Based on published reports and our findings in this study, we propose a model (depicted in Fig. 5M), in which telomeric DNA damage from insults—such as cell over-activation and proliferation, chronic viral infection, cancer, inflammatory cytokines, oxidative stress, aberrant T cell homeostasis, and neurodegenerative and cardiovascular diseases—can activate p53, which in turn represses PGC-1α (a transcriptional coactivator of mitochondrial biogenesis via downstream NRF-1 and ERRα) and ultimately leads to compromised mitochondrial functions. Here, ESRRA is linked to cardiovascular disorder.