A5009102749- Telomeres, Telomerase, and Senescence
- Adipokines, Inflammation, and Metabolic Diseases
- Adipose Tissue and Metabolism
- Genetics, Aging, and Longevity in Model Organisms
- Glioma Diagnosis and Treatment
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Frailty in Older Adults
- Fatty Acid Research and Health
- Circadian rhythm and melatonin
- Mesenchymal stem cell research
- Nutrition and Health in Aging
- MicroRNA in disease regulation
- Diet and metabolism studies
- Skin Protection and Aging
- Immune cells in cancer
- Birth, Development, and Health
- Single-cell and spatial transcriptomics
- Cardiovascular Disease and Adiposity
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Multiple Myeloma Research and Treatments
- Growth Hormone and Insulin-like Growth Factors
- Epigenetics and DNA Methylation
- Muscle Physiology and Disorders
- Tissue Engineering and Regenerative Medicine
- Neuroinflammation and Neurodegeneration Mechanisms
Mayo Clinic
2016-2025
Mayo Clinic in Florida
2016-2025
Mayo Clinic in Arizona
2016-2025
Cedars-Sinai Medical Center
2024-2025
WinnMed
2016-2025
American Federation for Aging Research
2023
Armadale Health Service
2022-2023
Adolescent Health Clinic
2023
University Medical Center Groningen
2023
University of Minnesota Rochester
2023
The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same small molecules would have tremendous impact on quality life and burden age-related chronic diseases. Here, we describe rationale for identification validation new class drugs termed senolytics, which selectively kill cells. By transcript analysis, discovered increased expression pro-survival networks in cells, consistent with their established resistance to apoptosis. Using...
Abstract Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by interstitial remodelling, leading to compromised lung function. Cellular senescence markers are detectable within IPF tissue and senescent cell deletion rejuvenates health in aged mice. Whether how cells regulate or if their removal may be an efficacious intervention strategy unknown. Here we demonstrate elevated abundance of biomarkers lung, with p16 expression increasing severity. We show that the secretome...
Senescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate with ageing at etiological sites in multiple chronic diseases. Senolytics, including combination of Dasatinib Quercetin (D + Q), selectively eliminate senescent cells by transiently disabling pro-survival networks defend them against their own apoptotic environment. In first clinical trial senolytics, D Q improved physical function patients...
BackgroundCellular senescence is a key mechanism that drives age-related diseases, but has yet to be targeted therapeutically in humans. Idiopathic pulmonary fibrosis (IPF) progressive, fatal cellular senescence-associated disease. Selectively ablating senescent cells using dasatinib plus quercetin (DQ) alleviates IPF-related dysfunction bleomycin-administered mice.MethodsA two-center, open-label study of intermittent DQ (D:100 mg/day, Q:1250 three-days/week over three-weeks) was conducted...
Clearing senescent cells extends healthspan in mice. Using a hypothesis-driven bioinformatics-based approach, we recently identified pro-survival pathways human that contribute to their resistance apoptosis. This led identification of dasatinib (D) and quercetin (Q) as senolytics, agents target some these induce apoptosis preferentially cells. Among other regulators was Bcl-xl. Here, tested whether the Bcl-2 family inhibitors, navitoclax (N) TW-37 (T), are senolytic. Like D Q, N is senolytic...
Abstract The incidence of non-alcoholic fatty liver disease (NAFLD) increases with age. Cellular senescence refers to a state irreversible cell-cycle arrest combined the secretion proinflammatory cytokines and mitochondrial dysfunction. Senescent cells contribute age-related tissue degeneration. Here we show that accumulation senescent promotes hepatic fat steatosis. We report close correlation between markers hepatocyte senescence. elimination by suicide gene-meditated ablation p16 Ink4a...
Senescence is a tumor suppressor mechanism activated in stressed cells to prevent replication of damaged DNA. Senescent have been demonstrated play causal role driving aging and age-related diseases using genetic pharmacologic approaches. We previously that the combination dasatinib flavonoid quercetin potent senolytic improving numerous conditions including frailty, osteoporosis cardiovascular disease. The goal this study was identify flavonoids with more activity.
Significance A hallmark of aging is chronic sterile inflammation, which closely associated with frailty and age-related diseases. We found that senescent fat progenitor cells accumulate in adipose tissue acquire a senescence-associated secretory phenotype (SASP), increased production proinflammatory cytokines compared nonsenescent cells. These provoked inflammation induced macrophage migration. The JAK pathway activated aging, the SASP can be suppressed by inhibiting JAK1/2 inhibitors...
While reports suggest a single dose of senolytics may improve vasomotor function, the structural and functional impact long-term senolytic treatment is unknown. To determine whether improves vascular stiffness, intimal plaque size composition in aged or hypercholesterolemic mice with established disease. Senolytic (intermittent Dasatinib + Quercetin via oral gavage) resulted significant reductions senescent cell markers (TAF+ cells) medial layer aorta from mice, but not atherosclerotic...
Senescent cells accumulate with aging and at sites of pathology in multiple chronic diseases. Senolytics are drugs that selectively promote apoptosis senescent by temporarily disabling the pro-survival pathways enable to resist pro-apoptotic, pro-inflammatory factors they themselves secrete. Reducing cell burden genetic approaches or administering senolytics delays alleviates age- disease-related adverse phenotypes preclinical models. Reported include dasatinib, quercetin, navitoclax...
Aging is the main risk factor for many chronic degenerative diseases and cancer. Increased senescent cell burden in various tissues a major contributor to aging age-related diseases. Recently, new class of drugs termed senolytics were demonstrated extending healthspan, reducing frailty improving stem function multiple murine models aging. To identify novel more optimal senotherapeutic combinations, we established senescence associated β-galactosidase assay as screening platform rapidly that...
Senescent cells accumulate in fat with aging. We previously found genetic clearance of senescent from progeroid INK-ATTAC mice prevents lipodystrophy. Here we show that primary human progenitors secrete activin A and directly inhibit adipogenesis non-senescent progenitors. Blocking partially restored lipid accumulation expression key adipogenic markers differentiating exposed to cells. Mouse tissue increased Clearing 18-month-old naturally-aged reduced circulating A, blunted loss, enhanced...
Adipose tissue inflammation and dysfunction are associated with obesity-related insulin resistance diabetes, but mechanisms underlying this relationship unclear. Although senescent cells accumulate in adipose of obese humans rodents, a direct pathogenic role for these the development diabetes remains to be demonstrated. Here, we show that reducing cell burden mice, either by activating drug-inducible "suicide" genes driven p16