Senolytic

A senolytic (from the words senescence and -lytic, "destroying") is among a class of small molecules under basic research to determine if they can selectively induce death of senescent cells and improve health in humans.^[1] A goal of this research is to discover or develop agents to delay, prevent, alleviate, or reverse age-related diseases.^[2][3] A related concept is "senostatic", which means to suppress senescence.

Research[]

Possible senolytic agents are under preliminary research, including some which are in early-stage human trials.^{[4][clarification needed]} The majority of candidate senolytic compounds are repurposed anti-cancer molecules, such as the chemotherapeutic drug dasatinib and the experimental small molecule navitoclax.^[5][6]

Senolytic candidates[]

• FOXO4-related peptides. FOXO4 binding to p53 protein retains it in the nucleus, which prevents it from interacting with mitochondria in the cytosol where it would activate caspases, leading to apoptosis (programmed cell death).^[7] Instead, retention of p53 in the nucleus by FOXO4 promotes cellular senescence.^[7] A peptide that binds with FOXO4 disrupts the p53-FOXO4 interaction, releasing p53 into the cytosol and triggering cell death.^[7]
• Inhibitors of different members of the bcl-2 family of anti-apoptotic proteins.^[8] Studies of cell cultures of senescent human umbilical vein endothelial cells have shown that both fisetin and quercetin induce apoptosis by inhibition of the anti-apoptotic protein Bcl-xL (a bcl-2 family member).^[9]
• Src tyrosine kinase inhibitors.^[10]
• Inhibitors of USP7 (Ubiquitin-specific processing protease 7)^[11]
• Combination of dasatinib and quercetin^[8][12][13]
• Fisetin^[14]
• Navitoclax^[15]
• Piperlongumine^[16]
• Azithromycin and Roxithromycin^[17]
• SSK1 (senescence-specific killing compound 1): A gemcitabine (a cytotoxic chemotherapeutic) prodrug that is activated by lysosomal β-galactosidase (a common senescence marker)^[18]
• Crispr/Cas9 BIRC5 Gene Knockout: Crispr/Cas9 is used to trigger apoptosis in relation to a specified gene sequence such as a cancer gene sequence or damage marker sequences.^[19]
• Target the enzyme kidney-type glutaminase 1 (GLS1). Senescent cells have a low pH due to their high lysosomal content and leaking lysosomal membranes. This low pH forms the basis of senescence-associated beta-galactosidase (SA-β-gal) staining of senescent cells. To help neutralize their low pH, senescent cells produce high levels of GLS1; inhibiting the activity of this enzyme exposes senescent cells to unsurvivably severe internal acidity, leading to cell death.^[20]
• Glycoprotein nonmetastatic melanoma protein B (GPNMB): a protein that enrich senescent cells studied as molecular target for a senolytic vaccine.^[21][22]
• Cardiac glycosides^[23][24][25].

See also[]

• Autophagy
• Geroprotector
• Venetoclax
• Senotherapy
• Unity Biotechnology

References[]

External links[]

• Killing ‘zombie’ cells to improve health in old age. The Conversation, Dominick Burton, Aston University, 17 March 2017
• Can Destroying Senescent Cells Treat Age-Related Disease? The Scientist, Katarina Zimmer, 1 March, 2020