Background: Insulin Resistance (IR) has long been recognized as a characteristic of aging. Many studies recorded beneficial roles of Vitamin D3 (VD3) and L-Carnitine (LC) in obesity and type 2 diabetes. Aim of Study:To evaluate the role of VD3 versus LC in attenuating the age-related IR in a naturally aging rat model, clarifying their possible underlying mechanisms.Material and methods: Rats were divided into 4 groups; Young Control (YC), aged group, VD3-treated aged group (VD3-aged) and LC-treated aged group (LC-aged). Experimental procedures included measurement of body weight, Body Mass Index (BMI) and Oral Glucose Tolerance Tests (OGTT). The Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) index was also calculated. Assays of fasting serum glucose and insulin levels as well as serum tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6) and adiponectin levels were performed. Moreover, skeletal muscle Sirtuin-1 (SIRT-1), Triglycerides (TGs) and TNFa levels alongside with the glucose transporter-4 (GLUt4) mRNA expression were assessed.Results: Compared to YC rats, aged rats exhibited significant increase in fasting serum insulin and HOMA-IR as well as an abnormal OGTT. Serum TNFa and IL-6 levels were significantly increased, whereas serum adiponectin level was significantly decreased in old rats. Furthermore, the SIRT1 levels and GLUT 4 mRNA expression were significantly lower, whereas the TGs and TNF-a were significantly higher in skeletal muscle of aged rats compared to YC ones. On the other hand, these parameters, were equally and significantly attenuated in VD3 and LC supplemented rats compared to non-treated age matched group, except for the skeletal muscle SIRT-1 level which could be elevated only by VD3, while the anti-inflammatory and TGs lowering effects of LC were more prominent than VD3. Nevertheless, the overall effect of VD3 and LC on IR-related parameters were nearly equal. Conclusion:Both VD3 or LC administrations were equally effective in alleviating the age-related IR, thus may provide a possible therapeutic intervention in the aging population. 3673 3674 Vit D3 versus L Carnitine Supplement in Alleviating Age-Related Insulin Resistance ageing-related IR [11,12] . Silent information regulator-1 (sirtuin SIRT-1), a NAD + -dependent protein deacetylase, is found in various tissues and is considered to be a key metabolic regulator [13] . Recently, it had been concluded that, during aging, the decreased SIRT-1 in skeletal muscle fundamentally mediates IR [14] , whereas, increased SIRT1 expression restricts age associated-diabetes and promotes insulin sensitivity [15,16] . Moreover, a decline in the skeletal muscle Glucose Transporter-4 (GLUT-4) with aging had been recorded in both human [17] , and animal studies [18] . GLUT-4 is a glucose-transport protein which promotes the cellular uptake of glucose [19] . Several line of evidences indicate that the levels of GLUT4 mRNA expression in skeletal muscle are crucial for the regulation of total body glucose homeostasis [20] .