Glycerol 3-phosphate phosphatase/PGPH-2 counters metabolic stress and promotes healthy aging via a glycogen sensing-AMPK-HLH-30-autophagy axis in C. elegans

Elite Possik (), Laura-Lee Klein, Perla Sanjab, Ruyuan Zhu, Laurence Côté, Ying Bai, Dongwei Zhang, Howard Sun, Anfal Al-Mass, Abel Oppong, Rasheed Ahmad, Alex Parker, S.R. Murthy Madiraju, Fahd Al-Mulla and Marc Prentki ()
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Elite Possik: Université de Montréal, Montreal Diabetes Research Center, CRCHUM
Laura-Lee Klein: Université de Montréal, Montreal Diabetes Research Center, CRCHUM
Perla Sanjab: Université de Montréal, Montreal Diabetes Research Center, CRCHUM
Ruyuan Zhu: Université de Montréal, Montreal Diabetes Research Center, CRCHUM
Laurence Côté: Université de Montréal, Montreal Diabetes Research Center, CRCHUM
Ying Bai: Université de Montréal, Montreal Diabetes Research Center, CRCHUM
Dongwei Zhang: Kuwait University
Howard Sun: Université de Montréal, Montreal Diabetes Research Center, CRCHUM
Anfal Al-Mass: Université de Montréal, Montreal Diabetes Research Center, CRCHUM
Abel Oppong: Université de Montréal, Montreal Diabetes Research Center, CRCHUM
Rasheed Ahmad: Dasman Diabetes Institute
Alex Parker: CRCHUM
S.R. Murthy Madiraju: Université de Montréal, Montreal Diabetes Research Center, CRCHUM
Fahd Al-Mulla: Dasman Diabetes Institute
Marc Prentki: Université de Montréal, Montreal Diabetes Research Center, CRCHUM

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Metabolic stress caused by excess nutrients accelerates aging. We recently demonstrated that the newly discovered enzyme glycerol-3-phosphate phosphatase (G3PP; gene Pgp), which operates an evolutionarily conserved glycerol shunt that hydrolyzes glucose-derived glycerol-3-phosphate to glycerol, counters metabolic stress and promotes healthy aging in C. elegans. However, the mechanism whereby G3PP activation extends healthspan and lifespan, particularly under glucotoxicity, remained unknown. Here, we show that the overexpression of the C. elegans G3PP homolog, PGPH-2, decreases fat levels and mimics, in part, the beneficial effects of calorie restriction, particularly in glucotoxicity conditions, without reducing food intake. PGPH-2 overexpression depletes glycogen stores activating AMP-activate protein kinase, which leads to the HLH-30 nuclear translocation and activation of autophagy, promoting healthy aging. Transcriptomics reveal an HLH-30-dependent longevity and catabolic gene expression signature with PGPH-2 overexpression. Thus, G3PP overexpression activates three key longevity factors, AMPK, the TFEB homolog HLH-30, and autophagy, and may be an attractive target for age-related metabolic disorders linked to excess nutrients.

Date: 2023
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DOI: 10.1038/s41467-023-40857-y

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