Identification of distinct and age-dependent p16^High microglia subtypes.

Abstract

Cells expressing high levels of the cyclin-dependent kinase (CDK)4/6 inhibitor p16 (p16^High ) accumulate in aging tissues and promote multiple age-related pathologies, including neurodegeneration. Here, we show that the number of p16^High cells is significantly increased in the central nervous system (CNS) of 2-year-old mice. Bulk RNAseq indicated that genes expressed by p16^High cells were associated with inflammation and phagocytosis. Single-cell RNAseq of brain cells indicated p16^High cells were primarily microglia, and their accumulation was confirmed in brains of aged humans. Interestingly, we identified two distinct subpopulations of p16^High microglia in the mouse brain, with one being age-associated and one present in young animals. Both p16^High clusters significantly differed from previously described disease-associated microglia and expressed only a partial senescence signature. Taken together, our study provides evidence for the existence of two p16-expressing microglia populations, one accumulating with age and another already present in youth that could positively and negatively contribute to brain homeostasis, function, and disease.