Sci. Aging Knowl. Environ., 17 March 2004
Vol. 2004, Issue 11, p. nf28
[DOI: 10.1126/sageke.2004.11.nf28]


Riddled With Errors

Mutations mount in elderly sperm

Shawne Neeper

As a factory ages and parts deteriorate, new production errors can appear, resulting in damaged goods. The same might be true of men's testicles. A new study finds that old mice have more--and different--DNA damage in their sperm than do younger animals. The results might help clarify the roots of disorders that are linked to paternal age.

Chances of fathering a healthy child decline with age. Sluggish sperm and scarce semen deserve part of the blame (see "Farewell to Fatherhood"); DNA glitches might contribute to these problems. Sperm mutations become more common late in life, but researchers don't know why. Molecular biologist Christi Walter of the University of Texas Health Science Center in San Antonio and colleagues found that sperm stem cells in young mice contain more errors than do full-fledged swimmers, indicating that mutations are culled during sperm-making. But in very old mice, mature sperm can hold 10 times as many errors as stem cells do. Walter and colleagues set out to determine whether seniors' sperm factories make the same mistakes as the youngsters' do, but more frequently, or whether they create new types of errors.

The researchers cataloged mutations in sperm from young, middle-aged, and old mice that harbored an extra gene, lacI. Previous work showed that lacI carries more glitches in late-life sperm, as does other DNA. Mice of all ages showed numerous DNA base-swapping and insertion mistakes, but the prevalence of specific mutation types differed in elderly animals. For example, the seniors' lacI exchanged the DNA bases thymine or adenine for guanine or cytosine more often than younger animals' did. Furthermore, these types of blunders constituted a higher proportion of the total errors.

To confirm the difference, Walter and colleagues pinpointed the mutations. lacI glitches usually cluster at five vulnerable sites. As expected, errors collected at these "hot spots" in younger mice. But in oldster sperm, mutations were scattered around the gene. If the same bloopers were accumulating throughout life, they would appear in similar locations regardless of age, the researchers say. "This [work] tells us there's something different going on in the old animals compared to the young animals," says Walter. Shifted mutation types and locations suggest altered DNA-damage or -repair mechanisms in late-life sperm, she says.

The results are "quite interesting and look biologically relevant," says geneticist John Heddle of York University in Toronto, Canada. Some scientists argue that the bacterial gene lacI might mutate differently from native mammalian DNA, he says. "This concern is declining but hasn't gone away."

Co-author Ronald Walter, a molecular biologist at Southwest Texas State University in San Marcos, says that the observations fit with the known increase in inherited disease with human paternal age. To explore why lacI mutations change in old age, the researchers will next investigate whether DNA repair falters in late-life sperm, as it might in other tissues (see Sinclair Perspective, Walter Perspective, and Fry Review). The results could help pinpoint the causes of inherited disorders that rise with paternal age, such as achondroplasia, a form of dwarfism, and point to approaches that might keep men's sperm factories running smoothly.

March 17, 2004

Suggested by Holly Van Remmen and Arlan Richardson.

  1. C. A. Walter, G. W. Intano, J. R. McCarrey, C. A. McMahan, R. B. Walter, Mutation frequency declines during spermatogenesis in young mice but increases in old mice. Proc. Natl. Acad. Sci. U.S.A. 95, 10015-10019 (1998). [Abstract/Free Full Text]
  2. C. A. Walter et al., Mutation spectral changes in spermatogenic cells obtained from old mice. DNA Repair, 12 March 2004 [e-pub ahead of print]. [Abstract/Full Text]
Citation: S. Neeper, Riddled With Errors. Sci. Aging Knowl. Environ. 2004 (11), nf28 (2004).

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