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Introduction: The purpose of this study was to determine if pharmacological treatmentcould increase progenitor cell proliferation in the Sub-ventricular Zone of aged rats. Previous workhad shown that increasing progenitor cell proliferation in this region correlated well (R2=0.78; p=0.0007) with functional recovery in a damaged corpus callosum (white matter tract), suggesting thatprogenitor cell proliferation results in oligodendrocytes in this region. Methods: 10 month old male and female Sprague Dawley rats were fed the drugs for 30 days in cookiedough, then immunocytochemistry was performed on coronal brain sections, using Ki67 labeling todetermine progenitor cell proliferation. Results: Female rats showed low endogenous (control) progenitor cell proliferation, significantly differentfrom male rats (P<0.0001), at this age. Ascorbic Acid (20 mg/kg, daily for 30 days) increasedprogenitor cell proliferation overall, but maintained the innate gender difference in stem cell proliferation(P=0.001). Prozac (5 mg/kg, daily for 30 days) increased progenitor cell proliferation for femalesbut decreased stem cell proliferation for males, again showing a gender difference (P<0.0001).Simvastatin (1 mg/kg for 30 days) also increased progenitor cell proliferation in females and decreasedprogenitor cell proliferation in males, leading to a significant gender difference. Discussion: The three drug combinations (fluoxetine, simvastatin, and ascorbic acid, patent #9,254,281) led to ~ 4 fold increase in progenitor cell proliferation in females, while male progenitorcell proliferation was highest with 50 mg/kg ascorbic acid. However, the ascorbic acid increase in proliferationappears to be only on the sides of the ventricles, which is not the region that normally givesrise to oligodendrocytes. Conclusion: There are innate gender differences in progenitor cell proliferation at the Sub-VentricularZone at middle age in rats, possibly due to the loss of estrogen in females. We also see notable genderdifferences in progenitor cell proliferation in the Sub ventricular Zone in response to common drugs,such as fluoxetine, simvastatin and Vitamin C (ascorbic acid).