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1.
Nat Med ; 24(8): 1246-1256, 2018 08.
Article in English | MEDLINE | ID: mdl-29988130

ABSTRACT

Physical function declines in old age, portending disability, increased health expenditures, and mortality. Cellular senescence, leading to tissue dysfunction, may contribute to these consequences of aging, but whether senescence can directly drive age-related pathology and be therapeutically targeted is still unclear. Here we demonstrate that transplanting relatively small numbers of senescent cells into young mice is sufficient to cause persistent physical dysfunction, as well as to spread cellular senescence to host tissues. Transplanting even fewer senescent cells had the same effect in older recipients and was accompanied by reduced survival, indicating the potency of senescent cells in shortening health- and lifespan. The senolytic cocktail, dasatinib plus quercetin, which causes selective elimination of senescent cells, decreased the number of naturally occurring senescent cells and their secretion of frailty-related proinflammatory cytokines in explants of human adipose tissue. Moreover, intermittent oral administration of senolytics to both senescent cell-transplanted young mice and naturally aged mice alleviated physical dysfunction and increased post-treatment survival by 36% while reducing mortality hazard to 65%. Our study provides proof-of-concept evidence that senescent cells can cause physical dysfunction and decreased survival even in young mice, while senolytics can enhance remaining health- and lifespan in old mice.


Subject(s)
Dasatinib/pharmacology , Longevity/drug effects , Quercetin/pharmacology , Adipose Tissue/metabolism , Animals , Cell Transplantation , Cellular Senescence/drug effects , Cytokines/metabolism , Diet, High-Fat , Inflammation Mediators/metabolism , Mice, Inbred C57BL , Stress, Physiological/drug effects , Survival Analysis
3.
Nat Med ; 23(9): 1072-1079, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28825716

ABSTRACT

Aging is associated with increased cellular senescence, which is hypothesized to drive the eventual development of multiple comorbidities. Here we investigate a role for senescent cells in age-related bone loss through multiple approaches. In particular, we used either genetic (i.e., the INK-ATTAC 'suicide' transgene encoding an inducible caspase 8 expressed specifically in senescent cells) or pharmacological (i.e., 'senolytic' compounds) means to eliminate senescent cells. We also inhibited the production of the proinflammatory secretome of senescent cells using a JAK inhibitor (JAKi). In aged (20- to 22-month-old) mice with established bone loss, activation of the INK-ATTAC caspase 8 in senescent cells or treatment with senolytics or the JAKi for 2-4 months resulted in higher bone mass and strength and better bone microarchitecture than in vehicle-treated mice. The beneficial effects of targeting senescent cells were due to lower bone resorption with either maintained (trabecular) or higher (cortical) bone formation as compared to vehicle-treated mice. In vitro studies demonstrated that senescent-cell conditioned medium impaired osteoblast mineralization and enhanced osteoclast-progenitor survival, leading to increased osteoclastogenesis. Collectively, these data establish a causal role for senescent cells in bone loss with aging, and demonstrate that targeting these cells has both anti-resorptive and anabolic effects on bone. Given that eliminating senescent cells and/or inhibiting their proinflammatory secretome also improves cardiovascular function, enhances insulin sensitivity, and reduces frailty, targeting this fundamental mechanism to prevent age-related bone loss suggests a novel treatment strategy not only for osteoporosis, but also for multiple age-related comorbidities.


Subject(s)
Bone and Bones/drug effects , Cellular Senescence/drug effects , Janus Kinases/antagonists & inhibitors , Osteoblasts/drug effects , Osteoclasts/drug effects , Osteocytes/drug effects , Osteoporosis/metabolism , Pyrazoles/pharmacology , Absorptiometry, Photon , Animals , Apoptosis/genetics , Bone and Bones/metabolism , Cancellous Bone/drug effects , Cancellous Bone/metabolism , Caspase 8/genetics , Cell Differentiation , Cellular Senescence/genetics , Cortical Bone/drug effects , Cortical Bone/metabolism , Culture Media, Conditioned , Flow Cytometry , Gene Expression Profiling , In Vitro Techniques , Mice , Mice, Transgenic , Nitriles , Osteoblasts/cytology , Osteoclasts/cytology , Osteoporosis/genetics , Pyrimidines , Real-Time Polymerase Chain Reaction , Weight-Bearing , beta-Galactosidase
4.
J Bone Miner Res ; 31(11): 1920-1929, 2016 11.
Article in English | MEDLINE | ID: mdl-27341653

ABSTRACT

Cellular senescence is a fundamental mechanism by which cells remain metabolically active yet cease dividing and undergo distinct phenotypic alterations, including upregulation of p16Ink4a , profound secretome changes, telomere shortening, and decondensation of pericentromeric satellite DNA. Because senescent cells accumulate in multiple tissues with aging, these cells and the dysfunctional factors they secrete, termed the senescence-associated secretory phenotype (SASP), are increasingly recognized as promising therapeutic targets to prevent age-related degenerative pathologies, including osteoporosis. However, the cell type(s) within the bone microenvironment that undergoes senescence with aging in vivo has remained poorly understood, largely because previous studies have focused on senescence in cultured cells. Thus in young (age 6 months) and old (age 24 months) mice, we measured senescence and SASP markers in vivo in highly enriched cell populations, all rapidly isolated from bone/marrow without in vitro culture. In both females and males, p16Ink4a expression by real-time quantitative polymerase chain reaction (rt-qPCR) was significantly higher with aging in B cells, T cells, myeloid cells, osteoblast progenitors, osteoblasts, and osteocytes. Further, in vivo quantification of senescence-associated distension of satellites (SADS), ie, large-scale unraveling of pericentromeric satellite DNA, revealed significantly more senescent osteocytes in old compared with young bone cortices (11% versus 2%, p < 0.001). In addition, primary osteocytes from old mice had sixfold more (p < 0.001) telomere dysfunction-induced foci (TIFs) than osteocytes from young mice. Corresponding with the age-associated accumulation of senescent osteocytes was significantly higher expression of multiple SASP markers in osteocytes from old versus young mice, several of which also showed dramatic age-associated upregulation in myeloid cells. These data show that with aging, a subset of cells of various lineages within the bone microenvironment become senescent, although senescent myeloid cells and senescent osteocytes predominantly develop the SASP. Given the critical roles of osteocytes in orchestrating bone remodeling, our findings suggest that senescent osteocytes and their SASP may contribute to age-related bone loss. © 2016 American Society for Bone and Mineral Research.


Subject(s)
Bone and Bones/cytology , Cellular Microenvironment , Cellular Senescence , Animals , Biomarkers/metabolism , Cell Lineage , Cells, Cultured , Cyclin-Dependent Kinase Inhibitor p16/metabolism , DNA, Satellite/metabolism , Female , Male , Mice, Inbred C57BL , Myeloid Cells/metabolism , Osteoblasts/cytology , Osteoblasts/metabolism , Osteocytes/metabolism , Phenotype
5.
Aging Cell ; 15(5): 973-7, 2016 10.
Article in English | MEDLINE | ID: mdl-26864908

ABSTRACT

While reports suggest a single dose of senolytics may improve vasomotor function, the structural and functional impact of long-term senolytic treatment is unknown. To determine whether long-term senolytic treatment improves vasomotor function, vascular stiffness, and intimal plaque size and composition in aged or hypercholesterolemic mice with established disease. Senolytic treatment (intermittent treatment with Dasatinib + Quercetin via oral gavage) resulted in significant reductions in senescent cell markers (TAF(+) cells) in the medial layer of aorta from aged and hypercholesterolemic mice, but not in intimal atherosclerotic plaques. While senolytic treatment significantly improved vasomotor function (isolated organ chamber baths) in both groups of mice, this was due to increases in nitric oxide bioavailability in aged mice and increases in sensitivity to NO donors in hypercholesterolemic mice. Genetic clearance of senescent cells in aged normocholesterolemic INK-ATTAC mice phenocopied changes elicited by D+Q. Senolytics tended to reduce aortic calcification (alizarin red) and osteogenic signaling (qRT-PCR, immunohistochemistry) in aged mice, but both were significantly reduced by senolytic treatment in hypercholesterolemic mice. Intimal plaque fibrosis (picrosirius red) was not changed appreciably by chronic senolytic treatment. This is the first study to demonstrate that chronic clearance of senescent cells improves established vascular phenotypes associated with aging and chronic hypercholesterolemia, and may be a viable therapeutic intervention to reduce morbidity and mortality from cardiovascular diseases.


Subject(s)
Aging/pathology , Atherosclerosis/pathology , Atherosclerosis/physiopathology , Cellular Senescence/drug effects , Dasatinib/pharmacology , Quercetin/pharmacology , Vasomotor System/physiopathology , Animals , DNA Damage , Endothelium, Vascular/drug effects , Endothelium, Vascular/pathology , Endothelium, Vascular/physiopathology , Hypercholesterolemia/complications , Hypercholesterolemia/pathology , Mice , Nitric Oxide/metabolism , Signal Transduction/drug effects
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