Figure 4.

Restoring energy balance: Preventing two-compartment tumor metabolism. In the tumor stroma (and the aging host), oxidative stress activates two major transcription factors, namely, HIF1α and NFκB. Both are positive regulators of autophagy, mitophagy and aerobic glycolysis as well as the inflammatory response. In contrast, cancer cells could increase mitochondrial biogenesis via the activation of key transcription factors, such as PGC1a and NRF1. Thus, targeted therapies should reduce oxidative stress (NAC, N-acetyl-cysteine) or autophagy (chloroquine) in the tumor stroma (aging host). In contrast, tumor cell mitochondria could be targeted with mitochondrial inhibitors, such as Metformin. Both approaches would shut-down two-compartment tumor metabolism by normalizing metabolism or restoring homeostasis/energy balance.