Electrical pulses reverse aging in sea squirts, offering clues for extending human longevity

In brief:

• Stanford researchers found that brief pulses of electrical current can dramatically reverse stem cell damage in sea squirts and significantly extend their lifespans.
• The treatment triggers a two-phase molecular response the researchers call "reboot and rebound," mirroring what happens in the human body after vigorous exercise.
• The findings could point toward new approaches for slowing age-related decline in humans, treating infertility, and boosting the resilience of marine species facing warming, more acidic oceans.

WATCH RELATED VIDEO: https://www.youtube.com/shorts/-UsDenwm5DM

A tiny sea creature might hold the secret to reversing the aging process. When treated with a brief series of electrical pulses, sea squirts experience dramatic and long-lasting health improvements that can significantly extend their lifespans, according to a new study by researchers at Stanford and other institutions. 

The findings, published this week in PNAS, open new possibilities for protecting marine species from warming waters, learning what causes stem cells in our own bodies to degrade, and potentially finding new ways to use these cells to treat medical conditions.

“This treatment recharges stem cells,” said study co-senior author Ayelet Voskoboynik, an assistant professor of biology in the Stanford School of Humanities and Sciences. “Understanding this mechanism is the key to unlocking how we might one day slow stem cell aging and trigger rejuvenation pathways.” 

Spineless, gelatinous creatures that resemble tiny, brightly colored flower petals, sea squirts don't look much like humans, but they share about 70% of our genetic material, the legacy of a common ancestor from roughly 500 million years ago. 

Researchers commonly study sea squirts to answer questions about human immune systems and stem cells for several reasons. They rebuild all their body tissue about every week, making stem cell activity easy to observe. They also share about 70% of our genetic material, and they naturally form fusions with related colonies, creating a living laboratory for studying how the immune system distinguishes self from non-self. Research on these fused colonies helped launch the entire field of stem cell competition — a process now known to play a key role in human aging and disease. The only constant across all those cycles of weekly renewal is a population of stem cells — the body's master builders, capable of copying themselves and maturing into whatever cell types the body needs.

So, in a sense, sea squirts only really grow old – or show signs of aging – when their stem cells do. Researchers at Stanford's Hopkins Marine Station have been studying this process in the lab for more than 20 years, tracking changes across more than a thousand cycles of regeneration.

Rebooting the body

In 2020, amid nationwide COVID lockdowns, study co-senior author Jos Domen set out to help his teenage daughter and study coauthor, Erica Domen, find a science project to work on. Jos, a senior scientist in stem cell operations at the Stanford School of Medicine, thought it might be interesting to see how a pacemaker affected the tiny hearts of a colony of sea squirts – a species he had observed under a microscope before. Domen’s wife and study senior co-author, Kimberly Gandy, a congenital cardiac surgeon, suggested using a pacemaker often employed for heart surgeries. 

Every individual in a colony has its own heart, so many tiny hearts are working together to keep blood flowing in the colony's shared circulation. Observing these tiny hearts under the microscope led to the hypothesis that boosting or better coordinating their pace might affect the colony’s cycle and growth.

As the pacemaker’s electrical pulse increased, the sea squirt colony's heart rates sped up, and blood moved more freely through their systems. Within 48 hours, the colony looked healthier overall. In the days following treatment, the individual sea squirts grew larger and lighter in color. They were visibly rejuvenated. The sea squirts also grew faster and became more fertile, both of which are characteristic of youthful physiological states.

"Something very unexpected is happening here," Jos remembered thinking at the time. 

Working with other colleagues, Voskoboynik and the Domens repeated the experiment until they found a sweet spot of minimal stimulation – three rounds of five-minute pulses – and maximum beneficial health impact. They found that the treatment caused the sea squirts to shut down gene activity and then ramp up it back up.

By analyzing gene expression immediately following treatment and 24 hours later, the researchers saw that the pulse led to a "reboot and rebound” of many genes. They documented that some of the same genes impacted in sea squirts are those impacted in people after a hard workout or a long run – signs of stress and inflammation followed by signs of strengthening and repair.

Longer lives

Sea squirts rarely live more than a few months in the wild but can live for years in a lab with proper care. The 15 minutes of electrical stimulation the researchers applied to a sea squirt colony in a lab produced changes that lasted at least four months, acting directly on the stem cells that drive aging. When repeated over time, the process had similar effects for over four years, at which point the long-lived colony died. 

Sea squirts old and young enjoyed similar long-term rejuvenation from the process. 

The researchers hypothesize that the dramatic effects may be a product of the electrical current’s impact on the sea squirts’ mitochondria and metabolism, systems likely essential for physical rejuvenation. Just as an external electrical current can shock a stalled human heart back into a regular sinus rhythm, a precisely tuned bioelectric pulse can act like a jumper cable to rejuvenate a depleted mitochondria. The study suggests a model where the treatment “retrains” these networks to be more efficient, a process that could block “bioenergetic decline that typically characterizes aged biological systems.”

Small, wireless devices could one day deliver the same kind of electrical boost to coral reefs, boosting marine organisms’ immune systems to make them more resilient to warmer, more acidic waters, according to the researchers.

“An obvious question is whether this can be applied to humans,” said Jos. “This would take a different form than the sea squirt experiments and would focus on specific cell populations, like blood stem cells that can be stimulated in a similar way.”

The researchers are buoyed by the fact that the electrical stimulation regimen used in the study has been used in people for years to regulate heart rhythms. 

“This has huge potential for improving the survival of stems cells in people, treating fertility, and a range of other applications,” Gandy said. “There’s no reason for us to believe this would not be possible in humans. There is a clear pathway to get to clinical application.”

The researchers plan to continue these studies, aiming to understand the exact mechanisms through which electrical stimulation drive rejuvenation.

Erica Domen is an undergraduate student at the University of California, Berkeley. Study co-senior authors also include Irving Weissman, the Virginia & D.K. Ludwig Professor of Clinical Investigation in Cancer Research, a professor of pathology, and a professor of developmental biology at the Stanford School of Medicine; and Debashis Sahoo of the University of California, San Diego. Additional Stanford coauthors include Tom Levy, an instructor at the Institute for Stem Cell Biology and Regenerative Medicine in the Stanford School of Medicine; Karla Palmeri and Katherine Ishiszuka, research scientists in the biology department at Hopkins Marine Station; Chiara Anselmi, a postdoctoral fellow at Hopkins Marine Station; and Thomas Rolander, a research engineer at Hopkins Marine Station. Additional coauthors are from the University of California, San Diego and the Chan Zuckerberg Biohub SF.

The study was funded by the National Institute on Aging; the Wu Tsai Human Performance Alliance at the University of California, San Diego; the Chan Zuckerberg San Francisco Biohub; a Gruss Lipper Postdoctoral Fellowship; a Big Ideas for Oceans grant from the Oceans Department and the Stanford Woods Institute for the Environment in the Stanford Doerr School of Sustainability; Bio-X; and the ISCBRM Collaborative Seed Grant Program of the Stanford Institute for Stem Cell Biology and Regenerative Medicine.