Roles of the TORC1 Signaling in Stress Response and Chronological Lifespan Extension in Yeast

Calorie restriction (CR) without malnutrition has been demonstrated to retard ageing and to prevent the onset of many age-related diseases in mammals. Accumulated findings indicate that CR extends the healthy lifespan at least in part through downregulating the conserved target of rapamycin complex 1 (TORC1) pathway. In Saccharomyces cerevisiae, enhanced mitochondrial ROS signaling and hyper-accumulation of storage carbohydrates are the two major models to account for chronological lifespan (CLS) extension in TORC1-compromised cells. However, to what extent the two models can be integrated and the roles of TORC1-upstream regulators and downstream effectors in CLS regulation are largely unexplored. In Results chapter 1, CLS extension of tor1Δ mutants was found to depend on mitochondrial respiration and the accumulation of storage carbohydrates. Furthermore, there may be a threshold of mitochondrial respiration above which CLS extension of TORC1-compromised cells could be achieved. These data confirmed that the accumulation of storage carbohydrates and the concomitant activation of the stress response are the major pathways contributing to lifespan extension of yeast cells. Results chapters 2 and 3 focused on the upstream regulators of TORC1. Removal of the positive regulators (apart from Sea2p and Vam6p) leaded to enhanced accumulation of storage carbohydrates, increased expression of heat shock proteins and extended CLS. Deletion of GTR2 or PIB2, both required for TORC1 activation, also promoted the antioxidant defence systems. Analysing the transcriptome in active-growing cells suggest that TORC1-compromised cells may experience iron deficiency. The Results chapter 4 focused on the downstream effectors of TORC1, the Greatwall kinase Rim15p and the DYRK kinase Yak1p, both of which are activated in TORC1-inhibited cells. Hyper-accumulation of storage carbohydrate and elevated H₂O₂-scavenging activity in the gtr2Δ and pib2Δ cells were dependent on RIM15 and YAK1. Furthermore, chronologically ageing cells lacking RIM15 and YAK1 exhibited high levels of chromosomal rearrangements, which could only be partially rescued by supplementing N-acetyl cysteine to the cell cultures. These findings supported that the accumulation of storage carbohydrates and the activation of the anti-oxidant defence system are both important for genomic stability and CLS extension of wild-type cells and cells with reduced TORC1 signaling.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2021

Author dc:creator

• Zhang, Yunjia

Advisor dc:contributor.advisor

• Zhang, Nianshu

• Signaling pathway
• TORC1
• Ageing
• Lifespan extension

Licence

• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.82553

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/335118