Academic journal article Genetics

Different Mechanisms of Longevity in Long-Lived Mouse and Caenorhabditis Elegans Mutants Revealed by Statistical Analysis of Mortality Rates

Academic journal article Genetics

Different Mechanisms of Longevity in Long-Lived Mouse and Caenorhabditis Elegans Mutants Revealed by Statistical Analysis of Mortality Rates

Article excerpt

(ProQuest: ... denotes formulae omitted.)

THE aging process can be studied by investigating genetic variants that alter life span in model organisms (Finch and Ruvkun 2001; Hekimi 2006). For example, the fact that mutations of genes involved in the insulin/insulin-like signaling pathway can extend life span in Caenorhabditis elegans, Drosophila, and mice is considered to imply a role for this pathway in the aging process (Kenyon 2010). Likewise, a role for mitochondrial function in aging is suggested by the finding that impairments to mitochondrial function can extend lifespan in C. elegans and mice (Ewbank et al. 1997; Feng et al. 2001; Dillin et al. 2002; Lee et al. 2003; Liu et al. 2005; Hughes and Hekimi 2011; Wang and Hekimi 2015).

Another point of view is provided by the study of mutations in a number of genes that induce segmental progeroid syndromes and shorten life span in mice. The short life span of these mutant mice is accompanied by the accelerated expression of some of the phenotypes commonly encountered in aging (Mounkes et al. 2003; Wong et al. 2003; Baker et al. 2004; Chang et al. 2004; Trifunovic et al. 2004). While these have often been presented as representing alterations to the aging process, it remains possible that their shorter life spans are caused by the induction of specific pathologies that only mimic aspects of the actual aging process (Harrison 1994; Miller 2004).

It has also been argued that an extension of life span may not necessarily be concrete evidence of a retardation of the aging process (Orr et al. 2003; De Magalhaes et al. 2005; Ladiges et al. 2009). In this view, a life-span-extending intervention may simply remedy deficiencies in the environment or in the genetic makeup of one particular strain. The intervention would therefore extend life span by correcting specific flaws rather than altering the aging process. These considerations create a conundrum: If life span is not a reliable measure of aging, how can we confirm that a particular manipulation truly affects the aging process? One approach is to assess physiological phenotypes that are known to deteriorate with age, such as cognition or the functioning of the cardiovascular or immune systems, to detect similarities or discrepancies with the patterns observed in control strains. An alternative criterion is to consider whether a particular manipulation changes how mortality rates increase with age (Sacher 1977; Finch et al. 1990; De Magalhaes et al. 2005; Yen and Mobbs 2010). This is based on the hypothesis that the increased incidence of the age-related pathological changes that characterize the aging process is reflected in changing mortality rates.

Human mortality rates increase exponentially with age, as first noted and quantified by Benjamin Gompertz in 1825 (described by Olshansky and Carnes 1997). This property has subsequently been observed for the mortality rates of model organisms including mice, Drosophila, and C. elegans (Johnson 1987; Gavrilov and Gavrilova 1991; De Magalhaes et al. 2005). The Gompertz model of mortality is commonly expressed by the following equation, where the mortality rate (R) can be represented at any age (t) for a given population by


"G" describes the rate at which mortality rates accelerate with age and "A" represents the initial mortality rate at time 0 (Finch 1990). "A' is strictly theoretical as a mortality rate, since there can be no actual mortality at time 0. Instead, it can be determined by extrapolation from mortality rates at greater ages and does not necessarily correspond to true mortality rates at birth or during youth. Figure 1 shows how changes to the Gompertz parameters affect the survival curve of a hypothetical population of mice with a median life span of 2 years (solid black line). Decreasing A (solid blue lines) extends life span by shifting the inflection point of the curve rightward, such that it occurs proportionally later in age, relative to maximum life span. …

Search by... Author
Show... All Results Primary Sources Peer-reviewed


An unknown error has occurred. Please click the button below to reload the page. If the problem persists, please try again in a little while.