Chronological lifespan correlates with virulence within Candida albicans but long lifespan is not restricted to pathogenic Candida species

Abstract Yeast cells can remain viable for extended periods after entering stationary phase, a survival trait measured as chronological lifespan (CLS). Although CLS is well characterized in Saccharomyces cerevisiae as a model of postmitotic aging, its relevance to human-associated fungi remains poorly understood. Candida species of the CTG (CUG-Ser1) clade vary widely in ecology and clinical importance, raising the question of whether stationary-phase survival is linked to pathogenicity across species or among strains. Here, we combine an optimized CFU-based CLS assay with scalable flow cytometry of membrane integrity across Candida species and genetically diverse Candida albicans isolates. CLS varies extensively across species, yet caloric restriction extends survival in every species examined, revealing a remarkably consistent response to reduced glucose despite marked differences in baseline lifespan. Pathogenic species tend toward longer CLS, but long lifespan is not restricted to them, with the non-pathogenic C. sojae among the longest-lived species examined. Among 20 genetically diverse C. albicans clinical isolates, longer CLS is consistently associated with greater virulence. Our study establishes a methodological framework for comparative CLS analysis, reveals a broadly shared response to caloric restriction, and shows that the association between CLS and virulence emerges within C. albicans but not across Candida species. Highlights A dual-method framework enables scalable comparative analysis of CLS in Candida species and strains. CLS varies widely across Candida , while caloric restriction extends lifespan in all species examined. Long lifespan is not restricted to pathogenic Candida species. Longer lifespan is associated with higher virulence in Candida albicans .