Table 2.

Therapeutic options to target senescence.

Medication/Therapeutic Target	Mechanism of Action	FDA Approved or Experimental
AICAR: 5-aminoimidazole-4- carboxamide riboside	AMPK activation; reduces the expression of p16, p21, and p66shc [173]; reduces IL6 and IL8 in HBECs [173].	Experimental; only used in several investigations in humans [223,224,225].
Metformin	AMPK activation reduces elastase-induced emphysema and senescence in mice [173]; modifies glucose flow across respiratory cells [170,171,172].	Approved in 1995 for diabetes; used for PCOS; shown to inhibit the SASP [226].
Rapamycin	mTOR inhibition [44]; reduction of inflammation and mean alveolar space [175].	Approved in 1999 as an immunosuppressant agent [227,228].
Acumapimod Doramapimod Dabrafenib/Trametinib	p38 MAPK inhibition; regulation of NF-κB, and stabilization of SASP effector mRNA [177,178]; inhibition of CAM expression and leukocyte adhesion [183].	Experimental. Experimental. Approved in 2018 for the treatment of melanoma [172].
Navitoclax (ABT-263) Venetoclax (ABT-199)	BCL-2 inhibition leads to the induction of apoptosis through a SASP [184,185].	Approved, both in 2016 and 2020, for chronic lymphocytic leukemia and acute myeloid leukemia [229]. Tests were conducted in human cell lines in vitro [201].
Gamitrinib	HSP90 inhibition with anti-TNF-receptor associated protein 1 properties; activation of cyclophilin D; release of cytochrome c [189,223].	Experimental and undergoing clinical trials. Promising therapeutic advantages for pulmonary hypertension and senescence [230].
FOXO4-DRI	Blocks interaction of FOXO4 and p53 and prevents apoptosis [231].	Experimental promising senolytic [232]. Tests were conducted in human cell lines in vitro and in mice models [231].
25-Hydroxycholesterol	Interferes with CRYAB aggregation and decreases FAP and SC concentration [233]; localized in alveolar macrophages and pneumocytes in COPD patients [216].	Experimental. Currently considered for COVID-19 treatment [234]; evidence regarding possible role use in COPD [235].
Melatonin	Melatonin prevents senescence by activating Nrf2 and inhibiting ER stress [212] and p53 deacetylation induced by upregulation of SIRT1 [213]	Experimental.
Matrine	PI3K inhibition; Chinese herbal medication led to a reduced number of senescent cells; decreased IGF1 and pAKT [236].	Experimental. Found to induce apoptosis in acute myeloid leukemia [236].
Dasitinib + Quercetin	Src tyrosine kinase inhibition; PI3K pathway inhibition [206,233].	Approved in 2017 for the treatment of leukemia in pediatric patients. Quercetin shows anti-inflammatory potential [237].
Eicosanoids and COX2 inhibitors	Endogenous PGE2 suppressed inflammation via PGE Receptor 4 (PGER4) activation. The EP4 receptor agonist (ONO-AE1-329) modulated cytokine levels in asthma and COPD models [190]; Inhalation of exogenous PGE2 prevents bronchoconstriction provoked by aspirin [191,192]; Celecoxib inhibited interalveolar wall distance and pulmonary inflammation in the lungs of CS-treated rats [193].	Experimental. Celecoxib is typically used to treat mild to moderate pain and help relieve symptoms of arthritis.
Kaempferol Apigenin	NF-κB p65 inhibition via activation of the IRAK1/IκBα signaling pathway [238].	Experimental.
Azithromycin Roxithromycin	Macrolide antibiotics that induce aerobic glycolysis and autophagy [202]; suppression of cytokine release in COPD exacerbations [217].	Approved in 1987 and 2002; used for prevention and treatment of exacerbations in COPD [217]. Tests were conducted in human cell lines [202].
Ouabain Digoxin	Cardiac glycosides that inhibit the Na+, K+-ATPase, induce pro-apoptotic BCL-2 proteins and activate JNK, GSK3-β, and p38 in senescent cells [219].	Ouabain is not approved in the USA, France, or Germany, but digoxin was approved in 2002. Tests were conducted in human cell lines and mice models [221,222].
Gemcitabine	SSKI with potent cytotoxicity for aged cells through interaction with MAPK pathway [208].	Approved in 2011 for metastatic breast cancer treatment. Tests were conducted in mouse models [208].

AMPK: AMP-activated protein kinase; mTOR: mammalian target of rapamycin; MAPK: mitogen-activated protein kinase; NFκB: nuclear factor kappa B; SASP: senescence-associated secretory phenotype; CAM: cell adhesion molecule; BCL-2: B-cell lymphoma 2; HSP90: heat shock protein 90; Anti-TNF-receptor: anti-tumor necrosis factor receptor; FOXO4: forkhead box O4; CRYAB: crystallin alpha B; FAP: fibro/adipogenic progenitor; SC: satellite cell; COPD: chronic obstructive pulmonary disease; Nrf2: nuclear factor-erythroid factor-2 related factor 2; PI3K: phosphoinositide 3-kinase; IGF1: insulin-like growth factor 1; pAKT: phosphorylated serine/threonine kinase; IRAK1: interleukin 1 receptor-associated kinase 1; JNK: c-Jun N-terminal kinases; GSK3-β: glycogen synthase kinase 3; SSKI: senescence-specific killing compound.