Experimental drug rejuvenates aged rat livers, halving amyloid beta and LDL

An experimental drug that acts on the liver has reversed key hallmarks of cellular aging in aged rats, cutting blood levels of amyloid beta — the molecule that forms the plaques associated with Alzheimer's disease — in half and lowering "bad" cholesterol to levels normally seen in young animals. The study, led by researchers at the Keck School of Medicine of USC and published in the Journal of Biological Chemistry, focused on liver sinusoidal endothelial cells, a specialized population that lines the blood vessels of the liver and functions as a biological sieve. With age, the pores in this sieve shrink and close, stranding large molecules in the bloodstream.

A two-week course of the drug cinaciguat reopened those pores and restored the liver's ability to clear amyloid beta and low-density lipoproteins from circulation in aged rats. The researchers also traced the rejuvenation to a previously unknown signaling pathway used for local communication between liver cells, which they describe as a potential therapeutic target. The liver's job of clearing harmful substances from the body is so essential that the organ may have implications for diseases that appear unrelated to it, including Alzheimer's disease and the clogged arteries of heart disease.

Epidemiological research has consistently identified age as a major risk factor for both Alzheimer's and atherosclerosis, and liver damage as a risk factor for Alzheimer's. Laurie DeLeve, MD, PhD, professor and vice chair for scientific affairs in the USC Department of Medicine and corresponding author of the study, emphasized that the findings remain at an early stage. "We need to do further translational work to see whether our findings might point to new therapies," she said.

"We're hopeful, though, because the findings line up with a lot of epidemiological results showing age as a major risk factor for Alzheimer's and atherosclerosis, and liver damage as a risk factor for Alzheimer's." More broadly, the research suggests that medicating the liver may open a new path for preventing some of the most serious diseases associated with aging. At the center of the study is a little-studied population of liver cells called liver sinusoidal endothelial cells, or LSECs. These cells line the blood vessels of the liver and are shot through with holes, like tiny sieves.

The openings allow larger molecules in the circulation to reach hepatocytes, the cells that do the lion's share of the liver's work clearing compounds from the body. In normal aging, the holes in LSECs shrink and close up over time, leaving bigger molecules stranded in the bloodstream. The investigators built on earlier observations that aging curtails the liver's ability to clear one of these larger molecules: amyloid beta, which forms plaques in the brain associated with Alzheimer's disease.

The team hypothesized that the shrinking portals in LSECs may explain the increased circulation of amyloid beta with age, and that restoring the openings could bring the protein fragment back under hepatic control. To test that hypothesis, the researchers compared aged rats treated with cinaciguat for two weeks against two untreated control groups, one aged and the other young. The drug rejuvenated the LSECs, reopening the pores and restoring the cells' ability to clear substances from the body.

Amyloid beta levels in the treated rats were cut in half, dropping to the same levels measured in young rats, while the untreated aged rats showed no decrease. The result demonstrated, for the first time, that a drug can fully restore both the shape and the function of LSECs, including their clearance capacity. It also made the study the first to show a liver-directed treatment that normalizes amyloid beta levels elevated in aging.

Because the work was conducted in animals, the findings describe a mechanism and a treatment effect in rats rather than proven benefits for human patients. The experiment also produced an unexpected result that reshaped the project. Alongside amyloid beta, the researchers measured low-density lipoproteins, the so-called "bad" cholesterol that builds up in arteries and leads to heart disease.

LDL was supposed to serve as a control, because those particles are small enough that they do not require the holes in LSECs to leave circulation. According to the original hypothesis, LDL levels in aged rats that received cinaciguat should have remained unchanged. Instead, they dropped to the same levels as in young rats.

"We said, 'Wait, why did that go down? Clearly, there's more to this story,'" said first author Sam de Leve, MA, a USC lab technician. The surprise indicated that the drug was doing more than simply widening a physical filter, and it pushed the team to investigate how the liver's two main cell types communicate.

Building on the observation that hepatocytes perform better in the presence of LSECs, the team began examining the crosstalk between the two cell types. They uncovered a previously unknown biochemical chain reaction that controls local communication between liver cells. Cinaciguat activates a molecular messenger called soluble guanylate cyclase in LSECs.

This spurs the cells to release a specific growth factor, called HB-EGF, that boosts hepatocytes. Specifically, the growth factor prompts hepatocytes to change their cell surfaces so they can grab onto LDL and amyloid beta circulating in the blood. With age, LSECs lose the ability to release the growth factor, but cinaciguat restored that capacity in the aged animals.

The discovery reframes the liver's age-related decline not merely as a failure of individual cells but as a breakdown in the signaling conversation between them — a conversation that, at least in rats, a drug can restart. The two mechanisms work on different fronts. The reopening of the LSEC pores addresses the physical route by which large molecules leave the bloodstream and reach the hepatocytes that dispose of them.

The HB-EGF pathway addresses the active route: even when large molecules arrive at the hepatocytes, the cells must alter their surfaces to capture amyloid beta and LDL efficiently. The study is the first to demonstrate a liver-directed treatment that normalizes both amyloid beta and LDL levels elevated in aging, and the first to show that a drug can fully restore LSEC structure and function together. Taken together, the findings indicate that the liver's age-related loss of clearance capacity is reversible with a short course of treatment, at least in an animal model, and that a single drug can act on both the filter and the cells it feeds.

If the liver proves to be an impactful lever against Alzheimer's disease, the implications for drug development could be considerable. According to the researchers, this approach could make a big difference for Alzheimer's, because treatments aimed at the brain have a 98 percent failure rate in clinical trials. "If we're right that the liver is impactful, what do we do about that?" said Sam de Leve.

The results indicate that cinaciguat, or a related drug, has potential for reversing the effects of aging in the liver and, the researchers suggest, for helping prevent Alzheimer's disease and heart disease. That potential remains to be demonstrated beyond rats, and the team is explicit that further translational work is needed before the findings can inform new therapies. The next step is to continue the line of inquiry in rats, testing whether lowering amyloid beta with cinaciguat translates into measurable results in preventing Alzheimer's disease.

There may also be future opportunities to develop drugs that target HB-EGF directly, building on the newly described signaling pathway. The authors anticipate that the study's implications will spark curiosity well beyond liver biology. "We hope that people who are in fields like atherosclerosis research read this, and want to grab the idea for themselves," Sam de Leve said.

"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."

Other co-authors of the study are Xiangdong Wang, Helia Alavifard and Lily Dara, all of the Keck School of Medicine of USC. The research was federally funded by the National Institutes of Health, and the authors declare no conflicts of interest with the contents of the article. The work appeared in the Journal of Biological Chemistry under the title describing the reversal of liver sinusoidal endothelial aging and the restored clearance of amyloid-beta and LDL.

For now, the aged rat remains the testing ground as the team works to determine whether the liver's declining sieve can be enlisted, through a simple drug treatment, against two of the most burdensome diseases of human aging.

Subject of Research: Reversing liver sinusoidal endothelial cell aging to restore amyloid beta and LDL clearance in aged rats

Article Title: Treatment revives old liver cells in lab study, may help prevent Alzheimer’s and heart disease

Article References: Treatment revives old liver cells in lab study, may help prevent Alzheimer’s and heart disease. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: liver aging, liver sinusoidal endothelial cells, cinaciguat, amyloid beta, LDL cholesterol, Alzheimer's disease, atherosclerosis, soluble guanylate cyclase, HB-EGF, hepatocytes, rat study, Journal of Biological Chemistry