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

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.

An Organism-Level Quantitative Flux Model of Energy Metabolism in Mice

“…Unexpectedly, despite being 60% heavier than the wild type control mice on chow diet, the HFD mice showed generally moderate changes in f ox and fluxes ( Figures 5A-D ). The most striking change is the significantly increased production of glycerol from circulating glucose, i.e., the recently discovered glycerol shunt pathway ( Figures 5B ; S6, S7A )(Mugabo et al, 2016; Possik et al, 2023). This pathway is quantitatively negligible in WT; while it was elevated by 2-fold in ob/ob mice, it was more impressively activated by 4.5 fold in the HFD group.…”

Lack of T04C9.1, the Homologue of Mammalian APPL2, Leads to Premature Ageing and Shortens Lifespan in Caenorhabditis elegans

“…The autofluorescence of lipofuscin in C. elegans was quantified as an ageing index. For measurement of lipid accumulation, the Oil Red O staining was performed as previously described [ 16 , 17 ]. On day 7 of adulthood, a total of 20–30 nematodes from each group were collected and washed with M9 buffer containing 0.05% Triton X-100, followed by fixation in 60% isopropanol at room temperature for 3 min.…”