What hibernating animals — and cells — can teach us about aging

This article is part of our series on rejuvenation research at Whitehead Institute. Click here to view the entire collection. 

Much of biology is defined by activity: the rapid growth of an embryo, or the adventurous life cycle of a parasite, or the frenzied evolution of cancer cells. But for two Whitehead Institute researchers, there is much to learn by studying periods of rest. 

‘Hibernating’ cells 

Whitehead Institute Member Iain Cheeseman has been studying cell division for nearly 25 years. His work in the past has revealed key proteins in the kinetochore (the structure that enables chromosome segregation). But one very important question in Cheeseman’s lab pertains to cells that aren’t dividing at all. 

“Of the 30 trillion cells in our body, on a given day, about 50 billion of them are dividing, which is a lot,” Cheeseman said. “You have a lot of things you need to replenish every day, like blood or other cells that are lost over time. But that means that 29.95 trillion cells in your body today are not dividing, and some of those cells will not divide ever again.” 

These cells that cannot divide make up tissues such as the brain, the heart, and the muscle fibers. That’s one reason diseases of the heart and brain, as well as conditions such as muscular atrophy, are so hard to treat. 

But there is another class of cells, such as egg cells, liver cells, and some blood cells, that aren’t constantly dividing, but could if needed. Cells in this state are referred to as quiescent, and Cheeseman became fascinated with how they worked.

“A major change happened in our lab five or six years ago where it became really important to think about not only how cells divide, but how they persist,” Cheeseman said. “Some have to persist, not just for a day or a week or a month, but for years. So how do you create a structure and a system such that a cell can exist there, but still be able to divide?”

To study quiescence, Cheeseman turned to one cell type in particular.  “There's a lot of cells that need to hibernate and pause, but the cell in our body that I think is the champion of that is the oocyte,” he said. “Oocytes are made before a human is even born, and then those oocytes have to stay sitting there paused for decades before they are reactivated and used. That's a remarkable thing.”

But while they can remain on pause for decades, there is an eventual end to oocyte’s viability. “There are age-related decreases in human fertility, which can be a challenge in some cases,” he said. “Ultimately, human fertility is related to how effective and faithful cell division in oocytes can be.” 

Cheeseman, alongside former postdoctoral scholar Zak Swartz, found that an essential cell division protein called CENP-A is being constantly turned over in egg cells, allowing them to have fresh, working cell division machinery at the ready if they need it. 

The lab is now investigating methods to rejuvenate the centromeres of aging egg cells. Cheeseman, who was recently named a scholar of the Global Consortium for Reproductive Longevity and Equality, hopes the research will pave the way for treatments that could extend the window of female fertility. 

Overwintering animals 

While Cheeseman is investigating cellular states of rest, Whitehead Institute Member Siniša Hrvatin is studying a more organism-wide type of resting state called torpor. Animals such as birds, bats and some rodents employ torpor as a strategy to survive harsh conditions. To achieve this state, the animals must dramatically drop their metabolisms and body temperatures. 

“Just before I came here, I started wondering whether, if we induce the state of torpor, a kind of hibernation-like state, in animals, does that affect their aging?” said Hrvatin. “And we observed very preliminary but really remarkable results where it looked like certain markers of aging — specifically, these epigenetic clocks — seem to be slowing down dramatically in the animals that are in in torpor.” 

The “epigenetic clocks” include patterns of methylation — a type of genetic control that can activate or deactivate regions of DNA without changing their sequence — that change as an organism ages. “We can try to track those markers in animals that are out of torpor and in torpor, and we see that they are changing a lot more slowly when the animals are in torpor,” Hrvatin said.

Hrvatin hopes to eventually understand the effect of torpor on other physiological markers of aging, including frailty and lifespan. “A lot of those studies are still ongoing and we don't have a clear result there yet,” he said. In the long run, Hrvatin’s research could have applications for inducing similar states of “suspended animation” in humans. 

Cells and animals rest, but science keeps moving 

Cheeseman and Hrvatin’s labs, although they operate on very different scales, are complementary to each other, Cheeseman said. “Our labs have a lot of fun, constructive relationships and similarities,” he said. “There are different axes to this: There’s how an animal is responding to its environment, which is definitely on the Siniša side. Then there’s what hibernation means on a cellular level, which I think is intimately tied with quiescence.” 

Cheeseman hopes the synergy between the labs will continue. “We overlap on a lot of cellular questions, and I know how excited Siniša and his lab are about them,” he said. “I hope that there continues to be a lot of positive overlap.”