Objective: Cell growth involves cell division. This stops after reaching a certain limit. Some cells become inactive and unable to undergo apoptosis (programmed cell death). These cells accumulate at sites of tissue damage or disease, thus accelerating aging. They are called senescent cells. Therapeutic interventions that can either eliminate senescent cells (senolytics) or suppress their harmful effects (senomorphics) have been developed. Senescence (aging) is caused by the inter- and intramolecular interactions between the domains of forkhead (FHD) and transactivation (TAD), as well as C-terminal region 3 (CR3) and DNA binding (DBD). On the other hand, anti-senescent/senolytic (anti-aging) activities are achieved by disrupting these interactions with CR3- and forkhead box protein O4 (FOXO4)-based peptides, such as ES2 and DRI, respectively. In this study, we use a computerized procedure based on digital signal processing to systematically analyze the inter-molecular interactions between senolytics and their targets.
Methods: Informational spectrum method (ISM) is engaged.
Results: We obtained the sequences of the peptides from the interacting proteins of CR3 and FOXO4 and evaluated their ability to disrupt the inter-molecular interactions between FOXO4 and DRI and CR3 and BDB, which are responsible for senescence (aging). Our results show that the peptides have different degrees of senolytic (anti-aging) activity, depending on their affinity for CR3 and BDB, or FOXO4 and DRI. We found that enhanced senescence 2 (ES2) has a higher affinity for CR3 and BDB than FOXO4 and DRI, and that the interaction between CR3 and BDB is crucial for aging. Therefore, ES2 and other CR3-based peptides are more potent senolytics than FOXO4-based peptides. Our findings are consistent with previous studies and reveal new insights into the mechanisms of senescence and senolytics. ES2 is considered the best senolytic candidate, as it is 3-7 times more effective than DRI. We verified that ES2 has a weaker interaction with FOXO4 than CR3. However, the performance of DRI has been noted to depend on its intramolecular interactions and stability. Hence, intramolecular analyses using the digital signal processing-based technique has become very vital and will follow.
Conclusion: CR3-based peptides are promising candidates for senolytic therapy. Senolytics are linear chains of amino acids that can target and eliminate senescent cells, which are cells that have stopped dividing and contribute to aging and age-related diseases. By using this proposed, novel computerized technique that is based on digital signal processing, senolytics can be easily analyzed and optimized for their effectiveness and safety. This provides a more rational approach to enhancing our longevity and well-being by offering interventions that can delay or reverse aging and insights that can advance the field of gerontology. This procedure also will compliment other approaches such as molecular stimulation, etc.
Keywords: C‐terminal region 3; DNA binding; D‐retro‐inverso; digital signal processing; enhanced senescence 2; eterone 1; forkhead box protein O4; forkhead domain; senolytics; senomorphics.
© 2024 The Authors. Aging Medicine published by Beijing Hospital and John Wiley & Sons Australia, Ltd.