The mineralocorticoid receptor (MR) was originally identified as a regulator of blood pressure, able to modulate renal sodium handling in response to its principal ligand aldosterone. MR is expressed in several extra-renal tissues, including the heart, vasculature, and adipose tissue. More recent studies have shown that extra-renal MR plays a relevant role in the control of cardiovascular and metabolic functions and has recently been implicated in the pathophysiology of aging. MR activation promotes vasoconstriction and acts as a potent pro-fibrotic agent in cardiovascular remodeling. Aging is associated with increased arterial stiffness and vascular tone, and modifications of arterial structure and function are responsible for these alterations. MR activation contributes to increase blood pressure with aging by regulating myogenic tone, vasoconstriction, and vascular oxidative stress. Importantly, aging represents an important contributor to the increased prevalence of cardiometabolic syndrome. In the elderly, dysregulation of MR signaling is associated with hypertension, obesity, and diabetes, representing an important cause of increased cardiovascular risk. Clinical use of MR antagonists is limited by the adverse effects induced by MR blockade in the kidney, raising the risk of hyperkalaemia in older patients with reduced renal function. Therefore, there is an unmet need for the enhanced understanding of the role of MR in aging and for development of novel specific MR antagonists in the context of cardiovascular rehabilitation in the elderly, in order to reduce relevant side effects.

Stiffening of the vasculature with aging is a strong predictor of adverse cardiovascular events, independent of all other risk factors including blood pressure, yet no therapies target this process. MRs (mineralocorticoid receptors) in smooth muscle cells (SMCs) have been implicated in the regulation of vascular fibrosis but have not been explored in vascular aging. Comparing SMC-MR–deleted male mice to MR-intact littermates at 3, 12, and 18 months of age, we demonstrated that aging-associated vascular stiffening and fibrosis are mitigated by MR deletion in SMCs. Progression of cardiac stiffness and fibrosis and the decline in exercise capacity with aging were also mitigated by MR deletion in SMC. Vascular gene expression profiling analysis revealed that MR deletion in SMC is associated with recruitment of a distinct antifibrotic vascular gene expression program with aging. Moreover, long-term pharmacological inhibition of MR in aged mice prevented the progression of vascular fibrosis and stiffness and induced a similar antifibrotic vascular gene program. Finally, in a small trial in elderly male humans, short-term MR antagonism produced an antifibrotic signature of circulating biomarkers similar to that observed in the vasculature of SMC-MR–deleted mice. These findings suggest that SMC-MR contributes to vascular stiffening with aging and is a potential therapeutic target to prevent the progression of aging-associated vascular fibrosis and stiffness.

These data demonstrate that the delayed and steeper decline in cardiovascular function observed in aging females can be modeled in aging mice. Moreover, the mechanisms driving vascular and cardiac aging phenotypes are distinct between males and females. Mineralocorticoid receptors in smooth muscle cells play a significant role in cardiovascular aging in both sexes; however, they do so by distinct mechanisms. Overall, these findings suggest that sex-specific therapies may be necessary to retard the aging process and improve cardiovascular disease outcomes in the aging population.

Changes in cardiorespiratory fitness in response to a standardized exercise training protocol differ substantially between individuals. Results from cross-sectional, twin, and family studies indicate genetics contribute to individual differences in both baseline exercise capacity and the response to training. Exercise capacity and responses to training also vary between inbred strains of mice. However, such studies have utilized a limited number of inbred strains. Therefore, the aim of this study was to characterize exercise-training responses in a larger number of genetically diverse strains of inbred mice and estimate the contribution of genetic background to exercise training responses. Eight-week old male mice from 24 inbred strains (n = 4–10/strain) performed a graded exercise test before and after 4 weeks of exercise training. Before training, exercise capacity was significantly different between strains when expressed as time (range = 21–42 min) and work performed (range = 0.42–3.89 kg·m). The responses to training also were significantly different between strains, ranging from a decrease of 2.2 min in NON/ShiLtJ mice to an increase of 8.7 min in SWR/J mice. Changes in work also varied considerably between the lowest (−0.24 kg·m in NON/ShiLtJ) and highest (+2.30 kg·m in FVB/NJ) performing strains. Heart and skeletal muscle masses also varied significantly between strains. Two broad sense heritability estimates were calculated for each measure of exercise capacity and for responses to training. For change in run time, the intraclass correlation between mice within the same inbred strain (r_I) was 0.58 and the coefficient of genetic determination (g²) was 0.41. Heritability estimates were similar for the change in work: r_I = 0.54 and g² = 0.37. In conclusion, these results indicate genetic background significantly influences responses to exercise training.

Vascular stiffness increases with age and independently predicts cardiovascular disease risk. Epigenetic changes, including histone modifications, accumulate with age but the global pattern has not been elucidated nor are the regulators known. Smooth muscle cell-mineralocorticoid receptor (SMC-MR) contributes to vascular stiffness in ageing mice. Thus, we investigated the regulatory role of SMC-MR in vascular epigenetics and stiffness. Mass spectrometry-based proteomic profiling of all histone modifications completely distinguished 3 from 12-month-old mouse aortas. Histone-H3 lysine-27 (H3K27) methylation (me) significantly decreased in ageing vessels and this was attenuated in SMC-MR-KO littermates. Immunoblotting revealed less H3K27-specific methyltransferase EZH2 with age in MR-intact but not SMC-MR-KO vessels. These ageing changes were examined in primary human aortic (HA)SMC from adult vs. aged donors. MR, H3K27 acetylation (ac), and stiffness gene (connective tissue growth factor, integrin-α5) expression significantly increased, while H3K27me and EZH2 decreased, with age. MR inhibition reversed these ageing changes in HASMC and the decline in stiffness genes was prevented by EZH2 blockade. Atomic force microscopy revealed that MR antagonism decreased intrinsic stiffness and the probability of fibronectin adhesion of aged HASMC. Conversely, ageing induction in young HASMC with H₂O₂; increased MR, decreased EZH2, enriched H3K27ac and MR at stiffness gene promoters by chromatin immunoprecipitation, and increased stiffness gene expression. In 12-month-old mice, MR antagonism increased aortic EZH2 and H3K27 methylation, increased EZH2 recruitment and decreased H3K27ac at stiffness genes promoters, and prevented ageing-induced vascular stiffness and fibrosis. Finally, in human aortic tissue, age positively correlated with MR and stiffness gene expression and negatively correlated with H3K27me3 while MR and EZH2 are negatively correlated. These data support a novel vascular ageing model with rising MR in human SMC suppressing EZH2 expression thereby decreasing H3K27me, promoting MR recruitment and H3K27ac at stiffness gene promoters to induce vascular stiffness and suggests new targets for ameliorating ageing-associated vascular disease.

Objectives: Accumulating evidence suggests that physical activity (PA) is an efficient intervention to maintain functional capabilities and mitigate physiological changes in the older population. However, an attempt has yet to be made to comprehensively investigate the published landscape on the subject. Methods: This study had two aims. The first aim was to perform a bibliometric analysis for two keywords, “aging” and “PA”, to analyze the research trend. Since “frailty” was the most noticeable co-occurring keyword with the two keywords, the second aim was to investigate the effects of PA, particularly, resistance training (RT), on frailty using a meta-analysis to provide a summary of the current evidence base. Results: The bibliometric analysis revealed that the number of publications on this research topic has gradually increased, highlighting the importance of understanding the role of PA in aging. The meta-analysis found that RT had significant beneficial effects on physical frailty factors, including handgrip strength, lower limb strength, balance, gait speed, and stair-climbing ability. Conclusion: These findings demonstrate that RT is an effective intervention for improving physical function in frail populations; thus, it has important implications for the development of PA programs for older adults with frailty. Future research is warranted to explore the optimal dose, frequency, and duration of RT programs for older adults, as well as the potential benefits of combining RT with other forms of PA, such as aerobic or balance exercises.