Table 1.
Proteins that have senescence suppressor characteristics and positively affect replicative lifespan and differentiation of MSCs
| Proteins | Effects and mechanisms | Inducers or agonists |
|---|---|---|
| Nrf2 | Reduction of oxidative stress by inducing antioxidant enzymes | Dimethyl fumarate [181], α-lipoic acid [182, 183], sulforaphane [184], bardoxolone methyl [185] |
| Protection from inflammation-caused damage by inducing anti-inflammatory cytokines | ||
| Damage removal by inducing 20S proteasome | ||
| PrPC | Reduction of oxidative stress by potentiating CuZn-SOD and glutathione reductase | 3/689 [118] |
| BVR-A | Reduction of oxidative stress by producing bilirubin and inducing HO-1 | |
| HO-1 | Protection from inflammation-caused damage by inducing anti-inflammatory cytokines | Atrial natriuretic peptide [186] |
| Forms HO-1/BVR-A antioxidant loop | ||
| α-Klotho | Protection from inflammation-caused damage by suppressing pro-inflammatory cytokine expression | Rosiglitazone through PPAR γ [112] |
| PPAR γ & PPARδ | Reduction of oxidative stress by inducing antioxidative and anti- inflammatory enzymes | Rosiglitazone [112], Pioglitazone [113] for PPAR γ; GW501516 [109] for PPARδ |
| 20S proteasome | Damage removal | 18α-glycyrrhetinic acid [27, 45] |
| SIRT1 | Reduction of oxidative stress by inducing antioxidant enzymes via FOXO3 activation | SIRT1 activators [179] |
| Suppression of damage signaling by inhibiting p53 | ||
| Telomere maintenance by hTERT induction | ||
| Damage removal through autophagy activation | ||
| NAMPT | SIRT1 activation by increasing NAD+/NADH ratio | Nicotinamide works by potentiating Nampt effect, but, also has antioxidative effect |
| ECM materials | Increased cell survival signaling and decreased ROS production. | |
| Cellular rejuvenation (by young cell ECM) | ||
| Statins | Reduction of oxidative stress by downregulating NAD(P)H oxidase and upregulating catalase | Mevastatin [129] atorvastatin [135] but, simvastatin has pro-senescence effect [138] |
| Suppression of damage signaling by inhibiting CDK inhibitor | ||
| Upregulation of SIRT1 and PPAR α/β/δ/γ | ||
| Bmi-1a | Suppression of tumor suppressor function: repression of INK4a-Arf locus | |
| Wip1a | Suppression of DNA damage signaling | |
| hTERTa | Damage reduction by telomere maintenance (not-senescence supprossor) |
a Bm-1, Wip1, and hTERT are not suitable for in vitro expansion of MSC for stem cell therapy since their activation causes cell immortalization which can lead to tumorigenesis in vivo