A Reassessment of Genes Modulating Aging in Mice Using Demographic Measurements of the Rate of Aging

Abstract

Many studies have reported genetic interventions that have an effect on mouse life span; however, it is crucial to discriminate between manipulations of aging and aging-independent causes of life extension. Here, we used the Gompertz equation to determine whether previously reported aging-related mouse genes statistically affect the demographic rate of aging. Of 30 genetic manipulations previously reported to extend life span, for only two we found evidence of retarding demographic aging: Cisd2 and hMTH1 Of 24 genetic manipulations reported to shorten life span and induce premature aging features, we found evidence of five accelerating demographic aging: Casp2, Fn1, IKK-β, JunD, and Stub1 Overall, our reassessment found that only 15% of the genetic manipulations analyzed significantly affected the demographic rate of aging as predicted, suggesting that a relatively small proportion of interventions affecting longevity do so by regulating the rate of aging. By contrast, genetic manipulations affecting longevity tend to impact on aging-independent mortality. Our meta-analysis of multiple mouse longevity studies also reveals substantial variation in the controls used across experiments, suggesting that a short life span of controls is a potential source of bias. Overall, the present work leads to a reassessment of genes affecting the aging process in mice, with broad implications for our understanding of the genetics of mammalian aging and which genes may be more promising targets for drug discovery.

Keywords: Mus musculus; hazard rate; longevity; meta-analysis; progeria; survival.

Figure 1

Natural logarithm of mortality rates for wild-type (WT, blue diamonds) and experimental transgenic (Tg, red squares) cohorts. Lines represent estimated adult mortality trajectories based on Gompertz parameters for the WT (blue lines) and experimental (red lines) cohorts. (A) Cisd2. (B) Sirt1.

Figure 2

Natural logarithm of mortality rates for wild-type (WT, blue diamonds) and experimental (red squares) cohorts. Lines represent estimated adult mortality trajectories based on Gompertz parameters for the WT (blue lines) and experimental (red lines) cohorts. KO, knockout. (A) Casp2; (B) MBH-IKK-β; (C) Xrcc6; and (D) Htr1b with the green line and circles representing an alternative for the WT cohort (see text for details).

Figure 3

Comparison between control (x-axis) and experimental cohorts (y-axis) for α in life-extending manipulations (A), R₀ in life-extending manipulations (B), α in life span-reducing manipulations (C), and R₀ in life span-reducing manipulations (D).