We have a good idea of what makes individual cells old. Things like DNA damage, shortened chromosome ends, and a lack of proliferative ability can all cause cells to basically shut down—they don't die, but they stop dividing and become quiescent. But we don't have a strong sense of what makes an organism old. It could be the cumulative effect of lots of their cells getting old, or there may be additional means of registering an organism's age.

Now, a new study suggests at least part of the answer may be a mix of the two. The study, done using mice, indicates that having a small population of cells that have hit the wall due to aging can induce symptoms of age-related decline in otherwise young mice. And a drug combination that targets these cells can block these problems from taking root. The same drugs, when given to elderly mice, also reduce mortality and limit some of the symptoms of age.

Senescent

Cells pick up damage all the time, either through environmental exposures or simply as a byproduct of their normal metabolism. If the damage is sufficiently critical, the cell will respond by committing an orderly sort of suicide called apoptosis, which keeps it from causing any further problems. For lesser damage, there's a less drastic alternative called senescence, in which the cell remains active and contributes its normal functions to the organism's health, but it commits to no longer dividing. Over time, as animals age, more and more cells enter senescence, a process that's thought to contribute to aging.

But it has gradually become apparent that senescent cells don't just continue performing their normal function. They also produce a set of senescence-specific signaling molecules that can influence cells elsewhere in the body, including some that can trigger inflammation. The new work is based on the hypothesis that these signaling molecules might contribute to the changes that are associated with aging.

To test this, a large team of researchers did a relatively straightforward experiment: take senescent cells and implant them in an otherwise young and healthy mouse.

The authors chose fat cells, which typically don't trigger an immune response when transplanted to a new animal. To get lots of senescent cells, they induced DNA damage, using either a drug or radiation (both produced similar results). While it would have been more relevant to obtain senescent cells from an older mouse, this allowed them to obtain lots of the cells they needed to do the experiments.

At various times after the transplant, the team measured a series of physical traits that change with age: average walking speed, muscle strength, endurance on a treadmill, time spent active, food intake and body weight. And while some of these didn't change after the senescent cells were transplanted in, the young mice had clearly lost some strength by a month after the transplant: walking speed, endurance, and grip strength were all down significantly.

This change comes despite the fact that only about one in 10,000 cells in the body were senescent, transplanted cells. Obviously, this suggests that the cells are having an effect by talking to all the healthy ones around them. In fact, the researchers found that the transplanted cells' presence seemed to cause some of the young animal's cells to become senescent, amplifying their effect. Other experiments showed that the transplanted cells had stronger effects if the recipient was older or eating a high-fat diet.

For older mice receiving transplanted cells, one of the consequences was an increased chance of death. Risk of mortality was up by 5.2 fold, and there was no single cause of death or pathology that was increased by a similar amount. Instead, the animals just seemed to be less healthy.

Aging delayed

At this point, the researchers shift focus to what they call a "senolytic agent." That bit of jargon refers to a combination of two chemicals that cause senescent cells to die, possibly by shifting them from the senescence response over into the cell death response. The chemicals in question are quercetin, something found in a huge variety of plants (anyone who eats any vegetables undoubtedly ingests some of this every day). The second is called dasatinib, and you're very unlikely to come across this as part of your diet, since it's normally used as chemotherapy.

The combo of the two chemicals did what you'd expect. If they were administered immediately after the senescent cells were transplanted, the chemicals helped limit the cells' impact on strength and endurance. For mice that were simply aging normally, the two chemicals also helped limit the loss of strength and endurance, and increased the animals' daily activity relative to controls. In addition, the chemicals increased the average lifespan by 36 percent.

Could this work in humans? There's a hint that it might. The researchers obtained fat from obese people in for surgery; this normally contains senescent cells. The researchers confirmed that treating the fat with these chemicals reduced the number of senescent cells present.

Obviously, putting everyone on a chemotherapy drug once they hit 60 isn't going to happen—especially one that has a large collection of side effects like dasatinib. But the authors argue that the chemicals seem to work even if they're given for short courses weeks apart. This, they argue, could avoid most of the side effects. And the mice it was tested on were roughly the equivalent of a 75 year old human, so it seemingly can have positive effects even when given after signs of aging are apparent.

The paper would read a bit like an argument for conducting some safety tests in humans, except it indicates that clinical trials are already ongoing. But it's important to recognize that, even if they're successful, the treatment had no significant impact on a variety of symptoms of aging that the researchers also tested for. So, while senescent cells may be part of the picture, they're far from the whole story on aging.

Nature Medicine, 2018. DOI: 10.1038/s41591-018-0092-9 (About DOIs).