Senolytic
 | This article needs more primary sources. (January 2022) |  |
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]
Research
Possible senolytic agents are under preliminary research, including some which are in
Soluble
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]
Senolytic candidates
| This section needs more primary sources. (September 2023) | |
| Medication/target | Description | Tests as senolytic have been conducted in ... | |||||
|---|---|---|---|---|---|---|---|
| human cell lines in vitro | mice models | xenograft model
|
phase I trial | phase II trial | phase III trial | ||
| FOXO4-related peptides[13][17][12][6] | FOXO4 binding to 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] |
Yes[18] | Yes[18] | ||||
| BCL-2 inhibitors | Inhibitors of different members of the bcl-2 family of anti-apoptotic proteins.[13][19][20] 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).[6] | Yes[6] | |||||
| Src inhibitors | Src tyrosine kinase inhibitors: dasatinib[21] – see "Combination of dasatinib and quercetin" below | ||||||
| USP7 inhibitors | Inhibitors of USP7 (ubiquitin-specific processing protease 7)[17] | Yes[22] | Yes[22] | ||||
| Dasatinib and Quercetin (D+Q) | Combination of dasatinib and quercetin[20][19][14][13] | Yes | Yes | Yes[23][24] | |||
| Fisetin[13][19][12][6] | Yes[25] | Yes[25] | |||||
| Navitoclax[13][6] | xenograft | Yes[26] | |||||
| SSK1 | Senescence-specific killing compound 1: A β-galactosidase (a common senescence marker)[27] |
Yes[27] | |||||
| BIRC5 knockout | 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] |
Yes[28] | |||||
| GLS1 inhibitors | Target the enzyme 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] |
Yes[29] | |||||
| Anti-GPNMB vaccine | Glycoprotein nonmetastatic melanoma protein B (GPNMB). A protein that enrich senescent cells studied as molecular target for a senolytic vaccine in mice.[30] | Yes[30] | |||||
| Cardiac glycosides[13][12] | Yes[31][32][33] | xenograft | Yes[32] | ||||
25-hydroxycholesterol (25HC)[34] |
25-hydroxycholesterol targets CRYAB in multiple human and mouse cell types | Yes[34] | Yes[34] | ||||
| Procyanidin C1 | Yes[35] | Yes[35] | |||||
| EF-24[19][12] | Yes | ||||||
HSP90 inhibitors[36] |
|||||||
CUDC-907[37] |
|||||||
Senomorphics
Senolytics
See also
- Autophagy
- Biogerontology
- DNA repair § Senescence and apoptosis
- Geroprotector
- Hsp90
- Immunosenescence
- Invariant NKT (iNKT) cells
- Klotho (biology) § Effects on aging
- Life extension
- Senescence-associated beta-galactosidase, used as a biomarker
- Senotherapy
- Sirtuin-activating compound
- Unity Biotechnology
- Venetoclax
- YPEL3 § Cellular senescence
References
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- ^ PMID 32686219.
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- ^ PMID 33328614.
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- S2CID 258506382.
- PMID 37301862.
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- ^ PMID 28340339.
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- ^ S2CID 3534989.
- PMID 31619990.
- ^ PMID 32064756.
- PMID 31542391.
- PMID 30616998.
- ^ PMID 30279143.
- S2CID 15786367.
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- PMID 34355491.
- ^ PMID 31636264.
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- ^ PMID 35198901.
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- PMID 29886783.
- S2CID 257804078.
Further reading
- Arora S, Thompson PJ, Wang Y, Bhattacharyya A, Apostolopoulou H, Hatano R, et al. (August 2021). "Invariant Natural Killer T cells coordinate removal of senescent cells". Med. 2 (8): 938–950. S2CID 236546883.
- Kirkland JL, Tchkonia T (November 2020). "Senolytic drugs: from discovery to translation". Journal of Internal Medicine. 288 (5): 518–536. PMID 32686219., a review that is open accessand features a list of senolytics candidates
- Zhu Y, Prata LG, Gerdes EO, Netto JM, Pirtskhalava T, Giorgadze N, et al. (March 2022). "Orally-active, clinically-translatable senolytics restore α-Klotho in mice and humans". eBioMedicine. 77: 103912. S2CID 247443187.
- Dance A (2022-12-21). "Could getting rid of old cells turn back the clock on aging?". Knowable Magazine | Annual Reviews. S2CID 255055238.