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Msh2 promoter region hypermethylation as a marker of aging-related deterioration in old retired female breeder mice

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Abstract

Aging is a process where individuals decrease the performance of their physiological systems and cellular stress response, making them more susceptible to disease and death. The increase in DNA damage associated with age might be recognized as the accumulation of physiological and environmentally induced mutations accompanied with a decline in DNA repair. DNA mismatch repair (MMR) is the main postreplicative correction pathway, which is known to decrease with age. However, since infrequent occurrence of direct DNA damage contrasts with the extensive cell and tissue dysfunction seen in older individuals, the withdrawing of DNA-repairing systems might be also related to epigenetic changes, such as DNA methylation. It has been reported that the physiological stress related to breeding might accelerate the acquisition of aging-related markers; therefore, the aim of this work was to link age with epigenetic modifications in this animal population. Hence, the correlation of Msh2 gene silencing with the deterioration of breeding female mice associated to aging was determined. Combined bisulfite restriction analysis assay was used to compare methylation on DNA isolated from twelve-month-old retired breeders against nulliparous female mice aged-matched, and two-month-old young adults. Our experiments clearly reveal Msh2 promoter hypermethylation associated to the aging process. A higher degree methylation was additionally observed in breeding females DNA. Nevertheless, this additional methylation did not correlate with a further decrease Msh2 mRNA, suggesting that the increase in methylation in old retired breeder might account for further epigenetic changes that could additionally promote the aging process.

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Abbreviations

MMR:

DNA mismatch repair

COBRA:

Combined bisulfite restriction analysis assay

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Acknowledgments

The authors would like to thank R. González-Vieira MVZ who cared for the animals, Dr. FJ Perrino (UAMI) and Dr. MT Villarreal-Molina (INCMNSZ) for their help with the molecular biology and sequencing techniques. We also want to thank Dr. JP Issa and Drs. Wombak and Kroeger from the University of Texas M. D. Anderson Cancer Center for their guidance in the COBRA methodology. This work was supported by CONACyT′s grant CB-2006-1-59659. JC Conde-Pérezprina and A Luna-López are CONACYT scholarship holders.

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Authors and Affiliations

  1. Departamento de Ciencias de la Salud, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, A.P. 55-535, C.P. 09340, Mexico, DF, Mexico

    Juan C. Conde-Pérezprina, Armando Luna-López, Norma E. López-Diazguerrero & Mina Königsberg

  2. Programa de Posgrado en Biología Experimental, Universidad Autónoma Metropolitana-Iztapalapa, Mexico, DF, Mexico

    Juan C. Conde-Pérezprina & Armando Luna-López

  3. Depto. Biología de la Reproducción, DCBS, Universidad Autónoma Metropolitana-Iztapalapa, A.P. 55-535, C.P. 09340, Mexico, DF, Mexico

    Pablo Damián-Matsumura

  4. Depto. Bioquímica, Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán” & Depto. Medicina Genómica y Toxicología Ambiental, IIB-UNAM, Mexico, DF, Mexico

    Alejandro Zentella

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  1. Juan C. Conde-Pérezprina
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  2. Armando Luna-López
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Correspondence to Mina Königsberg.

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Conde-Pérezprina, J.C., Luna-López, A., López-Diazguerrero, N.E. et al. Msh2 promoter region hypermethylation as a marker of aging-related deterioration in old retired female breeder mice. Biogerontology 9, 325–334 (2008). https://doi.org/10.1007/s10522-008-9144-8

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  • DOI: https://doi.org/10.1007/s10522-008-9144-8

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