Repurposing digoxin for geroprotection in patients with frailty and multimorbidity

Lee, Helena; Wilson, Daisy; Bunting, Karina V; Kotecha, Dipak; Jackson, Thomas

doi:10.1016/j.arr.2023.101860

Cited by 7 publications

(4 citation statements)

References 116 publications

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“…Recent studies also showed that digoxin could be used for geroprotection in patients with frailty and multimorbidity. 15 Although it is a therapeutic drug, the narrow therapeutic window makes it a less safe drug. The individual difference in drug use is large, and it can pass through the placenta and the blood–brain barrier.…”

Section: Resultsmentioning

confidence: 99%

“…Its role in the treatment of cardiovascular-related diseases is to increase myocardium contractility to increase blood pressure and reduce the heart rate of patients. Recent studies also showed that digoxin could be used for geroprotection in patients with frailty and multimorbidity . Although it is a therapeutic drug, the narrow therapeutic window makes it a less safe drug.…”

Section: Resultsmentioning

confidence: 99%

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Immunosensor for Rapid and Sensitive Detection of Digoxin

et al. 2023

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Digoxin is a cardiac glycosylated steroid-like drug with a positive inotropic effect and has been widely used in treating congestive heart failure, atrial fibrillation, atrial flutter, and other heart diseases. Digoxin is also a dangerous drug, which can cause drug poisoning at a low blood drug concentration (2.73–3.9 nmol/L, i.e., 2.14–3.05 ng/mL). Therefore, the timely detection of a patient’s blood drug concentration plays a significant role in controlling blood drug concentration, reducing the occurrence of drug poisoning events, and maximizing the role of drug therapy. In this study, a DNA vector for the expression of the antidigoxin antibody Fab fragment was constructed. With the vector, Fab was expressed in E. coli and purified, and 1.2 mg of antibodies was obtained from 100 mL of culture. An immunofluorescent sensor based on the mechanism of photoinduced electron transfer was constructed by labeling additional cysteines in the heavy chain variable region and light chain variable region of the antibody Fab fragment with fluorescent dyes. The assay for digoxin with the immunosensor could be finished within 5 min with a limit of detection of 0.023 ng/mL, a detectable range of 0.023 ng/mL to 100 μg/mL, and an EC50 of 0.256 ng/mL. A new approach for the rapid detection of digoxin was developed and will contribulte to therapeutic drug monitoring.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Immunosensor for Rapid and Sensitive Detection of Digoxin

et al. 2023

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“…Another previously established drug class, cardiac glycosides has recently been described for their senotherapeutic properties ( 61 , 62 , 155 ). This class of drug is FDA approved for the treatment of heart failure and arrythmias such as atrial fibrillation ( 156 , 157 ).…”

Section: Preclinical Evidence For Senotherapeuticsmentioning

confidence: 99%

“…This class of drug is FDA approved for the treatment of heart failure and arrythmias such as atrial fibrillation ( 156 , 157 ). Acting with Na+/K+ ATPase pump inhibition, cardiac glycosides target SCs with higher H+ concentrations and slightly depolarized membranes ( 62 , 155 ). On the in vitro scale, the cardiac glycoside digoxin had significant senotherapeutic activity against A549 tumor cells, primary human BJ fibroblasts, and osteoarthritic chondrocytes ( 62 ).…”

Section: Preclinical Evidence For Senotherapeuticsmentioning

confidence: 99%

The potential for senotherapy as a novel approach to extend life quality in veterinary medicine

Williams,

Chow,

Dow

et al. 2024

Front. Vet. Sci.

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Cellular senescence, a condition where cells undergo arrest and can assume an inflammatory phenotype, has been associated with initiation and perpetuation of inflammation driving multiple disease processes in rodent models and humans. Senescent cells secrete inflammatory cytokines, proteins, and matrix metalloproteinases, termed the senescence associated secretory phenotype (SASP), which accelerates the aging processes. In preclinical models, drug interventions termed “senotherapeutics” selectively clear senescent cells and represent a promising strategy to prevent or treat multiple age-related conditions in humans and veterinary species. In this review, we summarize the current available literature describing in vitro evidence for senotheraputic activity, preclinical models of disease, ongoing human clinical trials, and potential clinical applications in veterinary medicine. These promising data to date provide further justification for future studies identifying the most active senotherapeutic combinations, dosages, and routes of administration for use in veterinary medicine.

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Systemic aging fuels heart failure: Molecular mechanisms and therapeutic avenues

Fang,

Raza,

Song

et al. 2024

ESC Heart Failure

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Systemic aging influences various physiological processes and contributes to structural and functional decline in cardiac tissue. These alterations include an increased incidence of left ventricular hypertrophy, a decline in left ventricular diastolic function, left atrial dilation, atrial fibrillation, myocardial fibrosis and cardiac amyloidosis, elevating susceptibility to chronic heart failure (HF) in the elderly. Age‐related cardiac dysfunction stems from prolonged exposure to genomic, epigenetic, oxidative, autophagic, inflammatory and regenerative stresses, along with the accumulation of senescent cells. Concurrently, age‐related structural and functional changes in the vascular system, attributed to endothelial dysfunction, arterial stiffness, impaired angiogenesis, oxidative stress and inflammation, impose additional strain on the heart. Dysregulated mechanosignalling and impaired nitric oxide signalling play critical roles in the age‐related vascular dysfunction associated with HF. Metabolic aging drives intricate shifts in glucose and lipid metabolism, leading to insulin resistance, mitochondrial dysfunction and lipid accumulation within cardiomyocytes. These alterations contribute to cardiac hypertrophy, fibrosis and impaired contractility, ultimately propelling HF. Systemic low‐grade chronic inflammation, in conjunction with the senescence‐associated secretory phenotype, aggravates cardiac dysfunction with age by promoting immune cell infiltration into the myocardium, fostering HF. This is further exacerbated by age‐related comorbidities like coronary artery disease (CAD), atherosclerosis, hypertension, obesity, diabetes and chronic kidney disease (CKD). CAD and atherosclerosis induce myocardial ischaemia and adverse remodelling, while hypertension contributes to cardiac hypertrophy and fibrosis. Obesity‐associated insulin resistance, inflammation and dyslipidaemia create a profibrotic cardiac environment, whereas diabetes‐related metabolic disturbances further impair cardiac function. CKD‐related fluid overload, electrolyte imbalances and uraemic toxins exacerbate HF through systemic inflammation and neurohormonal renin‐angiotensin‐aldosterone system (RAAS) activation. Recognizing aging as a modifiable process has opened avenues to target systemic aging in HF through both lifestyle interventions and therapeutics. Exercise, known for its antioxidant effects, can partly reverse pathological cardiac remodelling in the elderly by countering processes linked to age‐related chronic HF, such as mitochondrial dysfunction, inflammation, senescence and declining cardiomyocyte regeneration. Dietary interventions such as plant‐based and ketogenic diets, caloric restriction and macronutrient supplementation are instrumental in maintaining energy balance, reducing adiposity and addressing micronutrient and macronutrient imbalances associated with age‐related HF. Therapeutic advancements targeting systemic aging in HF are underway. Key approaches include senomorphics and senolytics to limit senescence, antioxidants targeting mitochondrial stress, anti‐inflammatory drugs like interleukin (IL)‐1β inhibitors, metabolic rejuvenators such as nicotinamide riboside, resveratrol and sirtuin (SIRT) activators and autophagy enhancers like metformin and sodium‐glucose cotransporter 2 (SGLT2) inhibitors, all of which offer potential for preserving cardiac function and alleviating the age‐related HF burden.

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Repurposing digoxin for geroprotection in patients with frailty and multimorbidity

Cited by 7 publications

References 116 publications

Immunosensor for Rapid and Sensitive Detection of Digoxin

Immunosensor for Rapid and Sensitive Detection of Digoxin

The potential for senotherapy as a novel approach to extend life quality in veterinary medicine

Systemic aging fuels heart failure: Molecular mechanisms and therapeutic avenues

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