Summary: A new study reveals blood cell DNA remains steady, even after transplant. The findings shed new light on human aging.
Source: Case Western Reserve University.
Blood cells could hold the key to aging, according to new research out of Case Western Reserve University School of Medicine. In a study published in Aging Cell, researchers found human blood cells have an intrinsic clock that remains steady even after transplant. The researchers say the clock could control human aging and may underlie blood cancers.
Shigemi Matsuyama, DVM, PhD, cell biologist and associate professor of medicine at Case Western Reserve University School of Medicine, led an international team of researchers in studying the clock. The team measured cellular age in blood cells transplanted from healthy donors to leukemia patients, focusing on donor-recipient pairs of very different ages.
“This study is related to the fountain of youth,” Matsuyama said. “We found young blood cells stay young in older people. There was no accelerated aging of young blood cells in an older human body.” Matsuyama’s team found the other direction was also true–blood cells from adult donors transferred to a child stay older. The cells retained their intrinsic age nearly two decades after transplant.
Their inherent steadiness suggests blood cells could be the master clock of human aging, as they are not easily influenced by their environment, Matsuyama said.
The study showed blood cells retain epigenetic patterns in DNA methylation–chemical groups attached to DNA–that can be used to calculate their age. Despite substantial age differences between donor and recipient (up to 49 years), the DNA methylation age of transplanted blood reflected the age of the donor, even after many years of exposure to the recipient’s body, wrote the authors. Said Matsuyama, “DNA functions as a timekeeper of our age.”
DNA methylation as a predictor of age was first described in 2013 by Matsuyama’s collaborator on the study, biostatistician Steve Horvath, PhD, of the University of California, Los Angeles. “He found the formula. The mechanism, and whether cells in the body synchronize DNA methylation age, wasn’t clear,” Matsuyama explained. “I’m not a mathematician. I’m a cell biologist. So, we collaborated to investigate the mechanism of the epigenetic clock in an experimental system in my lab.”
Matsuyama tested blood samples collected regularly as part of transplant monitoring, with help from the Case Comprehensive Cancer Center. He expanded his sample repository via leukemia researchers at the University of Oslo, in Norway, who heard about his work at the 2016 Keystone Symposia on aging held in Santa Fe, New Mexico. Horvath crunched cellular ages using 353 distinct methylation sites found on blood cell DNA.
Together, the researchers provided the first experimental evidence that the aging clock of blood cells is cell-intrinsic, and not set by interactions with other cell types in the body.
They are now working to identify mechanisms that can change the clock. “In cancer cells, the clock is broken,” Matsuyama said. DNA methylation patterns are unstable in cancerous blood cells and often show odd aging–200 or 5 years old in a 50 year old patient, for example. “It does not match at all with the actual age.” Matsuyama cautions that this is why, although it may sound appealing, he doesn’t yet recommend “therapeutic” cell infusions to try to maintain one’s youth.
“We don’t know if blood cells serve as a master clock that could synchronize other cells. We just don’t know yet,” he said.
Instead, Matsuyama’s team is working to understand why epigenetic age differences exist in cancer cells, and how they could be overcome. “It may be by turning on or off certain genes within the cells, we can reset the clock.”
Recent studies show the DNA age of human cells can be used as a biomarker to predict the risk of age-associated diseases, such Alzheimer’s disease, cardiovascular disease, and others. Last year, Horvath and Matsuyama helped publish an article reporting that DNA age is significantly accelerated in Progeria patients who suffer from premature aging. Matsuyama and his colleagues now have several studies underway to uncover the mechanism of age-dependent DNA methylation, and to understand how factors such as diet, exercise, and oxygen levels influence epigenetic clocks.
Funding: This work was supported by the National Institutes of Health.
Source: Ansley Gogol – Case Western Reserve University
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Original Research: Open access research for “Epigenetic age is a cell‐intrinsic property in transplanted human hematopoietic cells” by Arne Søraas, Mieko Matsuyama, Marcos de Lima, David Wald, Jochen Buechner, Tobias Gedde‐Dahl, Camilla Lund Søraas, Brian Chen, Luigi Ferrucci, John Arne Dahl, Steve Horvath, and Shigemi Matsuyama in Aging Cell. Published February 2 2019.
Epigenetic age is a cell‐intrinsic property in transplanted human hematopoietic cells
The age of tissues and cells can be accurately estimated by DNA methylation analysis. The multitissue DNA methylation (DNAm) age predictor combines the DNAm levels of 353 CpG dinucleotides to arrive at an age estimate referred to as DNAm age. Recent studies based on short‐term observations showed that the DNAm age of reconstituted blood following allogeneic hematopoietic stem cell transplantation (HSCT) reflects the age of the donor. However, it is not known whether the DNAm age of donor blood remains independent of the recipient’s age over the long term. Importantly, long‐term studies including child recipients have the potential to clearly reveal whether DNAm age is cell‐intrinsic or whether it is modulated by extracellular cues in vivo. Here, we address this question by analyzing blood methylation data from HSCT donor and recipient pairs who greatly differed in chronological age (age differences between 1 and 49 years). We found that the DNAm age of the reconstituted blood was not influenced by the recipient’s age, even 17 years after HSCT, in individuals without relapse of their hematologic disorder. However, the DNAm age of recipients with relapse of leukemia was unstable. These data are consistent with our previous findings concerning the abnormal DNAm age of cancer cells, and it can potentially be exploited to monitor the health of HSCT recipients. Our data demonstrate that transplanted human hematopoietic stem cells have an intrinsic DNAm age that is unaffected by the environment in a recipient of a different age.