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.
journal_name
Nat Medjournal_title
Nature medicineauthors
Xu M,Pirtskhalava T,Farr JN,Weigand BM,Palmer AK,Weivoda MM,Inman CL,Ogrodnik MB,Hachfeld CM,Fraser DG,Onken JL,Johnson KO,Verzosa GC,Langhi LGP,Weigl M,Giorgadze N,LeBrasseur NK,Miller JD,Jurk D,Singh RJ,Allisondoi
10.1038/s41591-018-0092-9subject
Has Abstractpub_date
2018-08-01 00:00:00pages
1246-1256issue
8eissn
1078-8956issn
1546-170Xpii
10.1038/s41591-018-0092-9journal_volume
24pub_type
杂志文章相关文献
NATURE MEDICINE文献大全abstract::Some individuals remain uninfected with human immunodeficiency virus type-1 (HIV-1) despite multiple high-risk sexual exposures. We studied a cohort of 25 subjects with histories of multiple high-risk sexual exposures to HIV-1 and found that their CD8+ lymphocytes had greater anti-HIV-1 activity than did CD8+ lymphocy...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0496-412
更新日期:1996-04-01 00:00:00
abstract::Whereas uncoupling protein 1 (UCP-1) is clearly involved in thermogenesis, the role of UCP-2 is less clear. Using hybridization, cloning techniques and cDNA array analysis to identify inducible neuroprotective genes, we found that neuronal survival correlates with increased expression of Ucp2. In mice overexpressing h...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm903
更新日期:2003-08-01 00:00:00
abstract::HIV infection can cause extensive neuronal loss and clinically a severe dementia. The cause of the neurotoxicity remains unclear as neurons are not infected, but disturbance of glutamate-linked calcium entry has been implicated. In this study, we have shown a decrease in HIV-infected brain of the expression of mRNA an...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1195-1174
更新日期:1995-11-01 00:00:00
abstract::Iron is an essential component of the erythrocyte protein hemoglobin and is crucial to oxygen transport in vertebrates. In the steady state, erythrocyte production is in equilibrium with erythrocyte removal. In various pathophysiological conditions, however, erythrocyte life span is compromised severely, which threate...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.4146
更新日期:2016-08-01 00:00:00
abstract::White fat stores excess energy, whereas brown and beige fat are thermogenic and dissipate energy as heat. Thermogenic adipose tissues markedly improve glucose and lipid homeostasis in mouse models, although the extent to which brown adipose tissue (BAT) influences metabolic and cardiovascular disease in humans is uncl...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/s41591-020-1126-7
更新日期:2021-01-01 00:00:00
abstract::The notoriously drug-resistant bug MRSA has made headlines for years, but a whole other class of bacteria may prove even more troublesome. These microbes, Gram-negative bacteria, are increasingly a threat--and yet not a single late-stage drug in development specifically targets them. Christian Torres follows one man's...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0610-628
更新日期:2010-06-01 00:00:00
abstract::1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces clinical, biochemical and neuropathologic changes reminiscent of those which occur in idiopathic Parkinson's disease. 7-Nitroindazole (7-NI) is a relatively selective inhibitor of the neuronal isoform of nitric oxide synthase (NOS) that blocks MPTP neurotoxi...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0996-1017
更新日期:1996-09-01 00:00:00
abstract::Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort of patients with melanoma (n = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcripto...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/s41591-019-0654-5
更新日期:2019-12-01 00:00:00
abstract::The HIV-1-specific cytotoxic T lymphocyte (CTL) response is temporally associated with the decline in viremia during primary HIV-1 infection, but definitive evidence that it is of importance in virus containment has been lacking. Here we show that in a patient whose early CTL response was focused on a highly immunodom...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0297-205
更新日期:1997-02-01 00:00:00
abstract::The inwardly rectifying K(+) channel Kir6.1 forms K(+) channels by coupling with a sulfonylurea receptor in reconstituted systems, but the physiological roles of Kir6.1-containing K(+) channels have not been determined. We report here that mice lacking the gene encoding Kir6.1 (known as Kcnj8) have a high rate of sudd...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0502-466
更新日期:2002-05-01 00:00:00
abstract::Peroxisome proliferator-activated receptor-delta (PPAR-delta; also known as PPAR-beta) is expressed at high levels in colon tumors, but its contribution to colon cancer is unclear. We examined the role of PPAR-delta in colon carcinogenesis using PPAR-delta-deficient (Ppard(-/-)) mice. In both the Min mutant and chemic...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1026
更新日期:2004-05-01 00:00:00
abstract::Owing to recent medical and technological advances in neonatal care, infants born extremely premature have increased survival rates1,2. After birth, these infants are at high risk of hypoxic episodes because of lung immaturity, hypotension and lack of cerebral-flow regulation, and can develop a severe condition called...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/s41591-019-0436-0
更新日期:2019-05-01 00:00:00
abstract::Direct evidence in humans for the impact of the microbiome on nutrient absorption is lacking. We conducted an extended inpatient study using two interventions that we hypothesized would alter the gut microbiome and nutrient absorption. In each, stool calorie loss, a direct proxy of nutrient absorption, was measured. T...
journal_title:Nature medicine
pub_type: 杂志文章,随机对照试验
doi:10.1038/s41591-020-0801-z
更新日期:2020-04-01 00:00:00
abstract::Sepsis remains a global clinical problem. By using the mouse cecal ligation and puncture model of sepsis, here we identify an important aspect of mast cell (MC)-dependent, innate immune defenses against Gram-negative bacteria by demonstrating that MC protease activity is regulated by interleukin-15 (IL-15). Mouse MCs ...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1615
更新日期:2007-08-01 00:00:00
abstract::Members of the suppressor of cytokine signaling (SOCS) family are involved in the pathogenesis of many inflammatory diseases. SOCS-3 is predominantly expressed in T-helper type 2 (T(H)2) cells, but its role in T(H)2-related allergic diseases remains to be investigated. In this study we provide a strong correlation bet...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm896
更新日期:2003-08-01 00:00:00
abstract::Matrix-producing osteoblasts and bone-resorbing osteoclasts maintain bone homeostasis. Osteoclasts are multinucleated, giant cells of hematopoietic origin formed by the fusion of mononuclear pre-osteoclasts derived from myeloid cells. Fusion-mediated giant cell formation is critical for osteoclast maturation; without ...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1514
更新日期:2006-12-01 00:00:00
abstract::The glycosylation of the circulating immunoglobulin-gamma (IgG) antibody molecules changes in rheumatoid arthritis. The extent of the changes correlates with the disease severity and reverses in remission. We demonstrate here that the alteration in glycosylation associated with rheumatoid arthritis can create a new mo...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0395-237
更新日期:1995-03-01 00:00:00
abstract::Sphingosine-1-phosphate (S1P) signaling influences bone metabolism, but its therapeutic potential in bone disorders has remained unexplored. We show that raising S1P levels in adult mice through conditionally deleting or pharmacologically inhibiting S1P lyase, the sole enzyme responsible for irreversibly degrading S1P...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/s41591-018-0005-y
更新日期:2018-05-01 00:00:00
abstract::Low oxygen tension influences tumor progression by enhancing angiogenesis; and histone deacetylases (HDAC) are implicated in alteration of chromatin assembly and tumorigenesis. Here we show induction of HDAC under hypoxia and elucidate a role for HDAC in the regulation of hypoxia-induced angiogenesis. Overexpressed wi...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/86507
更新日期:2001-04-01 00:00:00
abstract::In the version of this article originally published, Dimitry G. Sayenko's affiliations were not correct. The following affiliation for this author was missing: Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, USA. This affiliation has been added for the autho...
journal_title:Nature medicine
pub_type: 已发布勘误
doi:10.1038/s41591-018-0248-7
更新日期:2018-12-01 00:00:00
abstract::Neutrophil extracellular traps (NETs) are released as neutrophils die in vitro in a process requiring hours, leaving a temporal gap that invasive microbes may exploit. Neutrophils capable of migration and phagocytosis while undergoing NETosis have not been documented. During Gram-positive skin infections, we directly ...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.2847
更新日期:2012-09-01 00:00:00
abstract::Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs)...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/s41591-018-0116-5
更新日期:2018-08-01 00:00:00
abstract::The dorsomedial hypothalamic nucleus harbors leptin sensitive neurons and is intrinsically connected to hypothalamic nuclei involved in feeding behavior. However, it also receives ascending input from the visceroceptive neurons of the brainstem. We have identified a unique glucagon-like-peptide-2 containing neuronal p...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/77535
更新日期:2000-07-01 00:00:00
abstract::Systemic inflammation induces various adaptive responses including tachycardia. Although inflammation-associated tachycardia has been thought to result from increased sympathetic discharge caused by inflammatory signals of the immune system, definitive proof has been lacking. Prostanoids, including prostaglandin (PG) ...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1231
更新日期:2005-05-01 00:00:00
abstract::Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that compromise its chloride channel activity. The most common mutation, p.Phe508del, results in the production of a misfolded CFTR protein, which has residual channel activity but is prematu...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.4305
更新日期:2017-05-01 00:00:00
abstract::The ubiquitin-proteasome pathway is the central mediator of regulated proteolysis in cells, and defects in this pathway are associated with cancer and neurodegenerative diseases. To assess 26S proteasome function in living animals, we developed a ubiquitin-luciferase reporter for bioluminescence imaging. The reporter ...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm894
更新日期:2003-07-01 00:00:00
abstract::Stimulating an immune response against cancer through adoptive transfer of tumor-targeting lymphocytes has shown great promise in hematological malignancies, but clinical efficacy against many common solid epithelial cancers remains low. Targeting 'neoantigens'-the somatic mutations expressed only by tumor cells-might...
journal_title:Nature medicine
pub_type: 杂志文章,评审
doi:10.1038/s41591-019-0596-y
更新日期:2019-10-01 00:00:00
abstract::The role of KRAS, when activated through canonical mutations, has been well established in cancer1. Here we explore a secondary means of KRAS activation in cancer: focal high-level amplification of the KRAS gene in the absence of coding mutations. These amplifications occur most commonly in esophageal, gastric and ova...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/s41591-018-0022-x
更新日期:2018-07-01 00:00:00
abstract::We determine here the functional integrity of auxiliary livers in containers fashioned from the small intestine. Liver microfragments from dipeptidyl peptidase 4 (DPP4)-deficient rats were transplanted into syngeneic normal animals with isolated intestinal segments characterized by mucosal denudation but intact vascul...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1057
更新日期:2004-07-01 00:00:00
abstract::During fasting, induction of hepatic gluconeogenesis is crucial to ensure proper energy homeostasis. Such induction is dysregulated in type 2 diabetes, resulting in the development of fasting hyperglycemia. Hormonal and nutrient regulation of metabolic adaptation during fasting is mediated predominantly by the transcr...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.2691
更新日期:2012-03-18 00:00:00