HTZ-1/H2A.Z expression sustains transcriptional programs that regulate Caenorhabditis elegans lifespan.

Animal lifespan depends on coordinated gene expression networks that regulate metabolic adaptation, proteostasis, and stress resilience in response to environmental challenges. Histone variants are key regulators of chromatin dynamics, orchestrating nucleosome remodeling, DNA accessibility, and gene expression. While the role of histone H3.3 in aging and animal survival has been explored across model systems, the contribution of other replication-independent histone variants remains less well-defined. Here, we demonstrate that the evolutionarily conserved histone variant HTZ-1/H2A.Z is essential for organismal survival. In the nematode Caenorhabditis elegans, loss of HTZ-1/H2A.Z disrupts gene expression programs associated with longevity, including those activated in insulin/IGF-1 deficient daf-2 mutants and in mitochondrial Complex I deficient animals. Together, our findings show that HTZ-1/H2A.Z regulates gene expression programs that coordinate metabolic and proteostatic pathways, thereby fine-tuning stress responses and promoting lifespan in animals.