Protein folding and clearance machineries are required for the maintenance and function of the proteome. Quality control systems and activation of stress signaling pathways have, therefore, profound consequences on the long-term health of the cell and, by extension, on lifespan. Aging is associated with loss of cellular function, increased vulnerability to stress, and enhanced susceptibility to disease. Over the course of a lifespan, proteome stability is substantially impacted by mutations, by processing errors, and by the acute effects of environmental stresses. Recently, the function of cellular protein quality control networks, as well as stress signaling pathways, was shown to be differentially regulated over the course of life, leading to reduced proteostasis capacity and decreased stress response activation during adulthood. Proteostatic collapse can be partially mitigated by overexpression of stress response transcription factors, such as HSF1, or by enhancing the activity of quality control systems, which can have significant beneficial effects on lifespan extension and suppression of age-related misfolding diseases. However, the link between proteostasis and lifespan can also be uncoupled, for example, by cell-nonautonomous stress signaling. Here, we will examine how proteostasis changes with age. We will then focus on HSF1 and review its roles in lifespan regulation, as well as how HSF1 function is modulated with age. Finally, we will examine the cell-nonautonomous regulation of HSF1, specifically during aging.
