Senescence suppressors: their practical importance in replicative lifespan extension in stem cells

Abstract

Recent animal and clinical studies report promising results for the therapeutic utilization of stem cells in regenerative medicine. Mesenchymal stem cells (MSCs), with their pluripotent nature, have advantages over embryonic stem cells in terms of their availability and feasibility. However, their proliferative activity is destined to slow by replicative senescence, and the limited proliferative potential of MSCs not only hinders the preparation of sufficient cells for in vivo application, but also draws a limitation on their potential for differentiation. This calls for the development of safe and efficient means to increase the proliferative as well as differentiation potential of MSCs. Recent advances have led to a better understanding of the underlying mechanisms and significance of cellular senescence, facilitating ways to manipulate the replicative lifespan of a variety of primary cells, including MSCs. This paper introduces a class of proteins that function as senescence suppressors. Like tumor suppressors, these proteins are lost in senescence, while their forced expression delays the onset of senescence. Moreover, treatments that increase the expression or the activity of senescence suppressors, therefore, cause expansion of the replicative and differentiation potential of MSCs. The nature of the activities and putative underlying mechanisms of the senescence suppressors will be discussed to facilitate their evaluation.

Fig. 1

The growth-arrest pathway towards senescence and four possible ways of intervention. The pathway begins with oxidative stress (inflammation also generates ROS), followed by damage on DNA (including telomere shortening and dysfunction), damage response (damage sensing followed by tumor suppressor pathway that is relayed through p53-p21-Rb or p16/p27-Rb), and the execution of growth arrest, which eventually develops to senescence. In “oxidative stress reduction”, senescence suppressors (azure box) reduce the level of oxidative stress or inflammation. PPARγ and δ, Nrf2, BVR-A directly induce antioxidative proteins and chemicals (dark khaki). SIRT1 does indirectly through activating Foxo3. PrP^C and nicotinamide (NAM) may function as antioxidants. Nampt (and NAM) works by enhancing SIRT1 activity. ECM suppresses ROS generation through integrin-mediated signaling. Statins also suppress ROS generation by inhibiting NAD(P)H oxidase and activating catalase. They also activate SIRT1 and PPAR transcription factors. α-Klotho and HO-1, which are activated by PPARγ and Nrf2, respectively, attenuate inflammation-induced ROS generation. In “damage reduction”, SIRT1 induces hTERT and thereby, activates telomerase, which prevents telomere dysfunction. And, in “damage removal”, Nrf2 enhances proteasome activity by inducing the 20S proteasome subunits, while SIRT1 enhances autophagy by activating autophagosome formation. In “tumor suppressor inhibition”, Wip1 and Bmi-1 attenuate either the p53/p21WAF1- or p16INK4a-tumor suppressor pathways. Statins may activate Akt, which suppresses FOXO3-mediated p27 expression. Finally, young ECM appears to cause reversal of arrest state and induce the progression of the cell cycle