Astaxanthin, meclizine, mitoglitazone, pioglitazone, alpha-ketoglutarate, mifepristone, methotrexate, and atorvastatin-telmisartan do not increase lifespan in UM-HET3 mice

The Interventions Testing Program (ITP) evaluated eleven compounds in genetically heterogeneous UM-HET3 mice to assess their potential to extend lifespan. These interventions included both novel agents and previously tested compounds administered at novel doses or starting ages. Despite prior evidence suggesting lifespan benefits of these proposed interventions in other models or under different conditions, none of the tested compounds significantly increased lifespan in male or female mice. Notably, astaxanthin, mitoglitazone, and meclizine-previously associated with lifespan extension in the ITP-showed no benefit when administered at different doses or starting at later ages. In females, astaxanthin, late-start mitoglitazone, and pioglitazone were associated with significantly reduced lifespan when pooling the data from all three sites. However, site-specific analysis revealed unusually long lifespans in control females at The Jackson Laboratory, prompting reanalysis using data from the other two sites and only showed a negative effect for mitoglitazone and pioglitazone. This study underscores the importance of rigorous, multi-site testing and highlights the challenges of translating promising initial findings into consistent lifespan benefits at other doses or with alternate starting ages. These results suggest that timing and dosage are critical variables in aging intervention studies and reinforce the need for cautious interpretation of single-site or single-cohort findings.