PKR: A kinase to remember

Aging is a major risk factor for many diseases including metabolic syndrome, cancer, inflammation, and neurodegeneration. Identifying mechanistic common denominators underlying the impact of aging is essential for our fundamental understanding of age-related diseases and the possibility to propose new ways to fight them. One can define aging biochemically as prolonged metabolic stress, the innate cellular and molecular programs responding to it, and the new stable or unstable state of equilibrium between the two. A candidate to play a role in the process is protein kinase R (PKR), first identified as a cellular protector against viral infection and today known as a major regulator of central cellular processes including mRNA translation, transcriptional control, regulation of apoptosis, and cell proliferation. Prolonged imbalance in PKR activation is both affected by biochemical and metabolic parameters and affects them in turn to create a feedforward loop. Here, we portray the central role of PKR in transferring metabolic information and regulating cellular function with a focus on cancer, inflammation, and brain function. Later, we integrate information from open data sources and discuss current knowledge and gaps in the literature about the signaling cascades upstream and downstream of PKR in different cell types and function. Finally, we summarize current major points and biological means to manipulate PKR expression and/or activation and propose PKR as a therapeutic target to shift age/metabolic-dependent undesired steady states.