Acceleration of ageing via disturbing mTOR‐regulated proteostasis by a new ageing‐associated gene PC4

Abstract

Research on ageing‐associated genes is important for investigating ageing and anti‐ageing strategies. Here, we firstly reported that the human positive cofactor 4 (PC4), a multifunctional and highly conserved nucleoprotein, is accumulated and activated during ageing and causes global accelerated ageing process by disrupting proteostasis. Mechanistically, PC4 interacts with Sin3‐HDAC complex and inhibits its deacetylated activity, leads to hyper‐acetylation of the histones at the promoters of mTOR‐related genes and causes mTOR signalling activation. Accordingly, mTOR activation causes excessive protein synthesis, resulting in impaired proteostasis and accelerated senescence. These results reveal a new biological function of PC4 in vivo, recognizes PC4 as a new ageing‐associated gene and provides a genetically engineered mouse model to simulate natural ageing. More importantly, our findings also indicate that PC4 is involved in histone acetylation and serves as a potential target to improve proteostasis and delay ageing.

Abstract

Proposed hypothesis for PC4 accelerating ageing process by activating mTOR signalling through promoting histone acetylation. PC4 is increased with age and inhibits the deacetylation activity of sin3a‐HDAC complexes, causing the transcriptional activation of the mTOR‐related genes and promoting the protein synthesis while the protein folding and the degradation of misfolding protein decreases with age, resulting in impaired proteostasis and cellular senescence.