Running or a senolytic drug pair kept aging mouse hearts younger, but together they did no better

As the years go by, some of our cells stop dividing for good but don't die. These senescent cells build up in many organs, including the heart, where they carry DNA damage and can release inflammatory signals. Scientists suspect they help make the aging heart stiffer and weaker.

There are two broad ideas for fighting them. One is senolytics, drugs that make senescent cells self-destruct while sparing healthy ones. The best-studied pair is dasatinib, a prescription cancer drug, and quercetin, a plant compound (together called D + Q). The other idea is plain aerobic exercise, which seems to have a similar “clean-up” effect in muscle. A team at McMaster University in Canada asked what happens in the heart when either is used for a long time, starting before old age, and whether the two together work better than either alone.

What they did

The researchers took mice aged 12 months, roughly middle age for a mouse, with equal numbers of males and females, and randomly split them into four groups of 20:

• a control group that got only the liquid the drugs were dissolved in;
• an exercise group that ran on a treadmill for 30 minutes twice a week;
• a senolytic group that got D + Q by mouth, on and off (every other week);
• a group that got both.

After nine months, when the mice were 21 months old (the start of old age), the team checked heart function with ultrasound, carried out by staff who didn't know which group each mouse was in. They then stained heart tissue for three common markers of senescence, the proteins p16 and p21 and a sign of DNA damage called γ‐H2AX. They counted marked cells among cardiomyocytes, the beating muscle cells, and among the smaller cells that sit between them. Ten young mice (4 months old) served as a reference. By the end, 12, 11, 15 and 16 mice remained in the four groups.

What they found

• Fewer senescent heart cells. All three treatments lowered the share of cells carrying the markers. For example, about 41 in every 100 muscle cells carried p16 in the control mice, against about 29 to 32 in the treated groups. For p21, the drop was 42 to 48% compared with controls. Most markers stayed higher than in young mice, though.
• A heart that relaxes better. In the control mice, the pause in which the heart muscle relaxes before refilling was about 40% longer, and an overall score of heart-muscle performance about 44% worse, than in the next-worst treated group. All three treated groups did significantly better than the controls, in some cases reaching the levels of the young mice. Exercise alone also improved a classic measure of how well the heart fills.
• Pumping strength barely changed. The share of blood pushed out with each beat trended lower in the controls but the difference was not statistically significant.
• No bonus from combining. Running plus D + Q was no better than either one alone on any measure.
• Mice with more marked cells had worse heart function, a correlation across all the animals.

What to keep in mind

• These are mice. Nothing here shows that exercise or senolytics do the same in human hearts.
• No single marker proves a cell is senescent. The team used three markers to be confident, but says it could not truly identify senescent cells, and looked only at muscle cells and the cells between them, not at specific types such as immune cells.
• The whole-heart picture was weaker. When the researchers ground up whole hearts, levels of p16 and p21 were higher in old than in young mice, but no treatment lowered them significantly. Typical inflammatory signals from senescent cells did not rise with age or change with treatment, in the heart or the blood.
• Possible downside of the drugs. Only exercise improved the filling measure; the senolytic groups did not. The authors raise the possibility that giving D + Q early might remove some heart muscle cells, which barely regrow, and say timing needs more study.
• The mice stopped at 21 months, which the authors note may be too early to see the full effects of old age. Groups were also fairly small, and some mice dropped out over the nine months.
• Dasatinib is a prescription cancer drug with real side effects. This study gives no basis for anyone to take it.

Why it matters

Most earlier senolytic studies treated mice that were already old, for a few weeks. This one tested long-term use starting in middle age, as prevention, and put exercise side by side with the drugs. The result that treadmill running did about as well as the drugs in the heart fits a growing idea that exercise has its own “senolytic-like” effect. That the two did not add up suggests they may act on the same pool of cells, a question the team says future work needs to sort out. For now it is a clean, careful mouse experiment, not a recipe.