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A MODEL FOR AGING BASED ON DIFFERENTIAL REPAIR OF SOMATIC MUTATIONAL DAMAGE K. LEMONE YIELDING* Introduction The accumulation of DNA damage in somatic cells with resultant mutations has attracted considerable attention as a mechanism for aging [1-5]. This idea is supported by the observation that the classic mutagen, X-irradiation, accelerates aging consistently [6-10], and, like spontaneous aging, results in chromosomal aberrations [11-14]. It has also been observed that elevated temperature affects the life span and mutation rates in Drosophila melanogaster in parallel fashions [15]. A major difficulty with the mutation mechanism has been in rationalizing how such single events at random loci in different cells could lead to the cumulative expression of the unifomly depressed function seen at the organ and organism levels. This is particularly troublesome since single mutations often suffice to eliminate a single biologic function completely. Thus, in a multicellular organism it is difficult to understand why such random mutant cells are not simply eliminated by normal selective pressures. The present model proposes that damage to DNA of somatic cells is indeed a basic mechanism, but due to specific variations in availability of the DNA to repair enzymes, the damage accumulates preferentially in chromosomal sectors which may not be transcribed actively. The major effect of this type of accumulation of DNA defects would be to disrupt the orderly replication and replenishing of cells rather than being limited to expression of specific point mutations. In this context the cumulative damage would be important principally in the quantitative sense, and cells with equal damage but at different loci could be viewed as being uniformly "abnormal" and equally impaired in their replicative ability. The model is consistent with a number of experimental observations and recognizes repair and differentiation as potentially important controlling factors for mutations and the aging process. ?Laboratory of Molecular Biology, School of Medicine, University ofAlabama, Birmingham Alabama 35294. Recipient of RCDA # GM-22698 from the National Institutes of Health. Perspectives in Biology and Medicine · Winter 1974 | 201 Description of the Model THE TARGET FOR MUTATION DAMAGE In the present discussion DNA is considered as a nonuniform substrate for somatic mutational damage by virtue of variations in function and physical accessibility. Chromatin will be classified as "active" and "inactive" to imply, respectively, those chromosomal sectors which are responsible for specific cell functions and, therefore, physically accessible for transcription and other enzymic processes; and those sectors which are functionally and physically masked throughout most of the cell cycle. Although euchromatin and heterochromatin also represent convenient morphologic classifications of chromatin with a variety of differences in properties, our present state of knowledge does not provide a precise definition of their functions, and, for example, important sectoring into active and inactive fractions may exist within both euchromatin and heterochromatin. The active fraction represents quantitatively a minor part of the total DNA and corresponds to the genes responsible for specific qualitative expression, plus those concerned with cell regulation (including "repression " of genes which are in the inactive sector). The inactive DNA, even though it may not be transcribed into gene products, must also be copied and "packaged" with each replication cycle, and since it represents most of the cellular DNA, its replication rather than that of the active genes may play the dominant role in the overall kinetics and staging of cell replication. Moreover, because of its relative size, the inactive sector could represent the major "target" for such mutational damage as radiation, thermal breaks, etc. Such lesions may be silent with respect to gene expression since they are not transcribed into RNA, but would exert a quantitative impediment to the processes of DNA synthesis and chromosomal organization for cell replication. Since the model does not require that hits in two cells have to be in identical inactive loci to produce the same quantitative effect, it is much less restrictive than the usual mutation model for producing uniform populations of abnormal cells. Obviously, the probability of two cells sustaining approximately the same amount of damage over a period of time is enormously greater than that for experiencing modifications in precisely the same genetic loci. The active DNA can also be an important target for DNA damage, of course...

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