New senolytic

The substance from grape seeds was suggested to be used against aging

Polina Loseva, N+1

Chinese and American scientists have discovered another substance that can kill aged cells in the body. This is procyanidin C1, there is a lot of it in grape seeds, but it is also found in extracts of cinnamon, cocoa and apple peel. It turned out to be non-toxic to healthy cells, and also extended the life of even very elderly mice. The study is published in the journal Nature Metabolism (Xu et al., The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice).

Gerontologists consider aged, or senescent, cells to be one of the causes of aging. This is a state into which a cell can come in different ways — for example, under the influence of severe stress (poisoning or inflammation), under the burden of mutations that have arisen, or after a large number of rounds of division. Senescent cells are not able to divide, but they do not die either. Instead, they secrete a group of proteins collectively called SASP, which trigger tissue rearrangement and inflammation. And this, in turn, can damage neighboring, healthy cells — and they, too, will age rapidly.

This cause of aging could be dealt with if we learn to selectively destroy senescent cells inside tissues. In 2016, scientists conducted the first such experiment — and indeed, the life expectancy of experimental mice has increased. However, in this work, the researchers genetically modified mice to make their senescent cells particularly sensitive to a particular drug. It is impossible to transfer such a technique to people directly, therefore, the search for drugs that by themselves would act only on senescent cells began. Such medications are called senolytics.

In recent years, several senolytics have been found. Among them there are antitumor drugs (for example, dasatinib), and long-known medications (heart stimulant ouabain), and dietary supplements (fisetin, which is contained, for example, in strawberries). Some of their combinations began to be tested on humans — and it turned out that they can really destroy senescent cells in vivo. But the clinical effect of such treatment has so far turned out to be insignificant.

Perhaps the fact is that not all senolytics work well on different types of senescent cells (which have come to this state in different ways and in different tissues). Or they do not work effectively enough in small concentrations — and in large ones they can be toxic. Therefore, Xu Qixia (Qixia Xu) from the Shanghai Institute of Nutrition and Health and a group of scientists from China and the United States went in search of new senolitics.

They took a culture of human prostate cells and treated them with bleomycin (a genotoxic drug for chemotherapy), as a result of which the cells turned into senescent. Then 46 herbal preparations were tested on them. Five worked best against senescent cells: four — known senolytics (including quercetin and fisetin), and another — grape seed extract. It turned out that in high concentrations it kills up to 80 percent of senescent (but not ordinary) cells, and in small concentrations it blocks the release of SASP. Thus, it turned out to be not only a senolytic, but also a cenomorphic (that is, reducing the effect of senescent cells).

To find out which of the components of grape seeds has this effect, the authors of the work disassembled them into separate substances. Procyanidin C1 (PCC1) was found among them — a substance already known for its ability to damage DNA. It was tested on different types of senescent cells — and it turned out that it triggers programmed death in the cells of the lungs, blood vessels and connective tissues, regardless of how they were turned into senescent.

The researchers then tested PCC1 on mice. They were implanted with ordinary or senescent fibroblasts that expressed luciferase (that is, they were able to glow), and then they were given either a placebo or procyanidin — and in the latter case, the intensity of the glow decreased several times.

Mice after injection of healthy (left) and senescent (right) cells. Some got a placebo (vehicle), others got a senolytic (PCC1). The more yellow and red, the more luciferase glows and the more transplanted cells are alive. Figures from the article by Xu et al.

In addition, PCC1 also improved the physical condition of mice. Usually, a month after the transplantation of senescent cells, the body weakens: mice begin to run slower and can hang less by holding on to the crossbar. But in animals that were injected with procyanidin within a week after transplantation, this deterioration did not occur.

Finally, the authors of the work tried to improve the condition of elderly mice with the help of a new senolytic. They injected PCC1 once every two weeks to animals aged 24 to 27 months (this is about 75-90 years in humans) and noticed that the rest of life in mice increased by 64.2 percent compared to their peers. At the same time, physical activity remained the same, and the causes of death did not change.

The survival curve of control mice (red) and those receiving senolytic (blue).

Thus, the newly discovered senolytic turned out to be not only safe for healthy cells, but also effective for different types of senescent ones. Nevertheless, the authors of the study admit that they have yet to find out in detail what mechanisms PCC1 extended the life of mice. They do not exclude that procyanidin got into different tissues in different concentrations and somewhere worked as a senolytic, and somewhere — as a cenomorphic. In addition, this does not mean that it will also effectively manifest itself in humans — however, researchers expect that it is devoid of many shortcomings that prevented its predecessors.

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