ZIP-5/bZIP transcription factor regulation of folate metabolism is critical for aging axon regeneration

Abstract

Aging is associated with reduced capacity for tissue repair, perhaps the most critical of which is a decline in the ability of aged neurons to recover after injury. Identifying factors that improve the regenerative ability of aging neurons is a prerequisite for therapy design and remains an enormous challenge, yet many of the genes that play a role in regeneration of youthful axons do not regulate axon regeneration in older animals 2,9 , highlighting the need to identify aging-specific regeneration mechanisms. Previously, we found that increased DAF-16/FOXO activity enhances the regenerative ability of mechanosensory axons in aged animals 9 . Here we show that DAF-16/FOXO mediates its pro-regenerative effects by upregulating folate metabolism genes via the ZIP-5 bZIP transcription factor. Remarkably, dietary folic acid supplementation improves the regeneration of aging C. elegans axons. Enzymes regulating folate metabolism are also up-regulated in regenerating zebrafish fins, and we show that dietary folic acid supplementation post-amputation enhances fin regrowth in aging zebrafish. Our results demonstrate that boosting folate metabolism is a conserved and non-invasive approach to increase the regenerative capacity of aging neurons and tissues. Given that lower folate status has been linked with reduced cognition in the elderly 17 , maintaining optimal folate metabolism may be a general strategy to achieve healthy brain aging.

The Neuron-specific IIS/FOXO Transcriptome in Aged Animals Reveals Regulatory Mechanisms of Cognitive Aging

“…S1f ). Previous studies showed that loss of genes including ins-6 34 , mec-7 36 , unc-4 , folt-2 19 , madd-4 37 , and fbf-1 31 lead to behavioral dysfunction in motility and chemosensory abilities; therefore, the decreased expression of these neuron type-specific genes with age may impact the function of individual neurons and disrupt neural circuit communication, ultimately contributing to the declines in behavior observed during aging ( Fig. 1g ).…”

“…While both young and old daf-2 adult worms display increased learning and memory relative to wild-type, the duration of this extension is not known, and the mechanisms by which daf-2 mutants maintain neuronal function in older worms is not yet understood. Compared to wild-type worms, daf-2 mutants maintain maximum velocity 8 , motility 16,17 , neuromuscular junctions, the ability to regenerate axons 18,19 , and neuronal morphology better with age 20–22 . (In particular, we previously showed that while daf-2 has lower observed motility on food 23 , this apparent is due to its high levels of a food receptor, ODR-10 8 , and its downregulation reveals the much higher mobility of daf-2 animals 8 , even on food, in addition to its much higher and maintained maximum velocity with age.)…”

Adult Single-nucleus Neuronal Transcriptomes of Insulin Signaling Mutants Reveal Regulators of Behavior and Learning

“…These newly-identified, daf-2 -regulated genes regulate many aspects of the nervous system. For example, ODR-2 regulates odor sensation and pheromone imprinting 5,51 , mec-7 encodes a beta-tubulin gene that regulates mechanosensory neuron development and touch sensitivity of worms 52 , and ZIP-5 regulates axon regeneration 15 and pathogen-induced pheromone responses 53 . The extended health and behaviors of daf - 2 animals may result from such neuron-specific gene changes that were previously masked.…”

“…In addition to their greatly extended lifespan, daf-2 mutants have improved and extended cognitive and neuronal behaviors 1,6,15,36 , some of which may depend on gene expression changes in individual neurons. We previously used pan-neuronal transcriptional profiling to identify genes whose expression is high in young wild-type neurons and declines with age 16 .…”

“…We previously found that the insulin/IGF receptor mutant, daf-2, has extended short-term associative memory 1 , and its long-term memory is extended as well, through increased CREB expression 1,2 . daf-2 mutants also better maintain motor functions and axon regeneration ability with age [13][14][15] , and maintain their memory ability with age for twice as long as wild-type worms 16 . We are interested in how the daf-2 mutation changes the AWC transcriptome, as well as the transcriptomes of other neurons, to change learning ability and allow extended memory function.…”