Cellular senescence entails essentially irreversible replicative arrest, apoptosis resistance, and frequently acquisition of a pro-inflammatory, tissue-destructive senescence-associated secretory ...phenotype (SASP). Senescent cells accumulate in various tissues with aging and at sites of pathogenesis in many chronic diseases and conditions. The SASP can contribute to senescence-related inflammation, metabolic dysregulation, stem cell dysfunction, aging phenotypes, chronic diseases, geriatric syndromes, and loss of resilience. Delaying senescent cell accumulation or reducing senescent cell burden is associated with delay, prevention, or alleviation of multiple senescence-associated conditions. We used a hypothesis-driven approach to discover pro-survival Senescent Cell Anti-apoptotic Pathways (SCAPs) and, based on these SCAPs, the first senolytic agents, drugs that cause senescent cells to become susceptible to their own pro-apoptotic microenvironment. Several senolytic agents, which appear to alleviate multiple senescence-related phenotypes in pre-clinical models, are beginning the process of being translated into clinical interventions that could be transformative.
•Cellular senescence is among the aging processes underlying chronic diseases, loss of resilience, and geriatric syndromes.•Senolytics selectively induce senescent cell apoptosis. They delay or alleviate multiple disorders in preclinical studies.•If senolytics are demonstrated to be effective and safe in clinical trials, they could be transformative.
Adipose tissue dysfunction occurs with aging and has systemic effects, including peripheral insulin resistance, ectopic lipid deposition, and inflammation. Fundamental aging mechanisms, including ...cellular senescence and progenitor cell dysfunction, occur in adipose tissue with aging and may serve as potential therapeutic targets in age-related disease. In this review, we examine the role of adipose tissue in healthy individuals and explore how aging leads to adipose tissue dysfunction, redistribution, and changes in gene regulation. Adipose tissue plays a central role in longevity, and interventions restricted to adipose tissue may impact lifespan. Conversely, obesity may represent a state of accelerated aging. We discuss the potential therapeutic potential of targeting basic aging mechanisms, including cellular senescence, in adipose tissue, using type II diabetes and regenerative medicine as examples. We make the case that aging should not be neglected in the study of adipose-derived stem cells for regenerative medicine strategies, as elderly patients make up a large portion of individuals in need of such therapies.
•Adipose tissue is a highly relevant organ for the study of aging.•Age-related changes occur in adipose tissue.•Adipose tissue function impacts lifespan and healthspan.•Obesity and aging have shared mechanisms and effects on adipose tissue.•Improved knowledge of adipose tissue aging could impact diabetes treatments and regenerative medicine.
Sarcopenia is a loss of muscle mass and function in the elderly that reduces mobility, diminishes quality of life, and can lead to fall-related injuries, which require costly hospitalization and ...extended rehabilitation. This review focuses on the aging-related structural changes and mechanisms at cellular and subcellular levels underlying changes in the individual motor unit: specifically, the perikaryon of the α-motoneuron, its neuromuscular junction(s), and the muscle fibers that it innervates. Loss of muscle mass with aging, which is largely due to the progressive loss of motoneurons, is associated with reduced muscle fiber number and size. Muscle function progressively declines because motoneuron loss is not adequately compensated by reinnervation of muscle fibers by the remaining motoneurons. At the intracellular level, key factors are qualitative changes in posttranslational modifications of muscle proteins and the loss of coordinated control between contractile, mitochondrial, and sarcoplasmic reticulum protein expression. Quantitative and qualitative changes in skeletal muscle during the process of aging also have been implicated in the pathogenesis of acquired and hereditary neuromuscular disorders. In experimental models, specific intervention strategies have shown encouraging results on limiting deterioration of motor unit structure and function under conditions of impaired innervation. Translated to the clinic, if these or similar interventions, by saving muscle and improving mobility, could help alleviate sarcopenia in the elderly, there would be both great humanitarian benefits and large cost savings for health care systems.
•Cellular senescence is a dynamic process and appears to be a heterogenous cell fate.•We hypothesize that senescent cells can be of helper (H) or deleterious (D) subtypes.•Lowering the burden of the ...D-subtype below a threshold may alleviate co-morbidities and enhance health-span, while reducing adverse effects from targeting the H-subtype.
Cellular senescence, first observed and defined through cell culture studies, is a cell fate associated with essentially permanent cell cycle arrest and that can be triggered by a variety of inducers. Emerging evidence suggests senescence is a dynamic process with diverse functional characteristics. Depending on the tissue, type of inducer, and time since induction, senescent cells can promote tissue repair and re-modeling, prevent tumor development, or contribute to age-related disorders and chronic diseases, including cancers. Senescent cell characteristics appear to depend on multiple factors and be influenced by the milieu and other senescent cells locally and at a distance. We review diverse phenotypes of senescent cells originating from different cell types, senescence inducers over time since induction of senescence, and across conditions and diseases. This background is essential to inform further understanding about senescent cell subtypes and will point towards rational senescence-modulating strategies for achieving therapeutic benefit.
The Clinical Potential of Senolytic Drugs Kirkland, James L.; Tchkonia, Tamara; Zhu, Yi ...
Journal of the American Geriatrics Society (JAGS),
October 2017, Letnik:
65, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Senolytic drugs are agents that selectively induce apoptosis of senescent cells. These cells accumulate in many tissues with aging and at sites of pathology in multiple chronic diseases. In studies ...in animals, targeting senescent cells using genetic or pharmacological approaches delays, prevents, or alleviates multiple age‐related phenotypes, chronic diseases, geriatric syndromes, and loss of physiological resilience. Among the chronic conditions successfully treated by depleting senescent cells in preclinical studies are frailty, cardiac dysfunction, vascular hyporeactivity and calcification, diabetes mellitus, liver steatosis, osteoporosis, vertebral disk degeneration, pulmonary fibrosis, and radiation‐induced damage. Senolytic agents are being tested in proof‐of‐concept clinical trials. To do so, new clinical trial paradigms for testing senolytics and other agents that target fundamental aging mechanisms are being developed, because use of long‐term endpoints such as lifespan or healthspan is not feasible. These strategies include testing effects on multimorbidity, accelerated aging‐like conditions, diseases with localized accumulation of senescent cells, potentially fatal diseases associated with senescent cell accumulation, age‐related loss of physiological resilience, and frailty. If senolytics or other interventions that target fundamental aging processes prove to be effective and safe in clinical trials, they could transform geriatric medicine by enabling prevention or treatment of multiple diseases and functional deficits in parallel, instead of one at a time.
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