Killing “zombie cells” to stay young

Prof. Jacques Proust

Nescens, Clinique de Genolier

June 3, 2021

The cells in our body renew themselves through cell division; Two daughter cells develop from each mother cell. This division is preceded by a doubling of the cell content: possibly damaged cell components are dissolved by newly synthesized ones, which represents an efficient regeneration mechanism.

The phenomenon of cell division does not go on indefinitely, however, and human cells in culture can only replicate a certain number of times, which is known as “replicative senescence”.

Interestingly, the maximum number of divisions a cell can make decreases as the donor ages. However, there is considerable variability between individuals, and the theory that the number of cell divisions in vitro could reflect the donor’s physiological age and/or life expectancy is clearly incorrect.

When a young cell is damaged or impaired in its function, it stops dividing, activates a suicide program called apoptosis, and disappears from the body without causing an inflammatory response. It is a protective mechanism to prevent defects from being passed on to the daughter cell.

The situation is quite different with senescent cells that appear with aging. Although dysfunctional, these cells are resistant to apoptosis, do not die – hence the term zombie cell – and gradually accumulate in the various tissues of our body. Less than 1% of senescent cells are found in a young laboratory mouse, while the organism of a two-year-old mouse already has more than 20%.

A large number of these senescent cells form a so-called “secretory phenotype”, characterized by the production of various molecules (inflammatory mediators, collagen-destroying enzymes, oxidizing free radicals …) that are directly involved in the aging process itself and/or in the aggravation of those with advanced age pathologies. In addition, these cells contaminate neighboring cells and induce the senescent phenotype in them.

Senescent cells are able to contribute to general as well as local diseases and impairments. Experimentally, the transplantation of a small number of these senescent cells into the tissue surrounding a joint quickly leads to inflammatory phenomena at that joint that are similar to those seen in non-infectious osteoarthritis.

In a broader sense, the activation of transcription factors and genes that are involved in inflammatory mechanisms through the «secretion-forming» senescent cells contribute to chronic inflammation in old age, a phenomenon known as “inflammaging”. The production of free oxygen radicals oxidizes the various components of the neighboring cells and seriously disrupts their function. The release of proteolytic enzymes (metalloproteases) contributes to tissue breakdown and skin aging.

Recent studies show that the secretory phenotype of senescent cells plays an important role in the development of various age-related diseases, such as cancer, diabetes, atherosclerosis, cardiovascular diseases, emphysema, chronic obstructive pulmonary disease, pulmonary fibrosis, osteoarthritis, osteoporosis, disc degeneration, neurodegenerative diseases, macular degeneration, etc.

In mice, numerous studies have confirmed that even with only partial elimination of senescent cells, it is possible to prevent and even treat certain age-related physiopathological symptoms. The treated animals appear rejuvenated, are more physically active, and have a thicker coat. An improvement in kidney function, as well as heart and respiratory capacity and a cartilage repair, are noted. As a result, the average lifespan of these animals also increases by 25%.

In humans, in the near future, the elimination of aging cells will occupy an important place among the various biomedical procedures aimed at slowing down aging or limiting its consequences. One of the therapeutic strategies for eliminating these cells is to make them susceptible to apoptosis again. You can also activate the immune system so that its effector cells specifically destroy the senescent cells. New classes of so-called “senolytic” drugs will soon be included in the anti-aging pharmacopoeia.

However, senescent cells vary from tissue to tissue and have developed multiple strategies to avoid death. It will therefore be necessary to develop senolytic drugs that can specifically counteract these mechanisms. To date, 14 senolytic molecules have been identified.

On the other hand, senescent cells keep reappearing and have to be eliminated regularly, probably once a year, which is why it must be ensured in advance that these drugs do not have any long-term harmful side effects. Clinical studies to test the effectiveness of certain senolytics in various diseases that are classically considered to be age-related are currently in progress.

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