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The Journal of Clinical Investigation Jul 2022Mitochondrial dysfunction and cell senescence are hallmarks of aging and are closely interconnected. Mitochondrial dysfunction, operationally defined as a decreased... (Review)
Review
Mitochondrial dysfunction and cell senescence are hallmarks of aging and are closely interconnected. Mitochondrial dysfunction, operationally defined as a decreased respiratory capacity per mitochondrion together with a decreased mitochondrial membrane potential, typically accompanied by increased production of oxygen free radicals, is a cause and a consequence of cellular senescence and figures prominently in multiple feedback loops that induce and maintain the senescent phenotype. Here, we summarize pathways that cause mitochondrial dysfunction in senescence and aging and discuss the major consequences of mitochondrial dysfunction and how these consequences contribute to senescence and aging. We also highlight the potential of senescence-associated mitochondrial dysfunction as an antiaging and antisenescence intervention target, proposing the combination of multiple interventions converging onto mitochondrial dysfunction as novel, potent senolytics.
Topics: Cellular Senescence; Mitochondria; Phenotype
PubMed: 35775483
DOI: 10.1172/JCI158447 -
Nature Reviews. Cardiology Jan 2023Endothelial cells are located at the crucial interface between circulating blood and semi-solid tissues and have many important roles in maintaining systemic... (Review)
Review
Endothelial cells are located at the crucial interface between circulating blood and semi-solid tissues and have many important roles in maintaining systemic physiological function. The vascular endothelium is particularly susceptible to pathogenic stimuli that activate tumour suppressor pathways leading to cellular senescence. We now understand that senescent endothelial cells are highly active, secretory and pro-inflammatory, and have an aberrant morphological phenotype. Moreover, endothelial senescence has been identified as an important contributor to various cardiovascular and metabolic diseases. In this Review, we discuss the consequences of endothelial cell exposure to damaging stimuli (haemodynamic forces and circulating and endothelial-derived factors) and the cellular and molecular mechanisms that induce endothelial cell senescence. We also discuss how endothelial cell senescence causes arterial dysfunction and contributes to clinical cardiovascular diseases and metabolic disorders. Finally, we summarize the latest evidence on the effect of eliminating senescent endothelial cells (senolysis) and identify important remaining questions to be addressed in future studies.
Topics: Humans; Endothelial Cells; Cellular Senescence; Endothelium, Vascular; Cardiovascular Diseases
PubMed: 35853997
DOI: 10.1038/s41569-022-00739-0 -
Wounds : a Compendium of Clinical... Jun 2017Cellular senescence is a process that results from a variety of stresses and leads to a state of irreversible growth arrest. Senescent cells accumulate during aging and... (Review)
Review
Cellular senescence is a process that results from a variety of stresses and leads to a state of irreversible growth arrest. Senescent cells accumulate during aging and have been implicated in promoting a variety of age-related diseases. Cellular senescence may play an important role in tumor suppression, wound healing, and protection against tissue fibrosis; however, accumulating evidence that senescent cells may have harmful effects in vivo and may contribute to tissue remodeling, organismal aging, and many age-related diseases also exists. Cellular senescence can be induced by various intrinsic and extrinsic factors. The pathways for the proteins p53/p21 and p16Ink4a/retinoblastoma protein are important for irreversible growth arrest and senescent cells. Senescent cells secrete numerous biologically active factors; the specific secretion phenotype by senescent cell contributes to physiological and pathological consequences in organisms. The purpose of this article is to review the molecular basis of cell-cycle arrest and the senescent-associated secretory phenotype within these cells contributing to pathological consequences.
Topics: Aging; Cell Cycle Checkpoints; Cell Transformation, Neoplastic; Cellular Senescence; Chronic Disease; DNA Damage; Humans; Phenotype; Secretory Pathway; Wnt Signaling Pathway; Wound Healing
PubMed: 28682291
DOI: No ID Found -
International Journal of Molecular... Feb 2022Aging is the greatest risk factor for late-onset Alzheimer's disease (LOAD), which accounts for >95% of Alzheimer's disease (AD) cases. The mechanism underlying the... (Review)
Review
Aging is the greatest risk factor for late-onset Alzheimer's disease (LOAD), which accounts for >95% of Alzheimer's disease (AD) cases. The mechanism underlying the aging-related susceptibility to LOAD is unknown. Cellular senescence, a state of permanent cell growth arrest, is believed to contribute importantly to aging and aging-related diseases, including AD. Senescent astrocytes, microglia, endothelial cells, and neurons have been detected in the brain of AD patients and AD animal models. Removing senescent cells genetically or pharmacologically ameliorates β-amyloid (Aβ) peptide and tau-protein-induced neuropathologies, and improves memory in AD model mice, suggesting a pivotal role of cellular senescence in AD pathophysiology. Nonetheless, although accumulated evidence supports the role of cellular senescence in aging and AD, the mechanisms that promote cell senescence and how senescent cells contribute to AD neuropathophysiology remain largely unknown. This review summarizes recent advances in this field. We believe that the removal of senescent cells represents a promising approach toward the effective treatment of aging-related diseases, such as AD.
Topics: Aging; Alzheimer Disease; Animals; Astrocytes; Brain; Cellular Senescence; Humans; Neurons
PubMed: 35216123
DOI: 10.3390/ijms23041989 -
International Journal of Molecular... Dec 2021Cellular senescence entails a state of an essentially irreversible proliferative arrest in which cells remain metabolically active and secrete a range of... (Review)
Review
Cellular senescence entails a state of an essentially irreversible proliferative arrest in which cells remain metabolically active and secrete a range of pro-inflammatory and proteolytic factors as part of the senescence-associated secretory phenotype. There are different types of senescent cells, and senescence can be induced in response to many DNA damage signals. Senescent cells accumulate in different tissues and organs where they have distinct physiological and pathological functions. Despite this diversity, all senescent cells must be able to survive in a nondividing state while protecting themselves from positive feedback loops linked to the constant activation of the DNA damage response. This capacity requires changes in core cellular programs. Understanding how different cell types can undergo extensive changes in their transcriptional programs, metabolism, heterochromatin patterns, and cellular structures to induce a common cellular state is crucial to preventing cancer development/progression and to improving health during aging. In this review, we discuss how senescent cells continuously evolve after their initial proliferative arrest and highlight the unifying features that define the senescent state.
Topics: Aging; Animals; Cellular Senescence; DNA Damage; Humans; Inflammation; Senescence-Associated Secretory Phenotype; Signal Transduction
PubMed: 34884978
DOI: 10.3390/ijms222313173 -
Stem Cells Translational Medicine Apr 2022Aging is a multifaceted and complicated process, manifested by a decline of normal physiological functions across tissues and organs, leading to overt frailty,... (Review)
Review
Aging is a multifaceted and complicated process, manifested by a decline of normal physiological functions across tissues and organs, leading to overt frailty, mortality, and chronic diseases, such as skeletal, cardiovascular, and cognitive disorders, necessitating the development of practical therapeutic approaches. Stem cell aging is one of the leading theories of organismal aging. For decades, mesenchymal stem/stromal cells (MSCs) have been regarded as a viable and ideal source for stem cell-based therapy in anti-aging treatment due to their outstanding clinical characteristics, including easy accessibility, simplicity of isolation, self-renewal and proliferation ability, multilineage differentiation potentials, and immunomodulatory effects. Nonetheless, as evidenced in numerous studies, MSCs undergo functional deterioration and gradually lose stemness with systematic age in vivo or extended culture in vitro, limiting their therapeutic applications. Even though our understanding of the processes behind MSC senescence remains unclear, significant progress has been achieved in elucidating the aspects of the age-related MSC phenotypic changes and possible mechanisms driving MSC senescence. In this review, we aim to summarize the current knowledge of the morphological, biological, and stem-cell marker alterations of aging MSCs, the cellular and molecular mechanisms that underlie MSC senescence, the recent progress made regarding the innovative techniques to rejuvenate senescent MSCs and combat aging, with a particular focus on the interplay between aging MSCs and their niche as well as clinical translational relevance. Also, we provide some promising and novel directions for future research concerning MSC senescence.
Topics: Biomarkers; Cell Differentiation; Cellular Senescence; Mesenchymal Stem Cells
PubMed: 35485439
DOI: 10.1093/stcltm/szac004 -
Aging Cell Apr 2021The field of research on cellular senescence experienced a rapid expansion from being primarily focused on in vitro aspects of aging to the vast territories of animal... (Review)
Review
The field of research on cellular senescence experienced a rapid expansion from being primarily focused on in vitro aspects of aging to the vast territories of animal and clinical research. Cellular senescence is defined by a set of markers, many of which are present and accumulate in a gradual manner prior to senescence induction or are found outside of the context of cellular senescence. These markers are now used to measure the impact of cellular senescence on aging and disease as well as outcomes of anti-senescence interventions, many of which are at the stage of clinical trials. It is thus of primary importance to discuss their specificity as well as their role in the establishment of senescence. Here, the presence and role of senescence markers are described in cells prior to cell cycle arrest, especially in the context of replicative aging and in vivo conditions. Specifically, this review article seeks to describe the process of "cellular aging": the progression of internal changes occurring in primary cells leading to the induction of cellular senescence and culminating in cell death. Phenotypic changes associated with aging prior to senescence induction will be characterized, as well as their effect on the induction of cell senescence and the final fate of cells reviewed. Using published datasets on assessments of senescence markers in vivo, it will be described how disparities between quantifications can be explained by the concept of cellular aging. Finally, throughout the article the applicational value of broadening cellular senescence paradigm will be discussed.
Topics: Aging; Animals; Biomarkers; Cell Cycle Checkpoints; Cell Division; Cell Proliferation; Cell Size; Cellular Senescence; DNA Breaks, Double-Stranded; Humans; Phenotype; Telomere Shortening
PubMed: 33711211
DOI: 10.1111/acel.13338 -
The Journal of Cell Biology Jan 2018Aging is the major risk factor for cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. Although we are far from understanding the biological basis... (Review)
Review
Aging is the major risk factor for cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. Although we are far from understanding the biological basis of aging, research suggests that targeting the aging process itself could ameliorate many age-related pathologies. Senescence is a cellular response characterized by a stable growth arrest and other phenotypic alterations that include a proinflammatory secretome. Senescence plays roles in normal development, maintains tissue homeostasis, and limits tumor progression. However, senescence has also been implicated as a major cause of age-related disease. In this regard, recent experimental evidence has shown that the genetic or pharmacological ablation of senescent cells extends life span and improves health span. Here, we review the cellular and molecular links between cellular senescence and aging and discuss the novel therapeutic avenues that this connection opens.
Topics: Aging; Animals; Cellular Senescence; Humans; Mice; Telomere; Telomere Homeostasis
PubMed: 29114066
DOI: 10.1083/jcb.201708092 -
The Canadian Journal of Cardiology May 2016The sirtuins (SIRTs) constitute a class of proteins with nicotinamide adenine dinucleotide-dependent deacetylase or adenosine diphosphate-ribosyltransferase activity.... (Review)
Review
The sirtuins (SIRTs) constitute a class of proteins with nicotinamide adenine dinucleotide-dependent deacetylase or adenosine diphosphate-ribosyltransferase activity. Seven SIRT family members have been identified in mammals, from SIRT1, the best studied for its role in vascular aging, to SIRT7. SIRT1 and SIRT2 are localized in the nucleus and cytoplasm. SIRT3, SIRT4, and SIRT5 are mitochondrial, and SIRT6 and SIRT7 are nuclear. Extensive studies have clearly revealed that SIRT proteins regulate diverse cell functions and responses to stressors. Vascular aging involves the aging process (senescence) of endothelial and vascular smooth muscle cells. Two types of cell senescence have been identified: (1) replicative senescence with telomere attrition; and (2) stress-induced premature senescence without telomere involvement. Both types of senescence induce vascular cell growth arrest and loss of vascular homeostasis, and contribute to the initiation and progression of cardiovascular diseases. Previous mechanistic studies have revealed in detail that SIRT1, SIRT3, and SIRT6 show protective functions against vascular aging, and definite vascular function of other SIRTs is under investigation. Thus, direct SIRT modulation and nicotinamide adenine dinucleotide stimulation of SIRT are promising candidates for cardiovascular disease therapy. A small number of pilot studies have been conducted to assess SIRT modulation in humans. These clinical studies have not yet provided convincing evidence that SIRT proteins alleviate morbidity and mortality in patients with cardiovascular diseases. The outcomes of multiple ongoing clinical trials are awaited to define the efficacy of SIRT modulators and SIRT activators in cardiovascular diseases, along with the potential adverse effects of chronic SIRT modulation.
Topics: Aging; Cardiovascular Diseases; Cell Survival; Cellular Senescence; Endothelium, Vascular; Homeostasis; Humans; Myocytes, Smooth Muscle; Sirtuins; Telomere
PubMed: 26948035
DOI: 10.1016/j.cjca.2015.11.022 -
Cell Cycle (Georgetown, Tex.) Jul 2022A hallmark of cellular senescence is proliferation-like activity of growth-promoting pathways (such as mTOR and MAPK) in non-proliferating cells. When the cell cycle is... (Review)
Review
A hallmark of cellular senescence is proliferation-like activity of growth-promoting pathways (such as mTOR and MAPK) in non-proliferating cells. When the cell cycle is arrested, these pathways convert arrest to senescence (geroconversion), rendering cells hypertrophic, beta-Gal-positive and hyperfunctional. The senescence-associated secretory phenotype (SASP) is one of the numerous hyperfunctions. Figuratively, geroconversion is a continuation of growth in non-proliferating cells. Rapamycin, a reversible inhibitor of growth, slows down mTOR-driven geroconversion. Developed two decades ago, this model had accurately predicted that rapamycin must extend life span of animals. However, the notion that senescent cells directly cause organismal aging is oversimplified. Senescent cells contribute to organismal aging but are not strictly required. Cell senescence and organismal aging can be linked indirectly via the same underlying cause, namely hyperfunctional signaling pathways such as mTOR.
Topics: Aging; Animals; Cell Proliferation; Cellular Senescence; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 35358003
DOI: 10.1080/15384101.2022.2054636