Phloretic acid requires the insulin/IGF-1 pathway and autophagy to enhance stress resistance and extend the lifespan of Caenorhabditis elegans

Bo Li; Li Dong; Wei Meng; Shi-Ying Xiong; Gui-Sheng Wu; Wen-Zhe Ma; Huai-Rong Luo

doi:10.3389/fphar.2024.1384227

Phloretic acid requires the insulin/IGF-1 pathway and autophagy to enhance stress resistance and extend the lifespan of Caenorhabditis elegans

Front Pharmacol. 2024 Mar 27:15:1384227. doi: 10.3389/fphar.2024.1384227. eCollection 2024.

Authors

Bo Li^#^{1

2

3

4}, Li Dong^#², Wei Meng^#², Shi-Ying Xiong^{1

3

4}, Gui-Sheng Wu^{3

4}, Wen-Zhe Ma¹, Huai-Rong Luo^{1

3

4}

Affiliations

¹ State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
² The Affiliated Traditional Chinese Medicine Hospital, Luzhou, China.
³ Key Laboratory of Luzhou City for Aging Medicine, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.
⁴ Central Nervous System Drug Key Laboratory of Sichuan Province, Luzhou, China.

^# Contributed equally.

Abstract

Objective: In humans, aging is associated with increased susceptibility to most age-related diseases. Phloretic acid (PA), a naturally occurring compound found in Ginkgo biloba and Asparagus, exhibits has potential as an anti-aging agent and possesses antioxidant, anti-inflammatory, and immunomodulatory properties. This study aimed to investigate the effects of PA on longevity and stress resistance in Caenorhabditis elegans (C.elegans) and the mechanisms that underlie its effects. Methods: First, we examined the effects of PA on lifespan and healthspan assay, stress resistance and oxidative analysis, lipofuscin levels. Second, we examined the insulin/insulin-like pathway, mitochondria, autophagy-related proteins, and gene expression to explain the possible mechanism of PA prolonging lifespan. Results: Our findings demonstrated that PA dose-dependently extended the C.elegans lifespan, with 200 μM PA showing the greatest effect and increased the C.elegans lifespan by approximately 16.7%. PA enhanced motility and the pharyngeal pumping rate in senescent C.elegans while reducing the accumulation of aging pigments. Further investigations revealed that daf-16, skn-1, and hsf-1 were required for mediating the lifespan extension effect of PA in C.elegans since its impact was suppressed in mutant strains lacking these genes. This suggests that PA activates these genes, leading to the upregulation of downstream genes involved in stress response and senescence regulation pathways. Furthermore, PA did not extend the lifespan of the RNAi atg-18 and RNAi bec-1 but it attenuated SQST-1 accumulation, augmented autophagosome expression, upregulated autophagy-related gene expression, and downregulated S6K protein levels. These findings suggest that the potential life-extending effect of PA also involves the modulation of the autophagy pathway. Conclusion: These findings results highlight the promising anti-aging effects of PA and warrant further investigation into its pharmacological mechanism and medicinal development prospects.

Keywords: Caenorhabditis elegans; Phloretic acid; anti-aging; autophagy; stress response.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from the National Natural Science Foundation of China (82171555), the Central Nervous System Drug Key Laboratory of Sichuan Province (230003-01SZ), and the Luzhou Science and Technology Program (2022S WMU4).