The Heart of Aging

By Alomone Team • May 2024

Targeted molecular interventions could rejuvenate aging hearts in mice.

Aging comes with inevitable changes to our heart’s structure and function, which makes conditions like systolic and diastolic dysfunction highly prevalent among the elderly. At the heart of this age-related decline is Bridging Integrator 1 (BIN1), a protein whose levels and distribution change with age, impacting cardiac cellular mechanisms significantly. Recent research published in Nature Communications has explored the potential of knocking down BIN1 as a way to rejuvenate cardiac function in aging mice, giving us a new look into the mechanisms behind these cardiac changes, as well as flagging possible interventions for human heart health as we age.

A Spread of Assays

The research on BIN1 knockdown was meticulously structured. Old mice were injected two weeks before experiments with an adeno-associated virus engineered to reduce BIN1 expression. This genetic intervention aimed to mimic the conditions of low BIN1 levels observed in younger animals, thereby potentially rejuvenating the aging cardiac tissue.

The study used a broad selection of assays – performed on cardiomyocytes – to really understand what was happening here, and eventually confirmed their conclusions with in vivo echocardiography. Ca_V1.2 currents were recorded using patch clamp electrophysiology, a crucial approach for understanding the underlying ionic mechanism. Additionally, calcium transient recordings were conducted using a fluorescent dye to observe changes in intracellular calcium for cardiac contraction analysis. They also used total internal reflection fluorescence (TIRF) imaging of live transduced cardiomyocytes, immunoassays and quite of molecular approaches. Finally, single-molecule localization microscopy (SMLM) provided a detailed look into the nanoscale distribution and organization of cardiac proteins, highlighting the molecular changes induced by the dynamic level of BIN1.

Restoring Youth to Aging Hearts

The study found that BIN1 knockdown significantly enhanced systolic function in aging mice, as seen by echocardiography results showing improved cardiac contractility. More specifically, the treatment restored the intracellular calcium dynamic in cardiomyocytes and their response to β-adrenergic stimulation, which are crucial for cardiac muscle contractions. This suggests that BIN1 plays a pivotal role in the age-related decline of heart function, and adjusting its levels can partially reverse this decline, at least in the studied mouse model.

Single-Molecule Localization Microscopy Reveals Cardiac Protein Dynamics

SMLM in conjunction with our Anti-Ca_V1.2 (CACNA1C) Antibody (#ACC-003) revealed an increased level of BIN1 in old mice. This change lead to re-distribution and clustering of key cardiac proteins, specifically Ca_V1.2 and RyR2 (Figure 1), which are restored by BIN1 knockdown. Before the intervention, these proteins in aged mice showed disrupted configurations that are associated with poor cardiac function. Post-treatment, a more organized and youthful arrangement of these proteins was evident, suggesting improved cellular function that mirrors healthier, younger cardiac tissue.

Age-dependent alterations in nanoscale distribution and clustering of CaV1.2 channels

Figure 1. Basal super-clustering and impaired β-AR responsiveness of Ca_V1.2 in aged myocytes. a Single-molecule localization microscopy (SMLM) map showing Ca_V1.2 channel localization and distribution in the t-tubules of young and old ventricular myocytes with or without ISO stimulation. Yellow boxes indicate the location of the regions of interest magnified in the top right of each image. b Dot-plots showing mean CaV1.2 channel cluster areas in young (control: N = 3, n = 16; ISO: N = 3, n = 16) and old (control: N = 4, n = 11; ISO: N = 4, n = 10) myocytes. Statistical analyses on data summarized in (b, d) were performed using two-way ANOVAs with multiple comparison post-hoc tests. Young data in b and d are from NIA young. Data are presented as mean ± SEM.

Future Directions

The implications of this research extend beyond the laboratory. If similar results can be replicated in human studies, this could lead to new therapeutic strategies targeting BIN1, to manage age-related cardiac decline. However, translating these findings from mice to humans requires careful consideration of physiological differences and potential side effects. Future research should also explore the long-term effects of BIN1 knockdown and its impact on other cardiac functions, potentially providing a broader understanding of its role in cardiac health.

This study highlights the promising potential of gene therapy in managing cardiac aging by manipulating BIN1 levels. As we continue to improve our understanding of cardiac biology and refine our techniques, approaches like this could become part of a targeted strategy to extend cardiovascular health into old age, enhancing the quality of life for the aging population.