pH modulation restores proteostasis and extend lifespan in a yeast model of Huntington’s Disease [polyQ]

Loss of proteostasis is a hallmark of the aging process and is associated with the onset of several neurodegenerative diseases, including Huntington’s Disease (HD) where aberrant polyglutamine (polyQ) expanded Huntingtin aggregates into insoluble inclusions bodies (IBs) associated with toxicity in neuronal cells. In yeast, chronological lifespan (CLS) assays are used to model aging of non-dividing cells such as neurons. During CLS, acidification of the culture media due accumulation of acetic acid is one of the major cell extrinsic factors responsible for cell death. Thus, buffering media pH to prevent acidification significantly extends longevity. Here, we found that cells expressing pathogenic polyQ expansions display increased sensitivity to acetic acid and shortened CLS. Buffering media pH promotes both polyQ aggregation into IBs and longevity. We found that growth at higher pH induces the activation of heat shock response (HSR) in young cells. Such hormetic HSR activation subsequently allowed aged cells to mount a proper HSR in response to stresses such as heat shock or polyQ misfolding, leading to lifespan extension. Thus, our study provides new insight into how pH can promote proteotoxic stress resistance and longevity. mRNA of strains expressing 25 polyglutamine compared to strains expressing 46 polyglutamine