A New, Discontinuous 2 Phases of Aging Model: Lessons from Drosophila melanogaster

Abstract

Abstract Aging is commonly described as being a continuous process affecting progressively organisms as time passes. This process results in a progressive decrease in individuals fitness through a wide range of both organismal – decreased motor activity, fertility, resistance to stress – and molecular phenotypes – decreased protein and energy homeostasis, impairment of insulin signaling. In the past 20 years, numerous genes have been identified as playing a major role in the aging process, yet little is known about the events leading to that loss of fitness. We recently described an event characterized by a dramatic increase of intestinal permeability to a blue food dye in aging flies committed to die within a few days. Importantly, flies showing this so called ‘Smurf’ phenotype are the only ones, among a population, to show various age-related changes and exhibit a high-risk of impending death whatever their chronological age. Thus, these observations suggest that instead of being one continuous phenomenon, aging may be a discontinuous process well described by at least two distinguishable phases. In this paper we addressed this hypothesis by implementing a new 2-Phases of Aging mathematiCal model (2PAC model) to simulate longevity curves based on the simple hypothesis of two consecutive phases of lifetime presenting different properties. We first present a unique equation for each phase and discuss the biological significance of the 3 associated parameters. Then we evaluate the influence of each parameter on the shape of survival curves. Overall, this new mathematical model, based on simple biological observations, is able to reproduce many experimental longevity curves, supporting the existence of 2-phases of aging exhibiting specific properties and separated by a dramatic transition that remains to be characterized. Moreover, it indicates that Smurf survival can be approximated by one single constant parameter for a broad range of genotypes that we have tested under our environmental conditions. Author Summary The perception we can have of a process directly affects the way we study it. In the literature, aging is generally described as being a continuous process, progressively affecting organisms through a broad range of molecular and physiological changes ultimately leading to a dramatic decrease of individuals’ life expectancy. As such, aging studies focus on changes occurring in groups of individuals through time, considering individuals taken at a given time as being all equivalent. Instead, the recently described Smurf phenotype [1] suggested that any given time, a population could be divided in two subpopulations each characterized by a significantly different risk of impending death. By formalizing here the concept of a discontinuous aging process using a mathematical model based on simple experimental observations, we propose a theoretical framework in which aging is actually separated in two consecutive phases characterized by three parameters easily quantifiable in vivo . Thus, the model we present here brings new tools to assess the events occurring during aging using a novel angle that we hope will open a better understanding of the very processes driving aging.