Nintedanib as a Potential Senolytic Drug

Senescent cells accumulate with age, and their presence contributes to chronic inflammation and many other age-related disruptions to normal tissue function. Academia and industry are engaged in many programs aimed at the creation of senolytic treatments that can selectively destroy senescent cells. The most proven senolytic treatment to date is the dasatinib and quercetin combination, shown to partially clear senescent cells from tissues in both old mice and old humans. Dasatinib is a tyrosine kinase inhibitor, and here researchers report their evidence in support another tyrosine kinase inhibitor, nintedanib, to be usefully senolytic.

Will nintedanib prove to be better or worse than dasatinib? That is hard to say, and different members of the same class of drugs can vary widely in all characteristics. The evidence here should be balanced against the history of nintedanib, given that it is approved for use in slowing the progression of idiopathic pulmonary fibrosis, and has been used for some years in that role. Senescent cells are thought to contribute to the development of idiopathic pulmonary fibrosis, and the dasatinib and quercetin combination showed promise in a small clinical trial for idiopathic pulmonary fibrosis patients. Animal data suggests dasatinib to be much less senolytic on its own, without quercetin, but no-one has yet earnestly tried to combine nintedanib and quercetin. Time will tell as to which senolytic approaches are the most useful.

Nintedanib induces senolytic effect via STAT3 inhibition

Selective removal of senescent cells, or senolytic therapy, has been proposed to be a potent strategy for overcoming age-related diseases and even for reversing aging. We found that nintedanib, a tyrosine kinase inhibitor, selectively induced the death of primary human dermal fibroblasts undergoing replicative senescence. Similar to ABT263, a well-known senolytic agent, nintedanib triggered intrinsic apoptosis in senescent cells. Additionally, at the concentration producing the senolytic effect, nintedanib arrested the cell cycle of nonsenescent cells in the G1 phase without inducing cytotoxicity.

Interestingly, the mechanism by which nintedanib activated caspase-9 in the intrinsic apoptotic pathway differed from that of ABT263 apoptosis induction; specifically, nintedanib did not decrease the levels of Bcl-2 family proteins in senescent cells. Moreover, nintedanib suppressed the activation of the JAK2/STAT3 pathway, which caused the drug-induced death of senescent cells. STAT3 knockdown in senescent cells induced caspase activation. Moreover, nintedanib reduced the number of senescence-associated β-galactosidase-positive senescent cells in parallel with a reduction in STAT3 phosphorylation and ameliorated collagen deposition in a mouse model of bleomycin-induced lung fibrosis. Consistently, nintedanib exhibited a senolytic effect through bleomycin-induced senescence of human pulmonary fibroblasts.

Overall, we found that nintedanib can be used as a new senolytic agent and that inhibiting STAT3 may be an approach for inducing the selective death of senescent cells. Our findings pave the way for expanding the senolytic toolkit for use in various aging statuses and age-related diseases.


My Father who just turned 84 was diagnosed with Idopathic Pulmonary fibrosis, and has just started on 150mg x 2 course of Nintedanib.

I have been busy finding supplements that would compliment the range of medication he is on, including, Vitamin K2, D3, Omega 3, Mg, Zn. Then MNM, Resveratrol and of course Quercetin.

So I was very pleased to find your article about Nintedanib, a slightly different to Dasatanib, but both tyrosine kinase inhibitors.

I understand, many tests have been run combining Quercetin and Dasatanib, but none so far as I can find with Nintedanib.

Unfortunately, the healthcare that prescribed Ninetedanib is advising my father not to take Quercetin, as in their words 'It diminishes the anti-fibrotic effects of the Ninetedanib'.

I was hoping that as a potentially beneficial anti-senolytic combination, that this could be tried for a period of 3-6 months only, and perhaps not even every day.

It is of course, my great hope that a reduction in senescent cells, would actually reduce the IPF, so that over time, the dosage of Ninetedanib could be reduced.

Would value any advice you may have.

Posted by: Bill at October 3rd, 2023 12:55 PM
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