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New discovery unveils heterochromatin disorganization as potential driver of human aging

Updated: 2015-05-12

Human aging has become a global issue which brings tremendous challenge and opportunities. As the aged population suffering more from aging related chronic diseases which significantly affect their life quality, “Ageing well” has become a global priority and a challenge to the biomedical research field. Lately, a group of scientists led by Prof. Guang-Hui Liu of the Institute of Biophysics, Chinese Academy of Sciences, reported that they had discovered an important new potential driver of human aging, a finding that could have vast implications for human longevity and the treatment of age-related diseases such as diabetes, Alzheimer's disease, and cancer.

Werner syndrome, also known as adult progeria, is a rare disease with symptoms that mimic premature aging. Patients with this disease usually go gray in their 20s, develop cataracts and osteoporosis in their 30s, and die before 60. In studying the genetic mutations underlying Werner syndrome using a stem cell based disease model, researchers discovered that the disorganization of the cellular heterochromatin might be the cause of the accelerated aging of the disease.

Manifested symptoms of Werner syndrome suggest cellular defects in patients’ mesenchymal stem cells (MSCs), a specialized stem cell type that is the source of fat, cartilage, and bone cells. When the team introduced the WRN gene mutation into human embryonic stem (ES) cells and subsequently differentiated them into MSCs, WRN deficient cells appeared to age more rapidly compared to wild type counterparts. Those cells gradually lost the ability to divide and showed profound signs pointing to a stagnant state known as cellular senescence, such as unregulated inflammation signals and shorter-than-normal telomeres. Previously, enormous efforts studying biological basis of aging had focused on mutations on DNA; however, the new study showed that WRN deficiency in MSCs causeda global loss of H3K9me3 marks and changes in heterochromatin architecture, which are epigenetic alternations well acknowledged with cellular senescence. Further investigation showed that WRN protein associates with heterochromatin proteins SUV39H1 and HP1α and nuclear lamina-heterochromatin anchoring protein LAP2β. Targeted knock-in of catalytically inactive SUV39H1 in wild type MSCs recapitulated accelerated cellular senescence, resembling defects in WRN-deficient MSCs. Even more excitingly, decreases in WRN protein and heterochromatin hallmarks were detected in MSCs samples from old individuals. These new observations uncovered an unprecedented role of WRN in maintaining heterochromatin stability and highlighted heterochromatin disorganization as a potential determinant of human aging. More importantly, though cautious and more extensive studies shall be conducted in the future, the current report suggests a novel possibility to slow down or even reverse human cellular aging by keeping DNA more stably packed together in the cells, which implicates a new hope for anti-aging therapy.

This new discovery has been highlighted by many media reports and commented by influential scientists. Washington Post said, “this work has led to a gold-rush mentality among some entrepreneurs to create "anti-aging pills" or other magic bullets for aging.” "This is a beautiful example of how genomics, human stem cells and the new gene editing technologies conjoin to provide major insights into human disease," said Rick Horwitz, executive director of the Allen Institute for Cell Science, who is on leave from his position as a professor at the University of Virginia.

Professor Guang-hui Liu, a scientist from Chinese Academy of Sciences who is the senior author of the paper and collaborated with researchers from Peking University and Salk Institute (California, USA), reported this new finding in SCIENCE magazine on April. 30th, 2015.


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