p53 regulated senescence mechanism and role of its modulators in age-related disorders

Biochem Pharmacol. 2021 Aug;190:114651. doi: 10.1016/j.bcp.2021.114651. Epub 2021 Jun 9.

Abstract

Multiple co-morbidities are associated with age, and there is a need for the broad-spectrum drug to prevent multiple regimens that may cause an adverse effect in the geriatric population. Cellular senescence is a primary mechanism for ageing in various tissues. p53, a tumor suppressor protein, plays a significant role in forming DNA damage foci and post different stress responses. DNA damage foci can be transient or persistent that can progress to DNA-SCARS inducing senescence. p53 also plays a role in apoptosis and negative regulation of SASP. Few upstream targets like FOXO4, MDM2, MDM4, USP7 control the availability of p53 for apoptosis. Hence, the senolytic therapies, modulating p53 upstream targets, can be a good approach for preventing age-related disorders. This review discusses the insights on the role of p53 in the formation of DNA-SCARS, various upstream target proteins, and pathways involved in p53 regulation. Further, the review aimed to include recently discovered small molecules acting on these upstream targets, and those can be modified using medicinal chemistry approaches to give successful senotherapeutics.

Keywords: Age-related disorder; Neurodegeneration; Senescence; Senolytic drugs; p53 regulation.

Publication types

  • Review