Cross-Linkage Hypothesis of Aging: DNA Adducts in Chromatin as a Primary Aging Process

Cutler, Richard G.

doi:10.1007/978-1-4757-1662-7_21

Cited by 19 publications

(5 citation statements)

References 121 publications

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“…Our data are consistent with this, but also support a general mechanism of aging (4)(5)(6)(7)(8). Here, the transformed cell would be a special case of a more general type of dedifferentiation, which leads more frequently to a less functional aged cell in the nontransformed state.…”

Section: Resultssupporting

confidence: 79%

Age-dependent relaxation of gene repression: Increase of endogenous murine leukemia virus-related and globin-related RNA in brain and liver of mice

Ono

Cutler

1978

Proc. Natl. Acad. Sci. U.S.A.

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A progressive loss in the ability of cells to maintain their normal specialized states of differentiation could be the common denominator underlying much of the physiology and pathology associated with the mammalian aging process. We investigated this possibility by searching for an age-dependent derepression of endogenous genes in tissues in which they are not normally expected to be expressed. Complementary DNA (cDNA) probes to globin genes and to the murine leukemia type C RNA virus (MuLV) genome were used to detect the presence of RNA complementary to these genes in RNA extracted from brain and liver in young and old mice. Significant amounts of globin RNA were found in brain nuclei and cytoplasm. No age difference was found in the globin RNA sequences present, but the number of globin RNA molecules increased from about 15 in 6-month to 34 in 27-month-old animals for nuclei and 280 in 6-month to 500 in 27-month-old animals for cytoplasm. Similar results were found for liver. RNA complementary to the MuLV cDNA probe was also found but, in contrast to globin, the different RNA sequences increased in both brain and liver nuclei from about 45% of the MuLV genome in 6-month to 72% in 27-month-old animals. The number of MuLV-related RNA molecules remained constant at about 22 and 38 per nuclei for brain and liver, respectively. Derepression of genes of this magnitude could result in a time-dependent increase in virus-related diseases and a general deterioration of the organism.

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Section: Resultssupporting

confidence: 79%

Age-dependent relaxation of gene repression: Increase of endogenous murine leukemia virus-related and globin-related RNA in brain and liver of mice

Ono

Cutler

1978

Proc. Natl. Acad. Sci. U.S.A.

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“…Smith (1976a,b), Han (1976), andCutler (1976) have reviewed the possible role of nucleic-acid-protein cross-linking, including cross-linking induced by UV light, in causing biological damage such as death on the cellular level and aging on the level of the organism. In this section we briefly discuss a couple of papers, other than those described in the previous sections, that have appeared since the above reviews and suggest that DNA-protein cross-linking as a cause of observed biological effects of UV light.…”

Section: Biological Consequences Of Uv-induced Dna-protein Cross-linkingmentioning

confidence: 99%

Cross-Linking of Proteins to Nucleic Acids by Ultraviolet Light

Shetlar

1980

Photochemical and Photobiological Reviews

100

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“…If the information stability of DNA proves to be a major factor governing aging rate (9,66), then an interesting prediction of these results is that mutation rate, acting as a primary aging process, may have actually decreased during the evolution of the primates. Other data have also indicated a decrease in mutation rate, and several explanations have been suggested (43,47,55,56,67).…”

Section: Zoology: Cutlermentioning

confidence: 99%

Evolution of human longevity and the genetic complexity governing aging rate.

Cutler¹

1975

Proc. Natl. Acad. Sci. U.S.A.

157

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Genetic complexity of processes governing the aging rate of man was estimated by determining the maximum rate lifespan has evolved along the hominid ancestral-descendant sequence. Maximum lifespan potential was found to have increased approximately 2-fold over the past 3 million years, reaching a maximum rate of increase of 14 years per 100,000 years about 100,000 years ago. It is estimated that about 0.6% of the total functional genes have received substitutions leading to one or more adaptive aminoacid changes during this 100,000-year time-period. This suggests that aging is not the result of an expression of a large number of independently acting processes. Instead, primary aging processes appear to exist where only a few genetic changes are necessary to decrease uniformly the aging rate of many different physiological functions.Maximum lifespan (MLS) potential is defined as the maximum observed lifespan of a species (1-3). This value is usually obtained with animals living under favorable conditions but does not vary greatly even over a wide range of living conditions. There is about a 50-fold range of MLS potential for the mammalian species (1-4). However, the various types of age-dependent physiological dysfunctions and diseases are quite similar and are expressed in similar temporal patterns. This is not surprising, considering the similarities at the physiological, biochemical, and molecular levels for the mammalian species, and particularly for the primates, where a 10-to 12-fold difference in MLS potential is found (5-7). Thus, mammalian species appear to age qualitatively in the same manner, by the same types of biological processes, but at different rates that can vary over a 50-fold range (3,(8)(9)(10).These types of observations had suggested that the genetic processes governing aging rate may not be too complex (8,11,12). However, there are other arguments that suggest that the aging process is highly diverse and complex, involving many different genes acting independently of one another (13)(14)(15)(16)(17)(18). If this were true, then a uniform increase in lifespan, maintaining the qualitative aspects of the aging process, would require a change in all of these genes.In this paper, the genetic complexity of the processes governing aging rate in man is estimated by determining the highest rate at which MLS potential has evolved along the hominid ancestral-descendant sequence leading to modern man. This rate is compared to the range of evolutionary rates of other characteristics of mammals and to estimates of the maximum rate new genes could have evolved during this time period. RESULTS

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Cross-Linkage Hypothesis of Aging: DNA Adducts in Chromatin as a Primary Aging Process

Cited by 19 publications

References 121 publications

Age-dependent relaxation of gene repression: Increase of endogenous murine leukemia virus-related and globin-related RNA in brain and liver of mice

Age-dependent relaxation of gene repression: Increase of endogenous murine leukemia virus-related and globin-related RNA in brain and liver of mice

Cross-Linking of Proteins to Nucleic Acids by Ultraviolet Light

Evolution of human longevity and the genetic complexity governing aging rate.

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