25 October 2022

Insidious zombie cells

Scientists have declared the dangers of anti-aging drugs

RIA Novosti, Vladislav Strekopytov

American biologists have found out that cells that have served their time are needed by the body, and getting rid of them is associated with certain risks. In addition, treatment with senolytics — anti—aging drugs that purify aging cells - can give dangerous side effects.

"Elderly" cells

Scientists identify nine main causes of aging. Each is associated with a specific biological mechanism, but all somehow come down to the accumulation of damage at the molecular or cellular level. Age-related weakening of cell activity is called cellular aging. At some stage, cells stop dividing, their energy exchange slows down, the synthesis of RNA and proteins, and the efficiency of DNA repair decreases.

Part of the cells disintegrate as a result of apoptosis — programmed cell death. Others are destroyed by the immune system. But over the years, both mechanisms are acting worse and worse, and spent "zombie cells" accumulate in the body, as they were dubbed by the famous British biogerontologist Aubrey de Grey.

Old cells are called senescent, and the process of their accumulation is called senescence. The danger is primarily that cytokines produced by zombie cells cause systemic inflammation, leading to atherosclerosis, arthritis, arthrosis, various forms of fibrosis, retinal degeneration, Alzheimer's disease. In addition, sometimes due to mutations, these cells suddenly begin to divide again. If the body does not destroy them in time, they can be reborn into malignant and cause cancer.

Anti-aging Pills

Numerous experiments on model organisms show that the removal of aging cells is beneficial and increases life expectancy. There is a whole class of drugs — senolytics that "wash out" such cells and restore tissue health.

This is considered one of the promising approaches in the fight against aging and age-related diseases. By destroying cells that create a toxic environment around themselves, senolytics not only rejuvenate tissues, but also treat cancer, arthritis, heart disease, dementia.

Now several pharmaceutical companies are conducting preclinical and clinical trials of such drugs. The main task is to eliminate the danger of carcinogenesis that occurs if zombie cells, as a result of exposure, again acquire the ability to actively divide. Therefore, the main requirement is that senolytics should also have an antitumor effect, that is, along with senescent ones, oncogenic cells should be removed.


Not only harmful, but also useful

Genetic markers are used to distinguish zombie cells from normal ones. One of the main signs of the cell's transition to the path of irreversible aging is the activation of the p16INK4a gene, which prevents apoptosis. Most senolytics target precisely the cells expressing this gene.

American biologists from the University of California in San Francisco have developed a more effective method of imaging senescent cells. After the fusion of the p16INK4a gene with the green fluorescent protein GFP, a glow occurs in the ultraviolet spectrum.

As a result, scientists saw "markers of aging", including in young healthy cells, for example, in fibroblasts of the basement membrane of the lungs. Fibroblasts are the most common connective tissue cells, and the basement membrane is its thin layer underlying the epithelium. Moreover, senescent cells appear in connective tissue almost immediately after birth, and this has nothing to do with aging.

By observing the action of p16INK4a-positive fibroblasts in the lungs and other organs with barrier functions, such as the small intestine, colon and skin, biologists have established that these cells perform a very important function. Located in the basement membrane next to the stem cells of the epithelium, they transmit a signal to them in case of inflammation or tissue damage. And this triggers regeneration.

Based on this, the researchers suggested that the use of anti-aging drugs is associated with the risk of impaired regenerative function. Conducted an experiment. Mice were exposed to a toxic substance — naphthalene, which causes lung damage, and divided into two groups. In one, animals were given a common combination of senolytics — dasatinib with quercetin, the second was a control.

In those receiving senolytic drugs, healing was slower than in mice from the control group, in which senescent cells stimulated the respiratory tract stem cells to regenerate the epithelium with their secretion. Earlier, American scientists from the Mayo Clinic pointed out that the accumulation of aging cells in the kidneys contributes to the restoration of this organ after injuries, acute damage and chronic diseases.

This means that the zombie cells targeted by anti-aging therapy are also needed. If they are removed indiscriminately, the body loses the ability to restore the barrier that prevents the penetration of foreign cells and harmful chemicals into the body. And this threatens serious diseases — from infections to cancer.

The authors emphasize that all this does not negate the benefits of senolytics, but their action should be selective and not affect the beneficial cells involved in immune processes and regeneration.

Dangerous rejuvenation

There is no clear answer to the question of whether or not to take anti-aging drugs. On the one hand, cellular aging leads to various harmful consequences, including chronic inflammation, immune deficiency and depletion of stem cells. As a result, osteoporosis, metabolic syndrome, type 2 diabetes mellitus, cancer, reproductive aging, atherosclerosis, dementia, glaucoma, chronic kidney disease occur. On the other hand, aging cells play an important role in physiology and homeostasis, especially in embryonic development, wound healing and protection from oncogenesis.

There is no complete clarity with drugs, the long-term effect of which has not yet been studied. In addition to disrupting the function of tissue regeneration, senolytics can give other side effects. Some provoke dangerous changes in the bones associated with the loss of spongy bone tissue, which contains the main organ of hematopoiesis — the red bone marrow. Others, such as navitoclax, can cause neutropenia — leaching from the blood of one of the varieties of leukocytes — neutrophils. Because of this, a person becomes more susceptible to bacterial infections — up to a fatal outcome. Cases of stroke and liver diseases have also been recorded.

Anti-aging therapy should be treated with caution. Senolytics should be prescribed by an experienced specialist based on the individual characteristics of the patient. Otherwise, the harm from them will outweigh the potential benefit.

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