Scientists reverse liver cell aging and cut Alzheimer’s-linked protein in half

In a new study involving older rats, researchers at the Keck School of Medicine of USC found that an experimental drug called cinaciguat reversed important signs of aging in specialized liver cells. After just two weeks of treatment, levels of amyloid beta, a protein associated with Alzheimer’s disease, dropped by half. Levels of LDL, commonly called bad cholesterol, also returned to those seen in younger animals.

The findings, published in the Journal of Biological Chemistry, also revealed a previously unknown way that liver cells communicate with one another. This discovery could help scientists develop treatments that restore the liver’s ability to remove potentially harmful substances from the blood, possibly reducing the risk of Alzheimer’s disease and atherosclerosis, a condition in which fatty deposits accumulate inside arteries.

Why the Liver Could Be Important for Alzheimer’s

Although Alzheimer’s primarily affects the brain, scientists are increasingly interested in how other organs might influence the disease. The liver plays a central role in filtering the blood and removing unwanted compounds, including substances that may contribute to disease when they accumulate.

The USC findings suggest that restoring this natural cleaning process could offer a different approach to preventing certain age-related illnesses. However, the results have so far been demonstrated only in rats, and additional studies are needed to establish whether the same benefits occur in humans.

“We need to do further translational work to see whether our findings might point to new therapies,” said corresponding author Laurie DeLeve, MD, PhD, professor and vice chair for scientific affairs in the USC Department of Medicine. “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.”

Targeting the liver could be particularly valuable in Alzheimer’s research, where efforts to develop treatments acting directly in the brain have faced an estimated 98% failure rate in clinical trials. One major obstacle is the blood-brain barrier, a protective system that limits which substances can enter the brain from the bloodstream. While this barrier helps shield the brain from harmful compounds, it also makes delivering certain medications extremely difficult.

“If we’re right that the liver is impactful, what do we do about that?” said first author Sam de Leve, MA, a USC lab technician and child of Laurie DeLeve. “Rather than trying to get a drug through the blood-brain barrier, which is obnoxiously difficult, we could direct drugs to the liver, an organ where there might be more therapeutic impact and certainly an easier job of drug delivery.”

Scientists Restore the Aging Liver’s Natural Filters

To understand how liver aging affects the bloodstream, the researchers focused on a relatively understudied group of cells known as liver sinusoidal endothelial cells (LSECs).

These cells form the lining of tiny blood vessels inside the liver. Unlike most blood vessel walls, they contain numerous microscopic openings that function somewhat like the holes in a sieve. These openings allow larger molecules circulating in the blood to reach neighboring cells called hepatocytes, which carry out much of the liver’s work processing and removing substances from the body.

As the liver ages, the openings in LSECs gradually become smaller or disappear. This makes it harder for certain large molecules to reach the cells responsible for clearing them, allowing more of these substances to remain in circulation.

One substance affected by this change is amyloid beta. This protein is especially important in Alzheimer’s research because it can accumulate in the brain and form plaques, one of the disease’s defining features.

Previous observations showed that the liver becomes less effective at removing amyloid beta as it ages. The researchers suspected that the gradual closing of the openings in LSECs might help explain why more of the protein remains in the bloodstream of older animals.

To investigate, they administered cinaciguat to aged rats for two weeks. They then compared the treated animals with two untreated groups, one consisting of older rats and the other of younger rats.

The results were striking. Cinaciguat restored the structure and function of the aging LSECs, reopening their microscopic pores and improving their ability to help clear substances from the blood. Amyloid beta concentrations fell by approximately 50%, reaching levels comparable to those in young rats. The untreated older animals showed no similar improvement.

An Unexpected Drop in Bad Cholesterol

The researchers also measured low-density lipoproteins (LDL), often referred to as “bad” cholesterol because elevated levels contribute to fatty deposits inside arteries. Over time, these deposits can restrict blood flow and increase the risk of heart disease.

Initially, LDL was included as a comparison measure rather than a substance expected to respond to treatment. Unlike larger molecules, LDL particles are small enough to leave the bloodstream without passing through the microscopic openings in LSECs. The scientists therefore expected cinaciguat to have little or no effect on LDL levels.

Instead, they discovered that LDL concentrations in treated older rats also fell to levels observed in young animals.

“We said, ‘Wait, why did that go down? Clearly, there’s more to this story,'” Sam de Leve said.

The unexpected finding suggested that the drug was doing more than simply reopening the liver’s aging filters. It appeared to be restoring another important aspect of liver function.

Because previous research had shown that hepatocytes function better when LSECs are present, the team began examining how these two types of cells communicate.

Their investigation uncovered a previously unknown sequence of biochemical signals that helps coordinate the liver’s ability to remove substances from the bloodstream.

A Hidden Communication Pathway Between Liver Cells

The researchers found that cinaciguat activates an enzyme called soluble guanylate cyclase inside LSECs. This triggers the cells to release a growth factor known as HB-EGF, which sends a signal to nearby hepatocytes.

In response, hepatocytes alter their surfaces in ways that allow them to capture more LDL and amyloid beta from the blood. This helps explain why the treatment reduced both substances, even though they do not rely on the same filtering mechanism.

Normally, aging interferes with the ability of LSECs to release HB-EGF. Cinaciguat restored this signaling process, allowing the liver cells to communicate more effectively and supporting the removal of substances that otherwise tend to accumulate with age.

The discovery identifies a potential new target for future drugs. Rather than focusing exclusively on the physical openings in LSECs, researchers may be able to develop therapies that restore the chemical signals responsible for helping the liver work efficiently.

Could Liver Rejuvenation Help Prevent Alzheimer’s and Heart Disease?

According to the researchers, this is the first study to demonstrate that a drug can fully restore the structure and function of aging LSECs, including their ability to support the clearance of substances from the bloodstream.

It is also the first to show that a treatment directed at the liver can bring age-related elevations in circulating amyloid beta and LDL back to youthful levels.

These findings raise the possibility that cinaciguat, similar medications, or treatments targeting HB-EGF could eventually be used to counteract certain effects of liver aging. If those changes translate into meaningful protection against disease, they could provide new strategies for preventing Alzheimer’s and cardiovascular problems.

For now, however, the findings represent an early step. Lowering amyloid beta in the bloodstream does not necessarily mean that amyloid plaques in the brain will decrease or that Alzheimer’s disease can be prevented.

The researchers plan to continue studying cinaciguat in rats to determine whether its effects on amyloid beta actually translate into measurable protection against Alzheimer’s disease.

They also hope the findings will encourage scientists studying other conditions, particularly atherosclerosis, to investigate how restoring liver function might influence disease development.

“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.”

Study Authors and Funding

Additional researchers involved in the study include Xiangdong Wang, Helia Alavifard and Lily Dara, all affiliated with the Keck School of Medicine of USC.

The research received federal funding from the National Institutes of Health [R56AG071480, 5R01DK100580].