A multi-organ spatiotemporal transcriptomics atlas unveils immune niches of complement pathway and serine protease inhibitor activation in aging and infection
Aging is a multifactorial and complex physiological process, affecting every part of the body with characteristic manifestations and understanding its molecular mechanisms appears crucial to target many age-related disorders. The general speed of cellular aging is modulated by certain morbidities, most prominently severe infectious diseases, however the underlying principles are poorly understood. Here, we employ spatial transcriptomics at scale to establish a multi-organ atlas (brain, heart, kidney, liver, lung, and spleen) and to map spatiotemporal RNA expression patterns across the mouse lifespan (4, 17 and 26 months). Using 111 high-quality fresh-frozen tissue samples, we find organ-specific and cross-organ gene dysregulation upon aging at an unbiased molecular resolution. We identified aging-specific trajectories in gene expression and cell state, some only detectable within their spatial context, which we validated at subcellular resolution with the Stereo-seq platform. The strongest effects are driven by an organism-wide immune system activation consisting of spatially variable components. We thus evaluated the hypothesis whether aging mimics certain phenotypes underlying systemic infection and generated another 42 spatial transcriptomics slices from young mice infected with Plasmodium berghei, comparing aging against malaria disease. While the effect sizes of the infection cohort outweighed those of the aging cohort, we reveal a shared activation of the early complement pathway (C4b) and serine protease inhibitors (Serpin gene family) within distinct spatial niches. We show that this signature is driven by tissue dependent cell types, rendering them a primary functional target for future mechanistic and drug discovery studies. Our study provides for the first time an in-depth cross-organ transcriptomics reference atlas to systematically study aging and infection at spatiotemporal resolution.