Characterisation of novel Markers role in Senescence and targeting them to eliminate senescent cells

Abstract

Ageing is a deterioration of organ function that increases the susceptibility for diseases. This deterioration is due to an impairment of cellular homeostasis occurred in response to the nine hallmarks of senescence is considered one of these hallmarks, which was observed first by Leonard Hayflicks and Paul Moorhead which defined as a cell cycle arrest in response to genetic or environmental stresses such as UV radiation, oncogene stress, telomere attrition and DNA damage. Senescent cells are metabolically active cells characterized by an irreversible cell cycle arrest and resistance to apoptosis. Senescence has two opposite impacts on organisms, as it has a beneficial effect such as tissue repair, wound healing and tumor suppression. However, accumulation of senescent cells has a detrimental effect found to enhance ageing and age-related pathologies such as Alzheimer disease, diabetes, fibrosis and cancer. Therefore, clearance of senescent cells could ameliorate the symptoms of ageing and age-related diseases thus increasing the healthspan and lifespan of organisms. However, there is no yet specific marker used to detect and eliminate senescent cells. Consequently, it is important to find a marker or combination of markers that are specifically identify senescent cells and use them as therapeutic tool to target and eliminate the accumulation of senescent cells. Here, we illustrated that Ibrutinib, a clinically approved chemical inhibitor of BTK, decreased the accumulation of senescent cells in vivo, leading to extended lifespan and mitigating age related decline in physical fitness. Besides, Ibrutinib demonstrated a pivotal role in maintaining heart function with age by effectively reducing the accumulation of senescent cells. Additionally, we examined three potential markers of senescence identified by proteomic screening, evaluating their expression levels with age and after Ibrutinib treatment. Specifically, we sought to understand the impact of ibrutinib on these markers with age by comparing treated mice to untreated counterparts and young controls in mouse tissues. Moreover, we assessed the binding of RGD peptide to integrin αVβ3, a protein identified by proteomic screening as expressed more in senescent cells. The investigation aimed to determine the potential utility of the RGD peptide as a drug delivery tool for future applications.