Tissue-origin transcriptomic interactions as indicators of inflammatory aging and aging gene discovery.

Abstract

Aging is an inevitable process in living organisms, characterized by significant immunological and physiological alterations that increase susceptibility to diseases. Despite decades of research on the interplay between aging and immunity, identifying precise immunogenetic aging markers from high-dimensional (HD) transcriptomics data remains challenging due to the lack of effective pattern-discovery methods for such complex data. Recognizing the crucial role of gene-gene interactions in biological processes, and that aging is reflected in tissue-specific change in these interaction patterns, we first sought a holistic way to represent the intricate relationships among genes within the cells of each tissue. This is technically achieved by converting the scRNA-seq data of a cell into a semantically meaningful image representation, termed a "genomap", through the spatial encoding of the transcriptomic interactions. We then leverage this representation to unveil changes in interaction patterns associated with aging, rather than focusing solely on variations in gene expression profiles. This approach enables the construction of a highly accurate, tissue-specific inflammatory aging clock. Our clock significantly outperforms traditional aging-prediction methods based on blood tests, miRNA, and proteomics data. We illustrate a potential application of our framework in aging interventions via an in silico study targeting the Map3k1/Map2k4/JNK pathway, which may reverse aging-associated declines in B cell function and antibody production, thus mitigating chronic diseases linked to B cells deterioration. Thus, our strategy and pipeline may have broad implications for aging and developmental biology.