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] Removal of senescent cells with senolytics has been proposed as a method of enhancing immunity during aging.[4]
A related concept is "senostatic", which means to suppress senescence.[5]
According to reviews, it is thought that senolytics can be administered intermittently while being as effective as continuous administration. This could be an advantage of senolytic drugs and decrease adverse effects, for instance circumventing potential off-target effects.[6][12][13][14]
Recently, artificial intelligence has been used to discover new senolytics, resulting in the identification of structurally distinct senolytic compounds with more favorable medicinal chemistry properties than previous senolytic candidates.[15][16]
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).[18] Instead, retention of p53 in the nucleus by FOXO4 promotes
cellular senescence.[18] A peptide that binds with FOXO4 disrupts the p53-FOXO4 interaction, releasing p53 into the cytosol and triggering cell death.[18]
Senescence-specific killing compound 1: A
gemcitabine (a cytotoxic chemotherapeutic)
prodrug that is activated by lysosomal
β-galactosidase (a common senescence marker)[27]
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.[28]
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.[29]
Glycoprotein nonmetastatic melanoma protein B (
GPNMB). A protein that enrich senescent cells studied as molecular target for a senolytic vaccine in mice.[30]
^
abGe M, Hu L, Ao H, Zi M, Kong Q, He Y (April 2021). "Senolytic targets and new strategies for clearing senescent cells". Mechanisms of Ageing and Development. 195: 111468.
doi:
10.1016/j.mad.2021.111468.
PMID33741395.
S2CID232246367.
^
abcdLi W, Qin L, Feng R, Hu G, Sun H, He Y, Zhang R (July 2019). "Emerging senolytic agents derived from natural products". Mechanisms of Ageing and Development. 181: 1–6.
doi:
10.1016/j.mad.2019.05.001.
PMID31077707.
S2CID147704626.
^Shoemaker AR, Mitten MJ, Adickes J, Ackler S, Refici M, Ferguson D, et al. (June 2008). "Activity of the Bcl-2 family inhibitor ABT-263 in a panel of small cell lung cancer xenograft models". Clinical Cancer Research. 14 (11): 3268–3277.
doi:
10.1158/1078-0432.CCR-07-4622.
PMID18519752.
S2CID15786367.
^
abSuda M, Shimizu I, Katsuumi G, Yoshida Y, Hayashi Y, Ikegami R, et al. (December 2021). "Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice". Nature Aging. 1 (12): 1117–1126.
doi:
10.1038/s43587-021-00151-2.
PMID37117524.
S2CID245068564.