Fig. 2 ∣. Neuroendocrine-mediated pathways driving biological ageing following activation of the stress response.

The sympathetic nervous system (SNS) releases the catecholamines noradrenaline and adrenaline from nerve fibres and the adrenal gland, thus promoting the release of glucose and lipids from storage. These catecholamines also upregulate cellular metabolic activity, which produces reactive oxygen species (ROS), a source of tissue damage^105-108. Damage to DNA and telomeres can lead to cellular senescence^48,290. The hypothalamic–pituitary–adrenal (HPA) axis is activated during a stress response with release of glucocorticoids from the adrenal gland, thus further promoting metabolic activity^85,109, leading to increased levels of glucose and lipids as well as of oxidative stress and inflammation^291-293. Activation of the HPA axis also promotes decreased telomerase activity¹¹⁰ and impairs the function of DNA damage and repair pathways¹⁰⁶. Damaged, necrotic and senescent cells release inflammatory signals, including damage-associated molecular patterns (DAMPs) and cytokines and chemokines that are characteristic of the senescence-associated secretory phenotype (SASP)^111-113.