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Research Paper|Volume 12, Issue 24|pp 25700—25717

Inhibition of PAR-1 delays aging via activating AMPK in C. elegans

Di Wu1, Waijiao Cai2, Xuan Zhang1, Jianfeng Lan3, Lina Zou1, Samuel J. Chen4, Zixing Wu1, Di Chen1
  • 1State Key Laboratory of Pharmaceutical Biotechnology, Model Animal Research Center of Medical School, Nanjing University, Pukou, Nanjing 210061, Jiangsu, China
  • 2Institute of Traditional Chinese and Western Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China
  • 3Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China
  • 4Department of Mechanical, Aerospace, and Nuclear Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
* Equal contribution
Received: June 10, 2020Accepted: September 22, 2020Published: November 20, 2020
https://doi.org/10.18632/aging.104180

Copyright: © 2020 Wu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

The antagonistic pleiotropy theory of aging suggests that genes essential for growth and development are likely to modulate aging later in life. Previous studies in C. elegans demonstrate that inhibition of certain developmentally essential genes during adulthood leads to significant lifespan extension. PAR-1, a highly conserved serine/threonine kinase, functions as a key cellular polarity regulator during the embryonic development. However, the role of PAR-1 during adulthood remains unknown. Here we show that inhibition of par-1 either by a temperature-sensitive mutant or by RNAi knockdown only during adulthood is sufficient to extend lifespan in C. elegans. Inhibition of par-1 also improves healthspan, as indicated by increased stress resistance, enhanced proteotoxicity resistance, as well as reduced muscular function decline over time. Additionally, tissue-enriched RNAi knockdown analysis reveals that PAR-1 mainly functions in the epidermis to regulate lifespan. Further genetic epistatic and molecular studies demonstrate that the effect of par-1 on lifespan requires the AMP-activated protein kinase (AMPK), and RNAi knockdown of par-1 results in age-dependent AMPK activation and reduced lipid accumulation in the metabolic tissue. Taken together, our findings reveal a previously undescribed function of PAR-1 in adulthood, which will help to understand the molecular links between development and aging.