Distinct secretomes in p16- and p21- positive senescent cells across tissues DOI Creative Commons
Dominik Saul, Diana Jurk, Madison L. Doolittle

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Дек. 5, 2023

SUMMARY Senescent cells drive age-related tissue dysfunction via the induction of a chronic senescence-associated secretory phenotype (SASP). The cyclin-dependent kinase inhibitors p21 Cip1 and p16 Ink4a have long served as markers cellular senescence. However, their individual roles remain incompletely elucidated. Thus, we conducted comprehensive examination multiple single-cell RNA sequencing (scRNA-seq) datasets spanning both murine human tissues during aging. Our analysis revealed that transcripts demonstrate significant heterogeneity across distinct cell types tissues, frequently exhibiting lack co-expression. Moreover, identified tissue-specific variations in SASP profiles linked to or expression. study underscores extraordinary diversity senescence SASP, emphasizing these phenomena are inherently cell- tissue-dependent. few factors consistently contribute shared “core” SASP. These findings highlight need for more nuanced investigation wide array biological contexts.

Язык: Английский

Cellular senescence in skeletal disease: mechanisms and treatment DOI Creative Commons
Xu He, Wei Hu, Yuanshu Zhang

и другие.

Cellular & Molecular Biology Letters, Год журнала: 2023, Номер 28(1)

Опубликована: Окт. 27, 2023

Abstract The musculoskeletal system supports the movement of entire body and provides blood production while acting as an endocrine organ. With aging, balance bone homeostasis is disrupted, leading to loss degenerative diseases, such osteoporosis, osteoarthritis, intervertebral disc degeneration. Skeletal diseases have a profound impact on motor cognitive abilities elderly, thus creating major challenge for both global health economy. Cellular senescence caused by various genotoxic stressors results in permanent cell cycle arrest, which considered be underlying mechanism aging. During senescent cells (SnCs) tend aggregate trigger chronic inflammation releasing senescence-associated secretory phenotypic factors. Multiple signalling pathways are involved regulating cellular marrow microenvironments. Targeted SnCs alleviate age-related diseases. However, association between remains unclear. This review summarises fundamental role skeletal highlights that mediate senescence, discusses potential therapeutic strategies targeting SnCs. Graphical

Язык: Английский

Процитировано

33
Multiparametric senescent cell phenotyping reveals targets of senolytic therapy in the aged murine skeleton DOI Creative Commons
Madison L. Doolittle, Dominik Saul, Japneet Kaur

и другие.

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июль 31, 2023

Senescence drives organismal aging, yet the deep characterization of senescent cells in vivo remains incomplete. Here, we apply mass cytometry by time-of-flight using carefully validated antibodies to analyze at single-cell resolution. We use multiple criteria identify mesenchymal that are growth-arrested and resistant apoptosis. These p16 + Ki67-BCL-2+ highly enriched for senescence-associated secretory phenotype DNA damage markers, strongly associated with age, their percentages increased late osteoblasts/osteocytes CD24

Язык: Английский

Процитировано

27
Cellular senescence in brain aging and cognitive decline DOI Creative Commons
Areez Shafqat, Saifullah Khan, Mohamed H. Omer

и другие.

Frontiers in Aging Neuroscience, Год журнала: 2023, Номер 15

Опубликована: Ноя. 23, 2023

Cellular senescence is a biological aging hallmark that plays key role in the development of neurodegenerative diseases. Clinical trials are currently underway to evaluate effectiveness senotherapies for these However, impact on brain and cognitive decline absence neurodegeneration remains uncertain. Moreover, patient populations like cancer survivors, traumatic injury obese individuals, obstructive sleep apnea patients, chronic kidney disease patients can suffer age-related changes prematurely, suggesting they may accelerated brain. Understanding neurocognitive deficits linked conditions crucial, especially considering rapidly evolving field senotherapeutics. Such treatments could help alleviate early significantly reducing morbidity healthcare costs. This review provides translational perspective how cellular decline. We also discuss important caveats surrounding mainstream senolytics senomorphics, present emerging evidence hyperbaric oxygen therapy immune-directed therapies as viable modalities senescent cell burden.

Язык: Английский

Процитировано

24
The roles of bone remodeling in normal hematopoiesis and age-related hematological malignancies DOI Creative Commons
Hengwei Zhang, Jane L. Liesveld, Laura M. Calvi

и другие.

Bone Research, Год журнала: 2023, Номер 11(1)

Опубликована: Март 14, 2023

Abstract Prior research establishing that bone interacts in coordination with the marrow microenvironment (BMME) to regulate hematopoietic homeostasis was largely based on analyses of individual bone-associated cell populations. Recent advances intravital imaging has suggested expansion stem cells (HSCs) and acute myeloid leukemia is restricted microdomains during a distinct stage remodeling. These findings indicate dynamic remodeling likely imposes additional heterogeneity within BMME yield differential clonal responses. A holistic understanding role regulating niche how these interactions are altered age-related hematological malignancies will be critical development novel interventions. To advance this understanding, herein, we provide synopsis cellular molecular constituents participate turnover their known connections compartment. Specifically, elaborate coupling between after treatment bone-targeting approaches. We then discuss unresolved questions ambiguities remain field.

Язык: Английский

Процитировано

23
Targeting Cell Senescence and Senolytics: Novel Interventions for Age-Related Endocrine Dysfunction DOI Creative Commons
Masayoshi Suda, Karl H. Paul, Utkarsh Tripathi

и другие.

Endocrine Reviews, Год журнала: 2024, Номер 45(5), С. 655 - 675

Опубликована: Март 19, 2024

Multiple changes occur in hormonal regulation with aging and across various endocrine organs. These are associated multiple age-related disorders diseases. A better understanding of responsible underling biological mechanisms could help the management over above hormone replacement therapy (HRT). Cellular senescence is involved processes pathologies common elderly individuals. senescence, which occurs many older individuals but also lifespan association tissue damage, acute chronic diseases, certain drugs, genetic syndromes, may contribute to such as osteoporosis, metabolic syndrome, type 2 diabetes mellitus. Drugs that selectively induce senescent cell removal, "senolytics,", drugs attenuate tissue-destructive secretory state cells, "senomorphics," appear delay onset or alleviate including not limited diabetes, complications obesity, cancers well atherosclerosis, kidney disease, neurodegenerative disorders, others. More than 30 clinical trials senolytic senomorphic agents have already been completed, underway, planned for a variety indications. Targeting cells novel strategy distinct from conventional therapies HRT, thus might address unmet medical needs can potentially amplify effects established drug regimens, perhaps allowing dose decreases reducing side effects.

Язык: Английский

Процитировано

14
Mechanisms and therapeutic strategies for senescence-associated secretory phenotype in the intervertebral disc degeneration microenvironment DOI Creative Commons
Yang Liu,

Yiming Dou,

Xun Sun

и другие.

Journal of Orthopaedic Translation, Год журнала: 2024, Номер 45, С. 56 - 65

Опубликована: Март 1, 2024

As a permanent state of cell cycle arrest, cellular senescence has become an important factor in aging and age-related diseases. central regulator physiology pathology associated with senescence, the secretory phenotype can create inflammatory catabolic environment through autocrine paracrine ways, ultimately affecting tissue microstructure. disease, correlation between intervertebral disc degeneration been confirmed by many studies. Various pathological factors microenvironment promote senescent cells to produce accumulate express excessive phenotype. In this case, received considerable attention as potential target for delaying or treating degeneration. Therefore, we reviewed latest research progress phenotype, related regulatory mechanisms treatment strategies. It is expected that further understanding underlying mechanism will help formulate reasonable regulation strategies, so achieve ideal therapeutic effects.

Язык: Английский

Процитировано

12
The Achilles’ heel of cancer survivors: fundamentals of accelerated cellular senescence DOI Creative Commons
Shameel Shafqat,

Evelyn Arana Chicas,

Areez Shafqat

и другие.

Journal of Clinical Investigation, Год журнала: 2022, Номер 132(13)

Опубликована: Июнь 30, 2022

Recent improvements in cancer treatment have increased the lifespan of pediatric and adult survivors. However, treatments accelerate aging survivors, which manifests clinically as premature onset chronic diseases, such endocrinopathies, osteoporosis, cardiac dysfunction, subsequent cancers, geriatric syndromes frailty, among others. Therefore, treatment-induced early accounts for significant morbidity, mortality, health expenditures One major mechanism driving this accelerated is cellular senescence; induce senescence tumor cells normal, nontumor tissue, thereby helping mediate several diseases. Studies on clinical monitoring therapeutic targeting made considerable progress recent years. Large-scale trials are currently evaluating senotherapeutic drugs, inhibit or eliminate senescent to ameliorate treatment-related aging. In article, we survey literature phenotypes mechanisms survivors provide an up-to-date review preclinical translational evidence a well insight into potential drugs. only with time will effect senotherapies be visible.

Язык: Английский

Процитировано

30
“Bone-SASP” in Skeletal Aging DOI Creative Commons

Ching‐Lien Fang,

Bin Liu, Mei Wan

и другие.

Calcified Tissue International, Год журнала: 2023, Номер 113(1), С. 68 - 82

Опубликована: Май 31, 2023

Abstract Senescence is a complex cell state characterized by stable cycle arrest and unique secretory pattern known as the senescence-associated phenotype (SASP). The SASP factors, which are heterogeneous tissue specific, normally include chemokines, cytokines, growth adhesion molecules, lipid components that can lead to multiple age-associated disorders eliciting local systemic consequences. skeleton highly dynamic organ changes constantly in shape composition. Senescent cells bone marrow produce diverse factors induce alterations of through paracrine effects. Herein, we refer cell-associated “bone-SASP.” In this review, describe current knowledge cellular senescence SASP, focusing on role senescent mediating pathologies during natural aging premature syndromes. We also summarize bone-SASP glucocorticoids-induced damage. addition, discuss development osteoarthritis, highlighting mechanisms drives subchondral metabolic syndrome-associated osteoarthritis.

Язык: Английский

Процитировано

19
Immunotherapeutic approach to reduce senescent cells and alleviate senescence‐associated secretory phenotype in mice DOI Creative Commons
Niraj Shrestha,

Pallavi Chaturvedi,

Xiaoyun Zhu

и другие.

Aging Cell, Год журнала: 2023, Номер 22(5)

Опубликована: Март 26, 2023

Abstract Accumulation of senescent cells (SNCs) with a senescence‐associated secretory phenotype (SASP) has been implicated as major source chronic sterile inflammation leading to many age‐related pathologies. Herein, we provide evidence that bifunctional immunotherapeutic, HCW9218, capabilities neutralizing TGF‐β and stimulating immune cells, can be safely administered systemically reduce SNCs alleviate SASP in mice. In the diabetic db/db mouse model, subcutaneous administration HCW9218 reduced islet β resulting improved glucose tolerance, insulin resistance, aging index. naturally aged mice, durably level SASP, lower expression pro‐inflammatory genes peripheral organs. treatment also reverted pattern key regulatory circadian gene mice levels observed young impacted associated metabolism fibrosis liver. Single‐nucleus RNA Sequencing analysis further revealed differentially changed transcriptomic landscape hepatocyte subtypes involving metabolic, signaling, cell‐cycle, pathways Long‐term survival studies showed physical performance without compromising health span Thus, represents novel immunotherapeutic approach clinically promising new class senotherapeutic agents targeting cellular diseases.

Язык: Английский

Процитировано

17
Recent advances in senescence-associated secretory phenotype and osteoporosis DOI Creative Commons
Haonan Fan, Zhi Qiao, Jitian Li

и другие.

Heliyon, Год журнала: 2024, Номер unknown, С. e25538 - e25538

Опубликована: Фев. 1, 2024

The worldwide elderly population is on the rise, and aging a major osteoporosis risk factor. Senescent cells accumulation can have detrimental effect body as we age. senescence-associated secretory phenotype (SASP), an essential cellular senescence hallmark, important mechanism connecting to osteoporosis. This review describes in detail characteristics of SASPs their regulatory agencies, shed fresh light how from different senescent contribute development. Furthermore, summarized various innovative therapy techniques that target lower burden discussed potential challenges SASPs-based for new clinical trial.

Язык: Английский

Процитировано

7