OBJECTIVE: Although the quest for longevity is as old as civilization itself, 
only recently have technical and conceptual advances in genomics research 
brought us to the point of understanding the precise molecular events that make 
us age. This heralds an era when manipulations of these will enable us to live 
longer, healthier lives. The present review describes how recent experimental 
strategies have identified key genes and intracellular pathways that are 
responsible for ageing and longevity.
FINDINGS: In diverse species transcription factors belonging to the 
forkhead/winged helix box gene, group O (FOXO) subfamily have been found to be 
crucial in downstream suppression of the life-shortening effects of 
insulin/insulin-like growth factor-I receptor signalling pathways that, when 
upregulated, accelerate ageing by suppression of FOXO. The various adverse 
processes activated upon FOXO suppression include increased generation of 
reactive oxygen species (ROS). ROS are pivotal for the onset of various common 
conditions, including hypertension, atherosclerosis, type 2 diabetes, cancer and 
Alzheimer's disease, each of which shortens lifespan. In humans, FOXO3a, as well 
as FOXO1 and -4, and their downstream effectors, could hold the key to 
counteracting ageing and common diseases. An understanding of the processes 
controlled by these FOXOs should permit development of novel classes of agents 
that will more directly counteract or prevent the damage associated with diverse 
life-threatening conditions, and so foster a life of good health to a ripe old 
age. Just like caloric restriction, lifespan can be increased in various species 
by plant-derived polyphenols, such as resveratrol, via activation of sirtuins in 
cells. Sirtuins, such as SIRT1 in mammals, utilize FOXO and other pathways to 
achieve their beneficial effects on health and lifespan.
CONCLUSION: Lifespan is tractable and basic mechanisms are now known. Longevity 
research complements and overlaps research in most major medical disciplines. 
Current progress bodes well for an ever-increasing length of healthy life for 
those who adapt emerging knowledge personally (so-called 'longevitarians').