Cells die in 2 ways — scientists may have found a life-extending workaround

No buts about it, aging is a journey towards a universal destination: death. Though we all get there eventually, we don't always take the same route.

New research suggests that there are two major highways the body usually takes towards that final destination. Its findings also suggest that, with intervention, we may soon open up a longer, scenic route that could extend the journey.

Ultimately, aging is just a decline in the function of all the bits and pieces within your body. Protective caps on chromosomes shorten, muscle cells struggle to recover from damage, and DNA gains unwanted ornaments.

A study of yeast cells released Thursday in Science shows that cells naturally follow one of two natural aging pathways, which set this domino chain of harmful effects in motion.

The aging pathways appear to hinge on the eventual failure of two organelles within each cell. The first pathway is defined by the slow degradation of the nucleolus in the structure that sits in the middle of the cell's nucleus. The second pathway involves the slow death of mitochondria, structures that help the cell produce energy.

However, the study's senior author Nan Hao, an assistant professor at the University of San Diego, tells Inverse that there may be a workaround that could, in the far future, help scientists reprogram how cells age. His team created a third pathway that allowed cells to live twice as long compared to the other two aging pathways.

"Our genetic perturbations counteract the molecular and cellular declines in either aging route," he tells Inverse.

The two natural aging pathways – This research is focused on a sample Saccharomyces cerevisiae cells, a species of yeast that's commonly used in baking and brewing. The lifespan of a yeast cell is usually measured in how many times it is able to replicate before it loses that ability and "dies."

Those two pathways are defined by differences in gene expression, the actual shape of the daughter cells produced by each cell, and the shapes of the organelles inside each cell, Hao explains. Ultimately, one route produces increasingly long cells until death. The other produces especially round cells until death.

Along the "nucleolus" route of aging, daughter cells tend to become strangely elongated as they divide. As that happens the nucleoli themselves become enlarged and then fragmented, the authors report. The team calls this route of aging mode 1.

Those nucleoli become swollen and fragmented because the genetic material that codes for ribosomal RNA becomes unstable. Ribosomal RNA is one crucial thing that ribosomes (little cellular machines that help make proteins) use to do their job. Unless it is maintained, the interior organization of the cells begins to suffer, the study shows.

The mitochondrial route is responsible for the round cells. As cells age, they continuously produce smaller, rounder daughter cells until death. The team calls this route of aging mode 2.

In those round cells, the scientists found that levels of heme, an iron-capturing compound, decreased as the cells aged. Heme plays a key role in ensuring that mitochondria continue to function normally, and as it declines mitochondrial function tanks.

It appears that cells are about equally likely to follow either path. Approximately 47.3 percent of cells followed the nucleolus route (mode 1) and 52.7 percent followed the mitochondrial route (mode 2), the study reports.

However, they both have one thing in common: as they age, the cell cycle slows down. This suggests that the cell takes longer and longer to divide before it dies. That's something that the third scenic route can combat, Hao adds.

How to take the scenic route – Hao and his colleagues used a computer simulation to predict what might happen if they engineered cells to maintain the integrity of the nucleolus, and make sure that heme levels stay relatively stable over time.

Those changes created a "distinct" third aging route, in which the speed of the cell cycle was similar to that of young, normal cells.

"Finally, it has a dramatically extended lifespan, about twice of that of naturally aging cells," Hao explains.

Ultimately, Hao suggests that this research is one step towards extending lifespan. A human body is composed of trillions of cells. In each and every one, it's possible that this progression towards aging is happening alongside all the different and chaotic processes of keeping a body running.

To extend lifespan, he'll have to see if this pattern he developed holds up when cells have to interact in the wider world of a human body. That's exactly where the lab is headed next.

"In the future, we hope to test our model and findings in more complex cells and organisms, with the ultimate hope of developing intervention strategies to effectively extend human healthspan," Hao says.

Abstract: 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. 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.