Young Again: How One Cell Turns Back Time

With every birth, cells begin anew.
Scientists have found a biological
mechanism underpinning the process
in worms, which one day may be
harnessed to restore our own damaged cells.

None of us was made from scratch. Every human being develops from the fusion of two cells, an egg and a sperm, that are the descendants of other cells. The lineage of cells that joins one generation to the next — called the germline — is, in a sense, immortal.

Biologists have puzzled over the resilience of the germline for 130 years, but the phenomenon is still deeply mysterious.

Over time, a cell’s proteins become deformed and clump together. When cells divide, they pass that damage to their descendants. Over millions of years, the germline ought to become too devastated to produce healthy new life.

“You take humans — they age two, three or four decades, and then they have a baby that’s brand new,” said K. Adam Bohnert, a postdoctoral researcher at Calico Life Sciences in South San Francisco, Calif. “There’s some interesting biology there we just don’t understand.”

On Thursday in the journal Nature, Dr. Bohnert and Cynthia Kenyon, vice president for aging research at Calico, reported the discovery of one way in which the germline stays young.

Right before an egg is fertilized, it is swept clean of deformed proteins in a dramatic burst of housecleaning.

The researchers discovered this process by studying a tiny worm called Caenorhabditis elegans. The worm has been a favorite of biologists for 50 years because its inner workings are much the same as our own.

C. elegans relies on many of the same genes that we do to control the division of cells, for example, and to program faulty cells to commit suicide.

In 1993, Dr. Kenyon discovered that a gene called daf-2 greatly influenced the life span of these worms. Shutting down the gene more than doubled the worm’s lifetime from 18 days to 42 days.

That finding, which Dr. Kenyon made while a professor at the University of California, San Francisco, led to the discovery of an entire network of genes involved in repairing cells, allowing animals to live longer. Humans depend on similar genes to repair our cells, too.

“Cynthia really pioneered the field of aging and rejuvenation using C. elegans,” said Irina M. Conboy, a biologist at the University of California, Berkeley.

The longest-lived mutant worms savored only an extra few weeks of life, but their germlines kept rolling along from one generation to the next.

Dr. Kenyon’s curiosity about the germline’s secrets was sharpened in 2010 by a study by Jérôme Goudeau and Hugo Aguilaniu, two biologists then at the University of Lyon in France. (Dr. Goudeau now works at Calico.) They took a close look at the proteins in the worm’s egg-like cells, called oocytes.

Most C. elegans are hermaphrodites, producing both eggs and sperm. As the eggs mature, they travel down a tube, at the end of which they encounter sperm.

Dr. Goudeau and Dr. Aguilaniu discovered that a worm’s eggs carry a surprisingly heavy burden of damaged proteins, even more than in the surrounding cells. But in eggs that were nearing the worm’s sperm, the researchers found far less damage.

Dr. Goudeau and Dr. Aguilaniu then ran the same experiment with a twist. They mutated a gene in the worms, leaving them unable to make sperm. The eggs in these entirely “female” worms were filled with damaged proteins and did not get repaired.

These experiments raised the possibility that the sperm were sending out a signal that somehow prompted the eggs to rid themselves of damaged proteins. In 2013, Dr. Kenyon and Dr. Bohnert set out to test that possibility. (They moved the research to Calico in 2015.)

Clumping proteins are involved in many diseases of old age, such as Alzheimer’s. Dr. Kenyon and Dr. Bohnert set up an experiment using a special strain of worms in which clumping proteins glowed.

 NYTimes