The NIA Interventions Testing Program (ITP) has recently published its latest results. Known for conducting rigorously controlled animal life span studies, the ITP often reveals that previously promising findings were incorrect. In this round of interventions, the most noteworthy outcome is that fisetin, which has been shown to clear senescent cells in mice and improve health measures, did not extend life. On the other hand, dasatinib and quercetin, the most well-studied senolytic, have been demonstrated by other groups to extend life in mice by up to 36% in one study. This outcome is puzzling indeed!
One possible explanation is that fisetin, at the senolytic doses used in the ITP study (which included more frequent dosing for a longer period of time than typical), may produce harmful side effects in comparison to the less frequent dosing of dasatinib and quercetin. Alternatively, an ITP-run life span study for dasatinib and quercetin treatment might also show no benefit to life span. However, the data is what it is. The ITP researchers are considering that the differences between mouse strains used in various fisetin studies could be a contributing factor. This possibility is also intriguing, as it suggests that senescent cell burden and type might vary enough between different strains to produce significantly different outcomes.
In addition to these findings, it was observed that astaxanthin and meclizine extended the lifespan in UM-HET3 male mice, while other agents such as fisetin, SG1002, dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate did not significantly affect lifespan in either sex at the tested doses and schedules.
One particularly interesting finding is that astaxanthin (Asta), an Nrf2 activator, extended the median male lifespan by 12%, while meclizine (Mec), an mTORC1 inhibitor, extended the male lifespan by 8%. It was noted that the amounts of dimethyl fumarate in the diet averaged 35% of the target dose, which may explain the lack of lifespan effects. The study also showed that body weight was not significantly affected in males by any of the test agents. However, late-life weights were lower in females fed Asta and Mec, despite their lifespan not being significantly affected. These male-specific lifespan benefits from Asta and Mec might provide valuable insights into sex-specific aspects of aging.
Another key finding is that senescent cells, which have been reported to play a significant role in aging, did not significantly decrease with fisetin treatment at the doses and route described in the study. This raises important questions about the potential effects of removing senescent cells on life span. Further studies are needed to clarify the types and location of senescent cells in different mouse models and their response to senolytic agents such as fisetin.
