Age is the strongest risk factor for cardiovascular morbidity and mortality, driven in part by aging leukocytes negatively impact cardiovascular health. This effect is particularly pronounced in men, who have a shorter average lifespan -approximately six years less than women, largely due to higher mortality rates in old age. One contributing factor is a male-specific aging blood phenotype characterized by the mosaic loss of the Y chromosome (mLOY), a condition in which a subset of blood cells lose the Y chromosome. mLOY is highly prevalent in elderly men, affecting 45% of those aged 70 and older. Recent studies have linked mLOY to increased early mortality, age-related pathologies, and cardiovascular disease, potentially explaining the observed sex discrepancy in life expectancy. Experimental studies have begun to uncover potential mechanisms related to leukocyte responses to cardiac injury and the polarization of macrophages that promote pro-fibrotic cytokine expression. Current evidence suggests that mLOY reflects an underlying aspect of biological aging related to genomic instability, which drives age-related diseases, including cardiovascular conditions. Although mLOY shares similarities with general age-related changes in the hematopoietic system, it may exert distinct effects on leukocytes that promote cardiovascular disease through enhanced tissue fibrosis pathways. These findings highlight that mLOY accumulates with age and contributes to cardiovascular disease through mechanisms that are independent of biological aging per se. Further investigation into mLOY-specific pathways in aging and age-related diseases may reveal novel therapeutic targets for a chronic condition that affects a large proportion of the elderly male population. This review discusses the current literature on mLOY and its connection to cardiovascular disease within the broader context of aging.

The heart’s metabolic plasticity, crucial for adapting to energy demands, is governed by epigenetic and epitranscriptomic mechanisms. Aging and cardiovascular diseases disrupt this equilibrium, leading to metabolic inflexibility, mitochondrial dysfunction, and pathological remodeling. This review explores how DNA methylation, histone modifications, and RNA methylation (e.g., m6A, m5C) dynamically regulate cardiac metabolism. Key findings reveal that age-related declines in SIRT1/NAD+ activity and FTO-mediated RNA demethylation impair fatty acid oxidation, while METTL3-driven m6A hypermethylation promotes glycolytic dependency. Dysregulation of TET enzymes and α-ketoglutarate (α-KG) further disrupts DNA hydroxymethylation and RNA modification, exacerbating oxidative stress and mitochondrial inefficiency. These alterations create self-reinforcing cycles of metabolic rigidity, contributing to heart failure, arrhythmias, and ischemia-reperfusion injury. Emerging therapeutic strategies, including BET inhibitors and NAD+ repletion, show promise in restoring metabolic flexibility by targeting epigenetic and epitranscriptomic pathways. Integrating multi-omics approaches and spatial epitranscriptomics offers novel insights into cell-specific regulatory networks, paving the way for precision interventions to counteract cardiac aging and disease.

Aim: The difference between cystatin C-based and creatinine-based estimated glomerular filtration rate (eGFR_diff) has been suggested to reflect factors distinct from kidney function that are associated with cardiovascular risk. This study aims to investigate the association between eGFR_diff and hypertension (HP) among the middle-aged and elderly population in China.

Methods: This study utilized a cross-sectional design based on retrospective data from the China Health and Retirement Longitudinal Study (CHARLS) cohort. We conducted a cross-sectional analysis of CHARLS data collected from 2011 to 2020. Hypertension was identified through self-reports or the use of antihypertensive medications. Participants younger than 45 years, those with kidney diseases, or individuals missing data on eGFR_diff, hypertension records, or baseline information were excluded from the study. Participants were categorized into three groups based on eGFR_diff: negative (< -15 mL/min/1.73 m²), midrange (-15 to 15 mL/min/1.73 m²), and positive (≥ 15 mL/min/1.73 m²). The primary outcome of interest was the prevalence of HP. We employed weighted multivariable-adjusted logistic regression to examine the association between eGFR_diff and HP.

Results: Among 12,621 participants, after adjusting for covariates, a lower eGFR_diff was found to be independently associated with a higher prevalence of hypertension. In comparison to the negative eGFR_diff group, the midrange group exhibited an odds ratio (OR) of 0.79 (95%CI, 0.70-0.90; P < 0.001), while the positive group demonstrated an OR of 0.52 (95%CI, 0.44-0.61; P < 0.001). Our findings further underscore the significance of specific factors, such as age, gender, body mass index (BMI), and alcohol consumption, in influencing the association between eGFR_diff and hypertension prevalence.

Conclusion: In the middle-aged and elderly population of CHARLS in China, lower eGFR_diff values were associated with a higher prevalence of hypertension, which may be influenced by specific factors such as age, gender, BMI, and alcohol consumption. These findings may have implications for the risk management of hypertension in the middle-aged and elderly population.

Introduction: Chronic exposure to an obesogenic diet (OBD) induces systemic inflammation and disrupts lipid-immune homeostasis, but its long-term effects and potential reversibility with aging remain unclear.

Aim: This study examined whether switching from an OBD to a control diet can restore lipid-immune homeostasis during aging and evaluated associated changes in myocardial infarction (MI) response, macrophage activation, and immune cell heterogeneity.

Methods and Results: Male C57BL/6J mice were fed either a control or OBD diet for six months, followed by continued OBD or dietary reversal (OBD-R) for an additional four months. Cardiac function, splenic and cardiac lipid mediators, leukocyte profiles, and gene expression were assessed at baseline and post-MI. Lipopolysaccharide (LPS)-induced macrophage activation assays and single-cell RNA sequencing (scRNA-seq) of CD45⁺ cells were performed to characterize immune memory. Chronic OBD induced cardiac strain dysfunction, expansion of CCR2⁺ macrophages, elevated 12-HETE levels, and depletion of specialized pro-resolving mediators (SPMs). Dietary reversal restored SPMs, normalized certain immune parameters, and improved post-MI responses, but persistent activation of the 12-HETE-driven CCL2-CCR2/ALOX5-ALOX5AP axis maintained proinflammatory macrophage memory. scRNA-seq revealed diet-dependent transcriptional remodeling of immune populations, and LPS assays confirmed heightened inflammatory memory in macrophages after chronic OBD exposure.

Conclusions: Dietary intervention can potentially resolve OBD-induced inflammation and mitigate related cardiovascular consequences during aging, with the 12-HETE-induced CCL2-CCR2/ALOX5-ALOX5AP axis playing a critical role in shaping macrophage phenotype and sustaining inflamed immune memory.