[Reading Science] Selectively Removing Senescent Cells... A New Path Opens for Treating Age-Related Diseases

'Senescent Cells' with Halted Tissue Regeneration
Do Not Reactivate Even with External Stimuli, Causing Cancer and Age-Related Diseases
Selective Removal of Senescent Cells Is Challenging
UNIST Research Team Develops Selective Removal Technology

As people age, it is inevitable that various cells, including those in the skin and organs, undergo aging. What if senescent cells could be selectively removed? It is expected that this could present a new vision for preventing and simultaneously treating various age-related diseases.

Cells that make up living organisms, including the human body, cannot proliferate indefinitely. According to data published in 2020 by Dr. Yang-ryeol Yang of the Korea Research Institute of Bioscience and Biotechnology, cells enter an irreversible growth arrest phase after a predetermined number of cell divisions due to a decline in proliferative capacity. This is known as cellular senescence. Senescent cells do not re-enter the cell cycle even when stimulated externally. Tissue regeneration is halted. The persistence of these senescent cells leads to a decline in the function of bodily organs, which is biological aging. No matter how much one cares about health or exercises, biological aging cannot be prevented.

In normal bodily organs, damaged cells are replaced by new cells proliferated and differentiated from stem cells. Senescent cells have a reduced ability to respond to such cellular damage, making normal physiological functions impossible. This is why the accumulation of senescent cells causes bodily aging. Ultimately, the likelihood of developing age-related diseases increases.

What causes cellular senescence? Various external stimuli and stress, known as the "enemy of modern people," are cited. It is known that accumulated cellular damage leads to cellular senescence. Therefore, to prevent or inhibit cellular senescence, factors causing cellular damage must be blocked, but this is easier said than done.

Primary causes at the cellular level include genomic instability, telomere (protective structures at chromosome ends) shortening, epigenetic changes, and loss of protein homeostasis. These factors stimulate cells, reduce nutrient sensitivity, and induce mitochondrial dysfunction (mitochondria are important organelles in eukaryotic cells where oxygen respiration occurs), leading to cellular aging.

According to a paper published in the international journal Nature in December last year by a research team at Pompeu Fabra University in Spain, senescent cells increase sharply after tissue injury with advancing age. Senescent cells induce inflammation and inhibit tissue regeneration. The senescence-associated secretory phenotype (SASP) secreted by accumulated senescent cells induces inflammation and tissue fibrosis, impairing the function of healthy surrounding cells. A representative example is the replacement of healthy skeletal muscle cells with fibrous tissue, leading to sarcopenia.

Cellular senescence occurs through several stages before cells become senescent. When the senescence process is initiated by cellular damage, the cell cycle is arrested by the regulation of proteins such as p53, p16, and p21. In the early stages, chromatin remodeling occurs, cells become flattened and enlarged, mitochondrial metabolism increases, autophagy is enhanced, SASP is expressed, and senescence-associated β-galactosidase (SA β-gal) expression occurs, activating the senescence program.

As humans age, normal cells have an increased likelihood of transforming into cancer cells. To prevent this, cells spontaneously become senescent. This is a natural cellular mechanism. However, the accumulation of senescent cells induces various inflammations and can transform surrounding cells into cancer cells. It is also a cause of age-related diseases. Therefore, attempts to remove senescent cells have continued.

Senescent cells coexist with healthy cells. Therefore, selectively removing only senescent cells has been difficult until now. Although many research institutions have studied the characteristics of cellular senescence and solutions, significant results have been hard to achieve.

Selective removal of senescent cells is called senolytic therapy. It is a solution to delay aging. The challenge lies in finding effective senolytic substances and methods.

◇ Prevention of cancer and age-related diseases by removing senescent cells = The selective senescent cell removal technology developed by Professor Ja-hyung Yoo’s team at UNIST’s Department of Chemistry and Professor Haewon Jeong’s team at Konkuk University is considered a significant advancement in this regard. The teams succeeded in developing a technology that forms artificial proteins inside the mitochondria of senescent cells to selectively remove them. The newly developed technology can selectively target receptors overexpressed on the membranes of senescent cells. Artificial protein complexes can also be formed mediated by reactive oxygen species (ROS), which are expressed at higher levels in senescent cells than in normal cells. Through this process, senescent cells can be selectively removed without adverse effects on normal cells.

The research teams studied methods to target senescent cells for treating age-related diseases. The carbon-based “organic molecules” consist of parts that can form disulfide bonds and parts that can target senescent cells. Disulfide bonds are formed by the oxidation of sulfur atoms, a process that can be promoted by substances such as reactive oxygen species.

Reactive oxygen species are byproducts generated during oxygen utilization, and mitochondria inside senescent cells overexpress these ROS. The overexpressed ROS promote disulfide bond formation, leading to the creation of oligomers?small polymers formed by molecular bonding.

The teams developed a technology to create artificial proteins with a helical structure called an “alpha helix” on the surface through the self-assembly of oligomers. These structures strongly bind to mitochondrial membranes, destroying them and inducing cell apoptosis.

The researchers applied the developed technology to a mouse model with age-related dry macular degeneration by inducing senescent cells. They confirmed that senescent cells were efficiently removed, restoring retinal tissue function to normal levels. They also confirmed selective removal of senescent cells in naturally aged mouse retinal tissues.

Professor Yoo explained, “We confirmed through actual experimental mice that targeting mitochondria in senescent cells induces dysfunction, leading to selective removal of senescent cells. This approach differs from existing anti-aging treatments and will present a new paradigm for treating age-related diseases.”