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Cell Jan 2023Aging is driven by hallmarks fulfilling the following three premises: (1) their age-associated manifestation, (2) the acceleration of aging by experimentally... (Review)
Review
Aging is driven by hallmarks fulfilling the following three premises: (1) their age-associated manifestation, (2) the acceleration of aging by experimentally accentuating them, and (3) the opportunity to decelerate, stop, or reverse aging by therapeutic interventions on them. We propose the following twelve hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. These hallmarks are interconnected among each other, as well as to the recently proposed hallmarks of health, which include organizational features of spatial compartmentalization, maintenance of homeostasis, and adequate responses to stress.
Topics: Cellular Senescence; Epigenesis, Genetic; Proteostasis; Stem Cells; Aging
PubMed: 36599349
DOI: 10.1016/j.cell.2022.11.001 -
Trends in Endocrinology and Metabolism:... Apr 2022Geroprotectors slow down aging and promote healthy longevity in model animals. Although hundreds of compounds have been shown to extend the life of laboratory model... (Review)
Review
Geroprotectors slow down aging and promote healthy longevity in model animals. Although hundreds of compounds have been shown to extend the life of laboratory model organisms, clinical studies on potential geroprotectors are exceedingly rare, especially in healthy elders. This review aims to classify potential geroprotectors based on the mechanisms by which they influence aging. These pharmacological interventions can be classified into the following groups: those that prevent oxidation; proteostasis regulators; suppressors of genomic instability; epigenetic drugs; those that preserve mitochondrial function; inhibitors of aging-associated signaling pathways; hormetins; senolytics/senostatics; anti-inflammatory drugs; antifibrotic agents; neurotrophic factors; factors preventing the impairment of barrier function; immunomodulators; and prebiotics, metabiotics, and enterosorbents.
Topics: Aged; Aging; Animals; Humans; Longevity; Signal Transduction
PubMed: 35183431
DOI: 10.1016/j.tem.2022.01.007 -
Ageing Research Reviews Jul 2023Aging is a complex process that features a functional decline in many organelles. Although mitochondrial dysfunction is suggested as one of the determining factors of... (Review)
Review
Aging is a complex process that features a functional decline in many organelles. Although mitochondrial dysfunction is suggested as one of the determining factors of aging, the role of mitochondrial quality control (MQC) in aging is still poorly understood. A growing body of evidence points out that reactive oxygen species (ROS) stimulates mitochondrial dynamic changes and accelerates the accumulation of oxidized by-products through mitochondrial proteases and mitochondrial unfolded protein response (UPR). Mitochondrial-derived vesicles (MDVs) are the frontline of MQC to dispose of oxidized derivatives. Besides, mitophagy helps remove partially damaged mitochondria to ensure that mitochondria are healthy and functional. Although abundant interventions on MQC have been explored, over-activation or inhibition of any type of MQC may even accelerate abnormal energy metabolism and mitochondrial dysfunction-induced senescence. This review summarizes mechanisms essential for maintaining mitochondrial homeostasis and emphasizes that imbalanced MQC may accelerate cellular senescence and aging. Thus, appropriate interventions on MQC may delay the aging process and extend lifespan.
Topics: Humans; Aging; Cellular Senescence; Mitochondria; Reactive Oxygen Species; Longevity
PubMed: 37196864
DOI: 10.1016/j.arr.2023.101955 -
Nature Reviews. Neurology Oct 2019Ageing is the primary risk factor for most neurodegenerative diseases, including Alzheimer disease (AD) and Parkinson disease (PD). One in ten individuals aged ≥65... (Review)
Review
Ageing is the primary risk factor for most neurodegenerative diseases, including Alzheimer disease (AD) and Parkinson disease (PD). One in ten individuals aged ≥65 years has AD and its prevalence continues to increase with increasing age. Few or no effective treatments are available for ageing-related neurodegenerative diseases, which tend to progress in an irreversible manner and are associated with large socioeconomic and personal costs. This Review discusses the pathogenesis of AD, PD and other neurodegenerative diseases, and describes their associations with the nine biological hallmarks of ageing: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion and altered intercellular communication. The central biological mechanisms of ageing and their potential as targets of novel therapies for neurodegenerative diseases are also discussed, with potential therapies including NAD precursors, mitophagy inducers and inhibitors of cellular senescence.
Topics: Aging; Brain; DNA Damage; Epigenesis, Genetic; Humans; Mitophagy; Neurodegenerative Diseases; Risk Factors
PubMed: 31501588
DOI: 10.1038/s41582-019-0244-7 -
Cardiovascular Research Mar 2022Cellular senescence is a state of irreversible cell cycle arrest associated with ageing. Senescence of different cardiac cell types can direct the pathophysiology of... (Review)
Review
Cellular senescence is a state of irreversible cell cycle arrest associated with ageing. Senescence of different cardiac cell types can direct the pathophysiology of cardiovascular diseases (CVDs) such as atherosclerosis, myocardial infarction, and cardiac fibrosis. While age-related telomere shortening represents a major cause of replicative senescence, the senescent state can also be induced by oxidative stress, metabolic dysfunction, and epigenetic regulation, among other stressors. It is critical that we understand the molecular pathways that lead to cellular senescence and the consequences of cellular senescence in order to develop new therapeutic approaches to treat CVD. In this review, we discuss molecular mechanisms of cellular senescence, explore how cellular senescence of different cardiac cell types (including cardiomyocytes, cardiac endothelial cells, cardiac fibroblasts, vascular smooth muscle cells, and valve interstitial cells) can lead to CVD, and highlight potential therapeutic approaches that target molecular mechanisms of cellular senescence to prevent or treat CVD.
Topics: Aging; Cardiovascular Diseases; Cellular Senescence; Endothelial Cells; Epigenesis, Genetic; Humans; Myocytes, Cardiac
PubMed: 33963378
DOI: 10.1093/cvr/cvab161 -
Nature Jul 2019For several decades, understanding ageing and the processes that limit lifespan have challenged biologists. Thirty years ago, the biology of ageing gained unprecedented... (Review)
Review
For several decades, understanding ageing and the processes that limit lifespan have challenged biologists. Thirty years ago, the biology of ageing gained unprecedented scientific credibility through the identification of gene variants that extend the lifespan of multicellular model organisms. Here we summarize the milestones that mark this scientific triumph, discuss different ageing pathways and processes, and suggest that ageing research is entering a new era that has unique medical, commercial and societal implications. We argue that this era marks an inflection point, not only in ageing research but also for all biological research that affects the human healthspan.
Topics: Aging; Biomedical Research; Circadian Clocks; Clinical Trials as Topic; Healthy Aging; Humans; Inflammation; Longevity; Mitochondria; Nutritional Status; Oxidative Stress; Rejuvenation; Signal Transduction
PubMed: 31292558
DOI: 10.1038/s41586-019-1365-2 -
Nature Reviews. Immunology Feb 2023Genomic instability is an important driver of ageing. The accumulation of DNA damage is believed to contribute to ageing by inducing cell death, senescence and tissue... (Review)
Review
Genomic instability is an important driver of ageing. The accumulation of DNA damage is believed to contribute to ageing by inducing cell death, senescence and tissue dysfunction. However, emerging evidence shows that inflammation is another major consequence of DNA damage. Inflammation is a hallmark of ageing and the driver of multiple age-related diseases. Here, we review the evidence linking DNA damage, inflammation and ageing, highlighting how premature ageing syndromes are associated with inflammation. We discuss the mechanisms by which DNA damage induces inflammation, such as through activation of the cGAS-STING axis and NF-κB activation by ATM. The triggers for activation of these signalling cascades are the age-related accumulation of DNA damage, activation of transposons, cellular senescence and the accumulation of persistent R-loops. We also discuss how epigenetic changes triggered by DNA damage can lead to inflammation and ageing via redistribution of heterochromatin factors. Finally, we discuss potential interventions against age-related inflammation.
Topics: Humans; DNA Damage; Aging; Cellular Senescence; Inflammation; Cell Death
PubMed: 35831609
DOI: 10.1038/s41577-022-00751-y -
Nature Jun 2021Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly. To define the contribution of immune system ageing to...
Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence in the immune system only. We show that Vav-iCre;Ercc1 mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre;Ercc1 or aged wild-type mice into young mice induced senescence in trans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre;Ercc1 mice with rapamycin reduced markers of senescence in immune cells and improved immune function. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.
Topics: Aging; Animals; DNA Damage; DNA Repair; DNA-Binding Proteins; Endonucleases; Female; Healthy Aging; Homeostasis; Immune System; Immunosenescence; Male; Mice; Organ Specificity; Rejuvenation; Sirolimus; Spleen
PubMed: 33981041
DOI: 10.1038/s41586-021-03547-7 -
Mechanisms of Ageing and Development Sep 2021The skin is comprised of different cell types with different proliferative capacities. Skin aging occurs with chronological age and upon exposure to extrinsic factors... (Review)
Review
The skin is comprised of different cell types with different proliferative capacities. Skin aging occurs with chronological age and upon exposure to extrinsic factors such as photodamage. During aging, senescent cells accumulate in different compartments of the human skin, leading to impaired skin physiology. Diverse skin cell types may respond differently to senescence-inducing stimuli and it is not clear how this results in aging-associated skin phenotypes and pathologies. This review aims to examine and provide an overview of current evidence of cellular senescence in the skin. We will focus on cellular characteristics and behaviour of different skin cell types undergoing senescence in the epidermis and dermis, with a particular focus on the complex interplay between mitochondrial dysfunction, autophagy and DNA damage pathways. We will also examine how the dermis and epidermis cope with the accumulation of DNA damage during aging.
Topics: Aging; Autophagy; Cellular Senescence; DNA Damage; Humans; Mitochondria; Skin; Skin Aging
PubMed: 34166688
DOI: 10.1016/j.mad.2021.111525 -
Nature Reviews. Genetics Dec 2022Age is the key risk factor for diseases and disabilities of the elderly. Efforts to tackle age-related diseases and increase healthspan have suggested targeting the... (Review)
Review
Age is the key risk factor for diseases and disabilities of the elderly. Efforts to tackle age-related diseases and increase healthspan have suggested targeting the ageing process itself to 'rejuvenate' physiological functioning. However, achieving this aim requires measures of biological age and rates of ageing at the molecular level. Spurred by recent advances in high-throughput omics technologies, a new generation of tools to measure biological ageing now enables the quantitative characterization of ageing at molecular resolution. Epigenomic, transcriptomic, proteomic and metabolomic data can be harnessed with machine learning to build 'ageing clocks' with demonstrated capacity to identify new biomarkers of biological ageing.
Topics: Humans; Aged; Proteomics; Aging; Biomarkers; Epigenomics; Metabolomics
PubMed: 35715611
DOI: 10.1038/s41576-022-00511-7