The ageing process: insulin signalling and mTOR signalling
Alterations in insulin/insulin-like growth factor 1 signalling (IIS) play a key role in lifespan extension in model organisms. For example, mice globally null for insulin receptor substrate protein 1 (IRS1), a major intracellular IIS effector, are both long-lived and have improved health during this long life. However, unlike long-lived GH dwarf mice and dietary restricted (DR) mice, Irs1 null mice combine an increased lifespan with lifelong insulin resistance. These findings suggest that enhanced insulin sensitivity is not a prerequisite for long-life. An additional signalling pathway that appears to plays a key and highly conserved role in longevity control is the target of rapamycin (TOR) pathway. Global deletion of ribosomal S6 protein kinase 1 (S6K1), a key effector of mTOR and IIS signalling, extends healthspan in female (but not male) mice. In addition, these mice are resistance to a range of age-related pathologies, including bone, immune and motor dysfunction. Unlike Irs1 nulls, 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 of 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.