TABLE 1.
Senolytic and senomorphic drugs.
| Agents | Function | References | Study design | Therapeutic field | Major findings |
|---|---|---|---|---|---|
| Navitoclax (ABT263) | Inhibitor of BCL-2 and BCL-xL | ||||
| In vitro studies and animal model | |||||
| Chang et al. (2016) | Animal model: oral administration of ABT263 to either sublethal irradiated or normally aged mice | Aged tissue stem cells | Increased hematopoietic and muscle stem cell function | ||
| Zhu et al. (2016) | In vitro study: induction of cellular senescence in HUVECs, IMR90 cells, and preadipocytes | Senescent cells | Reduced viability of senescent HUVECs, and IMR90 cells | ||
| Pan et al. (2017) | Animal model: mice model of ionizing radiation–induced pulmonary fibrosis | Chronic lung fibrosis | Reduced viability of senescent type II pneumocytes and decreased pulmonary fibrosis | ||
| Clinical studies | |||||
| Gandhi et al. (2011) | NCT00445198: interventional study (phase I/II) with 86 participants with small-cell lung cancer (SCLC) or other nonhematological malignancies | Small-cell lung cancer (SCLC) or other nonhematological malignancies resistant to chemotherapy-induced apoptosis | Phase I results: safety and toleration dose | ||
| Wilson et al. (2010) | NCT00406809: interventional study (phase I/II) with 81 participants with relapsed or refractory lymphoid malignancies | Relapsed or refractory lymphoid malignancies | Phase I results: safety and toleration dose | ||
| Roberts et al. (2015) | NCT00788684: interventional study (phase I) with 29 participants with CD20-positive lymphoid malignancies | Lymphoid tumors | Phase I results: safety dose in combination with rituximab | ||
| NCT01989585: interventional study (phase I/II) with 75 participants with BRAF mutant melanoma or solid tumors that are metastatic | BRAF mutant melanoma or solid tumors that are metastatic | NCT01989585: ongoing study (primary completion date: December 31, 2021) | |||
| NCT03366103: interventional study (phase I/II) with 79 participants with relapsed small-cell lung cancer and other solid tumors | Relapsed small-cell lung cancer and other solid tumors | NCT03366103: ongoing study (estimated study completion date: August 31, 2021) | |||
| Quercitin | Antioxidant activity and inhibitor of PI3K/AKT and p53/p21/serpines | ||||
| In vitro studies and animal model | |||||
| Kim et al. (2019) | Animal model: C57BL/6 J mice fed high-fat diet | Renal dysfunction in dyslipidemia and obesity setting | Amelioration of obesity-induced renal senescence | ||
| Quercitin + dasatinib | Antioxidant activity and inhibitor of PI3K-AKT and p53, p21, serpines, and tyrosine kinase inhibitor | ||||
| In vitro studies and animal model | |||||
| Zhu et al. (2015) | In vitro study: senescent preadipocytes and HUVECs | Aging and radiation damage | In vitro: reduced viability of senescent preadipocytes and HUVECs | ||
| Animal model: aging C57Bl/6 mice with or without radiation | In vivo: extension of lifespan, amelioration of cardiovascular function, and reduced radiation injury | ||||
| Xu et al. (2018) | Animal model: transplantation of senescent cells into young mice | Aging‐related disease | Extension of lifespan and amelioration of senescent cell-induced physical dysfunction | ||
| Wang et al. (2019) | Animal model: female C3H mice and male Sprague–Dawley rats with radiation ulcers | Aging and radiation ulcers | Elimination of senescent cells in radiation ulcers | ||
| Palmer et al. (2019) | Animal model: obese mice | Obesity‐induced metabolic dysfunction | Decrease of metabolic and adipose tissue dysfunction | ||
| Clinical studies | |||||
| Justice et al. (2019) | NCT02874989: open-label human pilot study in idiopathic pulmonary fibrosis with 26 participants | Idiopathic pulmonary fibrosis | Reduced pulmonary fibrosis | ||
| Hickson et al. (2019) | NCT02848131: open-label phase 1 pilot study with diabetic kidney disease in 16 participants | Chronic kidney disease | Reduced adipose tissue senescent cells, skin senescent cells, and circulating SASP factors | ||
| Quercetin + resveratrol | Antioxidant activity and inhibitor of PI3K-AKT and p53, p21, and serpines | ||||
| In vitro studies and animal model | |||||
| Abharzanjani et al. (2017) | In vitro study: human embryonic kidney cell (HEK-293) cultured in high-glucose conditions | Hyperglycemia and diabetic nephropathy | Increased expression levels of antioxidants and reduced aging markers in HEK cells in hyperglycemic conditions | ||
| JAK inhibitor (ruxolitinib) | Inhibitor of JAK (janus kinase) pathway | ||||
| In vitro studies and animal model | |||||
| Xu et al. (2018) | Animal model: old C57BL/6 male mice | Aging‐related disease | Reduced inflammation and alleviated frailty in aged mice | ||
| In vitro study: preadipocytes and HUVECs | |||||
| NBD peptide | Inhibitor of IKK/NFB pathway | ||||
| In vitro studies and animal model | |||||
| Tilstra et al. (2012) | Animal model: progeroid model mice | XFE progeroid syndrome | Reduced oxidative DNA damage and stress and delayed cellular senescence | ||
| KU-60019 | Inhibitor of ataxia-telangiectasia mutated (ATM) kinase | ||||
| In vitro studies and animal model | |||||
| Kang et al. (2017) | In vitro study: human diploid fibroblasts and ATM-deficient fibroblasts | Aging‐related disease | In vitro: functional recovery of thelysosome/autophagy system, mitochondrial functional recovery, and metabolic reprogramming | ||
| Animal model: wound healing assay in old C57BL/6 J mice | In vivo: accelerated | ||||
| JH4 | Interfering binding of progerin and lamin | ||||
| In vitro studies and animal model | |||||
| (Lee et al., 2014) | Animal model: HGPS-progeroid mice | Hutchinson–Gilford progeria syndrome and aging disease | Reduced nuclear deformation and senescence process | ||
| Extension of lifespan in the HGPS-progeroid mice | |||||
| Juglanin | Not reported | ||||
| In vitro studies and animal model | |||||
| Yang et al. (2014a) | In vitro study: adriamycin-induced human dermal fibroblast (HDF) senescence | Tissue repair and regeneration | Decreased senescence in HDFs | ||
| Quercetin-3-O-β-D-glucuronide | Not reported | ||||
| In vitro studies and animal model | |||||
| Yang et al. (2014b) | Animal model: adriamycin-induced HDF and HUVEC senescence | Tissue repair and regeneration | Decreased senescence in HDFs and HUVECs | ||
| Loliolide | Not reported | ||||
| In vitro studies and animal model | |||||
| Yang et al. (2015a) | Animal model: adriamycin-induced HDF and HUVEC senescence | Tissue repair and regeneration | Decreased senescence in HDFs and HUVECs | ||
| Quercetagetin 3,4′-dimethyl ether | Not reported | ||||
| In vitro studies and animal model | |||||
| Yang et al. (2015b) | In vitro study: adriamycin-induced HUVEC senescence | Tissue repair and regeneration | Decreased senescence in HUVECs | ||
| Rapamycin | Inhibitor of mTOR kinase | ||||
| In vitro studies and animal model | |||||
| Antonioli et al.( 2019) | In vitro study: primary human bone marrow (BM) MSC samples of five healthy young adults | Tissue engineering and cell-based therapies | Retard senescence and extend stemness properties | ||
| Chen et al. (2009) | Animal model: old C57BL/6 wild-type mice | Aging hematopoietic stem cells | Increased mice lifespan, self-renewal of hematopoietic stem cell, enabled vaccination | ||
| Arriola Apelo et al. (2016) | Animal model: old female C57BL/6 J mice | Aging‐related disease | Extension of mice lifespan | ||
| Wang et al. (2017) | Animal model: old WT and Nrf2 knockout mice | Aging‐related disease | Inhibition of the secretory phenotype of senescent cells | ||
| Lesniewski et al. (2017) | Animal model: old male B6D2F1 mice | Aging‐related disease | Improvement of arterial function, reduced oxidative stress, AMPK activation, and increased expression of proteins involved in the control of the cell cycle | ||
| RAD001 (analog of rapamycin) | Inhibitor of mTOR kinase | ||||
| In vitro studies and animal model | |||||
| Shavlakadze et al. (2018) | Animal model: old rats | Aging‐related disease | Modulation of age-regulated genes expression in the kidney and liver | ||
| Clinical studies | |||||
| Mannick et al. (2014) | Clinical study: 218 elderly volunteers ≥65 years of age | Aging-related disease | Amelioration of immuno-senescence to influenza vaccination | ||
| Metformin | Inhibition of NF-kB signaling and Nrf2 modulation | ||||
| In vitro studies and animal model | |||||
| Fang et al. (2018) | In vitro study: human diploid fibroblasts (HDF) and human mesenchymal stem cells (HMSCs) | Aging‐related disease | Amelioration of cellular aging | ||
| Not reported | (Park and shin 2017) | In vitro study: primary dermal fibroblasts derived from Hutchinson–Gilford progeria syndrome | Hutchinson–Gilford progeria syndrome | Amelioration of cellular aging | |
| Animal model: aged BALB/c mice | Reduction of ROS, γ-H2AX foci, and ATM | ||||
| Clinical studies | |||||
| Not reported | Not reported | Clinical trial: NCT02432287: 16 participants (older adults with impaired glucose tolerance (IGT)) | Aging‐related disease | Not reported | |
| Not reported | Barzilai et al. (2016) | Clinical study: TAME study: enrollment of 3,000 subjects, ages 65–79 years, in ∼14 lefts across the United States | Aging‐related disease (cardiovascular events, cancer, dementia, and mortality) | Ongoing study (recruitment started 2020) | |
Table summarizing the senotherapies recently discovered, with the indication of the model, type of disease, clinical trials, and references.