An AMP Kinase-pathway dependent integrated stress response regulates ageing and longevity.

The purpose of this article is to investigate the role of the AMP-kinase pathway (AMPK pathway) in the induction of a concomitant set of health benefits by exercise, numerous drugs, and health ingredients, all of which are adversely affected by ageing. Despite the AMPK pathway being frequently mentioned in relation to both these health effects and ageing, it appears challenging to understand how the activation of a single biochemical pathway by various treatments can produce such a diverse range of concurrent health benefits, involving so many organs. We discovered that the AMPK pathway functions as an integrated stress response system because of the presence of a feedback loop in it. This evolutionary conserved stress response system detects changes in AMP/ATP and NAD/NADH ratios, as well as the presence of potential toxins, and responds by activating a common protective transcriptional response that protects against aging and promotes longevity. The inactivation of the AMPK pathway with age most likely explains why ageing has a negative impact on the above-mentioned set of health benefits. We conclude that the presence of a feedback loop in the AMP-kinase pathway positions this pathway as an AMPK-ISR (AMP Kinase-dependent integrated stress response) system that responds to almost any type of (moderate) environmental stress by inducing various age-related health benefits and longevity.