Disrupted HSF1 regulation in normal and exceptional brain aging

Brain aging is a major risk factor for cognitive diseases including Alzheimer’s disease (AD) and vascular dementia. The rate of aging and appearance of age-related pathology are modulated by stress responses and repair pathways that gradually decline with age. However, recent reports indicate that exceptional longevity sustains and may even enhance the stress response. Whether normal and exceptional aging result in either attenuated or enhanced stress responses across all organs is unknown. This question arises from our understanding that biological age differs from chronological age and evidence that the rate of aging varies between organs. Thus, stress responses may differ between organs, especially if they are composed of poorly regenerative tissue and accumulate a lifespan of damaged proteins. To answer these questions, we assessed age-dependent changes in brain stress responses with normal aged wild type and long-lived Dwarf mice. Results from this study show that normal aging unfavorably impacts activation of the brain heat shock (HS) axis with key changes noted in the transcription factor, HSF1, that include decreased protein levels, changes in its phosphorylation and altered co-factors. Exceptional aging appears to preserve and strengthen many elements of HSF1 activation in the brain. These results support the possibility that reconstitution of aging brain stress responses requires a multi – factorial approach that addresses HSF1 protein levels, its DNA binding, and regulatory elements such as phosphorylation and protein interactions.