balance, apoptosis and numerous biosynthetic pathways, manifests a variety of ways in which alterations in mtDNA may contribute to tumour growth. However, the specific mechanisms by which mtDNA mutations contribute to tumour progression remain elusive and often contradictory. This review aims to consolidate current knowledge and describe future direction within the field.
Topics: Aging; DNA, Mitochondrial; Humans; Mitochondria; Mutation; Neoplasms
PubMed: 35842901
DOI: 10.1002/1878-0261.13291 -
Mechanisms of Ageing and Development Apr 2020Oncogene-induced senescence (OIS) is a powerful intrinsic tumor-suppressive mechanism, arresting cell cycle progression upon oncogene-activating genomic alterations. The... (Review)
Review
Oncogene-induced senescence (OIS) is a powerful intrinsic tumor-suppressive mechanism, arresting cell cycle progression upon oncogene-activating genomic alterations. The discovery and characterization of the senescence-associated secretome unveiled a rich additional complexity to the senescence phenotype, including extrinsic impacts on the microenvironment and engagement of the immune response. Emerging evidence suggests that senescence phenotypes vary depending on the oncogenic stimulus. Therefore, understanding the mechanisms underlying OIS and how they are subverted in cancer will provide invaluable opportunities to identify alternative strategies for treating oncogene-driven cancers. In this review, we primarily discuss the key mechanisms governing OIS driven by the RAS/MAPK and PI3K/AKT pathways and how understanding the biology of senescent cells has uncovered new therapeutic possibilities to target cancer.
Topics: Aging; Animals; Cellular Senescence; Humans; Neoplasms; Oncogenes; Signal Transduction; Tumor Microenvironment
PubMed: 32171687
DOI: 10.1016/j.mad.2020.111229 -
Histology and Histopathology Jun 2023Ageing is a biological process caused by the malfunctioning of multiple cellular mechanisms, ascribable to nine hallmarks: genomic instability, telomere attrition,... (Review)
Review
Ageing is a biological process caused by the malfunctioning of multiple cellular mechanisms, ascribable to nine hallmarks: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. These ageing pillars have three common traits: (i) they appear during normal ageing; (ii) their experimental intensification accelerates ageing; and (iii) their experimental reduction delays ageing. The evidence that the elderly are more prone to develop pathologies such as cancer, diabetes and degenerative diseases, together with data showing that the elderly population is steadily increasing, has stimulated an important effort to find specific countermeasures to physiological ageing. Unfortunately, the investigation of ageing processes and the search for countermeasures in humans is very difficult. Therefore, researchers must rely on a wide range of experimental models that span from unicellular to more complex organisms. Unfortunately, experimental models are not devoid of pitfalls, flaws or obstacles that can have an impact in ageing research. In the present review we describe the most exploited experimental models in the field, such as in vitro, animal and human models, highlighting the characteristics that justify their application in the laboratory routine, and translation to human research.
Topics: Aged; Animals; Humans; Aging; Cellular Senescence; Cell Communication; Stem Cells; Telomere
PubMed: 36602135
DOI: 10.14670/HH-18-576 -
Developmental Biology Aug 2021Recent advances in rapid medical detection and diagnostic technology have extended both human health and life expectancy. However, ageing remains one of the critical... (Review)
Review
Recent advances in rapid medical detection and diagnostic technology have extended both human health and life expectancy. However, ageing remains one of the critical risk factors in contributing to major incapacitating and fatal conditions, including cancer and neurodegeneration. Therefore, it is vital to study how ageing attributes to (or participates in) endangering human health via infliction of age-related diseases and what must be done to tackle this intractable process. This review encompasses the most recent literature elaborating the role of cell competition (CC) during ageing. CC is a process that occurs between two heterogeneous populations, where the cells with higher fitness levels have a competitive advantage over the neighbouring cells that have comparatively lower fitness levels. This interaction results in the selection of the fit cells, within a population, and elimination of the viable yet suboptimal cells. Therefore, it is tempting to speculate that, if this quality control mechanism works efficiently throughout life, can it ultimately lead to a healthier ageing and extended lifespan. Furthermore, the review aims to collate all the important state of the art publications that provides evidence of the relevance of CC in dietary restriction, stem cell dynamics, and cell senescence, thus, prompting us to advocate its contribution and in exploring new avenues and opportunities in fighting age-related conditions.
Topics: Aging; Animals; Cell Communication; Cell Competition; Cellular Senescence; Humans; Neoplasms
PubMed: 33753080
DOI: 10.1016/j.ydbio.2021.03.009 -
Ageing Research Reviews Jul 2023Ageing is a physiological/pathological process accompanied by the progressive damage of cell function, triggering various ageing-related disorders. Phosphatidylinositol... (Review)
Review
Ageing is a physiological/pathological process accompanied by the progressive damage of cell function, triggering various ageing-related disorders. Phosphatidylinositol 3-kinase (PI3K), which serves as one of the central regulators of ageing, is closely associated with cellular characteristics or molecular features, such as genome instability, telomere erosion, epigenetic alterations, and mitochondrial dysfunction. In this review, the PI3K signalling pathway was firstly thoroughly explained. The link between ageing pathogenesis and the PI3K signalling pathway was then summarized. Finally, the key regulatory roles of PI3K in ageing-related illnesses were investigated and stressed. In summary, we revealed that drug development and clinical application targeting PI3K is one of the focal points for delaying ageing and treating ageing-related diseases in the future.
Topics: Phosphatidylinositol 3-Kinase; Humans; Animals; Signal Transduction; Aging; Neurodegenerative Diseases; Metabolic Diseases; Heart Diseases; Neoplasms
PubMed: 37245633
DOI: 10.1016/j.arr.2023.101963 -
Ageing Research Reviews Dec 2022The prevalence of eye diseases increases considerably with age, resulting in significant vision impairment. Although the pathobiology of age-related eye diseases has... (Review)
Review
The prevalence of eye diseases increases considerably with age, resulting in significant vision impairment. Although the pathobiology of age-related eye diseases has been studied extensively, the contribution of immune-related changes due to aging remains elusive. In the eye, tissue-resident cells and infiltrating immune cells regulate innate responses during injury or infection. But due to aging, these cells lose their protective functions and acquire pathological phenotypes. Thus, dysregulated ocular innate immunity in the elderly increases the susceptibility and severity of eye diseases. Herein, we emphasize the impact of aging on the ocular innate immune system in the pathogenesis of infectious and non-infectious eye diseases. We discuss the role of age-related alterations in cellular metabolism, epigenetics, and cellular senescence as mechanisms underlying altered innate immune functions. Finally, we describe approaches to restore protective innate immune functions in the aging eye. Overall, the review summarizes our current understanding of innate immune functions in eye diseases and their dysregulation during aging.
Topics: Humans; Aging; Immunity, Innate; Immune System; Cellular Senescence; Eye Diseases
PubMed: 36280210
DOI: 10.1016/j.arr.2022.101768 -
F1000Research 2019The field of aging research has progressed significantly over the past decades. Exogenously and endogenously inflicted molecular damage ranging from genotoxic to... (Review)
Review
The field of aging research has progressed significantly over the past decades. Exogenously and endogenously inflicted molecular damage ranging from genotoxic to organellar damage drives the aging process. Repair mechanisms and compensatory responses counteract the detrimental consequences of the various damage types. Here, we discuss recent progress in understanding cellular mechanisms and interconnections between signaling pathways that control longevity. We summarize cell-autonomous and non-cell-autonomous mechanisms that impact the cellular and organismal aging process.
Topics: Aging; DNA Damage; Humans; Longevity; Signal Transduction
PubMed: 31448092
DOI: 10.12688/f1000research.19610.1