Mitochondrial Aging and Senolytic Natural Products with Protective Potential

Abstract

Living organisms do not disregard the laws of thermodynamics and must therefore consume energy for their survival. In this way, cellular energy exchanges, which aim above all at the production of ATP, a fundamental molecule used by the cell for its metabolisms, favor the formation of waste products that, if not properly disposed of, can contribute to cellular aging and damage. Numerous genes have been linked to aging, with some favoring it (gerontogenes) and others blocking it (longevity pathways). Animal model studies have shown that calorie restriction (CR) may promote longevity pathways, but given the difficult application of CR in humans, research is investigating the use of CR-mimetic substances capable of producing the same effect. These include some phytonutrients such as oleuropein, hydroxytyrosol, epigallo-catechin-gallate, fisetin, quercetin, and curcumin and minerals such as magnesium and selenium. Some of them also have senolytic effects, which promote the apoptosis of defective cells that accumulate over the years (senescent cells) and disrupt normal metabolism. In this article, we review the properties of these natural elements that can promote a longer and healthier life.

Emerging Therapeutic Approaches to Target the Dark Side of Senescent Cells: New Hopes to Treat Aging as a Disease and to Delay Age-Related Pathologies

“…Subsequently, these kinases cause the activation of various proteins, including checkpoint kinase 2 (Chk2). ATM phosphorylation fully activates Chk2 after triggering oligomerization and autophosphorylation of Chk2, which in turn transmits DNA damage signaling to several components involved in cell cycle arrest, apoptosis, and DNA repair, including phosphorylation and activation of the tumor suppressor protein p53, which initiates p21 expression [ 5 , 56 , 57 ]. P21 inhibits cyclin-dependent kinase 2 (CDK2), which prevents the phosphorylation of the retinoblastoma protein (Rb).…”

“…P21 inhibits cyclin-dependent kinase 2 (CDK2), which prevents the phosphorylation of the retinoblastoma protein (Rb). As a result, transcription of the proteins needed for the subsequent cell cycle stage (S Phase) is prevented, resulting in cell cycle arrest at the G1 phase [ 5 , 57 ]. Along with the Chk2-p53-dependent regulation of p21, cancer cells implement a p53-independent mechanism involving retrovirus-mediated expression of Chk2 kinase to transcribe p21 without requiring p53 protein [ 56 ].…”

“…In apoptosis, they produce two times more p53 than in senescence, in which p21 inhibits p53-mediated apoptosis. Doxorubicin treatment produced two outcomes in SK-N-SH neuroblastoma and colorectal cancer cells: decreased p21 expression and thus apoptosis due to high doses, versus increased p21 expression, leading to senescence with low doses [ 57 ].…”

“…Due to the fact that senescence and apoptosis have been considered as alternate cellular fates in the presence of injury and stress, pro-apoptotic cellular alterations are frequently actively anti-senescent, whereas senescent cells are extremely resistive to apoptosis. Multiple senescent molecular pathways substantially contribute to improved survival [ 57 , 193 ].…”

“…The best known pro-survival pathways are BCL-2 proteins family, as well as the p53 and PI3K/AKT pathways. Targeting these pathways can be exploited to remove senescent cells from damaged or aged tissues [ 57 , 193 ].…”