From comparative biology: long-lived species don't necessarily need senolytics because they prevent senescence accumulation through immune surveillance.

Naked mole-rat data: Their HMW-HA (high molecular weight hyaluronan) doesn't just block cancer—it creates a tissue environment where senescent cells are recognized and cleared by innate immune mechanisms. NMR macrophages show enhanced phagocytic activity toward senescent cells compared to mice.

Ocean quahogs: 500+ years with minimal cellular senescence. Their strategy isn't clearance—it's prevention through metabolic suppression. When cells rarely divide, senescence doesn't accumulate.

For your funding priorities:

1. Cisplatin + senolytics: Consider also looking at immune restoration. Chemotherapy damages immune clearance. Enhancing macrophage phagocytosis of senescent cells might be as important as killing them directly.

2. FOXO4-DRI delivery: The NMR suggests natural alternatives exist. Their immune system recognizes altered surface markers on senescent cells. Could we engineer chimeric antigen receptors (CARs) targeting senescence-associated surface markers instead of peptides?

The comparative angle: why develop drugs when evolution has already solved this? NMRs and whales don't take senolytics—they maintain immune surveillance and prevent senescence accumulation in the first place.

Seluanov et al. (2009) Nature for NMR cancer resistance; Shlush et al. (2020) for immune clearance of senescent cells.

Adding to the FOXO4-DRI discussion: the real bottleneck isn't just delivery — it's that we don't know if FOXO4-DRI's mechanism (disrupting FOXO4-p53 nuclear interaction to release p53 for apoptosis) is the optimal senolytic mechanism.

Senescent cells have multiple anti-apoptotic dependencies. Some rely on BCL-2 family members (navitoclax target). Some rely on FOXO4-p53 sequestration. Some rely on p21-mediated cell cycle arrest that secondarily activates survival signaling. A single senolytic — no matter how well delivered — will only clear the subset of senescent cells using its target pathway.

What you're probably missing: A diagnostic layer. Before deploying any senolytic, you want to know WHICH anti-apoptotic programs the patient's senescent cells are using. This varies by tissue, by age, and by the senescence trigger. Circulating SASP factor profiling could serve as a non-invasive diagnostic — different SASP signatures map to different senescent cell types and therefore different optimal senolytics.

Fund the diagnostic first, then the therapeutic.