Systemic administration of D-gal induced cognitive deficits, aggravated oxidative damage (increased karyopycnosis, AOD of 3-NT-IR, PC content, and MDA levels), destroyed the mitochondrial structure, reduced the mitochondrial content (decreased mitochondrial number, CS activity, and mtDNA copy number), decreased Nrf2 activation, upregulated senescence-associated (p16 and Ager) mRNA levels, and downregulated antioxidant (HO-1, NQO1, SOD2, CAT, and GPx1)-related and mitochondrial biogenesis (PGC-1α, NRF-1, and TFAM)-related gene expression. The gene discussed is CS; the disease is Cognitive impairment.