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Kinase inhibitor GW8510 rejuvenates yeast and mice through multiple pathways including SRC, PAKs, JAKs

ABSTRACT: Aging, a risk factor for many diseases, is largely attributable to cell senescence and impaired mitochondrial function. Here, we used connectivity map (CMAP) to predict the anti-aging effects of drugs based on age-related transcriptomic signatures. We found the kinase inhibitor GW8510 can extend lifespan of yeast, and C57BL/6J or ICR mice by 92.18%, 31.9%, and 142.9%, respectively. Mechanistically, GW8510 can ameliorate cellular senescence by enhancing mitochondrial function, decreasing SA-β-gal staining, p21 and SASP marker expression, and rescues age-related histomorphological changes in mouse hippocampus, heart, kidney and liver. In yeast, the action of GW8510 is dependent on STE20, and in human cells, GW8510 acts through various pathways such as SRC, PAKs, and JAKs. Furthermore, inhibiting these genes can delay cellular senescence. This work provides a valuable resource for mechanistic aging studies and suggests strong clinical potential for GW8510.

ORGANISM(S): Homo sapiens

PROVIDER: GSE216516 | GEO | 2023/10/30

REPOSITORIES: GEO

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A benzenesulfonamide GW8510 rejuvenates mice and yeast through interaction with p21-Activated kinases

Project description:Aging, a risk factor for many diseases, is largely attributable to cell senescence and impaired mitochondrial function. Here, we used connectivity map (CMAP) to predict the anti-aging effects of drugs based on age-related transcriptomic signatures. We found the kinase inhibitor GW8510 can extend lifespan of yeast, and C57BL/6J or ICR mice by 92.18%, 31.9%, and 142.9%, respectively. Mechanistically, GW8510 can ameliorate cellular senescence by enhancing mitochondrial function, decreasing SA-β-gal staining, p21 and SASP marker expression, and rescues age-related histomorphological changes in mouse hippocampus, heart, kidney and liver. The GW8510 mode of action depends on STE20 (yeast PAK1 homolog), and binds to PAK1 with Kd of 0.82 μM. The crystal structure shows that GW8510 binds to the PAK1 ATP binding pocket. Furthermore, inhibition of PAKs can delay the effects of aging in mice. This work provides a valuable resource for mechanistic aging studies and suggests strong clinical potential for GW8510.

2023-10-30 | GSE186887 | GEO

NAD+ supplementation counteracts senescence mediated by STING in Ataxia Telangiectasia models by improving mitophagy (Human)

Project description:Senescence phenotypes and mitochondrial dysfunction are implicated in aging and neurodegeneration, and in the premature aging disease, including A-T. Loss of mitochondrial function can drive age-related decline in the brain, but little is known about whether improving mitochondrial homeostasis alleviates senescence phenotypes. Here we demonstrate impaired mitochondrial function and increased senescence growth arrest with senescence-associated secretory phenotype (SASP) in A-T patient fibroblasts, and in ATM-deficient cells and mice. We find that boosting intracellular NAD+ levels with nicotinamide riboside (NR) reduces senescence, suppresses neuroinflammation, and improves motor function in Atm-/- mice. We further show that the senescence responses are mediated by stimulator of interferon genes (STING), which is activated by cytoplasmic mtDNA and that NR prevents senescence and neuroinflammation through stimulation of mitophagy. Our findings suggest a pivotal role for mitochondrial dysfunction induced senescence in A-T pathogenesis, and that enhancing mitophagy is a potential therapeutic intervention.

2021-05-25 | GSE152287 | GEO

NAD+ supplementation counteracts senescence mediated by STING in Ataxia Telangiectasia models by improving mitophagy (Mouse)

2021-05-25 | GSE152286 | GEO

Age-associated decline of MondoA drives cellular senescence through impaired autophagy and mitochondrial homeostasis

Project description:Accumulation of senescent cells affects organismal aging and the prevalence of age-associated disease. Emerging evidence suggests that activation of autophagy protects against age-associated diseases and promotes longevity, but the roles and regulatory mechanisms of autophagy in cellular senescence are not well understood. Here we identified the transcription factor, MondoA, as a novel regulator of cellular senescence, autophagy and mitochondrial homeostasis. MondoA protected against cellular senescence by activating autophagy partly through the suppression of an autophagy negative regulator, Rubicon. In addition, we identified peroxiredoxin 3 (Prdx3) as another downstream regulator of MondoA essential for mitochondrial homeostasis and autophagy. Rubicon and Prdx3 worked independently to regulate senescence. Furthermore, we found that MondoA knockout mice had exacerbated senescence during ischemic acute kidney injury (AKI), and a decrease of MondoA in the nucleus was correlated with human aging and ischemic AKI. Our results suggest that retaining MondoA activity protects from senescence and age-associated disease.

2022-03-01 | GSE179016 | GEO

Project description:Background: A gradual decline in renal function occurs even in healthy aging individuals. In addition to aging per se, concurrent metabolic syndrome and hypertension, which are common in the aging population, can induce mitochondrial dysfunction and inflammation, which collectively contribute to age-related kidney dysfunction and disease. Here we studied the role of the nuclear hormone receptors, the estrogen related receptors (ERRs) in regulation of age-related mitochondrial dysfunction and inflammation. Methods: ERRs were decreased in aging human and mouse kidneys and were preserved in aging mice with lifelong caloric restriction (CR). Pan-ERR agonist was used to treat 21-month-old mice for 8-weeks. Results: Remarkably, only an 8-week treatment with the pan-ERR agonist reversed the age-related increases in albuminuria and podocyte loss, mitochondrial dysfunction and inflammatory cytokines, including the cGAS-STING and STAT3 signaling pathways. A 3-week treatment of 21-month-old mice with a STING inhibitor reversed the increases in inflammatory cytokines and the senescence marker p21 but also unexpectedly reversed the age-related decreases in PGC-1α, ERRα, mitochondrial complexes and MCAD expression. Conclusions: Our studies identified ERRs as important modulators of age-related mitochondrial dysfunction and inflammation.

2020-07-09 | GSE154050 | GEO

ERR agonism reverses mitochondrial dysfunction and inflammation in the aging kidney

Project description:A gradual decline in renal function occurs even in healthy aging individuals. In addition to aging per se, concurrent metabolic syndrome and hypertension, which are common in the aging population, can induce mitochondrial dysfunction, and inflammation, which collectively contribute to age-related kidney disease. Here we studied the role of the nuclear hormone receptors, the estrogen related receptors (ERRs) in regulation of age-related mitochondrial dysfunction and inflammation. ERRs are decreased in aging human and mouse kidneys and preserved in aging mice with lifelong caloric restriction (CR). Our studies identified ERRs as important modulators of age-related mitochondrial dysfunction and inflammation. ERRα, ERRβ, and ERRγ levels are decreased in the aging kidney. Remarkably, only a 4-week treatment of 21-month-old mice with the pan ERR agonist reversed the age-related increases in albuminuria and podocyte loss, mitochondrial dysfunction and inflammatory cytokines, including the cGAS-STING and STAT3 signaling pathways. A 3-week treatment of 21-month-old mice with a STING inhibitor reversed the increases in inflammatory cytokines and the senescence marker p21 but also unexpectedly reversed the age-related decreases in PGC-1α, ERRα, mitochondrial complexes and Mcad expression.

2023-08-02 | PXD020051 | Pride

Polyamine metabolite spermidine rejuvenates the oocyte quality by enhancing mitophagy during female reproductive aging

Project description:Advanced age is a primary risk factor for female infertility due to reduced ovarian reserve and declining oocyte quality. However, as an important contributing factor, the role of metabolic regulation during reproductive aging is poorly understood. Here, we applied untargeted metabolomics to identify spermidine as a critical metabolite in ovaries to protect oocytes against aging. In particular, we found that spermidine level was reduced in aged ovaries and supplementation of spermidine promoted follicle development, oocyte maturation, early embryonic development and female fertility of aged mice. By micro-transcriptomic analysis, we further discovered that recovery of oocyte quality by spermidine was mediated by enhancement of mitophagy activity and mitochondrial function in aged mice, and this action mechanism was conserved in porcine oocytes under oxidative stress. Altogether, our findings demonstrate that spermidine supplementation is a potentially effective strategy to ameliorate oocyte quality and reproductive outcome of women at an advanced age.

2023-11-10 | GSE239551 | GEO

Oridonin delays aging through AKT signaling pathway

Project description:Aging is the major risk factor for chronic diseases and disability in human. There is no effective anti-aging clinical treatment. In this study, oridonin was selected based on the drug screening strategy of Connectivity MAP (CMAP) upon transcriptomes of 102 traditional Chinese medicines (TCM) treated cell lines. Oridonin is an anti-inflammatory drug and diterpenoid isolated from Rabdosia rubescens. Oridonin exhibited a variety of pharmacological activities, including anti-tumor, antibacteria and anti-inflammation. Here, we found that oridonin inhibited cellular senescence in human diploid fibroblasts (2BS and WI-38), indicated by decreased senescence-associated β-galactosidase (SA-β-gal) staining. Compared with the elderly control group, the positive cell rate in the oridonin intervention group was 48.5%, and the cell shape was similar to young cells. Oridonin prolonged the lifespan of yeast by 14.6%~48.9%, and prolonged the average life span of naturally aged mice by 21.6%. It also increased the healthspan of aged mice. In addition, oridonin also improved doxorubicin-induced cellular senescence and mouse senescence. Compared with the model group, the percentage of SA-β-gal positive cells in the oridonin treatment group was reduced to 59.8%. It prolonged the average life span of mice by 53.8% as well as the healthspan. Mechanistically, we show that oridonin delayed aging through the AKT signaling pathways and reverses the genetic changes caused by doxorubicin-induced cell senescence. Therefore, oridonin may be an ideal candidate for the development of anti-aging drugs, and it also provides therapeutic potential in other diseases.

2022-03-18 | GSE189789 | GEO

Transcriptomic landscape of mouse pulmonary alveolar cells upon chronological aging and/or anti-senescence intervention

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2023-09-05 | GSE217808 | GEO

Mitofusin 2 expression in muscle decreases during aging and generates a gene signature characteristic of aged muscle

Project description:Mitochondrial fusion and fission proteins regulate mitochondrial quality control and mitochondrial metabolism. In turn, mitochondrial dysfunction is associated with aging, although its causes are still under debate. Here, we show that aging is characterized by a progressive reduction of Mitofusin 2 (Mfn2) in mouse skeletal muscle and that skeletal muscle Mfn2 ablation in mice generates a gene signature linked to aging. Furthermore, muscle Mfn2-deficient mice show unhealthy aging characterized by altered metabolic homeostasis and sarcopenia. Mfn2 deficiency impairs mitochondrial quality control, which contributes to an exacerbated age-related mitochondrial dysfunction. Surprisingly, aging-induced Mfn2 deficiency triggers a ROS-dependent retrograde signaling pathway through induction of HIF1 transcription factor and BNIP3. This pathway ameliorates mitochondrial autophagy and minimizes mitochondrial damage. Our findings reveal that repression of Mfn2 in skeletal muscle during aging is determinant for the loss of mitochondrial quality, contributing to age-associated metabolic alterations and loss of muscle fitness. Quadriceps muscle from four mice per genotype were used (Control young (6 month-old), Mfn2KO young (6-month-old), control old (22-month-old) and Mfn2KO old (22-month-old)

2016-08-08 | E-GEOD-71501 | biostudies-arrayexpress

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