Molecular biologists and bioengineers at UC San Diego isolated two distinct paths that cells travel during the aging process and engineered a new way to genetically program these processes to extend lifespan in yeast cells.
A human lifespan is determined by the aging of individual cells. To understand whether different cells age at the same rate and by the same cause, the researchers studied aging in the budding yeast Saccharomyces cerevisiae, a model for investigating mechanisms of aging, including the aging paths of skin and stem cells.
The scientists discovered that cells of the same genetic material and within the same environment can age in strikingly distinct ways through different molecular and cellular trajectories. The researchers found about half of the cells age through a gradual decline in the stability of the nucleolus —
a region of nuclear DNA where key components of protein-producing "factories" are synthesized. In contrast, the other half age due to dysfunction of their mitochondria, the energy production units of cells.
The cells embark upon either the nucleolar or mitochondrial path early in life, and follow this "aging route" throughout their entire lifespan through decline and death. At the heart of the controls, the researchers found a master circuit that guides these aging processes.
"To understand how cells make these decisions, we identified the molecular processes underlying each aging route and the connections among them, revealing a molecular circuit that controls cell aging analogous to electric circuits that control home appliances," said Nan Hao, senior author of the study and an associate professor of molecular biology.
Having developed a new model of the aging landscape, Hao and his co- authors found they could manipulate and ultimately optimize the aging process. Computer simulations helped the researchers reprogram the master molecular circuit by modifying its DNA, allowing them to genetically create an aging route that features a dramatically extended lifespan.
"Our study raises the possibility of rationally designing gene or chemical-based therapies to reprogram how human cells age, with a goal of effectively delaying human aging and extending human healthspan," said Hao.
The researchers will now test their new model in more complex cells and organisms and eventually in human cells to seek similar aging routes. They also plan to test chemical techniques and evaluate how combinations of therapeutics and drug "cocktails" might guide pathways to longevity.
"Much of the work featured in this paper benefits from a strong interdisciplinary team that was assembled," said Biological Sciences Professor of Molecular Biology Lorraine Pillus, one of the study's co-authors. "One great aspect of the team is that we not only do the modeling but we then do the experimentation to determine whether the model is correct or not. These iterative processes are critical for the work that we are doing."
