HSF1/HSP pathway in the hippocampus is involved in SIRT1-mediated caloric restriction-induced neuroprotection after surgery in aged mice.

Postoperative cognitive dysfunction is common in the elderly. Endoplasmic reticulum stress (ER-stress) increases neuronal apoptosis after surgery, and chaperone molecules, such as heat shock proteins (HSPs), help reduce unfolded protein reactions, thereby promoting protein homeostasis. Mammal sirtuin1 (SIRT1)-mediated deacetylation of heat shock factor 1 (HSF1) upregulates HSF1 binding to the HSP70 promoter. Caloric restriction (CR) improves cognition in many neurodegenerative models. In this study, we evaluated whether CR improves impaired learning and memory after surgery by attenuating ER-stress in an SIRT1-dependent manner. Male 18-month-old C57BL/6J mice receiving a 12-week CR or an ad libitum (AL) diet pre-intervention were challenged with tibial open fracture surgery and anesthesia or no treatment. We found a significant protective effect of CR on memory in contextual fear conditioning test after surgery compared with the AL group. CR alleviated ER-stress and neuronal apoptosis in the hippocampus induced by surgery. CR increased HSP70 expression through the HSF1/HSP pathway in a SIRT1-mediated manner, and inhibition of SIRT1 in the hippocampus by lentivirus injection partially reduced the benefits of CR (increased HSP70, deacetylated HSF1, reduced ER-stress, and improved memory). Taken together, our results showed that CR alleviates memory impairment postoperatively via attenuation of ER-stress in the hippocampus in an SIRT1-dependent manner, and the SIRT1/HSF1/HSP70 pathway is involved in this process.