Inhibition of 3-phosphoinositide–dependent protein kinase 1 (PDK1) can revert cellular senescence in human dermal fibroblasts

Abstract

Cellular senescence is defined as a stable, persistent arrest of cell proliferation. Here, we examine whether senescent cells can lose senescence hallmarks and reenter a reversible state of cell-cycle arrest (quiescence). We constructed a molecular regulatory network of cellular senescence based on previous experimental evidence. To infer the regulatory logic of the network, we performed phosphoprotein array experiments with normal human dermal fibroblasts and used the data to optimize the regulatory relationships between molecules with an evolutionary algorithm. From ensemble analysis of network models, we identified 3-phosphoinositide–dependent protein kinase 1 (PDK1) as a promising target for inhibitors to convert the senescent state to the quiescent state. We showed that inhibition of PDK1 in senescent human dermal fibroblasts eradicates senescence hallmarks and restores entry into the cell cycle by suppressing both nuclear factor κB and mTOR signaling, resulting in restored skin regeneration capacity. Our findings provide insight into a potential therapeutic strategy to treat age-related diseases associated with the accumulation of senescent cells.

β cell aging and age-related diabetes

“…Cellular senescence is a state of cell cycle arrest of previously replication-competent cells but remain metabolically active [ 9 , 88 , 89 ]. Senescent cells always display increased cell size and lysosomal β-galactosidase activity, characterized by activation of chronic DNA damage response (DDR), enhanced expressions of cyclin-dependent kinase inhibitors and apoptosis resistance.…”

Systems biology for reverse aging

“…An et al reconstructed an ensemble of 5000 Boolean network models that can represent senescence, quiescence, and proliferation phenotypes by integrating information from the literature, network databases and phosphoprotein array data of dermal fibroblasts they measured [4]. In their models, cellular senescence is induced by simultaneous activation of DNA damage signal (doxorubicin) and growth signal (IGF-1 plus serum), which coincides with the geroconversion theory [4,6].…”

“…An et al reconstructed an ensemble of 5000 Boolean network models that can represent senescence, quiescence, and proliferation phenotypes by integrating information from the literature, network databases and phosphoprotein array data of dermal fibroblasts they measured [4]. In their models, cellular senescence is induced by simultaneous activation of DNA damage signal (doxorubicin) and growth signal (IGF-1 plus serum), which coincides with the geroconversion theory [4,6]. They identified 3-phosphoinositide-dependent protein kinase 1 (PDK1) as the optimal protein target that can safely revert senescence to quiescence while avoiding uncontrolled proliferation, through extensive computer simulation analysis of the ensemble model.…”

“…Therefore, a novel therapeutic strategy without such critical limitations is highly needed. Cellular senescence is caused by complex interactions among biomolecules that govern cell cycle, DNA damage response, energy metabolism and cytokine secretion [4]. Recent studies showed that cellular senescence, previously considered as an irreversible biological phenomenon, can be reversed, but due to the nature of such complex interactions governing cellular senescence, the mechanism by which cellular senescence can be reversed has not been revealed [2,5].…”

“…Moreover, when senescent cells are reverted without sufficient mechanistic understanding, those reverted cells can contribute to the development of uncontrolled proliferation, leading to cancer [3,5]. To identify protein targets capable of reversing cellular senescence without inducing cancer and to elucidate the underlying mechanism, An et al [4] conducted a systems biology study by comprehensively analyzing the complex regulatory interactions involved in senescence.…”