Rutin is a potent senomorphic agent to target senescent cells and can improve chemotherapeutic efficacy DOI Creative Commons
Hanxin Liu,

Qixia Xu,

Halidan Wufuer

et al.

Aging Cell, Journal Year: 2023, Volume and Issue: 23(1)

Published: July 20, 2023

Abstract Aging is a major risk factor for most chronic disorders, which cellular senescence one of the central hallmarks. Senescent cells develop pro‐inflammatory senescence‐associated secretory phenotype (SASP), significantly contributes to organismal aging and age‐related disorders. Development senotherapeutics, an emerging class therapeutic agents target senescent cells, allows effectively delay alleviate pathologies. Here we report preliminary outputs from screening natural medicinal agent (NMA) library senotherapeutic candidates validated several with prominent potential as senomorphics. Rutin, phytochemical constituent found in number plants, showed remarkable capacity targeting by dampening expression full spectrum SASP. Further analysis indicated that rutin restrains acute stress‐associated (ASAP) specifically interfering interactions ATM HIF1α, master regulator systemic homeostasis activated during senescence, TRAF6, part key signaling axis supporting ASAP development toward Conditioned media produced stromal enhanced malignant phenotypes prostate cancer including vitro proliferation, migration, invasion, more importantly, chemoresistance, while remarkably downregulated these gain‐of‐functions. Although classic chemotherapy reduced tumor progression, treatment outcome was substantially improved upon combination chemotherapeutic rutin. Our study provides proof concept senomorphic agent, presents effective avenue alleviating pathologies cancer.

Language: Английский

Hallmarks of aging: An expanding universe DOI Creative Commons
Carlos López-Otı́n, Marı́a A. Blasco, Linda Partridge

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(2), P. 243 - 278

Published: Jan. 1, 2023

Language: Английский

Citations

2710
Autophagy in healthy aging and disease DOI Open Access
Yahyah Aman, Tomas Schmauck‐Medina, Malene Hansen

et al.

Nature Aging, Journal Year: 2021, Volume and Issue: 1(8), P. 634 - 650

Published: Aug. 12, 2021

Language: Английский

Citations

878
Alzheimer's disease drug development pipeline: 2021 DOI Creative Commons
Jeffrey L. Cummings, Garam Lee,

Kate Zhong

et al.

Alzheimer s & Dementia Translational Research & Clinical Interventions, Journal Year: 2021, Volume and Issue: 7(1)

Published: Jan. 1, 2021

Abstract Introduction The number of individuals worldwide with Alzheimer's disease (AD) is growing at a rapid rate. New treatments are urgently needed. We review the current pipeline drugs in clinical trials for treatment AD. Methods interrogated ClinicalTrials.gov, federal registry to identify trials. Results There 126 agents 152 assessing new therapies AD: 28 Phase 3 trials, 74 2, and 24 1. majority (82.5%) target underlying biology AD intent modification; 10.3% putative cognitive enhancing agents; 7.1% being developed reduce neuropsychiatric symptoms. Discussion This analysis shows that biological processes more diversified, biomarkers regularly used, repurposed explored determine their utility

Language: Английский

Citations

414
cGAS–STING drives ageing-related inflammation and neurodegeneration DOI Creative Commons
Muhammet F. Gülen,

Natasha Samson,

Alexander Keller

et al.

Nature, Journal Year: 2023, Volume and Issue: 620(7973), P. 374 - 380

Published: Aug. 2, 2023

Low-grade inflammation is a hallmark of old age and central driver ageing-associated impairment disease1. Multiple factors can contribute to inflammation2; however, the molecular pathways that transduce aberrant inflammatory signalling their impact in natural ageing remain unclear. Here we show cGAS-STING pathway, which mediates immune sensing DNA3, critical chronic functional decline during ageing. Blockade STING suppresses phenotypes senescent human cells tissues, attenuates ageing-related multiple peripheral organs brain mice, leads an improvement tissue function. Focusing on brain, reveal activation triggers reactive microglial transcriptional states, neurodegeneration cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity microglia, defining mechanism by engaged brain. Single-nucleus RNA-sequencing analysis microglia hippocampi gain-of-function mouse model demonstrates engagement sufficient direct states leading bystander cell inflammation, neurotoxicity impaired memory capacity. Our findings establish pathway as blockade potential strategy halt neurodegenerative processes age.

Language: Английский

Citations

395
Immunosenescence: a key player in cancer development DOI Creative Commons
Jingyao Lian, Ying Yue,

Weina Yu

et al.

Journal of Hematology & Oncology, Journal Year: 2020, Volume and Issue: 13(1)

Published: Nov. 10, 2020

Immunosenescence is a process of immune dysfunction that occurs with age and includes remodeling lymphoid organs, leading to changes in the function elderly, which closely related development infections, autoimmune diseases, malignant tumors. T cell-output decline an important feature immunosenescence as well production senescence-associated secretory phenotype, increased glycolysis, reactive oxygen species. Senescent cells exhibit abnormal phenotypes, including downregulation CD27, CD28, upregulation CD57, killer cell lectin-like receptor subfamily G, Tim-3, Tight, cytotoxic T-lymphocyte-associated protein 4, are tightly The role tumors sophisticated: many factors involved include cAMP, glucose competition, oncogenic stress tumor microenvironment, can induce senescence cells, macrophages, natural dendritic cells. Accordingly, these senescent could also affect progression. In addition, effect on response checkpoint blocking antibody therapy so far ambiguous due low participation elderly cancer patients clinical trials. Furthermore, other senescence-related interventions be possible genetic pharmacological methods, mTOR inhibition, interleukin-7 recombination, NAD+ activation. Overall, this review aims highlight characteristics its impact immunotherapy, especially future directions treatment through senescence-focused strategies.

Language: Английский

Citations

331
Meta-hallmarks of aging and cancer DOI Creative Commons
Carlos López-Otı́n, Federico Pietrocola, David Roiz‐Valle

et al.

Cell Metabolism, Journal Year: 2023, Volume and Issue: 35(1), P. 12 - 35

Published: Jan. 1, 2023

Language: Английский

Citations

263
Biomarkers of aging for the identification and evaluation of longevity interventions DOI Creative Commons
Mahdi Moqri, Chiara Herzog, Jesse R. Poganik

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(18), P. 3758 - 3775

Published: Aug. 1, 2023

Language: Английский

Citations

254
The landscape of aging DOI Open Access
Yusheng Cai, Wei Song, Jiaming Li

et al.

Science China Life Sciences, Journal Year: 2022, Volume and Issue: 65(12), P. 2354 - 2454

Published: Sept. 2, 2022

Language: Английский

Citations

239
Inflammation, epigenetics, and metabolism converge to cell senescence and ageing: the regulation and intervention DOI Creative Commons
Xudong Zhu, Zhiyang Chen,

Weiyan Shen

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: June 28, 2021

Remarkable progress in ageing research has been achieved over the past decades. General perceptions and experimental evidence pinpoint that decline of physical function often initiates by cell senescence organ ageing. Epigenetic dynamics immunometabolic reprogramming link to alterations cellular response intrinsic extrinsic stimuli, representing current hotspots as they not only (re-)shape individual identity, but also involve fate decision. This review focuses on present findings emerging concepts epigenetic, inflammatory, metabolic regulations consequences process. Potential therapeutic interventions targeting regulatory mechanisms, using state-of-the-art techniques are discussed.

Language: Английский

Citations

227
The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice DOI Creative Commons

Qixia Xu,

Qiang Fu, Zi Li

et al.

Nature Metabolism, Journal Year: 2021, Volume and Issue: 3(12), P. 1706 - 1726

Published: Dec. 6, 2021

Abstract Ageing-associated functional decline of organs and increased risk for age-related chronic pathologies is driven in part by the accumulation senescent cells, which develop senescence-associated secretory phenotype (SASP). Here we show that procyanidin C1 (PCC1), a polyphenolic component grape seed extract (GSE), increases healthspan lifespan mice through its action on cells. By screening library natural products, find GSE, PCC1 as one active components, have specific effects At low concentrations, appears to inhibit SASP formation, whereas it selectively kills cells at higher possibly promoting production reactive oxygen species mitochondrial dysfunction. In rodent models, depletes treatment-damaged tumour microenvironment enhances therapeutic efficacy when co-administered with chemotherapy. Intermittent administration either irradiated, cell-implanted or naturally aged old alleviates physical dysfunction prolongs survival. We identify senotherapeutic agent vivo activity high potential further development clinical intervention delay, alleviate prevent pathologies.

Language: Английский

Citations

202