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A putative gene causes variability in lifespan among genotypically identical mice

Nature Genetics volume 19, pages 114–116 (1998)Cite this article

Ageing is a complex process during which damage to multiple organ systems accumulates1. The time at which impairment of critical bodily functions becomes incompatible with life determines organismal longevity and is usually measured in a population as mean or maximal lifespan. Our current understanding of the genes affecting longevity, particularly in mammalian species, is rudimentary at best2. Here we studied the range of lifespans among individual animals within genetically identical recombinant inbred (RI) strains of mice. We found that the time between the deaths of the first and last members of a given strain fell into two temporal groups, despite the fact that strains may have had similar mean or maximal lifespans. The segregation of RI strains into wide and narrow ranges that roughly corresponded to characteristic lifespan ranges of the progenitor strains, suggested a genetic component. We therefore mapped a putative gene accounting for more than 60% of the phenotype to a genomic segment near the centromere on chromosome 11. This locus causes variability in the rate at which genetically identical members of a population die and, from a practical standpoint, affects the slope of a death curve for a population.

The phenotypic consequences of allelic variation at the putative quantitative trait locus (QTL) for six representative BXD strains—three with the 'B' allele and three with the 'D' allele (the best and worst fit in each case)—as reflected in the slopes of survival curves, is shown in Fig. 2b. To correct for the previously noted differences in mean lifespan among strains, we calculated the slopes of the curves starting on the day on which the first mouse within a given strain died. The intra-strain death rate (after the first death) was significantly higher in strains with the 'D' allele (Fig. 1c) comparing lifespan ranges. A simple linear regression model was found to best fit the mortality data and consequently the slopes of the regression lines for all strains were used to obtain the mapping result (Fig. 2a).

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Figure 1: Mapping a locus conferring variability on organismal longevity.
Figure 2: Phenotypic consequences of allelic variation at the putative locus conferring longevity variability.

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Acknowledgements

This work was supported by the Lucille P. Markey Cancer Center, the University of Kentucky Hospital and the Department of Internal Medicine. The original lifespan studies were carried out with support of NIH grant AG02329.

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Authors and Affiliations

  1. Blood and Marrow Transplant Program, Lucille P. Markey Cancer Center, University of Kentucky Medical Center, 800 Rose Street, Lexington, 40536-0093, Kentucky, USA

    Gerald de Haan & Gary Van Zant

  2. Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA

    Rebecca Gelman, Ada Watson & Edmond Yunis

  3. Harvard Medical School, Boston, 02115, Massachusetts, USA

    Rebecca Gelman & Edmond Yunis

  4. Department of Physiological Chemistry, University of Groningen, The Netherlands

    Gerald de Haan

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  1. Gerald de Haan
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  5. Gary Van Zant
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Correspondence to Gary Van Zant.

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de Haan, G., Gelman, R., Watson, A. et al. A putative gene causes variability in lifespan among genotypically identical mice. Nat Genet 19, 114–116 (1998). https://doi.org/10.1038/465

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