Bioinformatics procedure for investigating senolytic (anti-aging) agents: A digital signal processing technique

Area of Science:

• Gerontology and molecular biology.
• Cellular senescence and aging mechanisms.
• Development of therapeutic interventions for aging.

Background:

• Cellular senescence, characterized by irreversible growth arrest and resistance to apoptosis, contributes to aging and age-related diseases.
• Senescence arises from specific molecular interactions, including those involving forkhead (FHD) and transactivation (TAD) domains, and C-terminal region 3 (CR3) with DNA binding (DBD).
• Senolytics and senomorphics are therapeutic strategies aimed at eliminating or mitigating the effects of senescent cells.

Purpose of the Study:

• To systematically analyze intermolecular interactions between senolytics and their molecular targets using a digital signal processing (DSP) approach.
• To evaluate the senolytic (anti-aging) potential of CR3- and FOXO4-based peptides by assessing their ability to disrupt senescence-associated molecular interactions.
• To identify the most effective senolytic candidates for future therapeutic development.

Main Methods:

• Utilized a computerized procedure based on digital signal processing (DSP) and the Informational Spectrum Method (ISM).
• Obtained peptide sequences targeting CR3 and FOXO4 (forkhead box protein O4) interacting proteins.
• Assessed the disruption of interactions between FOXO4 and DRI, and CR3 and BDB (DNA binding domain) by these peptides.

Main Results:

• Peptides exhibited varying senolytic activities based on their binding affinity to CR3/BDB or FOXO4/DRI.
• Enhanced senescence 2 (ES2), a CR3-based peptide, demonstrated higher affinity for CR3/BDB compared to FOXO4/DRI, indicating CR3/BDB interaction is crucial for aging.
• ES2 proved to be a more potent senolytic than DRI, showing 3-7 times greater effectiveness and a weaker interaction with FOXO4, highlighting CR3-based peptides as superior senolytic candidates.

Conclusions:

• CR3-based peptides, particularly ES2, show significant promise as senolytic agents for combating aging and age-related diseases.
• The novel DSP-based technique offers a rational and efficient method for analyzing and optimizing senolytic drug candidates.
• This approach advances gerontology by providing tools to develop interventions that may delay or reverse aging, complementing other therapeutic strategies.