Elimination of senescent cells with senolytic host-directed therapy reduces tuberculosis progression in mice.

In studying the necrotic granuloma lesions unique tocharacteristic of Mtb-infected B6.Sst1S mice, we found that lung myeloid cells display elevated senescence markers including cell cycle arrest proteins p21 and p16, the DNA damage marker γH2A.X, senescence-associated β-Galactosidase activity, and senescence-associated secretory phenotype (SASP) proteins.

These same markers were also elevated in Mtb-infected aged wild type (WT) mice but not in young WT mice. Global transcriptomics data revealed activation of pro-survival (PI3K, MAPK) and anti-apoptotic pathways in TNFα- treated and Mtb- infected B6.Sst1S BMDMs. As senescent cells have been postulated shown to be long-lived, non-dividing cells which release tissue damaging signaling molecules, we treated Mtb-infected mice with a cocktail of three senolytic drugs (dasatinib, quercetin, and fisetin) designed to kill senescent cells.