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.

The landscape of longevity across phylogeny

“…We found that the effects of most lifespan-modulating interventions correspond to the displacement along such degeneracy manifolds on the longevity landscape. This is consistent with recent observations that most interventions in large-scale screens do not affect the mortality doubling rate (the rate of aging) (Liu and Acar, 2018;Nowak et al, 2018;Pedro de Magalhães et al, 2018).…”

SynergyAge, a curated database for synergistic and antagonistic interactions of longevity-associated genes

“…For example, the range of recorded lifespans in our database for wild type strains of C. elegans under various conditions varies between 17.2 and 34.5 days at 15 degrees (avg: 23.66 days; SD: 4.36 days), and between 10.95 and 26 days at 20 degrees (avg: 18.8 days; SD 2.67 days) (for full histograms of WT lifespan at various temperatures, see http://www.synergyage.info/details/wildtype/ ). This was somewhat expected and is in line with literature reports as significant differences between the lifespan of controls is reported even in mice 25 . Similarly, if we consider the lifespan variation for one of the most well-known long-lived mutants, daf-2(e1370) worms live between 32.3 and 48.7 days at 15 degrees (avg: 37.7 days; SD: 4.52 days), and between 21.86 and 60.8 days at 20 degrees (avg: 39 days; SD: 7.98 days).…”

SynergyAge: a curated database for synergistic and antagonistic interactions of longevity-associated genes

“…example, the range of recorded lifespans in our database for wild type strains of C. elegans under various conditions varies between 17.2 and 34.5 days at 15 degrees (avg: 23.66 days; SD: 4.36 days), and between 10.95 and 26 days at 20 degrees (avg: 18.8 days; SD 2.67 days) (for full histograms of WT lifespan at various temperatures, see http://www.synergyage.info/details/wildtype/). This was somewhat expected and is in line with literature reports as significant differences between the lifespan of controls is reported even in mice20 . Similarly, if we consider the lifespan variation for one of the most well-known long-lived mutants, daf-2(e1370) worms live between 32.3 and 48.7 days at 15 degrees (avg: 37.7 days; SD: 4.52 days), and between 21.86 and 60.8 days at 20 degrees (avg: 39 days; SD: 7.98 days).…”