Introduction
It has been reported that, with aging, variability in gene expression between cells increases. Even within the same tissue, individual cells exhibit different expression levels—a phenomenon known as “transcriptional noise,” which is known to become more pronounced with age. The increase in transcriptional noise can disrupt intercellular communication and tissue homeostasis, potentially contributing to age-related functional decline and the onset of diseases.
Background and Significance
Relationship Between Aging and Transcriptional Noise
Aging is a major risk factor for serious diseases such as cancer, cardiovascular diseases, and neurodegenerative disorders. Understanding the changes in biological function associated with aging is extremely important. Recent studies have shown that aging is accompanied by alterations in gene expression patterns, and that these changes are linked to disease onset and progression. In particular, the increased variability in gene expression between cells (i.e., transcriptional noise) is thought to disrupt information transfer and homeostasis within tissues (López-Otín et al., Cell, 2023; Bartz et al., Int J Mol Sci, 2023).
Mechanisms by Which Aging Disrupts Intercellular Coordination
Normally, cells within a tissue maintain stable functions through coordinated gene expression. However, when transcriptional noise increases, individual cells exhibit markedly different expression profiles, thereby undermining the overall consistency of tissue function. As a consequence, organs such as the heart, lungs, and brain may experience disruptions in tissue homeostasis and functional decline, potentially leading to age-related diseases. Indeed, single-cell analyses of mouse lungs have suggested that increased transcriptional noise, along with failures in epigenomic regulation, may be implicated in these processes.
Impact of Increased Transcriptional Noise on Tissue Homeostasis and Functional Decline
In tissues with high intercellular variability, reduced coordination among essential cellular processes such as stimulus response and metabolism has been reported. In other words, the loss of synchronized gene expression disrupts tissue organization, accelerating phenomena such as decreased stress tolerance and impaired regenerative capacity. Moreover, elevated transcriptional noise can lead to the inappropriate activation or suppression of gene expression in certain cells, making the tissue more prone to dysfunction and inflammation.
Current Knowledge and Unresolved Issues
Advances in single-cell RNA sequencing have led to numerous reports of age-related increases in transcriptional noise across various tissues in both humans and model organisms. However, why transcriptional noise increases with age, the underlying molecular mechanisms within cells, and how this noise contributes to tissue-level dysfunction and disease remain insufficiently understood. Unresolved questions include the causal relationships between decreased coordination of gene expression, epigenomic alterations, and the cell type–specific differences in noise levels. Elucidating the mechanisms underlying age-related increases in transcriptional noise is significant not only for deepening our understanding of the aging process but also for potentially developing interventions that preserve or restore intercellular coordination and tissue function, ultimately contributing to disease prevention and an extended healthy lifespan.
Research Objectives
The primary objective of this study is to elucidate the molecular basis of the age-related increase in transcriptional noise and to establish methods for its control. We will comprehensively analyze single-cell gene expression profiles in both young and aged tissues to quantify changes in expression heterogeneity and identify the molecular factors responsible for the increased noise. Ultimately, we aim to develop new strategies to suppress transcriptional noise and thereby maintain or improve tissue homeostasis.
Expected Outcomes and Potential Applications
This research is expected to provide detailed insights into the nature of the age-related increase in transcriptional noise and its impact on tissue function. In particular, by employing spatial omics techniques, we anticipate creating high-resolution maps of gene expression variability that will clarify the relationship between transcriptional noise and the onset of age-related diseases. The knowledge gained could serve as the foundation for developing novel interventions—such as targeted drugs or gene therapies—that modulate transcriptional noise to preserve tissue function, potentially extending healthy lifespan and improving quality of life.