While Allwood et al. found that CR transgenic overexpression of Ho1, an established downstream gene of Nrf2 in the heart (Li et al., 2009b), results in spontaneous development of heart failure at age of 1 year and exacerbates pressure overload-induced cardiomyopathy in mice (Allwood et al., 2014), we demonstrated that pathophysiological consequences of Nrf2 activation are linked to the functional integrity of autophagy in pressure overloaded mouse hearts (Qin et al., 2016). The gene discussed is NFE2L2; the disease is heart failure.