It is now well established that specific alterations in insulin/insulin-like growth factor 1 signalling (IIS) play a key role in lifespan extension in model organisms. For example, we have shown that female and male mice globally null for insulin receptor substrate protein 1 (IRS1), a major intracellular IIS effector, are both long-lived and have significantly improved health during this long life. However, unlike long-lived growth hormone deficient dwarf mice and dietary restricted (DR) mice, Irs1 null mice combine their long life with lifelong insulin resistance. These findings suggest that enhanced insulin sensitivity is not a prerequisite for long-life. One additional signalling pathway that has recently been identified as playing a critical and highly conserved role in longevity control is the target of rapamycin (TOR) pathway. We recently reported that global deletion of ribosomal S6 protein kinase 1 (S6K1), a key effector of mTOR and IIS signalling, extends lifespan in female (but not male) mice. These long lived mice are also resistance to a range of age-related pathologies, including bone, immune and motor dysfunction, and in contrast to Irs1 null mice, S6K1 null mice were insulin sensitivity in old age. S6K1 deletion also induced hepatic gene expression profiles similar to DR and Irs1 null mice, and muscle expression profiles of S6K1 null mice closely mimicked those seen in mice following AICAR treatment. Therefore, manipulation of mTOR (and AMPK) may mimic DR and may provide viable drug targets offering protection against diseases of aging.