Abstract
Reactive oxygen species (ROS) are constantly generated by cells and ROS-derived damage contributes to ageing. Protection against oxidative damage largely relies on the reductive power of NAPDH, whose levels are mostly determined by the enzyme glucose-6-phosphate dehydrogenase (G6PD). Here, we report a transgenic mouse model with moderate overexpression of human G6PD under its endogenous promoter. Importantly, G6PD-Tg mice have higher levels of NADPH, lower levels of ROS-derived damage, and better protection from ageing-associated functional decline, including extended median lifespan in females. The G6PD transgene has no effect on tumour development, even after combining with various tumour-prone genetic alterations. We conclude that a modest increase in G6PD activity is beneficial for healthspan through increased NADPH levels and protection from the deleterious effects of ROS.
Highlights
Reactive oxygen species (ROS) are constantly generated by cells and ROS-derived damage contributes to ageing
The impact of the glucose-6-phosphate dehydrogenase (G6PD)-Tg allele was measured first in erythrocytes, a cell type highly exposed to oxidative damage, and exclusively dependent on the phosphate pathway (PPP) to obtain NADPH13
Erythrocytes from G6PD-Tg mice present a fivefold increase in G6PD enzymatic activity compared to WT littermates (Fig. 1c)
Summary
Reactive oxygen species (ROS) are constantly generated by cells and ROS-derived damage contributes to ageing. Protection against oxidative damage largely relies on the reductive power of NAPDH, whose levels are mostly determined by the enzyme glucose-6-phosphate dehydrogenase (G6PD). G6PD-Tg mice have higher levels of NADPH, lower levels of ROS-derived damage, and better protection from ageing-associated functional decline, including extended median lifespan in females. G6PD catalyses the rate-limiting step in the pentose phosphate pathway (PPP), which provides nucleotide precursors for DNA replication, as well as NADPH reductive power for ROS detoxification and de novo lipid synthesis. Improved ROS detoxification and enhanced anabolism of nucleotides and lipids may favour tumoral growth We address these questions by generating transgenic mice with moderate ubiquitous overexpression of human G6PD under the control of its natural promoter
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