Deleting the Growth Hormone Receptor in Liver Cells Accelerates Aging in Mice

Deleting the receptor for growth hormone specifically in liver cells appears to speed up aging, according to a new study published in Aging Cell. Researchers at Dalian Medical University generated mice lacking the growth hormone receptor, known as GHR, only in their hepatocytes, the workhorse cells of the liver. These animals, called LiGHR knockout mice, developed a striking constellation of age-related problems: male mice lived shorter lives, lost fur, suffered cognitive decline, showed weakened bones, and carried elevated levels of inflammatory molecules in their blood. The findings reveal an unexpected role for liver growth hormone signaling in coordinating the pace of aging across the whole body, and they point to a specific mitochondrial enzyme as a potential drug target for slowing age-related liver disease.

Growth hormone, secreted by the pituitary gland, has long been known to influence lifespan. Mice engineered to lack the receptor everywhere in the body are dwarfs, but they are also the longest-lived laboratory mouse strain ever recorded, with enhanced insulin sensitivity and resistance to obesity-driven inflammation. Recent work has refined this picture by deleting the receptor in individual tissues. Removing it from fat cells modestly extends lifespan and improves frailty and cognition in aged mice, while removing it from the liver was previously shown to trigger fat-producing genetic programs and pathological lipid buildup. What remained unclear was whether hepatic growth hormone signaling influences aging itself rather than just metabolism.

To answer that question, the team crossed mice carrying floxed GHR alleles with Albumin-Cre transgenic animals, producing offspring in which the receptor was excised exclusively in hepatocytes. Polymerase chain reaction confirmed that the deletion was confined to the liver and absent from fat, heart, spleen, kidney, lung, brain, and intestine. The researchers then followed cohorts of male and female knockout and control mice for up to two years, feeding some a standard chow diet and others a high-fat diet to test whether metabolic stress would amplify any aging phenotype.

The results in males were dramatic. Survival curves showed that male LiGHR knockout mice died significantly earlier than controls, while females showed no significant difference, hinting at a sex-dependent effect. At 24 months of age, the knockout males weighed less, had sparser fur, and performed worse across a battery of behavioral tests. In the Y-maze, they spent less time exploring a novel arm of the maze; in the Morris water maze, they took longer to find a hidden platform and crossed its former location fewer times; and in the open field test, they traveled shorter distances in the central zone. Together, these assays indicated genuine deficits in spatial learning and memory rather than simple locomotor impairment.

The systemic picture was equally troubling. Serum levels of the proinflammatory cytokines tumor necrosis factor alpha, interleukin-6, and interleukin-1 beta were all elevated, a signature of the chronic low-grade inflammation often called inflammaging. Blood triglycerides and total cholesterol were increased. Micro-computed tomography of the right femur revealed reduced bone mineral density, lower bone volume fraction, and thinner trabeculae, hallmarks of musculoskeletal frailty. Glucose tolerance and insulin tolerance tests showed impaired metabolic resilience. The authors are careful to note an important caveat: because deleting hepatic GHR disrupts the normal feedback loop and raises circulating growth hormone, other tissues with intact receptors are bathed in excess hormone. The model therefore cannot fully separate liver-intrinsic effects from indirect effects of elevated growth hormone acting on fat, muscle, bone, and brain, and the team suggests inducible or reversible knockout strategies to resolve this in future work.

Inside the liver itself, the evidence of accelerated aging was unambiguous. Senescence-associated beta-galactosidase activity was markedly elevated, and the classic senescence markers p16, p21, and p53 were upregulated, along with gamma-H2AX, a marker of DNA damage. Masson’s trichrome staining revealed fibrotic scarring, alpha-SMA and collagen levels rose, and Oil Red O staining showed extensive lipid droplet accumulation. Hepatic triglyceride and cholesterol content climbed with age. A parallel experiment in young adult mice fed a high-fat diet for three months reproduced the pattern: more steatosis, more senescence markers, more fibrosis, worse liver enzymes, and dyslipidemia compared with diet-stressed controls. When the researchers compared 12-month-old knockout mice on chow versus those previously fed a high-fat diet, the diet group showed greater lipid accumulation and higher expression of senescence and inflammatory proteins, supporting a mechanistic link between ectopic lipid deposition and accelerated hepatic aging. In cell culture, knocking down GHR in AML12 hepatocyte-like cells and challenging them with a mixture of oleate and palmitate for a week synergistically increased senescence markers, lipid droplets, and inflammatory gene expression.

The mechanistic trail began in the fat. Because hepatic GHR loss disrupts the growth hormone feedback axis, the knockout mice had elevated serum growth hormone and reduced IGF1. Growth hormone is a potent lipolytic signal, and indeed the subcutaneous and epididymal fat depots of the knockout males were shrunken, with fewer and smaller lipid droplets. Lipolysis proteins including ATGL, HSL, and MGLL were upregulated in fat tissue, the thermogenic marker UCP1 increased, and serum non-esterified fatty acids rose. The liver, meanwhile, ramped up expression of CD36, the fatty acid transporter, providing a doorway for the flood of liberated fat to enter hepatocytes. The result was a perfect storm: fat exported from adipose tissue, actively imported by the liver, and deposited as ectopic lipid that feeds back into senescence and inflammation.

RNA sequencing of liver tissue pinpointed the signaling cascade behind this cascade of damage. Loss of GHR signaling reduced phosphorylation of the transcription factor STAT5b, which normally suppresses the nuclear receptor PPAR gamma. With that brake released, PPAR gamma expression and nuclear translocation increased, and cross-referencing its known target genes with the transcriptomic data highlighted CD36 and, most strikingly, PDK4, whose messenger RNA rose more than sevenfold. Dual-luciferase reporter assays in HEK293T cells confirmed that PPAR gamma directly activates the PDK4 promoter, and mutating the predicted binding motif abolished this activation. Overexpressing STAT5b in AML12 cells lowered both PPAR gamma and PDK4, while silencing PPAR gamma with small interfering RNAs reduced PDK4, cementing a GH-GHR-STAT5b-PPAR gamma-PDK4 axis. Additional pathway analysis showed reduced AMPK phosphorylation and SIRT1 alongside increased mTOR and NF-kappa B activity, indicating that multiple aging-related signaling networks were simultaneously deranged.

PDK4, pyruvate dehydrogenase kinase 4, is a mitochondrial enzyme that throttles glucose oxidation by inhibiting the pyruvate dehydrogenase complex, and it has previously been implicated in fatty liver disease, insulin resistance, and vascular calcification. In the knockout livers, reactive oxygen species accumulated, antioxidant enzymes including superoxide dismutase, catalase, and glutathione peroxidase declined, and transmission electron microscopy revealed mitochondria with ruptured membranes and disorganized cristae. Autophagy markers shifted in a pattern consistent with cellular stress. In cultured cells, Seahorse extracellular flux analysis showed that GHR knockdown plus free fatty acid treatment synergistically suppressed basal respiration, maximal respiratory capacity, ATP production, and spare respiratory capacity, while Mito-Tracker staining exposed grossly abnormal mitochondrial morphology. Lipid overload and mitochondrial failure thus formed a self-reinforcing pathological loop.

The therapeutic payoff came from a PDK4-specific inhibitor. Starting at 20 months of age, the researchers treated knockout and control mice weekly for 16 weeks with the compound at low and high doses. PDK4 levels fell, serum liver enzymes ALT and AST dropped, hepatic fat accumulation diminished, and electron microscopy showed restored mitochondrial ultrastructure with reduced reactive oxygen species. Inflammatory cytokines in blood and liver declined in a dose-dependent manner, fibrosis eased, and the senescence markers p16, p21, and gamma-H2AX were downregulated. Encouragingly, the inhibitor also reduced senescence and inflammation markers in naturally aged control mice, echoing earlier reports that late-life PDK4 inhibition extends median lifespan in aged animals. The authors conclude that hepatic growth hormone receptor signaling, acting through the STAT5b-PPAR gamma-PDK4 axis, is a meaningful contributor to liver aging and a promising target for interventions aimed at extending healthspan, though they caution that the systemic phenotypes likely reflect combined liver-intrinsic and hormone-driven effects that future inducible models will need to disentangle.

Subject of Research: Hepatocyte-specific growth hormone receptor deletion, hepatic mitochondrial dysfunction, and accelerated aging in mice

Article Title: Hepatocyte Growth Hormone Receptor Ablation Is Associated With Aging Phenotypes and Hepatic Mitochondrial Dysfunction

Article References: Yang, K., Jian, Y., Pang, F., Ying, M., Yang, Q., Liu, N., Wang, S., & Wu, Y. (2026). Hepatocyte Growth Hormone Receptor Ablation Is Associated With Aging Phenotypes and Hepatic Mitochondrial Dysfunction. Aging Cell, 25(10), Article e70741. https://doi.org/10.1111/acel.70741

Image Credits: AI Generated

DOI: 10.1111/acel.70741

Keywords: aging, growth hormone receptor, liver, mitochondrial dysfunction, PDK4, PPAR gamma, STAT5b, hepatic steatosis, cellular senescence, inflammaging, knockout mice, lipid metabolism