Oxidative stress, aging, metabolism, SIRT1, and the gut microbiota: the neurocardiac basis of cognitive loss.

Abstract

FactsCardiovascular disease, Alzheimer's disease, and multiple sclerosis share a neurocardiac basis linked by cellular metabolism and diabetes, indicating the presence of common pathological pathways.Current care remains symptomatic and prevention focused, and interventions targeting shared pathways such as oxidative stress, senescence, and autophagy are lacking.Apolipoprotein E (APOE), glucagon-like peptide-1 (GLP-1) agonism, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mitochondrial dynamics, and the gut microbiome are key modulators of the neurocardiac axis and are highly interdependent.Understanding the interactions among ferroptosis, pyroptosis, and apoptosis under comorbid conditions is essential for clinical translation.Open questionsIs oxidative stress a primary driver or a consequence of autophagy dysregulation that links cardiac dysfunction to cognitive decline?Are GLP-1 receptor agonists neuroprotective independent of glycemic control, and what is the optimal timing and disease stage?Which microbial metabolites influence mitochondrial dynamics and senescence, and can microbiome targeting improve both cardiac and cognitive outcomes?Is combined inhibition of ferroptosis and pyroptosis superior to single-pathway blockade, and how can strategies for different comorbidity profiles be chosen?How can APOE genotypes and individual metabolic states guide personalized therapies that simultaneously reduce cardiovascular risk and neurodegeneration? Cardiovascular disease and cognitive loss have a neurocardiac basis. Poor vascular perfusion can impair cognitive function in both Alzheimer's disease and multiple sclerosis. However, a treatment gap exists because current approaches do not adequately address the shared underlying cellular mechanisms responsible for cognitive dysfunction in these conditions. Current treatments for cognitive impairment in diseases such as cardiovascular disease, Alzheimer's disease, multiple sclerosis, and diabetes often fail to fully address the shared underlying cellular mechanisms. Consequently, the prevailing precision treatment strategy, which focuses on managing symptoms and preventing disease progression, is insufficient. This highlights the urgent need for innovative approaches capable of targeting these common cellular pathways across these diverse conditions. Novel investigations into oxidative stress, cellular senescence, programmed cell death with apoptosis, ferroptosis, pyroptosis, and autophagy, cellular metabolism with apolipoprotein E and glucagon-like peptide-1 receptor agonism, silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae), mitochondrial dynamics, and the gut microbiome offer the potential to address the risk factors and clinical treatments for cardiovascular disease and cognitive loss. These pathways are exquisitely dependent upon one another and require in-depth knowledge of the modulatory cellular mechanisms for effective translation to clinical care.