Biology subjects

Promislow, D. E.

Publications and source records attributed to Promislow, D. E..

3 recordsLinked to original sources

bioRxiv2021

Serotonin signaling modulates aging-associated metabolic network integrity in response to nutrient choice

Aging arises from complex interactions among multiple biochemical and metabolic products. Systems-level analyses of biological networks may provide insights into the causes and consequences of aging that evade single-gene or single-pathway studies. We have shown that dietary choice per se is sufficient to modulate aging and metabolic health in the vinegar fly, Drosophila melanogaster. In other words, how each meal is presented, or the way in which it is eaten, is influential, independent of the amount or type of nutrients that are consumed. For example, when major macronutrients were presented separately, male flies exhibited a rapid and significant increase in mortality rate and a reduced overall lifespan relative to those fed a single medium containing both sugar and yeast. These effects are mediated by specific components of serotonin signaling, as a mutation in serotonin receptor 2A (5-HT2A) eliminated the effects of dietary choice. Here we show that dietary choice influenced several measures of metabolic network integrity, including connectivity, average shortest distance, community structure, and robustness, with the effects of the latter two restricted to tissues in the head. These changes in network structure were associated with organism resilience and increased susceptibility to genetic perturbation, as measured by starvation survival. Our data suggest that the behavioral or perceptual consequences of exposure to individual macronutrients, involving serotonin signaling through 5-HT2A, qualitatively change the state of metabolic networks throughout the organism from one that is highly connected and robust to one that is fragmented, fragile, and vulnerable to perturbations.

genetics↗

bioRxiv2021

Pharmacokinetics of long-term low-dose oral rapamycin in four healthy middle-aged companion dogs

ObjectiveTo determine the blood concentration and pharmacokinetic parameters of rapamycin in companion dogs following long-term, low-dose oral administration of rapamycin. AnimalsFour healthy, middle-aged, medium-to-large breed privately owned dogs participated. ProceduresAll dogs had been receiving oral rapamycin at a dose of 0.025 mg/kg on Monday, Wednesday, and Friday mornings for at least one month. An initial blood sample was collected prior to morning rapamycin administration, and samples were collected at 1, 2, 6, and 24 hours after rapamycin was given. Blood samples were transferred to blood spot collection cards, air-dried and stored at -80{degrees}C. Rapamycin concentrations were determined via HPLC/MS. All blood collections occurred on Wednesdays, so that the previous dose of rapamycin had taken place 48 hours prior to blood collection. ResultsFor all dogs, rapamycin Tmax was 2 hours. Median Cmax was 1.47 ng/ml (0.912 - 2.13), and the median AUC0-last was 15.7 ng*hr/mL (1.30 - 36.3). Due to sample size and timing, the only estimates related to elimination rate reported are for mean residence time with a median of 4.70 hrs (0.90 - 7.30). Conclusions and Clinical RelevanceA 0.025 mg/kg oral dose of rapamycin, administered three times a week, resulted in concentrations of rapamycin in the blood capable of being measured in ng/ml.

pharmacology and toxicology↗

bioRxiv2020

Serotonin 2A receptor signaling coordinates central metabolic processes to modulate aging in response to nutrient choice

It has been recognized for nearly a century that diet modulates aging. Despite early experiments suggesting that reduced caloric intake augmented lifespan, accumulating evidence indicates that other characteristics of the diet may be equally or more influential in modulating aging. We demonstrate that behavior, metabolism, and lifespan in Drosophila are affected by whether flies are provided a choice of different nutrients or a single, complete medium, largely independent of the amount of nutrients that are consumed. Meal choice elicits a rapid metabolic reprogramming that indicates a potentiation of TCA cycle and amino acid metabolism, which requires serotonin 2A receptor. Knockdown of glutamate dehydrogenase, a key TCA pathway component, abrogates the effect of dietary choice on lifespan. Our results reveal a mechanism of aging that applies in natural conditions, including our own, in which organisms continuously perceive and evaluate nutrient availability to promote fitness and well-being.

genetics↗