Exploring the Evolution of Senotherapeutics Across Generations: A New Era in Human Dermal Fibroblast Senotherapy

Abstract

Background: The skin, as the body’s largest organ, plays a crucial role in systemic physiological processes. Dysfunction in the skin, often driven by cellular senescence, accelerates skin aging and contributes to systemic aging. The accumulation of senescent cells and the secretion of senescence-associated secretory phenotype (SASP) factors are central mechanisms underlying skin aging, particularly affecting dermal fibroblasts, which are key producers of collagen and elastin. Given these challenges, skin senotherapy has emerged as a promising strategy to mitigate skin aging by specifically targeting senescent cells. Objectives: The present study evaluates the therapeutic potential of advanced senotherapeutics targeting dermal fibroblasts, which are critical for maintaining skin structure and function. It highlights the integration of cutting-edge technologies, including targeted nanoparticles, chimeric antigen receptor T (CAR-T) cells, artificial intelligence, and gene editing, to address senescent cell heterogeneity and improve outcomes. Methods: Various senotherapeutics, including senolytic agents for eliminating senescent cells and senomorphic agents for modulating SASP, were assessed. Advanced technologies such as nanoparticles, CAR-T cells, and gene editing were evaluated for their ability to enhance targeting specificity and reduce off-target effects. The study focused on their efficacy in targeting senescent dermal fibroblasts and modulating inflammatory markers associated with SASP. Preclinical and in vitro models were used to test these approaches. Results: Advanced senotherapeutics demonstrated significant improvements in selectively targeting senescent dermal fibroblasts while minimizing off-target effects. These therapies effectively modulated SASP, leading to reduced inflammatory markers and an enhanced cellular environment for skin health. By addressing challenges such as senescent cell heterogeneity, these approaches showcased superior precision and efficacy compared to earlier generations, emphasizing their potential in mitigating both skin and systemic aging. Conclusions: These findings highlight advanced senotherapeutics as a promising strategy for addressing skin aging and its systemic implications. Through precise targeting of senescent fibroblasts and effective modulation of SASP, these therapies offer transformative potential for improving skin health and combating broader age-related challenges. The incorporation of cutting-edge technologies, including nanoparticles, CAR-T cells, and gene editing, marks a significant advancement in the pursuit of innovative and effective anti-aging solutions.