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Pharmacological activation of endogenous glucose-6-phosphate dehydrogenase (G6PD) to extend lifespan

Ashley Wong (1), David Sinclair (1, 2) and Lindsay Wu (1)

  1. School of Medical Sciences, UNSW, Sydney, Australia

  2. Harvard Medical School, Boston, MA, USA

Aged cells face multiple biochemical challenges including diminished de novo nucleotide synthesis for faithful DNA replication, impaired redox capacity, and decreased NAD+ required to maintain sirtuin activity. A common thread running through these challenges is the requirement for the pentose phosphate pathway, which declines with age due to reduced activity of the rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD). Over-expression of G6PD extends lifespan in Drosophila and mice, alongside improvements in metabolic homeostasis and motor coordination in old age. Outside of this genetic approach, pharmacological approaches to enhance endogenous G6PD activity could offer a clinically relevant opportunity to recapitulate the improved late-life health and extended lifespan observed during G6PD over-expression. We have performed a small molecule screen and identified a series of novel G6PD activators with drug-like properties that enhance G6PD activity, which work through allosteric modulation and stabilisation of the enzyme. These new compounds robustly increase lifespan in Caenorhabditis elegans, across four different structurally unrelated G6PD activators. These new compounds demonstrate for the first time that G6PD can be modulated by pharmacological approaches and represent a new class of drugs that can delay biological ageing and extend lifespan.