Researchers at the University of California San Diego Say they have unraveled key mechanisms behind the process of aging. They isolated two distinct paths that cells travel during aging and engineered a new way to genetically program these processes to extend lifespan.

Their study, “A programmable fate decision landscape underlies single-cell aging in yeast” appears in Science.

“Chromatin instability and mitochondrial decline are conserved processes that contribute to cellular aging. Although both processes have been explored individually in the context of their distinct signaling pathways, the mechanism that determines which process dominates during aging of individual cells is unknown,” write the investigators.

“We show that interactions between the chromatin silencing and mitochondrial pathways lead to an epigenetic landscape of yeast replicative aging with multiple equilibrium states that represent different types of terminal states of aging. The structure of the landscape drives single-cell differentiation toward one of these states during aging, whereby the fate is determined quite early and is insensitive to intracellular noise.”

“Guided by a quantitative model of the aging landscape, we genetically engineered a long-lived equilibrium state characterized by an extended life span.”

Our lifespans as humans are determined by the aging of our 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, their fates unfolding through different molecular and cellular trajectories. Using microfluidics, computer modeling, and other techniques, they found that about half of the cells age through a gradual decline in the stability of the nucleolus, where key components of protein-producing factories are synthesized. In contrast, the other half age due to dysfunction of their mitochondria.

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, PhD, senior author of the study and an associate professor in the Section of Molecular Biology, Division of Biological Sciences.

Having developed a new model of the aging landscape, Hao and his coauthors 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 a novel 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, PhD, one of the study’s coauthors. “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.”

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