-
Ageing Research Reviews Jan 2024Cellular senescence is a state of terminal cell cycle arrest associated with various macromolecular changes and a hypersecretory phenotype. In the brain, senescent cells... (Review)
Review
Cellular senescence is a state of terminal cell cycle arrest associated with various macromolecular changes and a hypersecretory phenotype. In the brain, senescent cells naturally accumulate during aging and at sites of age-related pathologies. Here, we discuss the recent advances in understanding the accumulation of senescent cells in brain aging and disorders. Here we highlight the phenotypical heterogeneity of different senescent brain cell types, highlighting the potential importance of subtype-specific features for physiology and pathology. We provide a comprehensive overview of various senescent cell types in naturally occurring aging and the most common neurodegenerative disorders. Finally, we critically discuss the potential of adapting senotherapeutics to improve brain health and reduce pathological progression, addressing limitations and future directions for application and development.
Topics: Humans; Aging; Cellular Senescence; Brain; Neurodegenerative Diseases; Cell Cycle Checkpoints
PubMed: 38030088
DOI: 10.1016/j.arr.2023.102141 -
Free Radical Biology & Medicine Aug 2018The Free Radical Theory of Ageing, was first proposed by Denham Harman in the mid-1950's, based largely on work conducted by Rebeca Gerschman and Daniel Gilbert. At its... (Review)
Review
The Free Radical Theory of Ageing, was first proposed by Denham Harman in the mid-1950's, based largely on work conducted by Rebeca Gerschman and Daniel Gilbert. At its core, the Free Radical Theory of Ageing posits that free radical and related oxidants, from the environment and internal metabolism, cause damage to cellular constituents that, over time, result in an accumulation of structural and functional problems. Several variations on the original concept have been advanced over the past six decades, including the suggestion of a central role for mitochondria-derived reactive species, and the proposal of an age-related decline in the effectiveness of protein, lipid, and DNA repair systems. Such innovations have helped the Free Radical Theory of Aging to achieve widespread popularity. Nevertheless, an ever-growing number of apparent 'exceptions' to the Theory have seriously undermined its acceptance. In part, we suggest, this has resulted from a rather simplistic experimental approach of knocking-out, knocking-down, knocking-in, or overexpressing antioxidant-related genes to determine effects on lifespan. In some cases such experiments have yielded results that appear to support the Free Radical Theory of Aging, but there are just as many published papers that appear to contradict the Theory. We suggest that free radicals and related oxidants are but one subset of stressors with which all life forms must cope over their lifespans. Adaptive Homeostasis is the mechanism by which organisms dynamically expand or contract the homeostatic range of stress defense and repair systems, employing a veritable armory of signal transduction pathways (such as the Keap1-Nrf2 system) to generate a complex profile of inducible and enzymatic protection that best fits the particular need. Viewed as a component of Adaptive Homeostasis, the Free Radical Theory of Aging appears both viable and robust.
Topics: Adaptation, Physiological; Aging; Animals; Free Radicals; Homeostasis; Humans; Oxidative Stress
PubMed: 29960100
DOI: 10.1016/j.freeradbiomed.2018.06.016 -
GeroScience Oct 2022One of the most striking findings in biogerontology in the 2010s was the demonstration that elimination of senescent cells delays many late-life diseases and extends... (Review)
Review
One of the most striking findings in biogerontology in the 2010s was the demonstration that elimination of senescent cells delays many late-life diseases and extends lifespan in mice. This implied that accumulation of senescent cells promotes late-life diseases, particularly through action of senescent cell secretions (the senescence-associated secretory phenotype, or SASP). But what exactly is a senescent cell? Subsequent to the initial characterization of cellular senescence, it became clear that, prior to aging, this phenomenon is in fact adaptive. It supports tissue remodeling functions in a variety of contexts, including embryogenesis, parturition, and acute inflammatory processes that restore normal tissue architecture and function, such as wound healing, tissue repair after infection, and amphibian limb regeneration. In these contexts, such cells are normal and healthy and not in any way senescent in the true sense of the word, as originally meant by Hayflick. Thus, it is misleading to refer to them as "senescent." Similarly, the common assertion that senescent cells accumulate with age due to stress and DNA damage is no longer safe, particularly given their role in inflammation-a process that becomes persistent in later life. We therefore suggest that it would be useful to update some terminology, to bring it into line with contemporary understanding, and to avoid future confusion. To open a discussion of this issue, we propose replacing the term cellular senescence with remodeling activation, and SASP with RASP (remodeling-associated secretory phenotype).
Topics: Animals; Mice; Cellular Senescence; Aging; Inflammation; Longevity
PubMed: 36068483
DOI: 10.1007/s11357-022-00652-x -
Nature Feb 2022The Dog Aging Project is a long-term longitudinal study of ageing in tens of thousands of companion dogs. The domestic dog is among the most variable mammal species in...
The Dog Aging Project is a long-term longitudinal study of ageing in tens of thousands of companion dogs. The domestic dog is among the most variable mammal species in terms of morphology, behaviour, risk of age-related disease and life expectancy. Given that dogs share the human environment and have a sophisticated healthcare system but are much shorter-lived than people, they offer a unique opportunity to identify the genetic, environmental and lifestyle factors associated with healthy lifespan. To take advantage of this opportunity, the Dog Aging Project will collect extensive survey data, environmental information, electronic veterinary medical records, genome-wide sequence information, clinicopathology and molecular phenotypes derived from blood cells, plasma and faecal samples. Here, we describe the specific goals and design of the Dog Aging Project and discuss the potential for this open-data, community science study to greatly enhance understanding of ageing in a genetically variable, socially relevant species living in a complex environment.
Topics: Aging; Animals; Biomarkers; Built Environment; Clinical Trials, Veterinary as Topic; Cross-Sectional Studies; Data Collection; Dogs; Female; Frailty; Gene-Environment Interaction; Genome-Wide Association Study; Goals; Healthy Aging; Humans; Inflammation; Information Dissemination; Informed Consent; Life Style; Longevity; Longitudinal Studies; Male; Models, Animal; Multimorbidity; Pets; Privacy; Sirolimus
PubMed: 35110758
DOI: 10.1038/s41586-021-04282-9 -
Mechanisms of Ageing and Development Jul 2020The functional decline that is observed in HSCs upon aging is attributed mainly to cell intrinsic factors that regulate quiescence, self-renewal and differentiation.... (Review)
Review
The functional decline that is observed in HSCs upon aging is attributed mainly to cell intrinsic factors that regulate quiescence, self-renewal and differentiation. MicroRNAs (miRs) have an indispensable role in the regulation of HSCs and have been shown to also regulate processes related to tissue aging in specific cell types. Here we discuss the role of miRs in the regulation of HSC self-renewal and differentiation throughout life and its implications for future research.
Topics: Aging; Animals; Cell Differentiation; Cellular Senescence; Hematopoietic Stem Cells; Humans; MicroRNAs
PubMed: 32512019
DOI: 10.1016/j.mad.2020.111281 -
Experimental Physiology Sep 2017What is the topic of this review? The reasons for the continuing increase in human life expectancy are examined in the light of progress in understanding the... (Review)
Review
What is the topic of this review? The reasons for the continuing increase in human life expectancy are examined in the light of progress in understanding the physiological basis of ageing. Prospects for further extending the health span - the period free of age-related disability and disease - are critically assessed. What advances does it highlight? No active programming directly causes ageing, which instead results as a side effect of how evolution optimises the physiological allocation of resources between growth, reproduction and maintenance. Under pressure of natural selection, there was insufficient priority in maintaining the body well enough that it could endure without progressive accumulation of multiple kinds of molecular and cellular damage. Understanding human ageing is a major challenge for the physiological sciences. It is made all the more urgent by the survival of inreasing numbers of people to advanced old age and by a shift in the underlying causes of the continuing increase in life expectancy. The previous increase was caused almost entirely by the prevention of deaths in the early and middle years of life; a process that has seen such success that in developed countries there remains little scope for significant further increase from this cause. The more recent increase is driven by something new. We are reaching old age in generally better health, and it is the death rates at advanced ages that are now falling fast. At the same time, biology has established that there is almost certainly no fixed programme for ageing, which is caused instead by the lifelong accumulation of damage. It is becoming evident that the ageing process is much more malleable than we used to think. We need urgently to establish the factors that govern this malleability and to identify the interactions between, on the one hand, intrinsic biological processes that drive the many chronic diseases and disabilities for which age is by far the largest risk factor and, on the other hand, the social and lifestyle factors that influence our individual trajectories of health in old age. Ageing is no longer as mysterious and intractable a process as used to be thought, offering new opportunities for contributions from other branches of the physiological sciences.
Topics: Aging; Animals; Chronic Disease; Humans; Life Expectancy; Selection, Genetic
PubMed: 28768061
DOI: 10.1113/EP086205 -
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 -
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 -
Mammalian Genome : Official Journal of... Aug 2016Stem cells maintain homeostasis in all regenerating tissues during the lifespan of an organism. Thus, age-related functional decline of such tissues is likely to be at... (Review)
Review
Stem cells maintain homeostasis in all regenerating tissues during the lifespan of an organism. Thus, age-related functional decline of such tissues is likely to be at least partially explained by molecular events occurring in the stem cell compartment. Some of these events involve epigenetic changes, which may dictate how an aging genome can lead to differential gene expression programs. Recent technological advances have made it now possible to assess the genome-wide distribution of an ever-increasing number of epigenetic marks. As a result, the hypothesis that there may be a causal role for an altered epigenome contributing to the functional decline of cells, tissues, and organs in aging organisms can now be explored. In this paper, we review recent developments in the field of epigenetic regulation of stem cells, and how this may contribute to aging.
Topics: Aging; Cellular Senescence; DNA Methylation; Epigenesis, Genetic; Genome; Homeostasis; Humans; Regeneration; Stem Cells
PubMed: 27229519
DOI: 10.1007/s00335-016-9645-8 -
Ageing Research Reviews May 2021Aging is characterized by a progressive loss of tissue integrity and functionality due to disrupted homeostasis. Molecular oxygen is pivotal to maintain tissue... (Review)
Review
Aging is characterized by a progressive loss of tissue integrity and functionality due to disrupted homeostasis. Molecular oxygen is pivotal to maintain tissue functions, and aerobic species have evolved a sophisticated sensing system to ensure proper oxygen supply and demand. It is not surprising that aberrations in oxygen and oxygen-associated pathways subvert health and promote different aspects of aging. In this review, we discuss emerging findings on how oxygen-sensing mechanisms regulate different cellular and molecular processes during normal physiology, and how dysregulation of oxygen availability lead to disease and aging. We describe various clinical manifestations associated with deregulation of oxygen balance, and how oxygen-modulating therapies and natural oxygen oscillations influence longevity. We conclude by discussing how a better understanding of oxygen-related mechanisms that orchestrate aging processes may lead to the development of new therapeutic strategies to extend healthy aging.
Topics: Cellular Senescence; Longevity; Oxygen; Phenotype; Reactive Oxygen Species
PubMed: 33556549
DOI: 10.1016/j.arr.2021.101267