Asymmetrically inherited multidrug resistance transporters are recessive determinants in cellular replicative ageing

Abstract

Cellular aging is known to correlate with the accumulation of many harmful agents1, but can aging also result from deterioration of certain poorly-renewed beneficial components? Here we found that a group of plasma membrane-associated transporters, belonging to the multidrug resistance (MDR) protein families, may represent the latter type aging determinants. These proteins are deposited before the birth of a virgin yeast cell. During the subsequent division of this cell, the original protein population remains tightly associated with the mother cortex, while the newly synthesized transporter proteins are deposited mostly into the bud. Thus, the new and old pools of membrane-bound MDR proteins are spatially segregated during yeast asymmetric cell division with the older pool stably inherited by the aging mother. A model based on the observed dynamics of MDR protein inheritance and turnover predicted a decline in MDR activity as the mother cell advances in replicative age. As MDR proteins play crucial roles in cellular metabolism, detoxification and stress response, their collective decline may lead to fitness loss at an advance age. Supporting this hypothesis, mutants lacking certain MDR genes exhibited a reduced replicative lifespan (RLS), while introduction of only one extra copy of these MDR genes extended RLS.