Yoko Itakura / Research Team for Aging Science
・Introduction
The heart is an organ that functions continuously throughout life. However, as we age, its function gradually declines. Ascertaining the heart's age-related changes and understanding the mechanisms of functional decline and disease onset are essential for maintaining a healthy and active life.
・ Structure and Function of the Heart
The heart consists of four chambers: the right atrium, right ventricle, left atrium, and left ventricle, each connected to major blood vessels: vena cava, pulmonary artery, pulmonary vein, and the aorta, respectively. Valves: the tricuspid, pulmonary, mitral, and aortic valves, are located between these vessels and the chambers to prevent blood from flowing backward. By means of the repeated contraction and relaxation of the ventricles, the heart pumps blood throughout the body (Figure 1). Generally, when assessing heart health, factors such as heart size, wall thickness, and cardiac output (heart rate per minute x volume of blood pumped with each beat) are used. The heart's most vital role is to serve as a pump that circulates blood through the entire body.
Figure 1: The heart acts as a pump that sends blood throughout the body via contraction and relaxation (left). Structures of the heart used in the experiment (right).
・Glycan-Based Aging Research
Glycans are familiar and essential biomolecules. They are often called the third chain of life after DNA and proteins because of their crucial biological functions (Figure 2). They are typically attached to proteins or lipids and play major roles in regulating cellular function especially on the cell surface. For example, glycans determine the ABO blood group and act as indicators for influenza virus infection. Glycans are involved in molecular recognition, maintenance of protein structure, and cell signaling. It is known that each cell type has its own characteristic set of glycans, allowing us to distinguish cell types and states (Reference 1). Based on this, we hypothesized that age-related changes in cells could also be detected using glycans, and we are conducting aging research focused on these glycans.
Figure 2: Glycans play key functional roles in the body. The three major chains of life (top). Examples of cell types constituting the heart and glyccosylated proteins (bottom).
Proteins that bind specifically to glycans are known as lectins. Each lectin has a distinct binding specificity, and by combining multiple lectins, it is possible to comprehensively analyze glycan structures. The technique applied to detect interactions between glycans and lectins is called the lectin microarray method (Figure 3, References 2 and 3). Using this method, we have identified that cells gradually undergo changes with aging (Reference 4).
Figure 3. Workflow of glycan analysis using the lectin microarray method. Proteins extracted from cells or tissues are fluorescently labeled, and their interactions with lectins are analyzed to comprehensively determine glycan structures.
・Glycan Changes in the Heart
Comprehensive glycan analysis using the lectin microarray method has already shown that, in cultured human cells that constitutes the heart, subtle glycan alterations occur as the cells age (Reference 5). But what kinds of changes occur within actual heart tissue during aging? To investigate this question, we collected proteins from multiple regions of mouse hearts, including the left ventricular wall, papillary muscle, and ventricular septum (Figure 1, right), and analyzed the glycan profiles within the tissue environment, which reflects the interactions among various cell types in vivo (Reference 6). We identified that the types of glycans present in the heart slightly differ between the inner and outer regions (Figure 4). Furthermore, glycans that appeared clearly along the cell membrane in young hearts became distorted, fragmented, or thickened with age (Figure 5). These findings suggest that such alterations may affect cell-cell adhesion mediated by glycans. Additionally, we observed that parts of specific glycans, such as sialic acid and α-galactose, decreased with aging. This analysis showed that the rate of glycan reduction varied among different regions of the heart, including the blood vessels and ventricular tissues.
In the heart, certain areas are more prone to structural changes as observed clinically. For example, the left ventricular wall may undergo sclerosis (hardening), hypertrophy (thickening), or thinning. Although multiple factors contribute to these conditions, the fact that some regions of the heart are more susceptible or change at different times suggests that the organ's structural balance can become distorted. Particularly, glycan alterations in the cells lining the blood vessels, which serve as the pathways for oxygen and nutrients, could impose a significant burden on the heart, given the key role of glycans in cell-cell interactions and signal transmission.
Figure 4: Characteristics of age-related glycan changes in the mouse heart. Schematic showing glycans predominantly found in the inner heart region (top). In inner regions, glycan changes appeared earlier and resembled those of adult mice, whereas in outer regions, changes tended to occur later (bottom).
Figure 5. In young hearts, the green line marking the cell membrane appears clear and continuous, whereas in aged hearts, it becomes distorted, interrupted, and unevenly thickened in places (adapted from Reference 6).
・What is Aging of the Heart?
We often notice when the body feels tired, the legs feel heavy, or we cannot think clearly owing to lack of sleep. But we rarely think, "My heart feels tired today." Even when the heartbeat increases after intense exercise, we cannot simply "let the heart rest." Yet, the heart continuously supports our body throughout life and inevitably ages with us. This aging process is reflected in changes seen in glycans. When the state of heart cells or tissues changes, it implies that alterations are occurring throughout the entire heart. As these changes accumulate, the risk of functional decline and disease onset increases. In other words, aging of the heart can be described as the gradual accumulation of molecular changes such as glycan alterations that eventually impair heart function. Therefore, it is essential to identify molecular markers and methods capable of detecting these changes early, before the condition progresses to a stage requiring surgical intervention.
・Conclusion
As discussed above, studying aging of the heart from the perspective of glycans offers several potential benefits: 1) enabling precise understanding of aging-related changes and distinguishing them from disease onset, 2) contributing to prevention and early diagnosis to maintain health, and 3) clarifying the mechanisms of functional decline and disease, leading to therapeutic and drug development efforts. Presently, we focus mainly on tissue samples. However, in the future, it may become possible to assess the "vitality" of the heart through non-invasive biological materials such as blood or urine biomarkers. Such advancements could make it increasingly feasible to grow older while staying healthy. Moving forward, we aim to further elucidate detailed glycan structures and the biological significance of their changes as the heart ages.
Finally, please take a moment to appreciate both your tirelessly working heart and yourself.
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・References
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