Senolytics – on the crossroads between cancer treatment and longevity

Highlights

• Senescence is a cell life stage when the cell is unable to divide and is resistant to cell death
• Senescent cells can develop a senescence-associated secretory phenotype (SASP) that negatively influences surrounding cells and lead to age-related diseases
• Senolytics are drugs that could remove senescent cells, examples of which are dasatinib and quercetin

Introduction

Anti-aging medicine is a research field focused on providing therapeutic solutions for age-related diseases and conditions. One of the fundamental processes underlying aging is cellular senescence, which leads the cells to stop dividing and start presenting senescence-associated secretory phenotype (SASP), negatively influencing healthy cells around them. Senescent cell numbers increase with age, which is connected with many age-related diseases. Senolytics are drugs that selectively clear senescent cells and are a novel possible strategy of anti-aging medicine for extending the healthspan and lifespan.

Senescent cells and the Senescence-Associated Secretory Phenotype (SASP)

 Senescence is a process that involves the loss of proliferative potential of cells that were able to divide before. Senescence can occur due to many cues. Firstly, in response to exceeding the Hayflick's limit – the maximum number of divisions connected with shortened telomeres (1). This type of senescence is called replicative senescence. Other triggers are e.g., activated oncogenes (oncogene-induced senescence), tumor suppression, genotoxic and oxidative stress, or tissue aging. Both replicative and oncogene-induced senescence are examples of potent mechanisms of tumor suppression due to cell proliferation arrest and their secretory phenotype (2).

Senescent cells are resistant to a type of cell death called apoptosis, have increased metabolic activity, and can develop SASP - a senescence-associated secretory phenotype. Cells with this phenotype release pro-inflammatory cytokines and chemokines as well as proteases that damage tissues. They also secrete hemostatic factors and factors that can impact the function and growth of stem cells and their descendants - progenitor cells. Examples of SASP factors are interleukins, monocyte chemoattractant protein-1, plasminogen-activated inhibitor-1, and many others. SASP expressing cells can have visible pathogenic effects both locally and systemically. It was shown that transplanting senescent cells around the knee joints of mice can induce an osteoporosis-like condition similar to osteoarthritis prevalent in elderly humans (3).

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