O-GlcNAcylation as an Evolutionary Timer: Testing Whether Post-Reproductive HBP Flux Serves Kin Selection by Modulating Proteostasis and Resource Allocation
We hypothesize that the age‑dependent rise in hexosamine biosynthetic pathway (HBP) flux functions as an evolutionarily conserved timer that actively drives senescence to enhance inclusive fitness. Specifically, increased UDP‑GlcNAc elevates O‑GlcNAcylation of the transcription factor FOXO and of the autophagy initiation complex, thereby dampening stress‑resistance genes and impairing clearance of damaged proteins. This creates a senescence‑associated secretory phenotype (SASP) that releases amino acids, lipids, and nucleotides into the extracellular milieu, which can be scavenged by nearby kin—particularly offspring or siblings sharing the same niche. In this view, HBP‑driven O‑GlcNAcylation is not a mere byproduct of metabolic noise but a selected mechanism that couples individual ageing to kin‑directed resource provisioning.
If this model is correct, experimentally lowering HBP flux after the reproductive period should extend somatic lifespan but simultaneously diminish the post‑reproductive nutrient boost available to relatives, reducing their survival or fecundity when resources are limiting. Conversely, in environments where kin competition is weak (e.g., low density or abundant exogenous nutrients), the same manipulation should prolong both individual and inclusive fitness.
We propose three testable predictions:
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Inducible, tissue‑specific knockdown of GFAT (the rate‑limiting enzyme of HBP) in adult Drosophila or mice, applied after peak reproduction, will increase median lifespan by ≥15 % without altering early‑life fecundity. HBP inhibition with azaserine prevents high-glucose-induced β-cell dysfunction; glucosamine bypasses the rate-limiting enzyme GFAT to impair glucose-stimulated insulin secretion even at normal glucose levels
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The lifespan extension will be accompanied by a measurable decrease in circulating O‑GlcNAc‑modified SASP factors (e.g., O‑GlcNAcylated IL‑6, MMP‑9) and a reduction in the release of free amino acids from somatic tissues, detectable by metabolomics of hemolymph or plasma. Hyper-O-GlcNAcylation impairs autophagy flux by modifying Beclin-1 and Bcl-2
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In low‑density or nutrient‑supplemented conditions, the same GFAT knockdown will improve both individual lifespan and the reproductive output of nearby kin; under high‑density, nutrient‑scarce conditions, kin survival or fecundity will decline despite the individual’s longevity gain. This trade‑off can be quantified by measuring offspring number or sibling survival in competitive versus cooperative assays.
Falsification would occur if post‑reproductive HBP attenuation lengthens lifespan without any detectable change in SASP composition, nutrient release, or kin‑directed fitness metrics, indicating that the pathway’s rise with age is merely a passive damage accumulation process rather than a programmed, kin‑selected timer.