The gut microbiota (GM) plays a critical role in regulating human physiology, with dysbiosis linked to various diseases, including heart failure (HF). HF is a complex syndrome with a significant global health impact, as its incidence doubles with each decade of life, and its prevalence peaks in individuals over 80 years. A bidirectional interaction exists between GM and HF, where alterations in gut health can worsen the disease’s progression. The “gut hypothesis of HF” suggests that HF-induced changes, such as reduced intestinal perfusion and altered gut motility, negatively impact GM composition, leading to increased intestinal permeability, the release of GM-derived metabolites into the bloodstream, and systemic inflammation. This process creates a vicious cycle that further deteriorates heart function. GM-derived metabolites, including trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), and secondary bile acids (BAs), can influence gene expression through epigenetic mechanisms, such as DNA methylation and histone modifications. These epigenetic changes may play a crucial role in mediating the effects of dysbiotic gut microbial metabolites, linking them to altered cardiac health and contributing to the progression of HF. This process is particularly relevant in older individuals, as the aging process itself has been associated with both dysbiosis and cumulative epigenetic alterations, intensifying the interplay between GM, epigenetic changes, and HF, and further increasing the risk of HF in the elderly. Despite the growing body of evidence, the complex interplay between GM, epigenetic modifications, and HF remains poorly understood. The dynamic nature of epigenetics and GM, shaped by various factors such as age, diet, and lifestyle, presents significant challenges in elucidating the precise mechanisms underlying this complex relationship. Future research should prioritize innovative approaches to overcome these limitations. By identifying specific metabolite-induced epigenetic modifications and modulating the composition and function of GM, novel and personalized therapeutic strategies for the prevention and/or treatment of HF can be developed. Moreover, targeted research focusing specifically on older individuals is crucial for understanding the intricate connections between GM, epigenetics, and HF during aging.

Cellular senescence is a hallmark of aging and a promising target for therapeutic approaches. The identification of senescent cells requires multiple biomarkers and complex experimental procedures, resulting in increased variability and reduced sensitivity. Here, we propose a simple and broadly applicable imaging flow cytometry (IFC) method. This method is based on measuring autofluorescence and morphological parameters and on applying recent artificial intelligence (AI) and machine learning (ML) tools. We show that the results of this method are superior to those obtained measuring the classical senescence marker, senescence-associated beta-galactosidase (SA-β-Gal). We provide evidence that this method has the potential for diagnostic or prognostic applications as it was able to detect senescence in cardiac pericytes isolated from the hearts of patients affected by end-stage heart failure. We additionally demonstrate that it can be used to quantify senescence “in vivo” and can be used to evaluate the effects of senolytic compounds. We conclude that this method can be used as a simple and fast senescence assay independently of the origin of the cells and the procedure to induce senescence.

Cellular senescence is a state of irreversible cell cycle arrest in response to several stressors, including DNA damage, increased cellular oxidative stress, telomere shortening, oncogene activation, and a deep epigenetic remodeling

Ageing represents a main risk factor for several pathologies. Among them, cardiovascular diseases (CVD) and type 2 diabetes mellitus (T2DM) are predominant in the elderly population and often require prolonged use of multiple drugs due to their chronic nature and the high proportion of co-morbidities. Hence, research is constantly looking for novel, effective molecules to treat CVD and T2DM with minimal side effects. Marine active compounds, holding a great diversity of chemical structures and biological properties, represent interesting therapeutic candidates to treat these age-related diseases. This review summarizes the current state of research on marine compounds for the treatment of CVD and T2DM, from pre-clinical studies to clinical investigations and approved drugs, highlighting the potential of marine compounds in the development of new therapies, together with the limitations in translating pre-clinical results into human application.

Major depressive disorder (MDD) is a severe psychiatric condition that significantly impacts the overall quality of life. Although MDD can occur across all age groups, it is notably prevalent among older individuals, with the aggravating circumstance that the clinical condition is frequently overlooked and undertreated. Furthermore, older adults often encounter resistance to standard treatments, experience adverse events, and face challenges associated with polypharmacy. Given that late-life MDD is associated with heightened rates of disability and mortality, as well as imposing a significant economic and logistical burden on healthcare systems, it becomes imperative to explore novel therapeutic approaches. These could serve as either supplements to standard guidelines or alternatives for non-responsive patients, potentially enhancing the management of geriatric MDD patients. This review aims to delve into the potential of microRNAs targeting Brain-Derived Neurotrophic Factor (BDNF). In MDD, a significant decrease in both central and peripheral BDNF has been well-documented, raising implications for therapy response. Notably, BDNF appears to be a key player in the intricate interplay between microRNA-induced neuroplasticity deficits and neuroinflammation, both processes deeply implicated in the onset and progression of the disease. Special emphasis is placed on delivery methods, with a comprehensive comparison of the strengths and weaknesses of each proposed approach. Our hypothesis proposes that employing multiple microRNAs concurrently, with the ability to directly influence BDNF and activate closely associated pathways, may represent the most promising strategy. Regarding vehicles, although the perfect nanoparticle remains elusive, considering the trade-offs, liposomes emerge as the most suitable option.

The homozygous genotype of the Longevity-Associated Variant (LAV) in Bactericidal/Permeability-Increasing Fold-Containing Family B member 4 (BPIFB4) is enriched in long-living individuals of three independent populations and its genetic transfer in C57BL/6J mice showed a delay in frailty progression and improvement of several biomarkers of aging and multiple aspects of health. The C57BL/6J strain is a suitable model for studying therapies aimed at extending healthy aging and longevity due to its relatively short lifespan and the availability of aging biomarkers. Epigenetic clocks based on DNA methylation profiles are reliable molecular biomarkers of aging, while frailty measurement tools are used to evaluate overall health during aging. In this study, we show that the systemic gene transfer of LAV-BPIFB4 in aged C57BL/6J mice was associated with a significant reduction in the epigenetic clock-based biological age, as measured by a three CpG clock method. Furthermore, LAV-BPIFB4 gene transfer resulted in an improvement of the Vitality Score with a reduction in the Frailty Index. These findings further support the use of LAV-BPIFB4 gene therapy to induce beneficial effects on epigenetic mechanisms associated with aging and frailty in aged mice, with potential implications for future therapies to prevent frailty in humans.