Aging has been targeted by dietary manipulation, drugs and antioxidants, to increase lifespan promotion of healthy aging. Pharmaceuticals, nutraceuticals and diets have been studied in various aging therapies with the ability to extend life span and postpone disease and dysfunction in animals. Starting from the metabolic theory of aging and the use of aging-mediator agent (D-galactose), this work was undertaken to demonstrate the possible role of Caloric Restriction (CR), Vitamin C (Vit C) and Metformin (Met) either alone or in combination to delay the aging process and promotion of health span and life extension in male albino rats; shedding the light on the cellular and molecular mechanisms underlying anti-age-related changes. Aging was induced by subcutaneous injection of D-galactose (D-gal) (100 mg/kg/d for 8 weeks). Liver samples were subjected to and relative mRNA and protein expression assessments. Additionally, the levels of serotonergic and dopaminergic neurotransmitters were estimated in the brain tissue. Histopathological examination of both liver and brain tissue were investigated as well. Aging (p53, Nrf-2, AKT, FoxO3 and JNK), apoptotic (Bax gene expression) and antiapoptotic (Bcl-2 gene expression), inflammatory (NF-κB and Cystatin C activity) and oxidative stress (MDA, GSH and CAT) markers were determined. D-Gal caused oxidative alterations of the liver observed via upregulation of aging, apoptotic, and inflammatory markers and downregulated the anti-apoptotic, antioxidant markers. Also, impairment in the neurotransmitters was observed. However, the combination between CR and Vit C and Met modulated the alteration in the parameters. Therefore, it can be concluded that the combination of CR and Vit C and Met were suitable for preventing some associated problems that could be used to maintain human health.