Aging is associated with an increase in oxidative stress and inflammation. Aging lung is particularly affected to this damage since alveolar epithelial cells are continuously exposed to environmental oxidants and antioxidant machinery seems to be weakened with age. Melatonin is a potent free radical scavenger and broad spectrum antioxidant that has been shown to counteract inflammation and apoptosis in healthy cells. Its effect on aging lung is, however, not yet fully understood. Thus, the aim of the present study was to investigate the effect of the exogenous administration of melatonin on the mRNA expression of inflammation markers tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), nuclear factor NF-kappa-B p100 subunit (NFκB2), heme oxygenase 1 (HO1) and apoptosis parameters Bcl-2-associated death promoter (BAD) and apoptosis inducing factor (AIF) in male senescence-accelerated prone mice (SAMP8). Young and old animals, aged 2 and 10 months respectively, were maintained under a 12:12 h light-dark cycle in an environmentally-controlled room and fed ad libitum. They were divided into 4 experimental groups: Young non-treated, old non-treated, old treated with 1 mg/kg/day melatonin, and old treated with 10 mg/kg/day melatonin. Young and old non-treated male senescence-accelerated resistant mice (SAMR1) were used as controls. Melatonin was dissolved in ethanol and added to the drinking water. Only ethanol was administered to the water of non-treated animals. After 30 days of treatment, animals were sacrificed and lungs were collected and immediately frozen in liquid nitrogen. mRNA expression was measured by means of RT-PCR using the SYBR Green PCR Master Mix (Applied Biosystems, Warrington, UK) and 300 nM concentrations of specific primers. For the normalization of cDNA loading in the PCR reaction, the amplification of 18S rRNA for every sample was used. Relative changes in gene expression were calculated using the 2-ddCt method. Mean values were analyzed by ANOVA. Old non-treated SAMP8 animals showed significantly increased (P<0.05) levels of TNF-α, IL-1β, NFκB2, and HO1 with respect to the values obtained in the young group. SAMR1 mice showed significantly decreased (P<0.05) mRNA levels of these pro-inflammatory markers in comparison with the old non-treated SAMP8 group. Melatonin treatment with either dose tested was able to reverse significantly (P<0.05) the aging-derived augmentation of these inflammatory markers. In addition, BAD and AIF expression rose with aging, the effect being significantly counteracted (P<0.05) with melatonin administration. Melatonin treatment may modulate the inflammatory and apoptosis status of the aging lung, exerting a protective effect on age-induced damage.