Glyceraldehyde 3–phosphate dehydrogenase (GAPDH) is a key glycolytic enzyme, which is crucial for the breakdown of glucose to provide cellular energy. Over the past decade, GAPDH has been reported to be one of the most prominent cellular targets of post-translational modifications (PTMs), which divert GAPDH toward different non-glycolytic functions. Hence, it is termed a moonlighting protein. During metabolic and oxidative stress, GAPDH is a target of different oxidative PTMs (oxPTM), e.g., sulfenylation, S-thiolation, nitrosylation, and sulfhydration. These modifications alter the enzyme’s conformation, subcellular localization, and regulatory interactions with downstream partners, which impact its glycolytic and non-glycolytic functions. In this review, we discuss the redox regulation of GAPDH by different redox writers, which introduce the oxPTM code on GAPDH to instruct a redox response; the GAPDH readers, which decipher the oxPTM code through regulatory interactions and coordinate cellular response via the formation of multi-enzyme signaling complexes; and the redox erasers, which are the reducing systems that regenerate the GAPDH catalytic activity. Human pathologies associated with the oxidation-induced dysregulation of GAPDH are also discussed, featuring the importance of the redox regulation of GAPDH in neurodegeneration and metabolic disorders.

In aging Caenorhabditis elegans, as in higher organisms, there is more than one cause of death. C. elegans exhibit early death with a swollen, infected pharynx (P death), and later death with pharyngeal atrophy (p death). Interventions that alter lifespan can differentially affect frequency and timing of each type of death, generating complex survival curve shapes. Here, we use mortality deconvolution analysis to investigate how reduction of insulin/IGF‐1 signaling (IIS), which increases lifespan (the Age phenotype), affects different forms of death. All daf‐2 insulin/IGF‐1 receptor mutants exhibit increased lifespan in the p subpopulation (p Age), while pleiotropic class 2 daf‐2 mutants show an additional marked reduction in P death frequency. The latter is promoted by pharyngeal expression of the IIS‐regulated DAF‐16 FOXO transcription factor, and at higher temperature by reduced pharyngeal pumping rate. Pharyngeal DAF‐16 also promotes p Age in class 2 daf‐2 mutants, revealing a previously unknown role for the pharynx in the regulation of aging. Necropsy analysis of daf‐2 interactions with the daf‐12 steroid receptor implies that previously described opposing effects of daf‐12 on daf‐2 longevity are attributable to internal hatching of larvae, rather than complex interactions between insulin/IGF‐1 and steroid signaling. These findings support the view that wild‐type IIS acts through multiple distinct mechanisms which promote different life‐limiting pathologies, each of which contribute to late‐life mortality. This study further demonstrates the utility of mortality deconvolution analysis to better understand the genetics of lifespan.

Evolutionary medicine argues that disease can arise because modern conditions do not match those in which we evolved. For example, a decline in exposure to commensal microbes and gastrointestinal helminths in developed countries has been linked to increased prevalence of allergic and autoimmune inflammatory disorders (the hygiene hypothesis). Accordingly, probiotic therapies that restore ‘old friend’ microbes and helminths have been explored as Darwinian treatments for these disorders. A further possibility is that loss of old friend commensals also increases the sterile, aging-associated inflammation known as inflammaging, which contributes to a range of age-related diseases, including cardiovascular disease, dementia, and cancer. Interestingly, Crowe et al., 2020 recently reported that treatment with a secreted glycoprotein from a parasitic nematode can protect against murine aging by induction of anti-inflammatory mechanisms. Here, we explore the hypothesis that restorative helminth therapy would have anti-inflammaging effects. Could worm infections provide broad-spectrum protection against age-related disease?