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 and senolytics: the path to the clinic DOI Open Access
Selim Chaib, Tamar Tchkonia, James L. Kirkland

и другие.

Nature Medicine, Год журнала: 2022, Номер 28(8), С. 1556 - 1568

Опубликована: Авг. 1, 2022

Язык: Английский

Процитировано

626
P16INK4A—More Than a Senescence Marker DOI Creative Commons

Hasan Safwan-Zaiter,

Nicole Wagner, Kay‐Dietrich Wagner

и другие.

Life, Год журнала: 2022, Номер 12(9), С. 1332 - 1332

Опубликована: Авг. 28, 2022

Aging is a biological feature that characterized by gradual degeneration of function in cells, tissues, organs, or an intact organism due to the accumulation environmental factors and stresses with time. Several have been attributed aging such as oxidative stress augmented production exposure reactive oxygen species, inflammatory cytokines production, telomere shortening, DNA damage, and, importantly, deposit senescent cells. These are irreversibly mitotically inactive, yet metabolically active The reason underlying their senescence lies within extrinsic intrinsic arms. arm mainly expression secretory profile known senescence-associated phenotype (SASP). results from impact several genes meant regulate cell cycle, tumor suppressor genes. P16

Язык: Английский

Процитировано

90
Cytotoxic CD4+ T cells eliminate senescent cells by targeting cytomegalovirus antigen DOI Creative Commons
Tatsuya Hasegawa, Tomonori Oka,

Heehwa G. Son

и другие.

Cell, Год журнала: 2023, Номер 186(7), С. 1417 - 1431.e20

Опубликована: Март 1, 2023

Язык: Английский

Процитировано

80
The Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis DOI Creative Commons
Kay‐Dietrich Wagner, Nicole Wagner

Cells, Год журнала: 2022, Номер 11(12), С. 1966 - 1966

Опубликована: Июнь 19, 2022

It is widely accepted that senescent cells accumulate with aging. They are characterized by replicative arrest and the release of a myriad factors commonly called senescence-associated secretory phenotype. Despite cell cycle arrest, these metabolically active functional. The SASP mostly thought to cause tissue dysfunction induce senescence in surrounding cells. As major markers for aging senescence, p16INK4, p14ARF/p19ARF, p21 established. Importantly, also implicated development, cancer, homeostasis. While many have been identified, none able unambiguously identify all However, increased levels cyclin-dependent kinase inhibitors p16INK4A often used phenotypes. We review here knowledge p16INK4A, embryonic postnatal development potential functions pathophysiology establishment senolytic therapies ultimate goal improve healthy requires care detailed about involvement proteins developmental processes homeostatic mechanism. contributes topics, summarizes open questions, provides some directions future research.

Язык: Английский

Процитировано

79
Cellular Senescence in Intervertebral Disc Aging and Degeneration: Molecular Mechanisms and Potential Therapeutic Opportunities DOI Creative Commons
Prashanta Silwal, Allison M. Nguyen-Thai,

Haneef Ahamed Mohammad

и другие.

Biomolecules, Год журнала: 2023, Номер 13(4), С. 686 - 686

Опубликована: Апрель 18, 2023

Closely associated with aging and age-related disorders, cellular senescence (CS) is the inability of cells to proliferate due accumulated unrepaired damage irreversible cell cycle arrest. Senescent are characterized by their senescence-associated secretory phenotype that overproduces inflammatory catabolic factors hamper normal tissue homeostasis. Chronic accumulation senescent thought be intervertebral disc degeneration (IDD) in an population. This IDD one largest age-dependent chronic often neurological dysfunctions such as, low back pain, radiculopathy, myelopathy. (SnCs) increase number aged, degenerated discs, have a causative role driving IDD. review summarizes current evidence supporting CS on onset progression The discussion includes molecular pathways involved as p53-p21CIP1, p16INK4a, NF-κB, MAPK, potential therapeutic value targeting these pathways. We propose several mechanisms including mechanical stress, oxidative genotoxic nutritional deprivation, stress. There still large knowledge gaps research, understanding which will provide opportunities develop interventions treat

Язык: Английский

Процитировано

79
SenNet recommendations for detecting senescent cells in different tissues DOI
Vidyani Suryadevara, Adam D. Hudgins,

Adarsh Rajesh

и другие.

Nature Reviews Molecular Cell Biology, Год журнала: 2024, Номер 25(12), С. 1001 - 1023

Опубликована: Июнь 3, 2024

Язык: Английский

Процитировано

79
Targeted clearance of p21‐ but not p16‐positive senescent cells prevents radiation‐induced osteoporosis and increased marrow adiposity DOI
Abhishek Chandra, Anthony B. Lagnado, Joshua N. Farr

и другие.

Aging Cell, Год журнала: 2022, Номер 21(5)

Опубликована: Апрель 1, 2022

Abstract Cellular senescence, which is a major cause of tissue dysfunction with aging and multiple other conditions, known to be triggered by p16 Ink4a or p21 Cip1 , but the relative contributions each pathway toward inducing senescence are unclear. Here, we directly addressed this issue first developing validating ‐ ATTAC mouse promoter driving “suicide” transgene encoding an inducible caspase‐8 which, upon induction, selectively kills ‐expressing senescent cells. Next, used established INK compare versus in cellular condition where phenotype (bone loss increased marrow adiposity) clearly driven senescence—specifically, radiation‐induced osteoporosis. Using RNA situ hybridization, confirmed reduction ‐driven transcripts following cell clearance both models. However, only +, not cells prevented osteoporosis adiposity. Reduction dysfunctional telomeres also reduced several pro‐inflammatory senescence‐associated secretory factors. Thus, comparing using two parallel genetic models, demonstrate that predominantly rather than ‐mediated senescence. Further, approach can dissect these pathways including across tissues.

Язык: Английский

Процитировано

74
Guidelines for minimal information on cellular senescence experimentation in vivo DOI Creative Commons
Mikołaj Ogrodnik, Juan Carlos Acosta, Peter D. Adams

и другие.

Cell, Год журнала: 2024, Номер 187(16), С. 4150 - 4175

Опубликована: Авг. 1, 2024

Cellular senescence is a cell fate triggered in response to stress and characterized by stable cell-cycle arrest hypersecretory state. It has diverse biological roles, ranging from tissue repair chronic disease. The development of new tools study vivo paved the way for uncovering its physiological pathological roles testing senescent cells as therapeutic target. However, lack specific broadly applicable markers makes it difficult identify characterize tissues living organisms. To address this, we provide practical guidelines called "minimum information cellular experimentation vivo" (MICSE). presents an overview rodent tissues, transgenic models, non-mammalian systems, human tumors their use identification specification cells. These uniform, state-of-the-art, accessible toolset improve our understanding vivo.

Язык: Английский

Процитировано

64
Senescent Cells: A Therapeutic Target in Cardiovascular Diseases DOI Creative Commons
Masayoshi Suda, Karl H. Paul, Tohru Minamino

и другие.

Cells, Год журнала: 2023, Номер 12(9), С. 1296 - 1296

Опубликована: Май 2, 2023

Senescent cell accumulation has been observed in age-associated diseases including cardiovascular diseases. cells lack proliferative capacity and secrete senescence-associated secretory phenotype (SASP) factors that may cause or worsen many Therapies targeting senescent cells, especially senolytic drugs selectively induce removal, have shown to delay, prevent, alleviate, treat multiple preclinical models. Some clinical trials already completed are underway for a number of geriatric syndromes. Understanding how cellular senescence affects the various types system, such as endothelial vascular smooth muscle fibroblasts, immune progenitor cardiomyocytes, is important facilitate translation senotherapeutics into interventions. This review highlights: (1) characteristics their involvement diseases, focusing on aforementioned types, (2) evidence about other senotherapeutics, (3) future path potential

Язык: Английский

Процитировано

49
Local senolysis in aged mice only partially replicates the benefits of systemic senolysis DOI Creative Commons
Joshua N. Farr, Dominik Saul, Madison L. Doolittle

и другие.

Journal of Clinical Investigation, Год журнала: 2023, Номер 133(8)

Опубликована: Фев. 21, 2023

Clearance of senescent cells (SnCs) can prevent several age-related pathologies, including bone loss. However, the local versus systemic roles SnCs in mediating tissue dysfunction remain unclear. Thus, we developed a mouse model (p16-LOX-ATTAC) that allowed for inducible SnC elimination (senolysis) cell-specific manner and compared effects senolysis during aging using as prototype tissue. Specific removal Sn osteocytes prevented loss at spine, but not femur, by improving formation without affecting osteoclasts or marrow adipocytes. By contrast, spine femur only improved formation, also reduced osteoclast adipocyte numbers. Transplantation into peritoneal cavity young mice caused induced senescence distant host osteocytes. Collectively, our findings provide proof-of-concept evidence has health benefits context aging, but, importantly, partially replicates senolysis. Furthermore, establish SnCs, through their senescence-associated secretory phenotype (SASP), lead to cells. Therefore, study indicates optimizing senolytic drugs may require instead targeting extend healthy aging.

Язык: Английский

Процитировано

45