Knocking out the growth hormone receptor in mouse liver alone accelerated its aging, even though the same whole-body knockout extends lifespan
Knocking out the growth hormone receptor in mouse liver alone accelerated its aging, even though the same whole-body knockout extends lifespan
Researchers at Dalian Medical University generated mice in which the growth hormone receptor (GHR) was deleted only in liver cells. Males showed accelerated liver aging, impaired memory, reduced bone density, and shortened lifespan, even though deleting the same receptor throughout the entire body extends lifespan. The authors traced the molecular chain behind this effect and identified a drug target whose inhibition partially reversed the damage in aged mice.
Since 2003, aging biology has known that mice lacking the growth hormone receptor gene in every cell of the body outlive any other laboratory mouse strain. The same deletion, performed in mice at one year of age, extended lifespan in females. Liver-specific knockout of the same receptor had been studied for a different reason: it caused fatty liver disease, and its connection to aging had never been tested. A paper published on September 25 tested exactly that: how does this knockout affect aging and lifespan?
The answer turned out to be the opposite. Males with the receptor deleted only in the liver died earlier than controls: by 24 months their survival had declined. No significant difference appeared in females; the authors attribute this to hormonal fluctuations but do not explain the mechanism. Surviving males showed impaired orientation and memory in maze tests, reduced bone density, elevated inflammatory proteins in the blood, and fatty infiltration of the liver. The knockout renders the liver vulnerable to metabolic stress at any age: in young mice on a high-fat diet, receptor-deficient liver sustained the same damage as in aged animals.
Without the receptor, the liver stops taking up growth hormone, and the resulting excess accumulates in the blood, driving adipose tissue to break down fat stores. The released fatty acids deposit in the liver via the CD36 transporter. The brain, bones, and immune cells retain the receptor, and excess circulating growth hormone is a plausible cause of their deterioration, but the authors acknowledge that the model cannot separate this effect from signals originating in the damaged liver itself. Inside liver cells, the chain has been demonstrated experimentally: loss of the receptor reduces activity of STAT5b, a protein that normally restrains the transcription factor PPARγ. Freed PPARγ activates transcription of CD36 and of the PDK4 gene, encoding an enzyme that normally restrains mitochondria but in excess destroys them and triggers oxidative stress. A point mutation in the DNA site where PPARγ binds abolished the effect, providing direct genetic proof of causality.
Disrupted lipid metabolism and damaged mitochondria set off a vicious cycle that accelerates liver aging and sustains chronic inflammation. A PDK4 inhibitor given to these mice starting at 20 months of age reduced liver fat, inflammation, and mitochondrial damage over four months, attenuating markers of cellular senescence. The same effect was observed in ordinary aged mice without the knockout. PDK4 blockade has already shown efficacy in an independent earlier study: an inhibitor of the same class, given to normal aged mice from 25 to 26 months (roughly 80 to 85 in human-equivalent years), extended their remaining lifespan by 29.6% and total lifespan by 4.2%, reducing mortality by 53.4%.
The same laboratory has already obtained the opposite result: knocking out the receptor in adipose tissue alone extends the healthy portion of lifespan and protects the brain from aging. One and the same growth hormone receptor can extend life or accelerate aging depending on the tissue where it is deleted: in adipose tissue the knockout protects, in the liver it harms.