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Pharmacological Reviews Jul 2023An increase in life expectancy in developed countries has led to a surge of chronic aging-related diseases. In the last few decades, several studies have provided... (Review)
Review
An increase in life expectancy in developed countries has led to a surge of chronic aging-related diseases. In the last few decades, several studies have provided evidence of the prominent role of cellular senescence in many of these pathologies. Key traits of senescent cells include cell cycle arrest, apoptosis resistance, and secretome shift to senescence-associated secretory phenotype resulting in increased secretion of various intermediate bioactive factors important for senescence pathophysiology. However, cellular senescence is a highly phenotypically heterogeneous process, hindering the discovery of totally specific and accurate biomarkers. Also, strategies to prevent the pathologic effect of senescent cell accumulation during aging by impairing senescence onset or promoting senescent cell clearance have shown great potential during in vivo studies, and some are already in early stages of clinical translation. The adaptability of these senotherapeutic approaches to human application has been questioned due to the lack of proper senescence targeting and senescence involvement in important physiologic functions. In this review, we explore the heterogeneous phenotype of senescent cells and its influence on the expression of biomarkers currently used for senescence detection. We also discuss the current evidence regarding the efficacy, reliability, development stage, and potential for human applicability of the main existing senotherapeutic strategies. SIGNIFICANCE STATEMENT: This paper is an extensive review of what is currently known about the complex process of cellular senescence and explores its most defining features. The main body of the discussion focuses on how the multifeature fluctuation of the senescence phenotype and the physiological role of cellular senescence have both caused a limitation in the search for truly reliable senescence biomarkers and the progression in the development of senotherapies.
Topics: Humans; Reproducibility of Results; Senotherapeutics; Cellular Senescence; Aging; Biomarkers; Chronic Disease
PubMed: 36732079
DOI: 10.1124/pharmrev.122.000622 -
Nature Reviews. Genetics Feb 2020The past two centuries have witnessed an unprecedented rise in human life expectancy. Sustaining longer lives with reduced periods of disability will require an... (Review)
Review
The past two centuries have witnessed an unprecedented rise in human life expectancy. Sustaining longer lives with reduced periods of disability will require an understanding of the underlying mechanisms of ageing, and genetics is a powerful tool for identifying these mechanisms. Large-scale genome-wide association studies have recently identified many loci that influence key human ageing traits, including lifespan. Multi-trait loci have been linked with several age-related diseases, suggesting shared ageing influences. Mutations that drive accelerated ageing in prototypical progeria syndromes in humans point to an important role for genome maintenance and stability. Together, these different strands of genetic research are highlighting pathways for the discovery of anti-ageing interventions that may be applicable in humans.
Topics: Aging; Animals; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Longevity; Mutation; Phenotype; Reproduction
PubMed: 31690828
DOI: 10.1038/s41576-019-0183-6 -
Nature Communications Mar 2023Vascular endothelial cells (ECs) senescence correlates with the increase of cardiovascular diseases in ageing population. Although ECs rely on glycolysis for energy...
Vascular endothelial cells (ECs) senescence correlates with the increase of cardiovascular diseases in ageing population. Although ECs rely on glycolysis for energy production, little is known about the role of glycolysis in ECs senescence. Here, we report a critical role for glycolysis-derived serine biosynthesis in preventing ECs senescence. During senescence, the expression of serine biosynthetic enzyme PHGDH is significantly reduced due to decreased transcription of the activating transcription factor ATF4, which leads to reduction of intracellular serine. PHGDH prevents premature senescence primarily by enhancing the stability and activity of pyruvate kinase M2 (PKM2). Mechanistically, PHGDH interacts with PKM2, which prevents PCAF-catalyzed PKM2 K305 acetylation and subsequent degradation by autophagy. In addition, PHGDH facilitates p300-catalyzed PKM2 K433 acetylation, which promotes PKM2 nuclear translocation and stimulates its activity to phosphorylate H3T11 and regulate the transcription of senescence-associated genes. Vascular endothelium-targeted expression of PHGDH and PKM2 ameliorates ageing in mice. Our findings reveal that enhancing serine biosynthesis could become a therapy to promote healthy ageing.
Topics: Animals; Mice; Cellular Senescence; Endothelial Cells; Glycolysis; Histones; Phosphoglycerate Dehydrogenase; Pyruvate Kinase; Serine; Aging
PubMed: 36899022
DOI: 10.1038/s41467-023-37094-8 -
Cellular and Molecular Life Sciences :... Jun 2023Ageing is characterized by the progressive loss of cellular homeostasis, leading to an overall decline of the organism's fitness. In the brain, ageing is highly... (Review)
Review
Ageing is characterized by the progressive loss of cellular homeostasis, leading to an overall decline of the organism's fitness. In the brain, ageing is highly associated with cognitive decline and neurodegenerative diseases. With the rise in life expectancy, characterizing the brain ageing process becomes fundamental for developing therapeutic interventions against the increased incidence of age-related neurodegenerative diseases and to aim for an increase in human life span and, more importantly, health span. In this review, we start by introducing the molecular/cellular hallmarks associated with brain ageing and their impact on brain cell populations. Subsequently, we assess emerging evidence on how systemic ageing translates into brain ageing. Finally, we revisit the mainstream and the novel rejuvenating strategies, discussing the most successful ones in delaying brain ageing and related diseases.
Topics: Humans; Aging; Brain; Longevity; Neurodegenerative Diseases
PubMed: 37354261
DOI: 10.1007/s00018-023-04832-6 -
Diabetologia Oct 2019Ageing and diabetes lead to similar organ dysfunction that is driven by parallel molecular mechanisms, one of which is cellular senescence. The abundance of senescent... (Review)
Review
Ageing and diabetes lead to similar organ dysfunction that is driven by parallel molecular mechanisms, one of which is cellular senescence. The abundance of senescent cells in various tissues increases with age, obesity and diabetes. Senescent cells have been directly implicated in the generation of insulin resistance. Recently, drugs that preferentially target senescent cells, known as senolytics, have been described and recently entered clinical trials. In this review, we explore the biological links between ageing and diabetes, specifically focusing on cellular senescence. We summarise the current data on cellular senescence in key target tissues associated with the development and clinical phenotypes of type 2 diabetes and discuss the therapeutic potential of targeting cellular senescence in diabetes.
Topics: Aging; Animals; Cellular Senescence; Diabetes Mellitus, Type 2; Humans
PubMed: 31451866
DOI: 10.1007/s00125-019-4934-x -
Ageing Research Reviews Jan 2022Improvements in public health and health care have resulted in significant increases in lifespan globally, but also in a significant increase in chronic disease... (Review)
Review
Improvements in public health and health care have resulted in significant increases in lifespan globally, but also in a significant increase in chronic disease prevalence. This has led to a focus on healthy ageing bringing a shift from a pathology-centered to an intrinsic capacity and function-centered view. In parallel, the emerging field of geroscience has promoted the exploration of the biomolecular drivers of ageing towards a transverse vision by proposing an integrated set of molecular hallmarks. In this review, we propose to take a step further in this direction, highlighting a gerophysiological perspective that considers the notion of homeostasis/allostasis relating to robustness/fragility respectively. While robustness is associated with homeostasis achieved by an optimal structure/function relationship in all organs, successive repair processes occurring after daily injuries and infections result in accumulation of scar healing leading to progressive tissue degeneration, allostasis and frailty. Considering biological ageing as the accumulation of scarring at the level of the whole organism emphasizes three transverse and shared elements in the body - mesenchymal stroma cells/immunity/metabolism (SIM). This SIM tryptich drives tissue and organ fate to regulate the age-related evolution of body functions. It provides the basis of a gerophysiology perspective, possibly representing a better way to decipher healthy ageing, not only by defining a composite biomarker(s) but also by developing new preventive/curative strategies.
Topics: Aging; Frailty; Geroscience; Healthy Aging; Humans; Longevity
PubMed: 34883201
DOI: 10.1016/j.arr.2021.101537 -
Ageing Research Reviews Nov 2020As human life expectancy keeps increasing, ageing populations present a growing challenge for clinical practices. Human ageing is associated with molecular, structural,... (Review)
Review
As human life expectancy keeps increasing, ageing populations present a growing challenge for clinical practices. Human ageing is associated with molecular, structural, and functional changes in a variety of organ systems, including the kidney. During the ageing process, the kidney experiences progressive functional decline as well as macroscopic and microscopic histological alterations, which are accentuated by systemic comorbidities like hypertension and diabetes mellitus, or by preexisting or underlying kidney diseases. Although ageing per se does not cause kidney injury, physiologic changes associated with normal ageing processes are likely to impair the reparative capacity of the kidney and thus predispose older people to acute kidney disease, chronic kidney disease and other renal diseases. Mechanistically, cell senescence plays a key role in renal ageing, involving a number of cellular signaling mechanisms, many of which may be harnessed as international targets for slowing or even reversing kidney ageing. This review summarizes the clinical characteristics of renal ageing, highlights the latest progresses in deciphering the role of cell senescence in renal ageing, and envisages potential interventional strategies and novel therapeutic targets for preventing or improving renal ageing in the hope of maintaining long-term kidney health and function across the life course.
Topics: Aged; Aged, 80 and over; Aging; Cellular Senescence; Humans; Hypertension; Kidney
PubMed: 32835891
DOI: 10.1016/j.arr.2020.101151 -
Nature Reviews. Cardiology Apr 2022Cellular senescence, classically defined as stable cell cycle arrest, is implicated in biological processes such as embryogenesis, wound healing and ageing. Senescent... (Review)
Review
Cellular senescence, classically defined as stable cell cycle arrest, is implicated in biological processes such as embryogenesis, wound healing and ageing. Senescent cells have a complex senescence-associated secretory phenotype (SASP), involving a range of pro-inflammatory factors with important paracrine and autocrine effects on cell and tissue biology. Clinical evidence and experimental studies link cellular senescence, senescent cell accumulation, and the production and release of SASP components with age-related cardiac pathologies such as heart failure, myocardial ischaemia and infarction, and cancer chemotherapy-related cardiotoxicity. However, the precise role of senescent cells in these conditions is unclear and, in some instances, both detrimental and beneficial effects have been reported. The involvement of cellular senescence in other important entities, such as cardiac arrhythmias and remodelling, is poorly understood. In this Review, we summarize the basic biology of cellular senescence and discuss what is known about the role of cellular senescence and the SASP in heart disease. We then consider the various approaches that are being developed to prevent the accumulation of senescent cells and their consequences. Many of these strategies are applicable in vivo and some are being investigated for non-cardiac indications in clinical trials. We end by considering important knowledge gaps, directions for future research and the potential implications for improving the management of patients with heart disease.
Topics: Aging; Biology; Cellular Senescence; Heart Diseases; Humans; Senescence-Associated Secretory Phenotype
PubMed: 34667279
DOI: 10.1038/s41569-021-00624-2 -
Nature Reviews. Endocrinology Jan 2023The activation of stress-related neuroendocrine systems helps to maintain homeostasis, but excessive stress can damage body functions. We review current evidence from... (Review)
Review
The activation of stress-related neuroendocrine systems helps to maintain homeostasis, but excessive stress can damage body functions. We review current evidence from basic sciences and epidemiology linking stress to the development and progression of metabolic disorders throughout life. Findings from rodents demonstrate that stress can affect features of metabolic dysfunction, such as insulin resistance, glucose and lipid homeostasis, as well as ageing processes such as cellular senescence and telomere length shortening. In human studies, stressors in the home, workplace and neighbourhood are associated with accelerated ageing and metabolic and immune alterations, both directly and indirectly via behavioural risks. The likelihood of developing clinical conditions, such as diabetes mellitus and hepatic steatosis is increased in individuals with adverse childhood experiences or long-term (years) or severe stress at work or in private life. The increased risk of metabolic disorders is often associated with other stress-related conditions, such as mental health disorders, cardiovascular disease and increased susceptibility to infections. Equally, stress can worsen prognosis in metabolic diseases. As favourable modifications in stressors are associated with reductions in incidence of metabolic disorders, further investigation of the therapeutic value of targeting stress in personalized medicine is warranted.
Topics: Humans; Metabolic Diseases; Aging; Cellular Senescence; Stress, Psychological; Insulin Resistance
PubMed: 36224493
DOI: 10.1038/s41574-022-00746-8 -
Signal Transduction and Targeted Therapy Jun 2021Remarkable progress in ageing research has been achieved over the past decades. General perceptions and experimental evidence pinpoint that the decline of physical... (Review)
Review
Remarkable progress in ageing research has been achieved over the past decades. General perceptions and experimental evidence pinpoint that the decline of physical function often initiates by cell senescence and organ ageing. Epigenetic dynamics and immunometabolic reprogramming link to the alterations of cellular response to intrinsic and extrinsic stimuli, representing current hotspots as they not only (re-)shape the individual cell identity, but also involve in cell fate decision. This review focuses on the present findings and emerging concepts in epigenetic, inflammatory, and metabolic regulations and the consequences of the ageing process. Potential therapeutic interventions targeting cell senescence and regulatory mechanisms, using state-of-the-art techniques are also discussed.
Topics: Aging; Cell Differentiation; Cellular Senescence; Epigenomics; Humans; Inflammation
PubMed: 34176928
DOI: 10.1038/s41392-021-00646-9