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. 2021 Jul 6;15:698126. doi: 10.3389/fncel.2021.698126

FIGURE 1.

FIGURE 1

Age-associated alterations in the brain innate immunity and the gut microbiota. Major crippling and life-threatening diseases, such as cancer, cardiovascular disease, and neurodegeneration, are all linked to advanced age. The innate immune cells are the first responders to insults in the brain, and are in constant communication with the microbiota. Aging has several facets on the brain, as well as the microbiota. The blood brain barrier (BBB) switches from ligand-receptor transport to a less specific caveolar transcytosis. The drainage of the CSF macromolecules declines and is associated to dysfunctional changes in the lymphatics and innate immune cells. Microglia, the brain resident macrophages, switch to an age-related phenotype in which microglia accumulate lipofuscin and lipid droplets, elicit a pro-inflammatory profile [elevation in major histocompatibility complex (MHC) class II, interferon gamma (IFN-γ), cluster of differentiation 86 (CD86), and cluster of differentiation 22 (CD22), and a reduction in interleukin-10 (IL-10) and cluster of differentiation 200 (CD200)], decreased phagocytic capacity and an induction of senescence-associated secretory phenotype (SASP). CNS- or border-associated macrophages (BAMs/CAMs) undergo numerous brain-maintaining functions in the healthy young brain that decline with age. BAMs/CAMs shit to CD38+MHCII+CCR2– and CD38–MHCII+CCR2– subsets in the aged brain. Classical dendritic cells (DCs) associated with the brain elicit an elevation in CD135+ and a drop in CD24+ subsets. Innate lymphoid cells (ILCs) switch from IL1C to IL2C transcriptomic profile and lessen the expression of the neuroprotective interleukin 5 (IL-5). Moreover, the microbiota interacts with cell populations of the brain both directly and indirectly through modulating the periphery. Multitudes of microbiota-derived molecules [short chain fatty acids (SCFAs), lipids, trimethylamines, amino acids] influence the activity of the brain innate immune cells and in turn modulate the brain functions. The levels of these bioactive metabolites are sensitive to age. The fine tuning of these molecules is disturbed in aging, due to compositional changes in the microbiota and the drop in the taxonomic diversity. Alterations in the microbiota are decisive to the dysregulation of immune function of the brain’s innate immunity in aging and requires more comprehensive research.