Scientists at UCLA have discovered a group of harmful immune cells that silently accumulate in aging tissues and in the livers of people with fatty liver disease. Removing these cells from the mice sharply reduced inflammation and reversed liver damage, despite continuing an unhealthy diet.
This research natural agingfocuses on cellular senescence, a stress-induced process in which cells stop dividing but do not die. These residual cells, often referred to as “zombie cells,” remain active within the tissue and emit a steady stream of inflammatory signals that can damage surrounding cells.
“Senescent cells are pretty rare, but think of them like a 405 broken down car,” says Anthony Covarrubias, senior author of the study and a member of UCLA’s Eli Edith Broad Center for Regenerative Medicine and Stem Cell Research. “Just one stalled car can back up traffic for miles. Then imagine five or 10 cars slowly accumulating. This is the effect these cells have on tissues. Even a small number can cause tremendous disruption.”
Solving the mysteries of macrophages
Researchers have long wondered whether macrophages, the immune cells that patrol the body and remove debris, can really age. Many believed that such a thing could not be done. One reason for the confusion is that healthy macrophages already exhibit some of the same molecular signatures seen in senescent cells, making it difficult to distinguish between normal and dysfunctional states.
The UCLA team approached this problem by identifying distinct molecular signatures. They found that a combination of two proteins, p21 and TREM2, can reliably mark macrophages that are truly aged and no longer functioning properly, but still cause inflammation in nearby tissues.
Researchers used this marker to observe dramatic age-related changes. In young mice, only about 5% of liver macrophages were senescent. In older mice, that number rose to 60-80%, roughly consistent with the age-related increase in chronic hepatitis.
Cholesterol as an important trigger
Aging is not the only cause of this accumulation. Researchers have found that excess cholesterol can also push macrophages into a senescent state. When healthy macrophages were exposed to high levels of LDL cholesterol in the lab, they stopped dividing, started releasing inflammatory proteins, and displayed the same p21-TREM2 signature.
“Physiologically, macrophages can handle cholesterol metabolism,” said Ivan Saladay Perez, lead author of the new study and a graduate student in the Covarrubias lab. “But when it becomes chronic, it becomes pathological. And when you look at fatty liver disease, which is caused by overnutrition and excess cholesterol in the blood, that excess cholesterol seems to be the main cause of the aging macrophage population.”
This raises the possibility that a diet high in fat and cholesterol accelerates macrophage aging not only in the liver but also in other organs such as the brain, heart, and adipose tissue, accelerating biological aging more broadly.
Eliminating senescent cells reverses liver damage
To test whether removing these cells would improve health, the research team treated mice with ABT-263, a drug designed to selectively remove senescent cells. The effect was dramatic. In mice fed a high-fat, high-cholesterol diet, liver size decreased from about 7 percent of body weight to a healthier 4 to 5 percent. Her weight also decreased by about 25%, from about 40 grams to about 30 grams.
The treated livers were smaller, healthier-looking, and had a normal red color compared to the enlarged, yellowish livers seen in untreated animals.
This result suggests that simply removing senescent macrophages can significantly improve metabolism, even without changing diet. “That’s what surprised me,” Saladay Perez said. “Eliminating senescent cells not only slows the progression of fatty liver disease, but actually reverses it.”
Evidence in human liver disease
To see if this finding applies to people, the researchers analyzed existing genomic datasets obtained from human liver biopsies. They found that the same aging macrophage characteristics were significantly higher in diseased livers than in healthy livers. This suggests that macrophage aging may also contribute to chronic liver disease in humans.
The problem is particularly pressing in Los Angeles, where an estimated 30 to 40 percent of residents have fatty liver disease, and the prevalence is even higher in the Latino community. Treatment options remain limited and early detection tools are still lacking.
“This is a major public health crisis emerging,” said Covarrubias, who is also an assistant professor of microbiology, immunology, and molecular genetics. “Fatty liver disease is occurring in younger and younger people, so we’re really excited to be able to make some progress in understanding what causes fatty liver disease and identifying cell types that may be targeted.”
Aiming for new treatments and broader impact
Although ABT-263 was effective in mice, it is too toxic for widespread use in humans. The research team plans to screen for safer compounds that can selectively eliminate aging macrophages without harmful side effects.
They are also investigating whether similar processes occur in other age-related diseases. For example, in the brain, microglia, the central nervous system’s macrophages, can age when they encounter large amounts of cellular debris in conditions like Alzheimer’s disease.
Common mechanisms of aging and disease
This finding supports the geriatric hypothesis, which proposes that a single process underlying aging can cause multiple diseases. In this case, the accumulation of senescent macrophages can contribute to a variety of conditions, from fatty liver disease to atherosclerosis, Alzheimer’s disease, and cancer.
“If we really understand the fundamental mechanisms that drive age-related inflammation, we could target the same mechanisms to treat not only fatty liver disease, but also atherosclerosis, Alzheimer’s disease and cancer,” said Professor Saladay Perez. “It all comes back to understanding how these cells develop in the first place.”
This research was supported by the National Institutes of Health, the Glenn Medical Research Foundation, the American Federation for Research on Aging, and the UCLA-UCSD Diabetes Research Center.
