Review Volume 7, Issue 10 pp 754—765

Figure 4. Key regulatory signaling pathways that become deregulated with age. The interactive developmentally and evolutionary conserved Notch, TGF-beta/BMP, Jak/Stat, p38, oxytocin/MAPK, and mTOR signaling pathways control function of tissue stem cells and change with age in ways that interfere with tissue maintenance and repair. Experimental modulation of these pathways enhanced the tissue regenerative capacity in old mammals. Beginning clockwise from top left. TGFβ and BMP pathway increase with age and activate pp38, transient inhibition of which is sufficient to restore myogenic potential in muscle stem cells. TGFβ and BMP also separately act through SMADs, inhibiting these SMADs was also found to rescue from some of the negative effects of these pathways pathogenic activation with age. JAK/STAT is a cytokine receptor pathway that increases with age. Many inflammatory cytokines act through this pathway. Inhibition of this pathway restores muscle satellite cell symmetric expansion. Delta/Notch signaling decreases with age, the activation of which in old muscle restores its regenerative potential. Oxytocin signaling decreases with age, restoring this signaling improves aged muscle satellite cell function. These intracellular signaling pathways are highly interactive. TGFβ acts through SMADs to influence downstream cytokine production which act on the Jak/Stat pathway, and SMAD3 and the Notch Intracellular Domain (NICD) interact directly to form a complex in the nucleus that binds to specific DNA sequences [8]. The MAPK/ERK pathway is activated by oxytocin, and the MAPK pathway is known to activate Notch signaling [9]. There is crosstalk between TGFβ signaling, Jak/Stat, and Erk1/2 mediated through mTOR.