TY - JOUR
T1 - New agents that target senescent cells
T2 - The flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463
AU - Zhu, Yi
AU - Doornebal, Ewald J.
AU - Pirtskhalava, Tamar
AU - Giorgadze, Nino
AU - Wentworth, Mark
AU - Fuhrmann-Stroissnigg, Heike
AU - Niedernhofer, Laura J.
AU - Robbins, Paul D.
AU - Tchkonia, Tamara
AU - Kirkland, James L.
N1 - Funding Information:
The authors are grateful for the assistance of Jacqueline L. Armstrong.This work was supported by NIH grant R37AG013925 (J.L.K.), P01AG043376 (Project 2 and Core A: P.D.R., Project 1 and Core B: L.J.N.), the Connor Group, and the Noaber and Ted Nash Foundations (J.L.K.).
PY - 2017
Y1 - 2017
N2 - Senescent cells accumulate with aging and at sites of pathology in multiple chronic diseases. Senolytics are drugs that selectively promote apoptosis of senescent cells by temporarily disabling the pro-survival pathways that enable senescent cells to resist the pro-apoptotic, pro-inflammatory factors that they themselves secrete. Reducing senescent cell burden by genetic approaches or by administering senolytics delays or alleviates multiple age- and disease-related adverse phenotypes in preclinical models. Reported senolytics include dasatinib, quercetin, navitoclax (ABT263), and piperlongumine. Here we report that fisetin, a naturallyoccurring flavone with low toxicity, and A1331852 and A1155463, selective BCL-XL inhibitors that may have less hematological toxicity than the less specific BCL-2 family inhibitor navitoclax, are senolytic. Fisetin selectively induces apoptosis in senescent but not proliferating human umbilical vein endothelial cells (HUVECs). It is not senolytic in senescent IMR90 cells, a human lung fibroblast strain, or primary human preadipocytes. A1331852 and A1155463 are senolytic in HUVECs and IMR90 cells, but not preadipocytes. These agents may be better candidates for eventual translation into clinical interventions than some existing senolytics, such as navitoclax, which is associated with hematological toxicity.
AB - Senescent cells accumulate with aging and at sites of pathology in multiple chronic diseases. Senolytics are drugs that selectively promote apoptosis of senescent cells by temporarily disabling the pro-survival pathways that enable senescent cells to resist the pro-apoptotic, pro-inflammatory factors that they themselves secrete. Reducing senescent cell burden by genetic approaches or by administering senolytics delays or alleviates multiple age- and disease-related adverse phenotypes in preclinical models. Reported senolytics include dasatinib, quercetin, navitoclax (ABT263), and piperlongumine. Here we report that fisetin, a naturallyoccurring flavone with low toxicity, and A1331852 and A1155463, selective BCL-XL inhibitors that may have less hematological toxicity than the less specific BCL-2 family inhibitor navitoclax, are senolytic. Fisetin selectively induces apoptosis in senescent but not proliferating human umbilical vein endothelial cells (HUVECs). It is not senolytic in senescent IMR90 cells, a human lung fibroblast strain, or primary human preadipocytes. A1331852 and A1155463 are senolytic in HUVECs and IMR90 cells, but not preadipocytes. These agents may be better candidates for eventual translation into clinical interventions than some existing senolytics, such as navitoclax, which is associated with hematological toxicity.
KW - Adipose-derived stem cells
KW - Aging
KW - Apoptosis
KW - BCL-X inhibitors
KW - Flavonoids
KW - Preadipocytes
KW - Senolytics
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U2 - 10.18632/aging.101202
DO - 10.18632/aging.101202
M3 - Article
C2 - 28273655
AN - SCOPUS:85016619121
SN - 1945-4589
VL - 9
SP - 955
EP - 963
JO - Aging
JF - Aging
IS - 3
ER -