Micrograph of kidney tissue from a mouse
Kidney tissue from a control mouse that received an injection of saline solution (left) compared with one that got a shot of stem cell–derived extracellular vesicles (right).

Aging is associated with increased frailty, reduced organ function, and an elevated risk of diseases such as cancer and neurodegeneration. In a study published today (October 19) in Science Advances, researchers report that they have temporarily delayed or reversed some of these age-related changes in mice using extracellular vesicles (EVs) derived from younger animals’ stem cells. Just two weeks of treatment increased older mice’s physical strength, triggered signs of regeneration in several tissues, and reduced certain organs’ biological age as measured by epigenetic biomarkers.

The findings add to existing evidence that stem cell–derived EVs might offer a promising therapeutic route for targeting age-related disease, says Paul Robbins, a researcher at the University of Minnesota’s Institute on the Biology of Aging and Metabolism who was not involved in the work. While the mechanisms underlying the reported effects aren’t completely clear, “the fact that short-term treatment had such an effect on multiple parameters of aging . . . was, I think, fairly remarkable and very exciting.”

A number of labs have explored how EVs, which can mediate intercellular communication by transporting microRNAs and other cargo between cells, might alleviate age-associated decline. Scientists are particularly interested in the use of EVs from mesenchymal stem cells, which are well known for their roles in tissue repair and regeneration.

Last year, Robbins’ team reported that treatment with stem cell–derived EVs reduced signs of cellular senescence in vitro and in mice. A handful of early-stage clinical trials are now beginning to investigate the use of these vesicles, sometimes known as exosomes, in patients with age-related diseases. (The US Food and Drug Administration, which has not approved any exosome-based medical treatment, has warned consumers of misinformation about these products and about adverse effects from unauthorized treatments.)

In the current study, researchers at the University of Valencia in Spain extracted stem cells from the fat tissue of young mice. They then harvested EVs produced by the cells in culture and injected them into the tail veins of older mice—once on day 1 of the experiment, and again on day 7.

The beneficial effects of extracellular vesicle treatment seemed to wear off after a month or so.

Two weeks after initial treatment, mice that had received the EV shot were already showing greater strength in behavioral tests compared to animals injected with saline solution. These improvements peaked at around the 30-day mark, with treated mice showing significantly better motor coordination and fatigue resistance than their counterparts.

Other physical features affected by aging, such as fur regeneration, also differed between the groups. After two weeks, most of the treated animals had completely regrown fur in an area that the researchers had plucked before the first treatment, while control animals still had thin patches.

The beneficial effects of EV treatment seemed to wear off after a month or so—at 60 days, there was no obvious difference between the groups’ performances on physical tests, says study coauthor Consuelo Borrás, who researches regenerative medicine in aging and led the work with postdoc Jorge Sanz-Ros.

The team also examined the physiological and molecular effects of the EV shots. One month in, the mice’s kidneys showed signs of regeneration such as cell proliferation, and compared to the tissues of control animals, there was a reduction in inflammatory biomarkers in the kidneys and muscles. Certain tissues also appeared biologically younger as measured by various so-called epigenetic clocks—biomarkers of aging developed by study coauthor Steve Horvath of the University of California, Los Angeles, and colleagues.

See “An Epigenetic Aging Clock for Mice

Matt Kaeberlein, a biogerontologist at the University of Washington in Seattle who was not involved in the work, says that the new study “fits into a larger body of literature going back decades,” including experiments suggesting that connecting the circulatory systems of old and young mice has positive effects on the older animals’ health. “It seems clear that ‘rejuvenating’ factors in young blood and tissues exist and, at least some of these are packaged into EVs,” he tells The Scientist in an email.

However, there are several aspects of the findings that have yet to be explained, he adds, such as variation in how different tissues responded to treatment in the new study. For example, “epigenetic age was positively modified in the kidney and liver, but not in the muscle or the spleen”—differences that “might be important,” he says.

Certain tissues also appeared biologically younger as measured by various so-called epigenetic clocks.

Shin-ichiro Imai, an aging and longevity researcher at Washington University in St Louis who did not contribute to the study, says it would be interesting to see if the mice treated with the team’s approach also received benefits in lifespan or overall activity levels. His group reported in 2019 that certain vesicles circulating in the blood promote physical activity and extend lifespan in mice.

The precise mechanisms underlying the effects reported in the current study are also unclear. Borrás postulates that young mice’s EVs, and specifically the microRNAs they contain, may help restore intercellular communication in tissues that have become damaged with age. Additional analyses of their microRNA data and comparisons with online databases suggested that at least some of the sequences present in the young mice’s EVs target biological pathways involved in tissue development and regeneration.

However, EVs also contain other cargo. Imai’s 2019 study, for example, identified a specific enzyme in circulating EVs that appeared to boost lifespan and physical activity in mice. Borrás says her team is now analyzing the proteins and other components inside mouse EVs. “I think that more than one component [likely contributes to] the effect,” she adds.

There are various hurdles to translating this sort of research into humans. For one thing, there are technical challenges to scaling up production of stem cell–derived EVs, notes Robbins, who consults for the Europe-based regenerative medicine company Unicyte. More pressingly, researchers are unsure of the correct dosage for EV–based treatments in people, although several groups are now digging into that problem, notes Imai, who is named as a co-inventor on a patent related to his group’s 2019 study and is working on translating the findings of the research into the clinic.

In the meantime, studies such as this one help shine light on what exactly drives aging in the first place, Imai says. “No matter what the content is, these EVs are a very important communication tool between multiple organs or tissues,” he says. As this kind of research underlines, “this inter-tissue communication is one of the important keys to understand the mechanism of aging and longevity.”