Andrew Verdesca has been studying the aging process since he was an undergraduate. As one of the “few universal human experiences,” the biology of aging has always fascinated Verdesca, who is now a Ph.D. student in Yale’s Graduate School of Arts and Sciences.

“It’s one thing we all do,” says Verdesca, who is part of Josien van Wolfswinkel’s lab in Yale’s Department of Molecular, Cellular and Developmental Biology. “And yet we know so little about it.”

But new research from Verdesca, van Wolfskwinkel, and others offers fresh insights into our understanding of aging — including an unexpected twist. Contrary to popular belief, cellular “wear and tear” is not the only culprit behind age-related decline, they find. It turns out that a breakdown in the body’s “internal positioning system” — which directs cellular location — may play a significant role, too.

Their findings are published in the journal Current Biology.

In the study, researchers focused on the planarian, a small flatworm famous for its long lifespan and its remarkable ability to regenerate. When cut into pieces, each flatworm section can regrow into a complete animal. Thanks to this constant renewal of cells, planarians have been dubbed “nearly immortal.”

But there is one glitch: The worms are only fertile for a few brief months. “It’s really strange,” Verdesca says, “because these animals live for years, if not decades, and the fact that they are able to reproduce for such a short period of time is surprising.”

To unravel the reasons behind this brief reproductive lifespan, the researchers tracked the worms over time, using microscopy to examine reproductive organs and how they aged. They then cut the worms in half to study the mechanisms behind their unique ability to “regenerate.”

“To our surprise, if you took aged, infertile worms that had not produced any offspring for at least a month and cut them in half and let them regenerate and mature, they began to lay offspring again,” Verdesca says.

But the fertility window was still narrow. Examining the worms further, the researchers discovered that the worms don’t become infertile because their reproductive cells and organs wear out. Rather, the problem appears to lie in how their bodies are organized. Over time, the worms’ reproductive systems became increasingly disordered.

Although new, functioning reproductive organs developed in each section of a split worm, over time their positioning changed. Ovaries slipped into the wrong places, for instance. Key cell types were lost, and essential connections between reproductive tissues broke down. The system essentially falls apart.

To Verdesca, this discovery echoed earlier research about the role of “polarity genes,” a set of genes found in many organisms, including humans, that direct which bodily organs need to be made in which locations, effectively creating a sort of “positional identity” map for body parts. Polarity genes are known to play crucial roles in embryonic development but have not been well-studied in the context of aging.

The researchers took a closer look at their aging worms and discovered that positional identity had begun to drift within their bodies, causing organs — especially ovaries — to form in incorrect positions, splitting their functions, and ultimately leading to infertility.

Researchers then took it a step further by altering the polarity genes and the positioning signals they emit. “By artificially altering the levels of the polarity genes we were able to slow down or accelerate the rate at which the flatworms underwent reproductive aging,” Verdesca says.

“These results are amazing because they highlight this previously understudied mechanism that may play a crucial role in the development of age-related pathologies —drift of positional identity.”

The discovery suggests that the effects of aging are not simply the result of damaged cells. Even with the constant cell renewal seen in flatworms, tissues can still fail if their organization breaks down. Resetting this organization could offer a powerful insight into managing age-related decline.

Going forward, van Wolfswinkel, as associate professor of molecular cellular and developmental biology and a member of Yale’s Faculty of Arts and Sciences, plans to follow up on the research.

“We know that planarians can use regeneration to reset their spatial information,” she says, “but further investigation into the causes of positional drift may reveal strategies that other organisms, such as humans, could also use to maintain a youthful state.”