UCLA researchers have identified a rogue immune cell population that silently accumulates in aging tissues and in the livers of patients with fatty liver disease. They found that removing these cells dramatically reduced inflammation and reversed liver damage in the mice, even if the mice continued to eat an unhealthy diet.
This research natural agingfocuses on a process called cellular senescence, a stress response in which cells stop dividing but refuse to die. Rather than quietly disappearing, these so-called “zombie cells” remain in tissues and send out a toxic cocktail of inflammatory signals.
“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 cause traffic to back up for miles. Now imagine them slowly accumulating in increments of 5 or 10. That’s what these cells do to tissues, and even in small numbers they wreak havoc. ”
Anthony Covarrubias, University of California, Los Angeles, Health Sciences
Scientists have been debating for years whether macrophages — large immune cells that patrol every tissue in the body, engulfing debris, pathogens, and dying cells — can really age. The prevailing view was that it was impossible. Part of the confusion stems from biology. Even when healthy, macrophages naturally display molecular markers of aging, making it difficult to distinguish between cells that are truly dysfunctional and those that are merely functioning.
The UCLA team solved this problem by identifying a molecular signature of two proteins, p21 and TREM2. These combinations reliably alert macrophages that are truly senescent, i.e., macrophages that are no longer functional but persistently inflame surrounding tissue.
Taking advantage of this feature, the researchers found that the proportion of senescent macrophages in the liver jumped from about 5% in young mice to nearly 60-80% in old mice, closely tracking the increase in chronic liver inflammation during normal aging. However, it turns out that aging is not the only trigger.
Researchers have found that excess cholesterol can also push macrophages into a senescent state. When the research team exposed healthy macrophages to high levels of LDL cholesterol in the lab, the cells developed hallmarks of aging. The cells stopped dividing, started secreting inflammatory proteins, and displayed the characteristic 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 finding raises broader questions that the research team is currently pursuing. The question is whether a high-cholesterol and high-fat diet accelerates biological aging by accelerating macrophage aging across multiple tissues (not just the liver, but potentially the brain, heart, and fat).
Targeting senescent cells to reverse liver damage
To test whether removing senescent macrophages would help, the researchers treated mice with ABT-263, a drug that selectively causes cell death in senescent cells. The results were amazing. In transgenic mice fed a high-fat, high-cholesterol diet, a model for human metabolic liver disease, the drug reduced liver weight from about 7% of total body weight to a healthy 4% to 5%. Their overall body weight also decreased by 25% from an average of 40 grams, returning to their normal level of about 30 grams. The treated livers were visibly smaller and had a healthier red color compared to the enlarged, yellowish and fatty livers of untreated animals.
The results of this study suggest that removing senescent macrophages from the liver is sufficient to produce significant metabolic benefits, even without dietary intervention. “That’s what surprised me,” Saladay Perez said. “Eliminating senescent cells not only slows the progression of fatty liver disease, but actually reverses it.”
To determine whether this finding could be relevant to human disease, the team looked to existing patient data. Analysis of publicly available genomic datasets obtained from liver biopsies found similar senescent macrophage signatures to be significantly elevated in diseased livers compared to healthy livers, suggesting that macrophage senescence is involved in chronic liver disease not only in mice but also in humans.
This discovery has particular urgency in Los Angeles. Fatty liver disease affects an estimated 30 to 40 percent of Los Angeles residents, and the rate is even higher in the Latino community. Currently, there are very few treatment options and limited non-invasive tools to diagnose the condition at an early stage.
“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.”
ABT-263 is effective in mice, but is too toxic for widespread use in humans. As a next step, the research team plans to conduct drug screening studies to identify new compounds that can selectively eliminate aging macrophages without side effects.
The researchers are also investigating whether the same cells play a pathological role in other age-related conditions, such as cancer and neurodegeneration. For example, in the brain, microglia, the central nervous system’s macrophages, may be susceptible to aging in conditions like Alzheimer’s disease, where they are exposed to large amounts of cell debris as neurons die.
The researchers consider their study to be proof of a geriatric hypothesis. The idea is that a single fundamental mechanism of aging, in this case the accumulation of senescent macrophages, may underlie not one but many of the diseases that shorten and shorten human lifespans.
“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.
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University of California, Los Angeles Health Sciences
