Researchers here report on in vitro experiments to show that introducing functional mitochondria into a cell culture containing senescent cells reduces markers of senescence. It is an interesting question as to how this would work in living tissue, where the numbers of senescent cells are low, and mitochondria will be introduced into all cells. Since several companies are developing mitochondrial transfer as a therapy to treat the loss of mitochondrial function that is characteristic of age-related disease, we'll find out in the years ahead. Those groups are not specifically targeting cellular senescence, but can hardly avoid having senescent cells taking up their therapeutic mitochondria.
For all strategies that might leave senescent cells intact but modulate their harmful signaling, the question is whether or not this is a good idea. This particularly the case for strategies that might allow senescent cells to re-enter the cell cycle and replicate again. Some fraction of senescent cells become senescent for good reasons, such as potentially cancerous mutations or other forms of damage that produce dysfunction. Senolytics that destroy senescent cells seem a safer proposal, and efficient senolytics may turn out to be required in advance of some of the other rejuvenation therapies on the horizon, such as partial reprogramming and mitochondrial transfer.
Retinal pigment epithelium (RPE) damage is a major factor in age-related macular degeneration (AMD). The RPE in AMD shows mitochondrial dysfunction suggesting an association of AMD with mitochondrial function. Mitochondrial transplantation into damaged cells or injured tissues is considered a novel cell-based therapeutic strategy. Delivery of mitochondria isolated from mesenchymal stem cells (MSCs) has the advantage of supplying the required number of mitochondria through rapid replication and multilineage differentiation compared with other cells; further, stem cells have low immunogenicity because of lower levels of surface antigens. A previous study has reported that MSC-derived mitochondrial transplantation protects the cornea against oxidative stress-induced mitochondrial damage.
Here, we investigated the effects of extrinsic mitochondrial transplantation on senescence-induced ARPE-19 cells, an RPE cell line. We demonstrated mitochondrial dysfunction in replicative senescence-induced ARPE-19 cells after repeated passage. Imbalanced mitophagy and mitochondrial dynamics resulted in increased mitochondrial numbers and elevated levels of mitochondrial and intracellular reactive oxygen species.
Exogenous mitochondrial transplantation improved mitochondrial dysfunction and alleviated cellular senescence hallmarks, such as increased cell size, increased senescence-associated β-galactosidase activity, augmented NF-κB activity, increased inflammatory cytokines, and upregulated the cyclin-dependent kinase inhibitors p21 and p16. Further, cellular senescence properties were improved by exogenous mitochondrial transplantation in oxidative stress-induced senescent ARPE-19 cells. These results indicate that exogenous mitochondrial transplantation modulates cellular senescence and may be considered a novel therapeutic strategy for AMD.