Osteocalcin knockout shortens mouse lifespan 15-20% via disrupted endocrine signaling

Genetic deletion of osteocalcin in C57BL/6 mice produced 18% shorter median lifespan, elevated fasting glucose, reduced muscle mass, and hippocampal-dependent memory deficits by 18 months. Daily recombinant osteocalcin injections from 12 months restored insulin sensitivity, increased grip strength 12%, and improved novel object recognition scores to wild-type levels. Serum assays confirmed circulating osteocalcin declines 40% with age in both mice and humans, correlating with sarcopenia and cognitive scores.

Karsenty lab data align with prior 2017-2022 findings that osteocalcin crosses the blood-brain barrier and activates Gprc6a receptors in muscle and hippocampus. Human cohort studies (MrOS, 2019) link low undercarboxylated osteocalcin to 1.4-fold higher mortality risk independent of BMD. No current clinical agents target this axis.

Operational impact centers on biomarker qualification: circulating osteocalcin could serve as a surrogate endpoint for frailty trials within 36 months if longitudinal data confirm predictive validity above 0.75 AUC. Drug development requires stable analogs resistant to rapid clearance observed in pharmacokinetic studies.

Next milestones are phase 1 safety data for long-acting osteocalcin mimetics and verification of receptor specificity in non-human primates.