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Ageing
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Nature
Niche-specific dermal macrophage loss promotes skin capillary ageing
All mammalian organs depend on resident macrophage populations to coordinate repair and facilitate tissue-specific functions1,2,3. Functionally distinct macrophage populations reside in discrete tissue niches and are replenished through a combination of local proliferation and monocyte recruitment4,5. Declines in macrophage abundance and function have been linked to age-associated pathologies, including atherosclerosis, cancer and neurodegeneration6,7,8. However, the mechanisms that coordinate macrophage organization and replenishment within ageing tissues remain largely unclear. Here we show that capillary-associated macrophages (CAMs) are selectively lost over time, contributing to impaired vascular repair and reduced tissue perfusion in older mice. To investigate resident macrophage behaviour in vivo, we used intravital two-photon microscopy in live mice to non-invasively image the skin capillary plexus, a spatially well-defined vascular niche that undergoes rarefication and functional decline with age. We find that CAMs are lost at a rate exceeding capillary loss, resulting in macrophage-deficient vascular niches in both mice and humans. CAM phagocytic activity was locally required to repair obstructed capillary blood flow, leaving macrophage-deficient niches selectively vulnerable under homeostatic and injury conditions. Our study demonstrates that homeostatic renewal of resident macrophages is less precisely regulated than previously suggested9,10,11. Specifically, neighbouring macrophages do not proliferate or reorganize to compensate for macrophage loss without injury or increased growth factors, such as colony-stimulating factor 1 (CSF1). These limitations in macrophage renewal may represent early and targetable contributors to tissue ageing.
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Nature
Single-cell transcriptomic and genomic changes in the ageing human brain
Over time, cells in the brain and in the body accumulate damage, which contributes to the ageing process1. In the human brain, the prefrontal cortex undergoes age-related changes that can affect cognitive functioning later in life2. Here, using single-nucleus RNA sequencing (snRNA-seq), single-cell whole-genome sequencing (scWGS) and spatial transcriptomics, we identify gene-expression and genomic changes in the human prefrontal cortex across lifespan, from infancy to centenarian. snRNA-seq identified infant-specific cell clusters enriched for the expression of neurodevelopmental genes, as well as an age-associated common downregulation of cell-essential homeostatic genes that function in ribosomes, transport and metabolism across cell types. Conversely, the expression of neuron-specific genes generally remains stable throughout life. These findings were validated with spatial transcriptomics. scWGS identified two age-associated mutational signatures that correlate with gene transcription and gene repression, respectively, and revealed gene length- and expression-level-dependent rates of somatic mutation in neurons that correlate with the transcriptomic landscape of the aged human brain. Our results provide insight into crucial aspects of human brain development and ageing, and shed light on transcriptomic and genomic dynamics.