The gerotherapeutic drugs rapamycin, acarbose, and phenylbutyrate extend lifespan and enhance healthy aging in house crickets

Abstract The house cricket ( Acheta domesticus ) is a promising preclinical geroscience model due to its short lifespan, low maintenance, age-associated functional decline, and responsiveness to geroprotective drugs. Continuous dosing with rapamycin, acarbose, and phenylbutyrate extends lifespan; whether intermittent dosing offers similar benefits remains unknown. We tested 274 sex-matched crickets given 2-week intermittent dosing of each drug starting at mid-age (8-weeks), followed by behavioral testing at 10-weeks (geriatric stage). Assays included Y-maze olfactory discrimination, open-field exploration, and treadmill performance. Locomotor gaits were identified by velocity-based K-means clustering (silhouette > 0.5). A subset was monitored for post-treatment survival using Kaplan-Meier analysis. Olfactory preference was preserved by all drugs ( d ’s = −1.82 to −1.28, P ’s < 0.01), with strongest effects in rapamycin-treated individuals. Rapamycin-treated males matched or exceeded juvenile locomotor activity; phenylbutyrate reduced male activity ( d = 1.49, P < 0.05) and acarbose increased walking-to-running ratios ( d = −0.75, P < 0.05). Rapamycin increased central exploration and freezing ( d = −1.55, P < 0.0001), while acarbose and phenylbutyrate increased peripheral freezing ( d = −0.76, P < 0.05). Rapamycin and phenylbutyrate extended maximum running time ( d ’s = −2.30 to −1.32, P ’s < 0.0001), with sex-specific jumping gains in rapamycin-treated females and acarbose-treated males. Post-treatment lifespan was prolonged by rapamycin ( HR = 0.42, P < 0.001) and reduced by acarbose in females ( HR ’s = 2.92 to 3.03, P ’s < 0.05). Intermittent rapamycin preserved survival, cognition, and locomotion, while acarbose and phenylbutyrate produced selective benefits, supporting A. domesticus as a scalable model for geroprotective drug discovery.