Biphasic Modeling of Mitochondrial Metabolism Dysregulation during Aging  Darren J. Baker, Shahaf Peleg  Trends in Biochemical Sciences  Volume 42, Issue 9, Pages 702-711 (September 2017) DOI: 10.1016/j.tibs.2017.06.005 Copyright © 2017 The Author(s) Terms and Conditions

Figure 1 Theoretical Models for Average Mitochondria-Associated Metabolic Rates during Aging in Cells. (A,B) Progressive single-phase model for average mitochondrial metabolic activity rate changes associated with aging, which can be characterized by either a consistent (A) or an age-dependent (B) rate of change. While these models are in agreement with a large body of literature, the benefits of caloric restriction and possible adaptation of cells during middle-age are not reflected. (C) Biphasic model where average metabolic activity increases during middle-age followed by metabolic decline with advancing age. (D) Multiphasic model integrating the range of metabolic flexibility. While the average metabolic rate is characterized by a biphasic model, the range of the metabolic spectrum is progressively limited with aging. For example, it has been shown that while young mice citrate levels are increased in response to a behavior challenge, induction of citrate does not occur in middle-aged mice [76]. The thickness of the line represents the metabolic bidirectional flexibility (range) at a given age. The red broken line marks the lower limit of life-sustaining metabolic rate. Trends in Biochemical Sciences 2017 42, 702-711DOI: (10.1016/j.tibs.2017.06.005) Copyright © 2017 The Author(s) Terms and Conditions

Figure I Example of a Survival Curve and Key Stages. A survival curve can be defined by general key stages. The first phase of the survival curve is the premortality plateau phase in which 10% of the general population is lost over a relatively long period of time. This phase is sometimes referred to as the healthy lifespan. It comprises three stages. The first two are the young group − an early stage of adolescence where an organism may still develop, change, and grow – and a later stage comprising young adults. Both of these groups are usually referred to as a ‘young group’ in various works. This can result in confusion, as a young-adolescent mouse aged 2–3 months, which is still growing, is not the same as a 7–10-month-old young adult. The middle-aged stage comprises the later part of the premortality plateau phase where the mortality rate is slightly accelerated; however, 90% of the population remains alive. Following the premortality plateau phase, the mortality rate is accelerated and the population size declines rapidly. This later phase constitutes the old-group stage, which is normally situated some distance from the middle-aged group. For example, Miller et al. used 10-month-old mice as a young-adult group, 20-month-olds as a middle-aged group, and 30-month-olds as an old group [57]. Trends in Biochemical Sciences 2017 42, 702-711DOI: (10.1016/j.tibs.2017.06.005) Copyright © 2017 The Author(s) Terms and Conditions