Among multiple structural and functional brain changes, aging is accompanied by an increase of inflammatory signaling in the nervous system as well as a dysfunction of the immune system elsewhere. Although the long-held view that aging involves neurocognitive impairment is now dismissed, aging is a major risk factor for neurodegenerative diseases such as Alzheimer;s disease, Parkinson;s disease and Huntington's disease, among others. There are many age-related changes affecting the brain, contributing both to certain declining in function and increased frailty, which could singly and collectively affect neuronal viability and vulnerability. Among those changes, both inflammatory responses in aged brains and the altered regulation of toll like receptors, which appears to be relevant for understanding susceptibility to neurodegenerative processes, are linked to pathogenic mechanisms of several diseases. Here, we review how aging and pro-inflammatory environment could modulate microglial phenotype and its reactivity and contribute to the genesis of neurodegenerative processes. Data support our idea that age-related microglial cell changes, by inducing cytotoxicity in contrast to neuroprotection, could contribute to the onset of neurodegenerative changes. This view can have important implications for the development of new therapeutic approaches.