Frailty assessment in naturally aged mouse models: classification, limitations, and future directions

Naturally aged mice provide an important platform for studying frailty because functional decline emerges during biological aging rather than through acute injury or artificial manipulation. This review critically examines major frailty assessment tools used in aged mice, including the mouse frailty index, mouse frailty phenotype, physical function score/vitality score, mouse social frailty index, and mouse cognitive frailty index. We compare their conceptual foundations, scoring procedures, dimensional coverage, reproducibility, mortality associations, intervention responsiveness, and translational correspondence with clinical models such as the Fried phenotype and deficit accumulation frailty index. We also discuss how biological mechanisms linked to the hallmarks of aging, including inflammaging, immunosenescence, mitochondrial dysfunction, cellular senescence, altered nutrient sensing, and impaired stress resilience, may contribute to frailty development. Current instruments capture complementary aspects of frailty but differ in their dependence on subjective observation, cohort-specific thresholds, testing conditions, and validation across sex, strain, laboratory, and outcome. Digital phenotyping, longitudinal trajectories, secondary prognostic models, and measures of latent vulnerability may extend current approaches, but these strategies remain exploratory. Alternative weighting systems and the proposed distinction between pre-frailty and subclinical frailty require prospective validation before they can be considered standardized methods. Clear separation of established instruments from conceptual future directions will improve methodological rigor and translational relevance.