Table 4.

Current approaches of rejuvenation biotechnology.

Naturally inspired novel drug generations
(i) rPDGF-AA might accelerate wound healing in a mouse model of impaired tissue repair.	[101]
(ii) FDA-approved antitumoral agent panobinostat is able to target accumulated senescent cells for their effective clearance.	[109]
(iii) Desatinib and quercetin clear senescent adipocyte and endothelial cells in atherosclerotic lesions. BH3 mimetic inhibitors, as ABT-199, ABT-263, and ABT-737, induce the clearance of senescent HSC and consequently increase the proliferation of the healthy ones.	[110, 111]
(iv) Administration of exogenous IL-10 or activators of SIRT-1 is particularly beneficial in the clinical treatment of myocardial infarction, by acting on the macrophages/fibroblast axis.	[112, 113]
(v) Intraperitoneal injection of recombinant GDF11 reverses age-related cardiac hypertrophy.	[114]
(vi) Administration of BPIFB4 increases the production of NO and stimulates relaxation, reversing endothelial cell senescence in atherosclerosis and other pathologies.	[115–119]
Stem cells for senescence protection
(i) Fetal MSCs secrete bioactive factors promoting proliferation and differentiation in aged MSCs.	[120]
(ii) MSC secretome has beneficial effects in the protection, differentiation, and regeneration of CSCs and ancillary cellular elements.	[121]
(iii) CSCs ameliorate cardiac functionality in the anthracycline-induced cardiomyopathic heart.	[113]
(iv) A significant positive correlation exists between BB treatment of donor patients and both successful CS isolation and CS-forming cells yield from primary explant cultures. A significantly faster and higher CS-forming capacity was detectable in BB explants compared to NBB. A significantly increased percentage of CD90+ cells was observed in NBB CDCs.	[122]
(v) CD90 expression in injected CDCs negatively correlated with infarct scar size reduction (CADUCEUS trial). This study supports the possible predictive and adjuvant role of β-blocker treatment in cardiac cell therapy applications, as recently suggested for MSC-based therapies. It also suggests novel insights on the influence of BB treatments on the quality and abundance of the cardiac reparative cellular pool.	[123, 124]
Stem cell engineering and reprogramming strategies
(i) Resveratrol/rapamycin induces an epigenetic cellular reprogramming in senescent CSCs derived from decompensated hearts, by increasing cell proliferation.	[125]
(ii) PIM overexpression in senescent CSCs reverses heart aging.	[126]
(iii) Pluripotency reprogramming is feasible in centenarian cardiac fibroblasts by OCT4, SOX2, c-MYC, KLF4, NANOG, and LIN28 overexpression.	[129]
(iv) Treatment with inhibitors of BMP-SMAD signaling, for example, Dorsomorphin, SMAD6, and SMAD7, generates iPSCs in p16-mediated senescent fibroblasts.	[130]
In vitro 3D tissue engineering platforms to model senescence and aging
(i) Evaluation of the effect of oxidative stress on a bioengineered tissue, constructed with a decellularized, MSC-secreted ECM scaffold and human umbilical cord-derived MSC. By comparison to an artificial matrix layer in fibronectin and collagen I, cells seeded onto decellularized scaffolds are less incline to develop senescence after H202 stimulation, through an effect mediated by SIRT-1 upregulation.	[131]
(ii) Age of cardiac fibroblasts is a determining factor in the electrical and mechanical performance of cocultured cardiomyocytes in an in vitro 3D cardiac tissue, composed of a mixture of hydrogel and fibroblasts in molds of polidymethylsiloxane. This model is useful to recapitulate in vitro the alterations observed in senescent fibroblasts of the adult heart.	[132]

rPDGF-AA: recombinant platelet-derived growth factor-AA; BPIFB4: bactericidal/permeability-increasing fold-containing family B member 4; MSCs: mesenchymal stem cells; CSCs: cardiac stem cells; CSs: cardiospheres; BB: β-blocker; NBB: non-β-blocker; iPSCs: induced pluripotent stem cells; ECM: extracellular matrix.