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MDI Biological Laboratory scientist identifies mechanism underlying ‘inflammaging’
Research by Samuel Beck, Ph.D., links age-related chronic inflammation with disruption of chromatin architecture.
BAR HARBOR – A research team led by Samuel Beck, Ph.D., of the MDI Biological Laboratory has identified disruption of chromatin architecture as the mechanism underlying inflammaging, a chronic, low-grade inflammatory response that has been linked to the chronic diseases of old age, including Alzheimer’s, cancer, diabetes, heart disease, macular degeneration and more, as well as to a shortened lifespan.
While science has long connected a chronic, progressive increase in inflammation with aging, the mechanism by which inflammation leads to aging has been unclear. In a recent paper, Beck demonstrated that this chronic inflammatory status, which has been dubbed “inflammaging,” is caused by disruption of the three-dimensional architecture of the chromatin, which is the part of the cell nucleus containing the chromosomes that carry genetic information in the form of genes.
Specifically, Beck demonstrated that age-related disruption of chromatin architecture leads to the misexpression of CGI- genes, which are genes that are expressed in specific tissues, as opposed to those that are broadly expressed throughout the body. In aging kidneys and hearts, for instance, he found that more than 30 percent of CGI- genes were misexpressed by comparison with young tissues, which leads not only to inflammation, but also to a loss of cellular identity and hence of cellular function.
“We believe the loss of the ability to precisely transcribe genetic information from CGI- genes with age is a hallmark of aging,” Beck said, referencing a seminal 2013 paper that elucidated nine hallmarks of aging. “With further study of the link between CGI- gene dysregulation and the pathogenesis of age-associated diseases, it should be possible to develop therapeutics that delay or ameliorate the degenerative changes that occur with aging, and thus to extend healthy human lifespan.”
The paper, entitled “Misexpression of Genes Lacking CpG Islands Is a Hallmark of Aging,” was recently published in the journal Science Advances. In addition to Beck, who is corresponding author, authors included James Godwin, Ph.D., of the MDI Biological Laboratory; Gary Churchill, Ph.D., and Ron Korstanje, Ph.D., both of The Jackson Laboratory; and Elliot H.H. Youth, a former undergraduate research assistant in Beck’s laboratory from Brown University.
Beck’s research is an outgrowth of his research on Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome, which are rare genetic conditions that have been linked with disruption of chromatin architecture. These diseases are characterized by the appearance of accelerated aging in children (HGPS) and older teens (Werner syndrome). Children who suffer from HGPS, for example, start aging when they are very young and die at an average age of 14.
The majority of Beck’s research was carried out through the large-scale computational analysis of publicly available genomic datasets, a technique that Beck, a computational biologist, calls “extracting knowledge from community wisdom.” The findings were then validated in mouse studies conducted in collaboration with Churchill and Korstanje of The Jackson Laboratory, also located in Bar Harbor, which is the world’s largest center of mammalian genetic research.
“Sam’s discovery represents a major advance in the field of aging biology,” said Hermann Haller, M.D., MDI Biological Laboratory president. “While many theories have been propounded to explain aging, Sam’s research demonstrates that CGI- gene misexpression caused by disruption of chromatin architecture is a common theme. His research provides a unifying theory to explain the age-related degenerative diseases that blight the later stages of life and reduce healthy lifespan for so many.”
The role of chromatin architecture in aging
While every cell carries the genetic blueprint for the entire body, not every gene is broadly translated, or expressed, into proteins that carry out the work of the body. In the language of science, tissue-specific genes are “silenced,” or inactive, in the parts of the body where they are not needed, which is a desirable quality since it isn’t necessary – and may even be harmful – for a gene in the brain, for example, to produce enzymes that are required for the liver to function properly.
In his research, Beck found that the role of chromatin architecture in aging is connected with DNA elements called CpG islands. In mammals, genes containing CpG islands (CGI+ genes), which are broadly expressed, make up about 60 percent of the total and genes lacking CpG islands (CGI- genes), which are expressed only in specific tissues, make up the remaining 40 percent. Whether or not CGI- genes are expressed depends on their location within the chromatin.
When they are inactive, CGI- genes reside in a tightly condensed compartment of the chromatin called the heterochromatin. The high degree of compaction in the heterochromatin inhibits access to the DNA in CGI- genes by transcription factors responsible for executing the genetic program, thus safeguarding them from misexpression. With aging, however, the heterochromatin unravels like a skein of yarn, with the result that previously inactive CGI- genes are aberrantly expressed.
In his paper, Beck showed that various aged tissue types, including brain, heart, kidney, liver and muscle, significantly misexpress CGI- genes. The uncontrolled expression of CGI- genes in contexts in which they should be silenced provides a molecular basis for explaining normal aging as well as inflammaging, which is directly associated with loss of function in organs and tissues, and premature aging diseases such as HGPS and Werner syndrome.
With regard to inflammaging, Beck found that CGI- gene misexpression leads to the secretion of toxic pro-inflammatory chemicals called SASP (senescence associated secretory phenotype) that disrupt intercellular communication and the tissue microenvironment. Because his research showed that SASP is secreted in the absence of cellular senescence, it upends the widely held cellular senescence theory of inflammaging, which holds that SASP is secreted by dying, or “senescent,” cells.
The research also found that CGI- gene misexpression can be suppressed by previously validated anti-aging interventions, which supports the role of CGI- gene misexpression as a driver of aging. Such interventions include calorie restriction, or the reduction of calorie intake without malnutrition; rapamycin, a drug that is under investigation as anti-aging therapy; and heterochronic parabiosis, the so-called “vampire” therapy in which aging mice are rejuvenated by infusions of blood from young, conjoined partners.
By identifying CGI- gene misexpression as the mechanism underlying age-related degenerative disease, Beck’s research ties together various theories of aging and opens the door to the development of drugs that prolong healthy lifespan by protecting, or even restoring, aging chromatin architecture. In collaboration with colleague Jarod Rollins, Ph.D., Beck has identified a family of drugs that is now being studied for its potential to treat neurodegenerative diseases such as Alzheimer’s and Parkinson’s.
Beck’s research also raises the possibility that age-associated CGI- gene misexpression could serve as a novel biomarker of aging, which would be of value in evaluating the efficacy of anti-aging drug candidates, and potentially as well in assessing a patient’s biological age, a measure of cellular and functional health. The early identification of patients vulnerable to age-related degenerative disease could support lifespan-enhancing interventions and promote the adoption of healthy lifestyles.
Beck’s research was supported by grants from the National Institute of General Medical Sciences (NIGMS), an institute of the National Institutes of Health (NIH), grant numbers P20GM103423 and P20GM104318, and a grant from the NIGMS and the National Institute on Aging (NIA), also an institute of the NIH, grant number R01AG068179.
About the MDI Biological Laboratory – We aim to improve human health and healthspan by uncovering basic mechanisms of tissue repair, aging and regeneration, translating our discoveries for the benefit of society and developing the next generation of scientific leaders. For more information, please visit mdibl.org.
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