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Accelerated accumulation of somatic mutations in the senescence-accelerated mouse

Nature Genetics volume 19, pages 116–117 (1998)Cite this article

The somatic mutation theory of ageing proposes that the accumulation of mutations in somatic cells is an important cause of ageing. One prediction of the theory, namely that somatic mutations will be observed to accumulate, has been confirmed for a variety of loci in human and mouse cells1. Another prediction is that manipulations that alter the rate of ageing will be associated with a corresponding alteration in the rate of mutation accumulation. This has been confirmed for dietary restriction2, which prolongs lifespan in rodents. Here, we report on further confirmation obtained from our study of the senescence-accelerated mouse (SAM) strain. SAM mice constitute a mouse model of accelerated senescence, produced by selective inbreeding, in which the features of senescence become apparent at four months3.

In adult animals (in which the total number of lymphocytes remains approximately constant), the mutation rate (per cell per unit time) equals the rate of increase of MF (ref. 6). We observed a plateau in the relationship between MF and age in surviving SAMP1 mice. This may indicate a true plateau in the underlying relationship between MF and age, which would suggest that MF increases with age in approximately a Gompertzian fashion. Alternatively, because the median lifespan of SAMP1 mice is 9.9 months, the 9-and 11-12-month data may have been biased if mice with higher MF die early. Given the difficulty in interpreting the observed plateau, we restricted our analysis to the first part of life by using the 3- and 6-month data from SAMP1 mice and the 3-, 6-, 9- and 11-12-month data from the SAMR1 and Balb/cA mice. We modelled an exponential increase of MF by calculating linear regressions between the logarithm (base 10) of MF and the age in months (Fig. 1). There was no significant differences in mean of mutation frequency between SAMP1 and SAMR1 mice at three months (Mann-Whitney U-test) but the gradients of the regression lines for SAMR1 mice differed significantly (t-test, P<0.01) from those for SAMP1 mice. The slopes of the regression lines indicate that the fractional increase in mutation rate per month in SAMP1 mice was approximately five-fold greater than that in SAMR1 mice during the early part of life. The time at which the increase in MF was observed in SAMP1 mice paralleled the time at which the phenotypic features of ageing developed.

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Figure 1: Mutation frequencies.

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Authors and Affiliations

  1. Division of Human Health Sciences, Yamanashi Prefectural College of Nursing, 1-6-1, Ikeda, Kofu, 400-0062, Yamanashi, Japan

    Youichi Odagiri

  2. Department of Public Health, Saitama Medical School, 38, Maorayama-machi, Iruma-gun, 350-0451, Saitama , Japan

    Hiroyuki Uchida & Kazuo Takemoto

  3. Department of Senescence Biology, Chest Disease Research Institute, Kyoto University, Sakyo-ku, Kyoto, 606-01 , Japan

    Masanori Hosokawa & Toshio Takeda

  4. Department of Haematology and Genetic Pathology, Flinders University and Flinders Medical Centre, Bedford Park, 5042, South Australia, Australia

    Alexander A. Morley

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  1. Youichi Odagiri
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  6. Toshio Takeda
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Correspondence to Youichi Odagiri.

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Odagiri, Y., Uchida, H., Hosokawa, M. et al. Accelerated accumulation of somatic mutations in the senescence-accelerated mouse. Nat Genet 19, 116–117 (1998). https://doi.org/10.1038/468

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