Accelerated Cellular Aging Associated With Mortality Seen in Depressed Individuals

AHA Publisher — Tue, 13 Apr 2021 07:00:25 +0000

Walter Reed Army Institute of Research via EurekAlert – Cells from healthy individuals with major depressive disorder were found to have higher than expected rates of methylation at specific sites on their DNA, when compared to cells from healthy individuals without MDD, according to a study by a multidisciplinary team of Walter Reed Army Institute of Research and University of California San Francisco scientists, in collaboration with others. Methylation is a process by which DNA is chemically modified at specific sites, resulting in changes in the expression of certain genes. Methylation of particular sets of genes, called “DNA methylation clocks,” typically change in predictable ways as people age, but the rate of these changes varies between people. Methylation patterns in individuals with MDD suggested that their DNA methylation cellular age was, on average, accelerated relative to matched healthy controls. In the study, published in Translational Psychiatry, blood samples from 49 individuals with MDD were compared to 60 healthy control subjects of the same chronological age using the ‘GrimAge’ clock–a mathematical algorithm designed to predict an individual’s remaining lifespan based on cellular methylation patterns. Individuals with MDD showed a significantly higher GrimAge score, suggesting increased mortality risk compared to healthy individuals of the same chronological age–an average of approximately two years on the GrimAge clock. The individuals with MDD were unmedicated prior to the study and showed no outward signs of age-related pathology, as they and the healthy controls were screened for physical health before entry into the study. The methylation patterns associated with mortality risk persisted even after accounting for lifestyle factors like smoking and BMI. These findings provide new insight into the increased mortality and morbidity associated with the condition, suggesting that there is an underlying biological mechanism accelerating cellular aging in some MDD sufferers. “This is shifting the way we understand depression, from a purely mental or psychiatric disease, limited to processes in the brain, to a whole-body disease,” said Katerina Protsenko, a medical student at UCSF and lead author of the study. “This should fundamentally alter the way we approach depression and how we think about it–as a part of overall health.” MDD is one of the most prevalent health concerns globally. According to the World health Organization, some 300 million people (4.4% of the population) suffer from some form of depression. MDD is associated with higher incidence and mortality related to increased rates of cardiovascular disease, diabetes, and Alzheimer’s disease among sufferers. “One of the things that’s remarkable about depression is that sufferers have unexpectedly higher rates of age-related physical illnesses and early mortality, even after accounting for things like suicide and lifestyle habits,” said Dr. Owen Wolkowitz, professor of psychiatry and a member of UCSF’s Weill Institute for Neurosciences, co-senior author of the study. “That’s always been a mystery, and that’s what led us to look for signs of aging at the cellular level.” The researchers say that they don’t yet know if depression causes altered methylation in certain individuals, or if depression and methylation are both related to another underlying factor. It is possible that some individuals may have a genetic predisposition to produce specific methylation patterns in response to stressors, but this has not been well-studied. Alterations in methylation patterns have previously been observed in individuals with post-traumatic stress disorder. “These findings will allow us to better understand the relationships between behavioral health disorders–for example, 60% of PTSD cases are co-morbid with MDD. Elucidating these mechanistic and biochemical underpinnings will improve efforts to develop targeted diagnostic and treatment strategies, ultimately improving patient care,” said Dr. Marti Jett, WRAIR chief scientist. Previous research from the group used GrimAge to study men with combat PTSD. Moving forward, the researchers hope to determine whether pharmacological treatments or therapy may mitigate some methylation changes related to MDD in hopes of normalizing the cellular aging process in affected individuals before it advances. Also, although the “GrimAge” methylation clock has been associated with mortality in other populations, no studies have yet prospectively determined whether this methylation pattern also predicts mortality in MDD. “As we continue our studies, we hope to find out whether addressing the MDD with anti-depressants or other treatments alters the methylation patterns, which would give us some indication that these patterns are dynamic and can be changed,” said Dr. Synthia Mellon, professor in the Department of Obstetrics, Gynecology and the Reproductive Sciences at UCSF and co-senior author of the study. To read the original article click here.

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Using Electric Current to Directly Control Gene Expression

AHA Publisher — Fri, 29 May 2020 07:00:46 +0000

ETH Zurich via News-Medical Net – A team of researchers led by ETH professor Martin Fussenegger has succeeded in using an electric current to directly control gene expression for the first time. Their work provides the basis for medical implants that can be switched on and off using electronic devices outside the body. This is how it works. A device containing insulin-producing cells and an electronic control unit is implanted in the body of a diabetic. As soon as the patient eats something and their blood sugar rises, they can use an app on their smartphone to trigger an electrical signal, or they can preconfigure the app do this automatically if the meal has been entered in advance. A short while afterwards, the cells release the necessary amount of insulin produced to regulate the patient’s blood sugar level. This might sound like science fiction but it could soon become reality. A team of researchers led by Martin Fussenegger, ETH Professor of Biotechnology and Bioengineering at the Department of Biosystems Science and Engineering in Basel, have presented their prototype for such an implant in a new paper in the journal Science. Their study is the first to examine how gene expression can be directly activated and regulated using electrical signals. When testing their approach in mice, the researchers established that it worked perfectly. The Basel-based scientists have a wealth of experience in developing genetic networks and implants that respond to specific physiological states of the body, such as blood lipid levels that are too high or blood sugar levels that are too low. Although such networks respond to biochemical stimuli, they can also be controlled by alternative, external influences like light. “We’ve wanted to directly control gene expression using electricity for a long time; now we’ve finally succeeded.” Martin Fussenegger, ETH Professor of Biotechnology and Bioengineering at the Department of Biosystems Science and Engineering in Basel. A Circuit Board and Cell Container Hold the Key The implant the researchers have designed is made up of several parts. On one side, it has a printed circuit board (PCB) that accommodates the receiver and control electronics; on the other is a capsule containing human cells. Connecting the PCB to the cell container is a tiny cable. A radio signal from outside the body activates the electronics in the implant, which then transmits electrical signals directly to the cells. The electrical signals stimulate a special combination of calcium and potassium channels; in turn, this triggers a signaling cascade in the cell that controls the insulin gene. Subsequently, the cellular machinery loads the insulin into vesicles that the electrical signals cause to fuse with the cell membrane, releasing the insulin within a matter of minutes. Coming Soon: the Internet of the Body Fussenegger sees several advantages in this latest development. “Our implant could be connected to the cyber universe,” he explains. Doctors or patients could use an app to intervene directly and trigger insulin production, something they could also do remotely over the internet as soon as the implant has transmitted the requisite physiological data. “A device of this kind would enable people to be fully integrated into the digital world and become part of the Internet of Things – or even the Internet of the Body,” Fussenegger says. When it comes to the potential risk of attacks by hackers, he takes a level-headed view: “People already wear pacemakers that are theoretically vulnerable to cyberattacks, but these devices have sufficient protection. That’s something we would have to incorporate in our implants, too,” he says. As things stand, the greatest challenge he sees is on the genetic side of things. To ensure that no damage is caused to the cells and genes, he and his group need to conduct further research into the maximum current that can be used. The researchers must also optimize the connection between the electronics and the cells. And a final hurdle to overcome is finding a new, easier and more convenient way to replace the cells used in the implant, something that must be done approximately every three weeks. For their experiments, Fussenegger and his team of researchers attached two filler necks to their prototype in order to replace the cells; they want to find a more practical solution. Before their system can be used in humans, however, it must still pass a whole series of clinical tests. To read the original article click here.

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Accelerated Cellular Aging Associated With Mortality Seen in Depressed Individuals

Using Electric Current to Directly Control Gene Expression