Study reports sex-specific circadian and behavioral phenotypes in aged growth hormone receptor knockout mice

A GeroScience study reports that aged growth hormone receptor knockout mice display distinct, sex-specific circadian and behavioral phenotypes, and that circadian disruption significantly exacerbates neuromuscular and cognitive vulnerability, particularly in females.

Researchers investigated the impact of growth hormone receptor knockout (GHR-KO)—a model of growth hormone insensitivity—on circadian activity, neuromuscular performance, and neurocognitive function in mice aged 17–21 months under standard conditions and experimental circadian disruption.

Under standard light-dark conditions, female wild-type (fGHR-WT) mice showed greater overall activity, higher circadian activity amplitude, and less fragmented daily activity rhythms than female knockout (fGHR-KO) mice.

Following an 8-hour phase advance, fGHR-KO mice re-entrained their circadian rhythms significantly faster than fGHR-WT mice, despite exhibiting a longer endogenous free-running period (τ) in constant darkness.

GHR-KO mice displayed superior neuromuscular performance, showing greater normalized grip strength and increased latency to fall in Rotarod testing compared to GHR-WT controls.

Experimental circadian disruption, induced by repeated phase advances, compromised day-to-day rhythm stability in all groups and led to significant declines in normalized grip strength and Y-maze working memory performance specifically in female mice of both genotypes.

The findings establish a bidirectional link between growth hormone signaling and circadian clock organization during aging, demonstrating that the lack of functional growth hormone receptor signaling produces a complex, sex-dependent functional phenotype rather than uniform impairment.

The study shows that while GHR-KO mice exhibit protective characteristics against age-related neuromuscular decline under baseline conditions, their response to environmental stressors like circadian desynchrony reveals distinct physiological vulnerabilities.

The pronounced decline in grip strength and working memory in female mice post-disruption highlights biological sex as a critical mediator of vulnerability to circadian and metabolic stress.

The distinct susceptibility of aged female models to cognitive and physical decline under circadian stress indicates that preclinical evaluation of longevity therapeutics targeting neuromuscular or cognitive endpoints must account for sex-specific baseline differences and environmental stressors.

The observed preservation of motor coordination and strength in aged GHR-KO mice supports continued exploration of the somatotropic axis as a source of targets for therapeutic interventions in age-related frailty.

These insights reinforce the programmatic focus of clinical-stage developers targeting age-related muscular preservation and cognitive resilience, confirming that endocrine and circadian networks are tightly integrated in aged biology.

Future research is expected to investigate the exact molecular and neuroendocrine pathways, including potential interactions between growth hormone and prolactin receptor signaling, that sustain cognitive and neuromuscular function in the absence of canonical growth hormone receptor signaling.