Targeting senescence induced by age or chemotherapy with a polyphenol-rich natural extract improves longevity and healthspan in mice
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ABSTRACT:
PROVIDER: PRJNA1105119 | ENA |
REPOSITORIES: ENA
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Project description:The accumulation of senescent cells within tissues contributes to age-related diseases through the senescence-associated secretory phenotype (SASP). To fight senescence and maintain a healthy tissue microenvironment, the quest for longevity-promoting compounds has resulted in promising discoveries from botanical sources. Here we show that daily administration with a low dose of Haenkenium (HK), a standardized extract of Salvia haenkei, extended the lifespan and healthspan of aged C57BL/6 mice by delaying senescence and consequently ameliorating systemic inflammation and fibrosis markers in multiple tissues including skin, muscle, cartilage, and kidney. Additionally, treated aged mice displayed increased muscle strength, vitality, and thicker fur coverage than age-matched controls. Notably, HK treatment also effectively reduced doxorubicin (Doxo)-induced senescence in p16LUC reporter mice and protected against Doxo-induced cardiotoxicity. The composition of HK was analyzed by UPLC-QTOF-MS, which revealed multiple polyphenols that were then screened for their putative anti-senescence activity in vitro. Among these, luteolin, luteolin- 7-O-glucuronide and 3,4-dicaffeoylquinic were identified as HK-derived constituents with comparable activity to HK. Mechanistically, we report that luteolin could disrupt the p16-CDK6 interaction, which was validated by surface plasmon resonance (SPR) and by in situ proximity ligation assay in vitro. Our findings suggest that phytoconstituents such as luteolin can alter the senescence phenotype by disrupting the activity of p16 which subsequently is associated with improved longevity in mice.
2024-05-01 | GSE266005 | GEO
Project description:A diet rich in dietary fiber and polyphenols supports the normal intestinal barrier function crucial for intestinal and overall health. Birch wood-derived fiber containing glucuronoxylans (GX)- and polyphenols have the potential in multiple food technological applications and have favorable effects on gut microbiota and colonic metabolism. However, their impact on intestinal barrier function is unknown. To elucidate their potential as new intestinal health-supporting food ingredients, we investigated the effect of GX- and polyphenol-rich extract (GXpoly ) and highly purified GX-rich extract (pureGX) on the gene expression of the colon mucosa.
2023-12-01 | GSE230139 | GEO
Project description:Abundant high molecular weight hyaluronic acid (HMW-HA) contributes to cancer resistance and possibly longevity of the longest-lived rodent, the naked mole-rat1,2. To study whether the benefits of increased HMW-HA could be transferred to other animal species, we generated a transgenic mouse overexpressing naked mole-rat hyaluronic acid synthase 2 gene (nmrHAS2). nmrHAS2 mice showed increase in hyaluronan levels in several tissues, and lower incidence of spontaneous and induced cancer, extended lifespan and improved healthspan. The transcriptome signature of nmrHAS2 mice shifted towards that of longer-lived species. The most striking change observed in nmrHAS2 mice was attenuated inflammation across multiple tissues. HMW-HA reduced inflammation via several pathways including direct immunoregulatory effect on immune cells, protection from oxidative stress, and improved gut barrier function during aging. These findings demonstrate that the longevity mechanism that evolved in the naked mole-rat can be exploited to other species, and open new avenues for using HMW-HA to improve lifespan and healthspan.
2023-06-12 | GSE234286 | GEO
Project description:Various anti-aging interventions exhibit potential in extending lifespan, yet most of these interventions are inefficacy or even have deleterious effects on healthspan. Ginkgolide B (GB) is a Ginkgo biloba-derived small molecule that reduces aging-related morbidities; however, the effects of GB on healthspan and longevity remain elusive. Here, we report that continuous oral GB administration in mice starting at 20 months extended their lifespan by 20% and reduced tumour incidence. Besides, GB administration significantly improved healthspan evidenced by enhancement in muscle quality, physical performance, grip strength, metabolism, frailty index, systemic inflammation, and senescence. Moreover, GB administration ameliorated aging-related pathologies without any apparent adverse effects. Single-nucleus RNA sequencing (snRNA-seq) revealed that GB improved aging-associated abnormal cell-type composition, intracellular signalling pathways, and cell-cell communication in skeletal muscles. GB also reduced the levels of aging-induced novel Runx1+ type 2B myonuclei, which are associated with apoptotic burden and aging-related signatures. Runx1 derived senescence, as shown by gain- and loss-of-function assays. Together, a new function of GB in extending the healthspan in aging is identified, which contributes to lifespan extension. The senomorphic effects of GB on the multifactorial aging process may provide new prospects for achieving healthy aging and longevity extension.
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Project description:Abundant high molecular weight hyaluronic acid (HMW-HA) contributes to cancer resistance and possibly longevity of the longest-lived rodent, the naked mole-rat1,2. To study whether the benefits of increased HMW-HA could be transferred to other animal species, we generated a transgenic mouse overexpressing naked mole-rat hyaluronic acid synthase 2 gene (nmrHAS2). nmrHAS2 mice showed increase in hyaluronan levels in several tissues, and lower incidence of spontaneous and induced cancer, extended lifespan and improved healthspan. The transcriptome signature of nmrHAS2 mice shifted towards that of longer-lived species. The most striking change observed in nmrHAS2 mice was attenuated inflammation across multiple tissues. HMW-HA reduced inflammation via several pathways including direct immunoregulatory effect on immune cells, protection from oxidative stress, and improved gut barrier function during aging. These findings demonstrate that the longevity mechanism that evolved in the naked mole-rat can be exploited to other species, and open new avenues for using HMW-HA to improve lifespan and healthspan
2023-09-08 | GSE234154 | GEO
Project description:Abundant high molecular weight hyaluronic acid (HMW-HA) contributes to cancer resistance and possibly longevity of the longest-lived rodent, the naked mole-rat1,2. To study whether the benefits of increased HMW-HA could be transferred to other animal species, we generated a transgenic mouse overexpressing naked mole-rat hyaluronic acid synthase 2 gene (nmrHAS2). nmrHAS2 mice showed increase in hyaluronan levels in several tissues, and lower incidence of spontaneous and induced cancer, extended lifespan and improved healthspan. The transcriptome signature of nmrHAS2 mice shifted towards that of longer-lived species. The most striking change observed in nmrHAS2 mice was attenuated inflammation across multiple tissues. HMW-HA reduced inflammation via several pathways including direct immunoregulatory effect on immune cells, protection from oxidative stress, and improved gut barrier function during aging. These findings demonstrate that the longevity mechanism that evolved in the naked mole-rat can be exploited to other species, and open new avenues for using HMW-HA to improve lifespan and healthspan.
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Project description:A proteomics strategy based on nano-liquid chromatography-tandem mass spectrometry (nano-LC-MS/MS) using an Orbitrap high-resolution mass spectrometer together with stable isotope dimethyl labeling (DML) is applied to quantitatively examine relative changes in the protein fraction of HT-29 human colon cancer cells treated with different concentrations of a polyphenol-enriched rosemary extract over the time. The objectives of this study were (i) to detect changes in amplitude and kinetics of proteins altered by the treatment over the time; and (ii) to identify proteomic differences between the cytostatic and cytotoxic effect of the natural extract tested in order to gain insights into the antiproliferative mechanisms induced by rosemary polyphenols.
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Project description:Transcriptome-based drug screening is emerging as a powerful tool to identify geroprotective compounds to intervene in age-related disease. We hypothesized that, by mimicking the transcriptional signature of the highly conserved longevity intervention of FOXO3 (daf-16 in worms) overexpression, we could identify and repurpose compounds with similar downstream effects to increase longevity. Our in silico screen, utilizing the LINCS transcriptome database of genetic and compound interventions, identified several FDA-approved compounds that activate FOXO downstream targets in mammalian cells. These included the neuromuscular blocker atracurium, which also robustly extends both lifespan and healthspan in C. elegans. This longevity is dependent on both daf-16 signaling and inhibition of the neuromuscular acetylcholine receptor. Other neuromuscular blockers tubocurarine and pancuronium caused similar healthspan benefits. Together, these data demonstrate the capacity to mimic genetic lifespan interventions with drugs, and in doing so, reveal that the neuromuscular acetylcholine receptor regulates the highly conserved FOXO/DAF-16 longevity pathway.
2021-07-06 | GSE149944 | GEO