Researchers at the Keck School of Medicine of USC report that an experimental drug made the liver cells of old rats act younger, restoring their ability to pull certain substances out of the blood1. The study was published in the Journal of Biological Chemistry1. The drug, called cinaciguat, brought blood levels of amyloid beta, a protein linked to Alzheimer’s disease, and LDL, the so-called “bad” cholesterol, down to the levels seen in young rats1.
The authors suggest that treating the liver could one day become a way to lower the risk of Alzheimer’s and clogged arteries2. That idea has not been tested in people, and the study did not measure Alzheimer’s or heart disease in the rats.
What the researchers did
The team looked at a little-studied group of liver cells called liver sinusoidal endothelial cells, or LSECs1. These cells line the liver’s blood vessels and are full of holes, like tiny sieves1. The holes let larger molecules in the blood reach hepatocytes, the main liver cells that do most of the work of clearing compounds from the body1.
In normal aging, those holes shrink and close up, leaving bigger molecules in the blood1. One of those larger molecules is amyloid beta, which forms plaques in the brain associated with Alzheimer’s1. The team’s starting idea was that the shrinking holes might explain why more amyloid beta circulates in the blood with age2.
To test this, they gave aged rats cinaciguat for two weeks and compared them with two untreated groups, one old and one young1. The university’s release posted on EurekAlert! describes the treated animals as “aged mice” in that sentence while calling them rats everywhere else, and the Medical Xpress version says rats throughout21. The sources do not say how many animals were used.
What changed in the rats
According to the researchers, the drug reopened the pores in the filter cells and restored their ability to clear substances from the body1. Amyloid beta levels in the treated rats were cut in half, falling to the same levels as in young rats, while untreated old rats showed no decrease1.
The bigger surprise came from cholesterol. The team measured LDL as a comparison, because LDL particles are small enough that they do not need the holes in the filter cells to leave the blood1. Under the original idea, LDL should not have changed in treated rats. Instead, it dropped to young-rat levels too1.
“We said, ‘Wait, why did that go down? Clearly, there’s more to this story,’”
said first author Sam de Leve, a USC lab technician2.
Following that lead, the researchers describe a previously unknown chain of signals between the two kinds of liver cells1. In their account, cinaciguat switches on a messenger molecule called soluble guanylate cyclase in the filter cells, which then release a growth factor called HB-EGF1. That growth factor prompts the main liver cells to change their surfaces so they grab onto LDL and amyloid beta1. With age, the filter cells lose the ability to release this growth factor, and the drug restored it, the team reported1.
The researchers say this is the first study to show a drug can fully restore the shape and function of these filter cells, and the first to show a liver-directed treatment that brings age-raised amyloid beta and LDL back to normal2.
What it does not show yet
This is a study in rats. It measured changes in liver cells and in blood levels of two substances. It did not show that the treated rats were protected from Alzheimer’s-like brain changes or from clogged arteries. The team says it will continue in rats and aims to test whether lowering amyloid beta with cinaciguat leads to measurable results in preventing Alzheimer’s2.
The corresponding author, Laurie DeLeve, a professor and vice chair for scientific affairs in the USC Department of Medicine, was cautious about what comes next:
“We need to do further translational work to see whether our findings might point to new therapies,”
she said1. She added that the team is hopeful because the findings line up with population studies showing age as a major risk factor for Alzheimer’s and atherosclerosis, and liver damage as a risk factor for Alzheimer’s1.
The sources do not report how long the effects lasted after treatment stopped, whether the drug caused side effects in the rats, or what doses were used. They also do not report any test of the drug for this purpose in people.
Who is behind it
The work comes from the DeLeve Lab at the Keck School of Medicine of USC1. First author Sam de Leve is the child of senior author Laurie DeLeve2. Other co-authors named in the release include Xiangdong Wang and Helia Alavifard2. Both news sources available to Biohack are versions of the university’s own press release, and neither describes the study’s funding or any company involvement. Biohack did not have the full paper.
The authors openly invited other labs to build on the work. “There are six different ways someone could go with this, and we can’t do them all. So please, scoop us. We’d love it,” Sam de Leve said2.
How it fits the field
The pitch behind the study is about where to deliver drugs. The release notes that Alzheimer’s treatments aimed at the brain have a 98% failure rate in clinical trials1. “Rather than trying to get a drug through the blood-brain barrier, which is obnoxiously difficult, we could direct drugs to the liver,” Sam de Leve said2.
Other researchers have also been looking at the liver’s relationship with amyloid beta, with a different emphasis. A 2024 study from the University Hospital of Tübingen in Germany, done mostly in mice, reported that amyloid beta helps keep the liver healthy, and that removing or blocking it led to signs of liver scarring3. One of those researchers, Lusine Danielyan, said the liver both clears amyloid beta and makes some itself, with beneficial effects3. That work does not test cinaciguat, but it suggests the role of amyloid beta in the liver is more than simple waste disposal.
The USC study also joins a wider search for ways to make aging liver tissue behave more like young tissue. A 2019 preprint, a paper not yet peer reviewed, reported that in adult mice a senolytic drug, one designed to clear worn-out “senescent” cells, improved the liver’s ability to regrow after part of it was removed4. Some scientists urge caution with that approach: Joao Pedro de Magalhaes of the University of Birmingham argued in Science in 2024 that senescent cells have useful roles, including in liver cells called hepatic stellate cells after injury, and that targeting them carries risks5. The USC team took a different route, aiming to restore lost function in one cell type rather than remove cells.
What to watch next
- More rat studies. The team plans to test whether lowering amyloid beta with cinaciguat translates into measurable protection against Alzheimer’s2.
- New drug targets. The researchers suggest cinaciguat or a related drug, or future drugs aimed at the growth factor HB-EGF, could be explored1.
- Independent checks. Whether other labs, including heart and artery researchers the authors hope to reach, repeat the cholesterol and amyloid findings2.
Until then, the result is a single animal study: a clear change in rat livers and blood, and an open question about what, if anything, it means for people.
