Midlife Growth Hormone Receptor Ablation Modestly Slows Aging in Mice
Despite considerable and growing effort put towards the development of novel means to slow and reverse aging over the past thirty years, the longest lived laboratory mice remain those lineages first established in the 1990s with mutations that disable growth hormone metabolism, such as via knockout of growth hormone or growth hormone receptor genes. These mice are small and vulnerable to cold, but live as much as 70% longer than their unmodified peers.
It seems likely that this has little relevance to human aging, as Laron syndrome is the analogous human inherited condition, usually caused by a growth hormone receptor loss of function mutation. Laron syndrome patients may have a lower incidence of some age-related conditions, but do not appear to live meaningfully longer than the rest of the human population. One of the most important lessons of the past thirty years of study of calorie restriction and growth hormone metabolism in the context of aging is that these interventions produce much larger effects in short-lived species than in long-lived species.
Nonetheless, disruption of growth hormone metabolism remains an active area of study. You might recall a paper published five years ago or so in which researchers showed that disruption of growth hormone metabolism starting in adult life, at six months of age in mice, still produced a slowing of aging. Here, the same team repeats the same effort starting at twelve months of age, mid-life for mice. The size of effect on life span is much the same in male mice when starting at this later age, but worse in female mice. In either case, the extension of life span is modest in comparison to life-long disruption of growth hormone metabolism, less than 10%. Like the existence of Laron syndrome, this argues against putting meaningful effort into attempts to build human therapies based on this mechanism.
Suppression of growth hormone (GH) signaling is known to be effective to extend lifespan in mammals, yet most models rely on congenital disruption of the GH/insulin-like growth factor-1 (IGF-1) axis. Whether modulation of this pathway later in life can still influence aging and the underlying cellular mechanisms remains incompletely understood. To address this, we ablated the growth hormone receptor (Ghr) at 12-months of age in mice (12mGHRKO), using a tamoxifen-inducible model.
This midlife Ghr disruption produced the expected endocrine signature of GH resistance, including reduced circulating IGF-1 and elevated GH levels. Importantly, lifespan was significantly extended in both sexes without major effects on somatic growth. Despite increased adiposity, male 12mGHRKO mice exhibited improved insulin sensitivity and protection against age-related deterioration of neuromuscular performance and bone microarchitecture. Single-nucleus RNA sequencing (snRNA-seq) of liver tissue identified a reduction of B-cells in both sexes and a dimorphic transcriptional remodeling, including a shift toward feminized gene expression in male hepatocytes, marked by reduced male-biased gene expression and increased female-biased transcriptional programs, consistent with impaired pulsatile GH-STAT5 signaling.
Together, these findings demonstrate that suppression of GH signaling initiated in middle age is sufficient to reshape hepatic transcriptional programs and promote healthy longevity, supporting the GH/IGF-1 axis as a promising target for gerotherapeutic interventions.