Age-associated differences in site-specific DNA methylation have been observed in both humans and animal models. We, and others, have also observed longitudinal changes in DNA methylation in humans, with an average interval between samples of more than a decade. Our published data indicate that it is likely that both genetic and environmental factors are involved with these changes. The absolute magnitude of the observed changes in humans is small but, by extrapolation from data in the mouse, may be considerably larger in some tissues. Moreover, we have observed that even small differences in DNA methylation can be associated with much larger differences in transcript level. Nevertheless, whether such age-related differences are a cause or a consequence of aging is a matter for discussion. Multiple epidemiological studies have identified maternal age as an additional factor influencing the longevity of offspring, with those offspring born to younger mothers living longer than offspring born to older mothers. We have examined site-specific DNA methylation in the offspring of mothers whose ages vary by more than 20 years. A number of genes exhibit maternal age-related differences in DNA methylation. Our observations indicate a potential role of maternal age-related methylation differences in the health and lifespan of offspring.