The secret to preventing or reversing premature aging may be found in a DNA “off switch” that humans share with common yeast, according to new research from the University of Toronto.
In a paper published in the journal Developmental Cell, Professor Karim Mekhail, of the Faculty of Medicine’s Department of Laboratory Medicine and Pathobiology, along with his colleagues, reports that the lifespan of a yeast cell can be impacted by unused DNA near a given cell’s nuclear envelope. And what’s true of simple yeast cells may be true of the human body, too.
The DNA of all cells is encapsulated in a ball-like structure called the nuclear envelope. While most cells in the human body have the same genes, each cell type uses a different set of genes; the genetic information needed to form skin or liver cells are very different. The fraction of DNA not used for a given cell is “switched off” and stored next to the nuclear envelope.
“That way of organizing DNA is consistent, whether we are considering humans or something as small and simple as a yeast cell, so that is crucial for the overall function of cells” said Mekhail, whose lab has identified for the first time that conserved proteins within that nuclear envelope physically anchor the “switched off” DNA – and those physical connections have a role in preserving the number of times a cell can make a copy of its DNA and divide.
“That cellular lifespan underlies our ability to properly regenerate cells and stay young. As that lifespan decreases, the result is we age,” Mekhail said.
Using advanced DNA imaging and yeast genetic tools, Mekhail and his colleagues were able to literally light up and track the “switched off” DNA regions. They found that cells with defective nuclear envelope proteins can “switch on” those DNA regions, which can disrupt gene expression. By bypassing the need for those DNA regions to be physically connected to the nuclear envelope, the researchers were able to switch the “on” regions back “off” and restore normal cellular lifespan.
“This may open the door for therapeutic interventions that correct for these DNA defects and possibly restore normal lifespan in premature aging patients,” Mekhail said. “And what works for premature aging could also be applied to normal aging.”
The researchers are now testing the ability of various drugs and treatments to restore the proper “switched off” state to DNA regions whose release from the nuclear envelope is linked to a shorter lifespan in both yeast and human cells.
Professor Mekhail’s laboratory is supported by a Canadian Institutes of Health Research (CIHR) grant and the Canada Research Chairs (CRC) program.Three members of Mekhail’s laboratory – Janet Chan, Betty Poon, and Jayesh Salvi – first-authored the study and the latter two authors are supported by CIHR graduate scholarships. Professor Andrew Emili of the Department of Molecular Genetics, and his graduate student Jonathan Olsen, are also authors on the study and Emili’s research group is supported by the Canada Foundation for Innovation as well as the Ontario Research Fund.