Rapamycin supplementation ofDrosophila melanogasterlarvae results in less viable adults with smaller cells

Abstract

The intrinsic sources of mortality relate to the ability to meet the metabolic demands of tissue maintenance and repair, ultimately shaping ageing patterns. Anti-ageing mechanisms compete for resources with other functions, including those involved in maintaining functional plasma membranes. Consequently, organisms with smaller cells and more plasma membranes should devote more resources to membrane maintenance, leading to accelerated intrinsic mortality and ageing. To investigate this unexplored trade-off, we reared Drosophila melanogaster larvae on food with or without rapamycin (a TOR pathway inhibitor) to produce small- and large-celled adult flies, respectively, and measured their mortality rates. Males showed higher mortality than females. As expected, small-celled flies (rapamycin) showed higher mortality than their large-celled counterparts (control), but only in early adulthood. Contrary to predictions, the median lifespan was similar between the groups. Rapamycin administered to adults prolongs life; thus, the known direct physiological effects of rapamycin cannot explain our results. Instead, we invoke indirect effects of rapamycin, manifested as reduced cell size, as a driver of increased early mortality. We conclude that cell size differences between organisms and the associated burdens of plasma membrane maintenance costs may be important but overlooked factors influencing mortality patterns in nature.

Heat tolerance in Drosophila melanogaster is influenced by oxygen conditions and mutations in cell size control pathways

“…For example, at high temperatures, small-celled fish species were found to tolerate hypoxia better than large-celled species [27]. In other studies, small-celled forms of adult D. melanogaster were induced developmentally by larval feeding with rapamycin, a drug that downregulates the activity of the TOR kinase in TOR complex 1, reducing downstream signalling coming from this part of the TOR/insulin pathways [63,64]. The small-celled flies in these studies showed better flight performance under hypoxia than large-celled flies, and this effect was temperature-dependent [26], but they suffered increased mortality during early adulthood [63].…”

“…In other studies, small-celled forms of adult D. melanogaster were induced developmentally by larval feeding with rapamycin, a drug that downregulates the activity of the TOR kinase in TOR complex 1, reducing downstream signalling coming from this part of the TOR/insulin pathways [63,64]. The small-celled flies in these studies showed better flight performance under hypoxia than large-celled flies, and this effect was temperature-dependent [26], but they suffered increased mortality during early adulthood [63]. Our results here suggest that the effects of variation in cell size between flies may also partially account for changes in heat tolerance when flies are engaged in metabolically demanding activities, such as flight and climbing.…”