Screening of Natural Products for Senolytic or Senostatic Activities on Human Senescent Cells (SenoNPs)

Cellular senescence is a permanent cell cycle arrest in which cells, despite metabolic activity, do not divide further. It's associated with DNA damage, mitochondrial dysfunction, and significant changes in morphology and metabolism, exhibiting a senescence associated secretory phenotype (SASP). [1] Senescence, triggered by various stressors from oncogenic to metabolic, plays an ambivalent role: it initially prevents tumor formation but later promotes tumorigenesis and age-related diseases. The development of therapies targeting this process, such as senomorphics that block SASP secretion and senolytics that remove senescent cells, has gained great attention recently. [2] At the Department of Bioorganic Chemistry (NWC) of the IPB, a library of around 30,000 plant and fungi-derived compounds has been established, with many showing anti-cancer, antifungal, and antibacterial properties. Our project aims to evaluate the effect of 2000 compounds on senescent human fibroblasts. These compounds were preselected using in silico methods.

We induced senescence in primary human fibroblasts (IMR90-ER:RAS) using 4-hydroxytamoxifen and incubated them with different concentrations of the natural products. After 72 h, the cells were fixed and characterized using high throughput imaging and immunoassays of senescence markers p-16 and IL-6.

In this project, we could identify several compounds with senolytic or senomorphic properties. Next, we will investigate their mechanisms by proteomic and metabolomic analysis. Thus, our research not only opens new avenues for the development of therapeutic strategies against age-associated diseases but also provides insights into the mechanisms of cellular senescence.