Mouse Models for Aging Research: Mechanistic Utility, Translational Relevance, and Practical Model Selection

Aging is a complex biological process characterized by the progressive decline of physiological and cognitive function, increased vulnerability to disease, and eventual mortality. Laboratory mice have been used as models for aging research due to their genetic tractability, short lifespan, and physiological similarities to humans. However, no single mouse model fully recapitulates the complexity of organismal aging, and substantial differences exist in the biological processes, aging hallmarks, and translational relevance represented by individual models. Consequently, selecting an appropriate model requires careful consideration of the specific aging mechanisms and research objectives. This review provides a comparative overview of six broad categories of murine aging models, highlighting their mechanisms, advantages, and limitations. Natural aging models such as C57BL/6, BALB/c, FVB/N, and SAMP8 mice most closely recapitulate physiological aging, while accelerated models such as Klotho⁻/⁻, Ercc1⁻/Δ, and Lmna^G609G offer mechanistic insights into genetic pathways of senescence. Chemically induced models, such as those induced by D-galactose and paraquat administration, provide rapid and cost-effective approaches to mimic oxidative stress-related aging phenotypes. Telomere and senescence models, such as the Terc⁻/⁻, p16^INK4a-reporter, and INK-ATTAC mice, allow for visualization and direct manipulation of cellular senescence. Metabolic and mitochondrial models (Polg^mut/mut "mutant" mice and Sod^-/- mice) link mitochondrial DNA instability and oxidative stress to various conditions associated with aging, including sarcopenia, presbycusis, anemia, and reduced fertility. Dietary and environmental models allow for lifestyle-related aging modeling through high fat diets, irradiation, dietary restriction, and chronic stress exposure. Modeled mechanisms include altered metabolism, cellular senescence, and immune system effects. Together, these models form a versatile toolkit for investigating cellular, organismal, and systemic aspects of aging, and serve as platforms for anti-aging drug development.