Ageing is a major risk factor for debilitating conditions. Interventions that target ageing hallmarks prevent disease and extend healthy lifespan in model organisms. To translate interventions into clinical practice, efficient targets need to be conserved and convergent. One essential chemical property for normal physiology that affects different aspects of ageing is pH, yet little is known about the role of acid-base balance in ageing and age-related disease. Here, extracellular pH homeostasis is proposed to be a novel hallmark of ageing. Drosophila is used as the model given its simple fluid compartmentalisation and short lifespan.
In flies, systemic acidification is shown to occur with age and to correlate with mortality rate, independently of strain, sex and diet. This correlates with insufficient acid excretion and to downregulation of genes proposed to be important for acid-base regulation in the fly excretory tract. Interventions that induce haemolymph acidification in independent ways shorten survival. With age, flies also become more sensitive to acidotic stress. Conversely, increasing haemolymph pH pharmacologically extends fly lifespan.
Acid-base imbalance promotes age- and diet-related lithiasis in fly tubules. Overnutrition through added sugar shortens fly survival independently of classically associated metabolic defects, such as insulin resistance. This study suggests fluid homeostasis, particularly acid-base balance, is a major determinant of health. Future research should further dissect the causes of age-related acidification and its impact on the pathophysiology of chronic diseases. Maintaining acid-base balance may be a preventive medicine strategy to promote a healthy lifespan.