#1

Rapamycin partial target at PKP4 only showed an effect on healthspan.

while PKP4 only shows a significant positive effect on healthspan but not in other traits.

But three genes out of 21 were also found to be associated with rapamycin treatment…

To gain further insights into the potential relevance of the identified longevity-associated genes in aging and interventions, we further compared their significance scores across different signatures of aging and longevity interventions (Fig. 4f)22,23. The signature analysis results in 69 significant associations after adjusting for multiple testing of 266 tests using FDR (Fig. 4f). It revealed that many of these genes (18 out of 21 tested) were also significantly associated with aging in humans and rodents, as well as with interventions known to extend lifespan, such as caloric restriction (ABCF3, CKAP2L, and CEP68), rapamycin treatment (PKP4, CTNND1, and RTRAF), growth hormone deficiency (HOGA1, ANKRD33, and MLXIP), as well as overall lifespan after intervention (HOGA1). Together, this multi-layered evidence supports the potential roles of these genes in regulating healthy aging and longevity. …
Mendelian randomization and multi-omic analyses on these genes identified RGP1, PCNX2, and ANO9 as longevity genes with consistent causal effects on multiple aging-related traits and altered expression during aging.

Depletion of loss-of-function germline mutations in centenarians reveals longevity genes, 2024.

Good news for Rapamycin and IGF-1 inhibition? Now we just need drug repurposing for these targets with consistent causal effects on multiple traits (PCNX2, ANO9, RGP1).

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