Abstract
Cells expressing high levels of the cyclin‐dependent kinase (CDK)4/6 inhibitor p16 (p16High) accumulate in aging tissues and promote multiple age‐related pathologies, including neurodegeneration. Here, we show that the number of p16High cells is significantly increased in the central nervous system (CNS) of 2‐year‐old mice. Bulk RNAseq indicated that genes expressed by p16High cells were associated with inflammation and phagocytosis. Single‐cell RNAseq of brain cells indicated p16High cells were primarily microglia, and their accumulation was confirmed in brains of aged humans. Interestingly, we identified two distinct subpopulations of p16High microglia in the mouse brain, with one being age‐associated and one present in young animals. Both p16High 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.
Highlights
Cyclin-dependent kinase (CDK)4/6 inhibitor p16INK4a levels gradually increase with age in multiple tissues and organisms (Herbig et al, 2006; Liu et al, 2009; Melk et al, 2004; Yousefzadeh et al, 2020). p16High cells actively contribute to aging and age-associated dysfunctions by restricting the regenerative potential of the tissue (Martin et al, 2014) and promoting chronic inflammation (Sanada et al, 2018)
Genetic or pharmacological ablation of p16High cells is able to increase health-and lifespan in mice (Baker et al, 2016; Xu et al, 2018). p16 expression is a common feature of cellular senescence (Liu et al, 2019), a state of stable and generally irreversible growth arrest originally described as a key process regulating cellular and organismal aging (Hayflick & Moorhead, 1961)
Tissue-resident macrophages of the central nervous system (CNS), is a heterogeneous cell population that change over the course of an organism lifespan
Summary
Cyclin-dependent kinase (CDK)4/6 inhibitor p16INK4a ( on referred to as p16) levels gradually increase with age in multiple tissues and organisms (Herbig et al, 2006; Liu et al, 2009; Melk et al, 2004; Yousefzadeh et al, 2020). p16High cells actively contribute to aging and age-associated dysfunctions by restricting the regenerative potential of the tissue (Martin et al, 2014) and promoting chronic inflammation (Sanada et al, 2018). Microglia exhibit a hypersensitive and pro-inflammatory phenotype, known as priming, in particular during aging and neurodegeneration (Norden & Godbout, 2013; Perry & Holmes, 2014; Raj et al, 2014). These primed microglia exert an increased inflammatory response and thereby alter CNS function (Norden & Godbout, 2013). A recent study has attempted to identify senescent cell types naturally occurring in the murine aging brain using single-cell transcriptomic profiling, and identified an enrichment of p16High cells in microglia and OPCs (Ogrodnik et al.,l., 2021). We aimed to identify p16High cell populations in the aging brain by using a transgenic mouse model that allows for the isolation of cells expressing p16 at the protein level, and perform validation of the findings in wild-type mice and humans
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