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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 Cell Biology Jun 2018Cellular senescence is a permanent state of cell cycle arrest that promotes tissue remodeling during development and after injury, but can also contribute to the decline... (Review)
Review
Cellular senescence is a permanent state of cell cycle arrest that promotes tissue remodeling during development and after injury, but can also contribute to the decline of the regenerative potential and function of tissues, to inflammation, and to tumorigenesis in aged organisms. Therefore, the identification, characterization, and pharmacological elimination of senescent cells have gained attention in the field of aging research. However, the nonspecificity of current senescence markers and the existence of different senescence programs strongly limit these tasks. Here, we describe the molecular regulators of senescence phenotypes and how they are used for identifying senescent cells in vitro and in vivo. We also highlight the importance that these levels of regulations have in the development of therapeutic targets.
Topics: Aging; Biomarkers; Cellular Senescence; DNA Damage; Genetic Markers; Humans; Phenotype
PubMed: 29477613
DOI: 10.1016/j.tcb.2018.02.001 -
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 -
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 -
Nature Nov 2016Although systemic diseases take the biggest toll on human health and well-being, increasingly, a failing brain is the arbiter of a death preceded by a gradual loss of... (Review)
Review
Although systemic diseases take the biggest toll on human health and well-being, increasingly, a failing brain is the arbiter of a death preceded by a gradual loss of the essence of being. Ageing, which is fundamental to neurodegeneration and dementia, affects every organ in the body and seems to be encoded partly in a blood-based signature. Indeed, factors in the circulation have been shown to modulate ageing and to rejuvenate numerous organs, including the brain. The discovery of such factors, the identification of their origins and a deeper understanding of their functions is ushering in a new era in ageing and dementia research.
Topics: Aging; Animals; Brain; Cell Communication; Humans; Inflammation; Neurodegenerative Diseases; Proteome; Rejuvenation
PubMed: 27830812
DOI: 10.1038/nature20411 -
Nature Sep 2018Longer human lives have led to a global burden of late-life disease. However, some older people experience little ill health, a trait that should be extended to the... (Review)
Review
Longer human lives have led to a global burden of late-life disease. However, some older people experience little ill health, a trait that should be extended to the general population. Interventions into lifestyle, including increased exercise and reduction in food intake and obesity, can help to maintain healthspan. Altered gut microbiota, removal of senescent cells, blood factors obtained from young individuals and drugs can all improve late-life health in animals. Application to humans will require better biomarkers of disease risk and responses to interventions, closer alignment of work in animals and humans, and increased use of electronic health records, biobank resources and cohort studies.
Topics: Aged; Aging; Animals; Biomarkers; Cellular Senescence; Disabled Persons; Electronic Health Records; Genome-Wide Association Study; Humans; Internationality; Life Style; Longevity; Models, Animal; Netherlands; Phenotype
PubMed: 30185958
DOI: 10.1038/s41586-018-0457-8 -
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 -
Physiological Research Sep 2020Ageing is accompanied by deterioration in physical condition and a number of physiological processes and thus a higher risk of a range of diseases and disorders. In... (Review)
Review
Ageing is accompanied by deterioration in physical condition and a number of physiological processes and thus a higher risk of a range of diseases and disorders. In particular, we focused on the changes associated with aging, especially the role of small molecules, their role in physiological and pathophysiological processes and potential treatment options. Our previously published results and data from other authors lead to the conclusion that these unwanted changes are mainly linked to the hypothalamic-pituitary-adrenal axis can be slowed down, stopped, or in some cases even reversed by an appropriate treatment, but especially by a life-management adjustment.
Topics: Aging; Animals; Hormones; Humans; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Receptors, Cell Surface; Small Molecule Libraries
PubMed: 33094624
DOI: 10.33549/physiolres.934523