For thousands of years great men such as Alexander the Great and Ponce de León have searched far and wide in their search for the fountain of youth and the hope of eternal life. But where they previously failed, an enterprising group of scientists may have now just succeeded! A report published recently in Science suggests that epigenetic disorganization may be one of the major determinants of human cellular aging, and they also suggest that this disorganization may be reversible. Have we discovered a molecular fountain of youth?
In this new report, researchers from the laboratories of Fuchou Tang, Guang-Hui Liu, and Juan Carlos Izpisua Belmonte studied Werner syndrome (WS), a rapid aging disease caused by mutations in the WRN gene. WS patients display premature aging, with notable defects in mesodermal tissues (bones, veins/arteries, hair, etc.) and so the authors sought to assess epigenetic alterations in the stem cell which gives rise to these tissues – the mesenchymal stem cell (MSCs). To this end, the group generated a WRN-null human embryonic stem cell line (ESC) using helper-dependent adenoviral (HDAd) vectors, and then differentiated these to MSCs.
- Serial passaging of the WRN-null MSCs in vitro induced signs of premature cellular aging which they correlated to:
- Loss of the heterochromatin-associated histone modification H3K9me3 which mediates chromatin compaction and gene silencing.
- Overt changes in heterochromatin structure.
- Further examination found that WRN forms a complex with the major histone methyltransferase for H3K9me3 (SUV39H1) and other factors that control heterochromatin structure (HP1α, and LAP2β).
- SUV39H1 or HP1α loss in wild-type MSCs led to heterochromatin defects and induced cellular aging in a similar manner to that observed in WRN-null MSCs.
- Importantly, HP1α gain upregulated H3K9me3 levels and repressed cellular aging in WRN-null MSCs.
- Assessment of patient samples also found a decrease in WRN, H3K9me3, HP1α, SUV39H1, and LAP2β levels in dental pulp MSCs from older patients as compared to younger patients.
Overall, this excellent study highlights heterochromatin disorganization as a common hallmark for physiological human stem cell aging. With this knowledge in mind, can small molecule drugs which mediate chromatic alterations inhibit or reverse age-related heterochromatic changes and thereby promote proper tissue function and increased longevity? Further studies will hopefully finish this story in the near future, but while you are still young, read this thought provoking paper here Science, April 2015.