Objective To investigate the gene expression profile of hypothalamus-pituitary-adrenal-thymus (HPAT) axis in aged rats and study the molecular mechanism of neurocrine and immunity senescence. Methods Differential gene expression of HPAT from 26-month-old rats or 7-month-old rats was studied with gene chip technology. Results Compared with young rats, the expression of those genes was down-regulated including several neurotransmitter and its receptors such as GABA-AR,al ER, Glu R, dopamine transporter, several gonadotropid hormone such as FSH, LH, GnRH, growth hormone and growth hormone releasing factor receptors, apopotosis-inhibiting genes including Cathepsin B, MTA1 and proliferation-promoting genes including Jaggedl, c-myc, c-fos, v-jun, Rgc32, Cyclin B1, Cyclin G-associated kinase. Meanwhile, in lymphocytes, the expression of apoptosis-promoting genes including Caspasel, Caspase2, CPP32β, Dnaser, PKC delta, Bnip31, p47 was lower in aged rats. Conclusions Hypothalamus-pituitary-gonad axis, hypothalamus-pituitary-growth hormone axis and immune system are most seriously damaged when aging. The lower expression of related genes such as neurotransmitter receptor genes, GH gene and gonadotropic hormone genes and the unbalance of the apoptosis-related and proliferation-related genes in immunocytes are the important molecular mechanisms of this damage.