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Using a novel biological aging clock and tissue samples, UCLA researchers find that obesity accelerates aging of the liver

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LOS ANGELES—Armed with a recently developed biomarker of aging known as an epigenetic clock, University of California, Los Angeles (UCLA) researchers working closely with a German team of investigators have discovered that obesity greatly accelerates aging of the liver and increases the odds of developing liver cancer. This finding was published Oct. 13 in the early online edition of the peer-reviewed journal Proceedings of the National Academy of Sciences.
Although it had long been suspected that obesity ages a person faster, it hadn’t been possible to prove the theory until first author Steve Horvath, a UCLA professor of human genetics and biostatistics, developed an epigenetic clock last year. A research team headed by Horvath and Prof. Jochen Hampe, from the University of Dresden in Germany, were able to show that carrying excessive weight can negatively impact select human tissues.
“This is the first study that evaluated the effect of body weight on the biological ages of a variety of human tissues,” Horvath said in a news release about the research. “Given the obesity epidemic in the Western world, the results of this study are highly relevant for public health.”
The idea for the study actually began in 2003 when Horvath downloaded a freely available liver DNA methylation data set from Gene Expression Omnibus, an online repository of data.
“I found a very strong correlation between body mass index (BMI) and epigenetic age acceleration in liver tissue,” Horvath tells DDNews. “I immediately contacted Prof. Jochen Hample in Germany, who was the senior author of this data set. He was happy to collaborate with me and generated additional validation data sets for this project. I also felt that it would be necessary to determine whether a similar effect could be observed in human adipose tissue, which is why I collaborated with several researchers from the Twins UK study: Tim Spector, Jordana Bell and Panos Deloukas.”
“About a year ago, I published an article (at genomebiology.com) that describes a novel biomarker of aging that allows one to measure the age of the vast majority of human tissues, organs and cell types,” he adds. “Recent data have convinced me that the epigenetic clock measures at least some aspects of biological age. Many people have asked me whether caloric restriction or certain diets keep us young. We do not yet know whether the epigenetic age of liver tissue relates to all causes of mortality or even to the onset of various age-related diseases. It is, of course, a plausible hypothesis that the age of the liver should have prognostic and diagnostic utility, but we will need prospective cohort studies to rigorously test these hypotheses.”
Also, it is well known that obese people are more susceptible to certain types of cancer, Horvath notes.
“But we don't quite understand why that is the case,” he adds.  “Our study points to an intriguing explanation. Since age is a major risk factor of many cancers, it would make sense that livers that are older than expected are also at an increased risk of malignant transformation.”
Horvath’s team also studied whether weight loss reverses the epigenetic age of liver tissue.
“Unfortunately, we could not observe a beneficial effect within nine months of bariatric surgery,” according to Horvath. “But it is unclear whether a rejuvenating effect due to weight loss can be observed after a longer follow-up. Incidentally, smoking had no effect on the age of the liver. I don't think our study points to new drugs and therapies for controlling obesity, per se. But it might lead to drugs that control the adverse effects of obesity. If we are lucky, more research would lead to therapies that prevent the increase of biological age due to obesity.”
“What is new in our study is the very strong effect observed in liver tissue: There, we find a strong correlation of 0.42 between BMI and epigenetic age acceleration,” he says. “At this point, only the epigenetic clock can be used to measure the ages of most human tissues and cell types, but there are several alternative epigenetic biomarkers of aging that can be applied to blood tissue.”
According to the Proceedings of the National Academy of Sciences article, Horvath’s theory  includes an aging clock which uses a previously unknown time-keeping mechanism in the body to accurately gauge the age of diverse human organs, tissues and cell types. He and his collaborators focused on a naturally occurring process called methylation, a chemical modification of the DNA molecule.
Horvath used this epigenetic clock to measure the biological age of several tissues in mouse model subjects. The aging clock proved accurate in matching biological to chronological age in lean subjects. But liver tissues from obese subjects tended to have a higher biological age than expected.
In this latest study, Horvath looked at almost 1,200 human tissue samples, including 140 liver samples, to study the relationship between epigenetic age acceleration and body weight. While obesity doesn’t affect the epigenetic age of fat, muscle or blood tissue, he and his collaborators found that on average, the epigenetic age of the liver increased by 3.3 years for every excess 10 body mass index (BMI) units.
For example, a woman who is 5-feet, 5-inches and weighs 140 pounds has a BMI of 23.3. A woman the same height but weighing 200 pounds would have a body mass index of 33.3. Her liver would be about three years older than the woman who weighed 140 pounds, the study found.
“This does not sound like a lot, but it is actually a very strong effect,” Horvath says. “For some people, the age acceleration due to obesity will be much more severe, even up to 10 years older.”
Going forward, Horvath and his team want to determine if the premature epigenetic aging of liver tissue in obese people can be prevented to possibly reduce their risk of diabetes and liver cancer. They plan to work on mouse models that allow them to dissect the exact molecular mechanisms behind this aging process—which is not known at this point—in order to find the right targets for therapy and prevention.
“The increased epigenetic age of liver tissue in obese individuals should provide insights into common liver-related comorbidities of obesity, such as insulin resistance and liver cancer,” the study states. “These findings support the hypothesis that obesity is associated with accelerated aging effects and stresses once more the importance of maintaining a healthy weight.”
The study was funded by the National Institutes of Health, the Virtual Liver Network, the Christian-Albrechts-University Kiel and the University Hospitals Schleswig-Holstein in Dresden, Germany.
Horvath will continue pursuing the research with Hampe, “a leading expert on the epigenomic underpinnings of non-alcoholic fatty liver disease and related complications,” he says. “At this point, it is too early to consider a potential marketing partner. I am looking for collaborators who would be interested in testing whether the epigenetic age of liver tissue is prognostic of adverse health outcomes for liver cancer. I am also looking for collaborators who are interested in developing drugs that prevent accelerated aging effects.”

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