Turning Down Growth Hormone at Midlife: Longer, Healthier Lives in Mice

Edited and Approved by Stephen C. Rose, PhD, MS

Growth hormone sounds like something we should want more of as we age. It helps children grow, supports protein synthesis, influences muscle and bone, and helps regulate how the body uses fat and glucose. Yet biology rarely rewards a simple more-is-better rule. In many laboratory animals, dialing down growth hormone signaling is linked to slower aging and longer life. The difficult question has been timing: must that low-growth state begin at birth, or can the pathway be changed after normal development is complete?

A new mouse study addresses that question unusually directly. Researchers deleted the growth hormone receptor gene throughout the body when mice were 12 months old, roughly midlife for the species. The animals had already reached normal adult size. Both male and female mice lived longer as groups, and several measures of late-life function improved, particularly in males. At the same time, single-nucleus sequencing showed that liver cells rewrote their genetic programs in sharply sex-specific ways [1]. The result is scientifically important, but it is not a recommendation to suppress growth hormone in healthy people.

What the growth hormone receptor does

Growth hormone, or GH, is released by the pituitary gland in pulses. It travels through the bloodstream and binds to growth hormone receptors on cells. The liver is one major target. When GH engages its receptor there, it activates signaling proteins, including STAT5, and stimulates production of insulin-like growth factor 1, or IGF-1. IGF-1 carries many growth-related signals to tissues throughout the body. GH also has direct effects on fat breakdown, glucose production, muscle, bone, and immune function.

The researchers used an inducible genetic system: five days of tamoxifen injections activated an enzyme that removed a critical portion of the Ghr gene. This was global receptor ablation, not a drug and not a liver-only intervention. The manipulated mice became resistant to GH, so circulating IGF-1 fell while GH rose because the usual feedback loop could no longer quiet the pituitary. Earlier work from the same group showed that deleting Ghr at six months improved insulin sensitivity in males and extended lifespan mainly in females [2]. A related study of deletion beginning at 12 months found a mixture of helpful and harmful tissue effects, including lower hypothalamic inflammation but impaired cortical bone morphology [3].

The lifespan result deserves careful wording

The longevity cohort contained about 30 to 35 mice in each sex-and-treatment group. Survival curves differed significantly between knockout and control animals in both sexes. Female median survival increased from 929 to 1,003 days, an 8% gain, and the longest-lived females also showed a statistically supported increase in maximal survival. Male median survival rose from 943 to 1,011 days, about 7%, but that specific median comparison and the tests of maximal lifespan were not statistically significant. In other words, the overall male survival pattern improved, but the strongest evidence for extending the far end of life belonged to females [1].

This gain was smaller than the dramatic longevity reported in mice born without normal GH action. That makes biological sense. Lifelong GH resistance changes development, adult body size, metabolism, stress responses, and disease trajectories for decades in mouse time. A midlife intervention has less time to reshape those systems. Even so, it answered the central question: in this model, altering the pathway after development was sufficient to affect survival. Reviews of GH-deficient and GH-resistant mice have long described improved insulin sensitivity, stress resistance, and delayed age-related dysfunction as possible contributors to their exceptional longevity [4].

Longer life did not mean universal improvement

The midlife knockout mice carried a higher percentage of body fat and a lower percentage of lean mass. That sounds unfavorable, yet male knockout mice became more insulin-sensitive and had lower fasting and nonfasting glucose. They also performed better on tests of balance, coordination, and grip strength after results were adjusted for lean mass. Their vertebral spongy bone had more trabeculae, less separation, and higher mineral density, although some bone dimensions changed in ways that complicate a simple stronger-bone conclusion. Female mice did not show the same improvements in insulin sensitivity or neuromuscular performance. Frailty scores were not significantly improved in either sex [1].

End-of-life examinations also found no significant reduction in fatal tumors or total disease burden. That matters because congenital GH-resistant mice are often protected from cancer. Starting at midlife may have been too late to prevent disease processes already under way. The animals may have reached similar causes of death later rather than avoiding them entirely. That interpretation is plausible, not proven. The study establishes a survival effect in a specific mouse model; it does not establish that one disease pathway explains it.

The liver revealed two different biological stories

At 19 months, the team analyzed liver tissue using single-nucleus RNA sequencing. Instead of averaging gene activity across the entire organ, this method reads RNA from thousands of individual nuclei and groups them by cell type and state. Four animals per genotype contributed to this sequencing analysis, so it is mechanistically informative but still a small experiment. Hepatocytes, the liver's main working cells, dominated the sample. B cells made up a smaller proportion of liver nuclei after receptor deletion in both sexes, but the meaning of that change remains uncertain. It could reflect altered immune recruitment, inflammation, or tissue composition rather than a direct anti-aging effect [1].

The most striking change occurred in male hepatocytes. Normal male mice release GH in pronounced pulses, while female mice have a more continuous secretion pattern. Those patterns help create sex-biased liver gene programs. Removing the receptor weakened canonical GH-STAT5 signals and shifted male liver cells toward a more female-like transcriptional profile. Female hepatocytes changed more modestly. Some drug-processing and detoxification genes, including cytochrome P450 pathways, declined, especially in females. That does not automatically mean the liver became less healthy; gene expression is not the same as measured detoxification capacity. It does mean that any future therapy could alter how other drugs are processed, a clinically important possibility.

Sex and timing are recurring themes in this biology. Experiments that lowered IGF-1 at different ages have produced different effects on cancer, function, and lifespan in male and female mice [5]. The current study adds cellular detail: the same intervention can extend survival in both sexes while producing very different metabolic and transcriptional responses. A future gerotherapy aimed at this axis would probably need sex-specific dosing, biomarkers, and safety monitoring rather than a single universal target level.

What human evidence can and cannot tell us

Humans with lifelong growth hormone receptor deficiency, sometimes called Laron syndrome, provide an intriguing natural comparison. A long-term Ecuadorian cohort had very low IGF-1, high insulin sensitivity, and unusually low reported rates of diabetes and cancer [6]. But these individuals were born with the condition, have short stature and distinctive physiology, and have not been shown conclusively to live longer than the general population. Their experience supports a relationship between GH signaling and disease biology; it does not tell us what would happen if an average adult began blocking GH at 50.

Medicine can already block the GH receptor. Pegvisomant is used for acromegaly, a disease of excessive GH action, and often normalizes IGF-1. It requires monitoring for liver abnormalities and pituitary tumor behavior [7]. Treating a serious hormone disorder is a very different risk-benefit calculation from treating aging in a healthy person. No clinical trial has shown that pegvisomant or another GH receptor blocker extends human healthspan or lifespan. The Endocrine Society's scientific review emphasizes that age-related endocrine changes are complex and that therapies require evidence for meaningful outcomes, not just movement in a biomarker [8].

The practical conclusion

This study strengthens a provocative idea: growth signaling remains modifiable late enough in life to influence mammalian aging. Its best contribution is not a ready-made anti-aging prescription but a better map of the trade-offs. Midlife Ghr deletion extended survival after normal development, improved several male metabolic and functional measures, and reorganized the liver in sex-specific ways. It also increased adiposity, failed to improve frailty or cancer burden, and changed pathways involved in processing foreign compounds.

The next steps should be more selective than deleting a receptor throughout the body: temporary or tissue-targeted inhibition, careful dose-response studies, replication in genetically diverse animals, and testing for interactions with bone health, muscle maintenance, immunity, and medications. Until human trials demonstrate net benefit, trying to lower GH or IGF-1 for longevity would be an experiment without an established therapeutic window. The finding is exciting because it shows that midlife is not biologically too late. It is sobering because the liver's response makes clear that turning down one growth signal rewrites many systems at once.

References

[1] Duran-Ortiz S, List EO, Young JA, et al. Midlife Growth Hormone Receptor Ablation Extends Healthy Lifespan and Induces Sex-Specific Hepatic Transcriptional Changes at Single-Cell Resolution. Aging Cell. 2026;25(9):e70695. doi:10.1111/acel.70695.

[2] Duran-Ortiz S, List EO, Ikeno Y, et al. Growth hormone receptor gene disruption in mature-adult mice improves male insulin sensitivity and extends female lifespan. Aging Cell. 2021;20(12):e13506. doi:10.1111/acel.13506.

[3] Poudel SB, Ruff RR, Basu R, et al. The impact of inactivation of the GH/IGF axis during aging on healthspan. Geroscience. 2025;47(3):3027-3042. doi:10.1007/s11357-024-01426-3.

[4] Bartke A. Healthspan and longevity can be extended by suppression of growth hormone signaling. Mamm Genome. 2016;27(7-8):289-299. doi:10.1007/s00335-016-9621-3.

[5] Ashpole NM, Logan S, Yabluchanskiy A, et al. IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan. Geroscience. 2017;39(2):129-145. doi:10.1007/s11357-017-9971-0.

[6] Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, et al. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med. 2011;3(70):70ra13. doi:10.1126/scitranslmed.3001845.

[7] Tritos NA, Biller BMK. Pegvisomant: a growth hormone receptor antagonist used in the treatment of acromegaly. Pituitary. 2017;20(1):129-135. doi:10.1007/s11102-016-0753-y.

[8] Cappola AR, Auchus RJ, El-Hajj Fuleihan G, et al. Hormones and Aging: An Endocrine Society Scientific Statement. J Clin Endocrinol Metab. 2023;108(8):1835-1874. doi:10.1210/clinem/dgad225.