Targeting Mitochondrial Dysfunction to Reduce the Burden of Cellular Senescence

Cellular senescence and mitochondrial dysfunction are entwined phenomena in aging. On the one hand senescent cells exhibit a form of mitochondrial dysfunction, while on the other hand the decline of mitochondrial function with age contributes to a rising burden of cellular senescence in tissues. The interesting part of this paper is the discussion of mitochondrial function as a target to reduce the burden of senescence cells, either by preventing cells from becoming senescent, reducing the harmful signals secreted by senescent cells, or forcing these errant cells to self-destruct.

We would like to speculate that the dysfunctional nature of senescent cell mitochondria could be an advantage for interventions that aim to induce senescent cell apoptosis. Anti-senescence interventions, including both senolytic approaches (which aim to specifically ablate senescent cells) and senostatic/senomorphic approaches (designed to block the senescence-associated secretory phenotype (SASP) and thus the proliferation of senescence via bystander signaling), have been extraordinarily successful in relieving a very wide range of broadly age-associated degenerative conditions in experimental mice, and clinical trials for many of these are ongoing.

The low mitochondrial membrane potential (MMP) of senescent cells might be advantageous. Like many cancer cells, senescent cells have less capacity to maintain MMP compared with normal cells and are thus exposed to prolonged mitochondrial permeability transition pore (mPTP) opening, suggesting MMP as a selective functional target for senescent cells. We expect that low doses of mitochondrial uncouplers, such as FCCP or CCCP, will lead to a persistent depolarization of the mitochondrial membrane in senescent cells, resulting in constant mPTP opening and cell death. However, the same doses of uncoupler should be well tolerated by non-senescent cells with their more robust OXPHOS machinery and thus better ability to maintain MMP.

Accordingly, combination of a senolytic drug with an uncoupler should enhance senolytic sensitivity and specificity, enabling therapeutic efficacy to be reached at substantially lower doses of senolytic drugs, thus broadening the therapeutic window and reducing the risk of side effects for senolytic interventions.

Link: https://doi.org/10.1172/JCI158447