Intermittent fasting attenuates CNS inflammaging - rebalancing the transposonome

A hallmark of CNS aging is sterile, chronic, low-grade neuroinflammation. Understanding how the aging CNS develops chronic inflammation is necessary to achieve extended healthspan. Characterisation of neuroinflammatory molecular triggers remains limited. Interventions that reduce neuroinflammation and extend health and lifespan could be useful in this regard. One such intervention is intermittent fasting (IF), but how IF impacts CNS inflammation is insufficiently understood. To address this, we performed deep RNA-sequencing on young, middle-aged, and old, mouse CNS regions. Additionally, we sequenced spinal cord in animals subject to adult lifelong IF. We found most differentially expressed genes (DEGs) at middle age were CNS region specific (~ 50–84%), whilst this effect weakened (~ 18–72%) in old age, suggesting emergence of a more general global aging profile. DEGs from all regions were enriched for inflammatory and immune ontologies. Surprisingly, SC was the most aging- and neuroinflammation-impacted region at both middle and old ages, with by far the highest number of DEGs, the largest net increase in expression of transposable elements (TEs), the greatest enrichment of immune-related ontologies, and generally larger increases in inflammatory gene expression. Overall, with normal aging we found upregulation of sensors of non-self, DNA/RNA, activation of specific inflammasomes, and upregulation of cGAS-STING1 and interferon response genes, across the CNS. Whilst IF animals still developed an inflammatory profile with aging in SC, average immune gene expression was lower by ~ 50% compared to age-matched controls. IF-specific DEGs were apparent, suggesting IF also acts on separate, potentially targetable, pathways to those impacted by normal aging. Expression of disease associated microglia, phagocytic exhaustion, sensors of non-self, DNA/RNA, STING1, and inflammasome genes were all decreased with IF. Significantly, the TE profile was reversed with a net expression decrease. In summary, we find SC is a CNS aging hotspot, and that IF attenuates neuroinflammaging potentially by rebalancing the transposonome.