A transient pulse of neuronal ATF4 installs a durable non-autonomous programme promoting healthy ageing

Stresses occurring transiently and early in life can have long-standing consequences for health, even long after the stress has resolved. Many environmental stressors converge on activating the integrated stress response (ISR), whose major effector is ATF4. However, it remains unknown whether transient ATF4-ISR activation early in life is a mediator of life and healthspan. Here we used inducible, reversible ATF4 gain-of-function in Drosophila to determine how the timing, duration and tissue of ATF4 activation determine ageing outcomes. We found that ATF4 induction confined to early adulthood extended healthspan, reducing mortality risk by approximately 50% across all ages and improving neuromuscular function in aged flies. Multi-organ transcriptomics showed that the acute ATF4 transcriptional response was transient, as expected, but replaced by a distinct, secondary transcriptional programme of metabolic remodelling that was associated with decreased total body protein content. By using tissue-specific ATF4 induction, we found that transient ATF4 activation in neurons was sufficient to extend lifespan, slow age-related locomotor decline and increase starvation resistance in old age. This neuron-restricted activation prevented the costs to body weight and fecundity induced by ubiquitous ATF4 activation. Transient neuronal ATF4 left a lasting non-autonomous imprint on the fat body at old age: induction of heterochromatin genes, reduced transposable element expression, and increased mitochondrial respiratory capacity. These findings show that the duration and tissue of ISR-ATF4 activation are the key determinants of ATF4 actions that promote healthy ageing, while revealing a brain-to-fat body axis initiated by neuronal ATF4 that results in lasting systemic adaptation.