Hemoglobin(HGB)in the blood carries oxygen from the lungs to other organs to produce energy. Calorie restriction has been shown to slow aging and extend lifespan. Thus, we hypothesized that HGB maybe associated with human longevity as a link to energy metabolism. To test this hypothesis, HGB levels in the blood of 60 centenarian(CEN) families were measured and its association with age(20-80 and 20-100 years)was studied, as well as the associations of CEN HGB with levels in first generation offspring (F1) and their spouses (F1SP). The results showed no association of HGB with age between 20 and 80 years (r=-0.097, p=0.160); however a strikingly inverse relationship with age between 20 and 100 years (r=-0.526, p<0.001)was revealed. After dividing the samples into four age groups (20-39, 40-59, 60-80 and ?100 years), the HGB in CEN were significantly lower than that of F1SP(p<0.001). Interestingly, the HGB levels of CEN were significantly associated with that of F1(r=0.379, p=0.015)but not with F1SP(r=0.022, p=0.451), suggesting that HGB could be a heritable phenotype. Furthermore, the genes methylenetetrahydrofolate reductase(MTHFR), nuclear receptor subfamily 2, group C, member 1(NR2C1)and NR2C2were differentially expressed in CEN when compared to F1SP, which may likely be responsible for the changes in HGB levels. In conclusion, our results suggest that HGB is a heritable phenotype which associates with familial longevity.