Caloric Restriction and Exercise as Natural Senolytics

The inflammation spewed out by our senescent “zombie cells” is thought to be why blood transfusions from older animals worsen the health status of younger animals. Researchers proved cause-and-effect by transplanting senescent cells into mice. All it took were a few. (such that they ended up with about 1 senescent cell per 10,000 normal cells). In young mice the infusion of senescent cells caused persistent age-related physical dysfunction, and in older mice it quintupled their mortality rate.

With causality established and the devasting effects of senescent cells now understood, the research world clambered to find ways to suppress SASP inflammation. But scientists at the Mayo Clinic had a better idea. What if you could treat the cause and simply do away with the senescent cells in the first place?

They had mice genetically engineered with a suicide gene to kill off senescent cells at-their-command. Once the mice reached midlife, the suicide switch was flipped. Despite the successful clearance of only about 30 percent of senescent cells, tumor development and age-related organ deterioration were profoundly delayed. The marked extension of healthspan and lifespan through senescent cell clearance sparked a gold rush to identify “senolytics,” compounds that can eliminate senescent cells. More than two dozen startups jockeyed into position.

Navitoclax was one of the first experimental senolytic drugs to emerge, killing off senescent cells in mice and petri dishes. In people, however, it also kills off nonsenescent cells, leading to a potentially life-threatening loss of white blood cells and platelets in about two out of three study subjects. There has got to be a better way.

How about preventing cellular senescence in the first place? When DNA is damaged beyond repair, cells are understandably forced into stasis before their time (so as not to become cancerous). This is called SIPS, stress-induced premature senescence. We can therefore prevent premature cellular senescence by preventing DNA mutations. We could stop smoking, for example. Current smokers appear to have double the senescent cells as they age.

I have a whole chapter in How Not to Age filled with tips to protect your DNA, but once senescent cells arise, how can you get rid of them? Dietary restriction has been shown to decrease the number of senescent cells in middle-aged mice. What about in people? One can imagine how caloric restriction could prevent cellular senescence by decreasing oxidative stress and improving cellular repair, for example by boosting autophagy. Could it also help eliminate senescent cells?

Internal organ biopsies were taken from late-middle-aged members of the Calorie Restriction Society (average age 62) who had been restricting their caloric intake by about 30% for an average of 10 years. Their tissue samples were compared to those taken from two groups eating regular diets—an age-matched group (average age 62) and a young group (average age 24).

As expected, the older group of regular dieters had significantly higher levels of senescence markers than the younger group, but the older caloric restriction group did not. The restrictors at age 62 had tissue senescence indicators that looked more like the 24-year-olds’. And note they had only been restricting their diets for 10 years, so started on average in their early 50s, suggesting that dietary restriction doesn’t just help prevent cellular senescence but may also help reverse it. As I’ve mentioned before, though, Calorie Restriction Society individuals don’t just tend to eat less food, but better food, which may have also played a role. For example, mice placed on low carb diets suffer accelerated senescence. Most of my chapter on natural senolytics in How Not to Age deals with dietary components, but what about exercise?

Voluntary exercise in mice made obese by a “fast-food diet” helps prevent the accumulation of senescent cells, though it’s not clear if this is due to enhanced elimination or just their prevention in the first place. In human studies, the more people exercise (both in frequency and amount) the fewer senescent cells they tend to have circulating in their bloodstream. You don’t know if it’s cause and effect, though, unless you put it to the test.

Young men got muscle biopsies before and after doing 6 sets of 12 repetitions of squat exercises at 70% of the maximum weight they were able to lift. Within 48 hours the number of senescent cells in their muscle decreased 48% (and ever more so—73%—in those given less protein). A systematic review entitled “Is Exercise a Senolytic Medicine?” concluded that while the optimal or the lowest effective dose of physical activity remains unclear, “the senolytic effect of exercise on senescent cells in humans and animals appears convincing.”