Age-associated structural alterations in senescent mouse brain DNA

Abstract

The maintenance of structural integrity in the DNA of aging mice has been examined with the amin in view of determining whether changes in genome structure constitute the molecular basis of aging. Cell lysate DNA from brains of differently aged mice was subjected to alkaline sucrose gradient sedimentation. The results show that brain DNA from young mice sediments mondispersely while that from senescent mice exhibits polydisperse sedimentation patterns, bainding in four peaks corresponding to number-average molecular weights of 1.4-10(8), 70-10(6), 15-10(6) and 3-10(6). When treated with nuclease S1, it was the 30 month mouse DNA whose sedimentation shifted to the top of the gradient indicating a reduction in its molecular weight as a result of nuclease digestion. The apparent increase in single strand breaks implies that the rate of breakage in old mouse brain DNA is faster than that of repair replication. The conclusion is drawn that senescence could result from an accumulation of defects in the genome.

Spontaneous mutation in Big Blue® mice from fetus to old age: Tissue‐specific time courses of mutation frequency but similar mutation types

“…The somatic mutation theory of aging proposes that the accumulation of mutations in somatic cells is an important cause of aging [Failla, 1958;Szilard, 1959;Curtis, 1971;Morley, 1998;Vijg, 2000]. A diversity of genetic alterations increase as a function of age, including sister chromatid exchange [Schneider et al, 1979], chromosome loss [Fenech, 1998], micronuclei [Dass et al, 1997;Bolognesi et al, 1999], chromosomal aberrations [Mukherjee and Thomas, 1997;Bolognesi et al, 1999], single-strand DNA breaks [Chetsanga et al, 1977;Ono et al, 1995] and rearrangements, point mutations, deletions, and insertions Stuart et al, 2000;Ono et al, 2000;Dolle et al, 2000]. In addition, senescence-accelerated mice, which have been bred to have a shortened life span, show an accelerated accumulation of somatic mutations [Odagiri et al, 1998].…”

The Influence of Aging on Lysosomal Acid DNase of the Rat Submandibular Gland

“…The accumulation of broken strands of DNA with age has been found in many tissues (Price et al, 1971;Massie et al, 1972;Ono and Okada, 1976;Chestsanga et al, 1977;Medvedev, 1984). Comfort (1966), Goto et al (1969), Price et al (1971), and Mizuno (1972) suggested that such changes in DNA could arise if the release of acid DNase from lysosomes is increased with age.…”

“…Yaegaki et al (1982Yaegaki et al ( , 1985 reported that while the salivary function and activity of acid DNase in human saliva decrease with age, the activity of neutral DNase is not significantly changed. On the other hand, other investigators found, with aging, an accumulation of DNA strand breaks in nuclei of many tissues (Price et al, 1971;Massie et al, 1972;Ono and Okada, 1976;Chestsanga et al, 1977;Medvedev, 1984). Comfort (1966) suggested that aging involves lysosomal DNase which is capable of cleaving DNA strands.…”

Molecular Biology of Aging Part I: An Introduction to Laboratory Techniques of Molecular Biology

“…Alkaline and neutral sucrose gradient sedimentation techniques allow estimation of single strand breaks 54,55 . However, these techniques are not specific for single strand breaks.…”