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Aging Brain: DNA Damage or Neuron Loss?
Posted on: February 23, 2006

Age-related molecular and cellular alterations in the central nervous system are known to show selectivity for certain cell types and brain regions. Among them age-related accumulation of nuclear (n) DNA damage can lead to irreversible loss of genetic information content.

Compelling evidence in the literature points to a central role of accumulation of nuclear (n) DNA damage in the aging process of postmitotic cells such as neurons in the central nervous system (CNS). However, the aging process does not affect the CNS uniformly. Rather various brain regions and types of neurons differ substantially in the amount of nDNA damage accumulation during aging. Specifically, more nDNA damage was found in the aging hippocampus than in the aging cerebellum. Furthermore, it has been shown for the mouse brain that hippocampal pyramidal and granule cells were affected by an age-related decline in the amount of spontaneous nDNA repair whereas cerebellar Purkinje cells were not. Noticeably, other studies on rodents have indicated an age-related reduction in the number of cerebellar Purkinje cells whereas no alterations in the number of hippocampal pyramidal and granule cells as well as in the number of cerebellar granule cells were found during aging. In this regard it is noteworthy to consider that at least hippocampal pyramidal cells as well as cerebellar granule and Purkinje cells are not replenished with age by neuronal progenitor cells. Thus, hippocampal pyramidal cells, cerebellar granule cells and cerebellar Purkinje cells which might be lost during aging cannot be replaced by new cells. It is hypothesized that neurons in the mammalian CNS show either an age-related increase in the amount of accumulated nDNA damage, connected with age-related decline in the ability to properly repair nDNA damage, or an age-related reduction in number.

The aim of the present study was to test this hypothesis for the aging mouse brain. For this aim, both the relative amount of nDNA single-strand breaks and the total numbers of cells were measured for hippocampal pyramidal and granule cells as well as for cerebellar granule and Purkinje cells in adult and aged animals taken from the same cohort of mice aged under controlled conditions.

In the aging mouse brain, scientists have observed a substantial increase in the amount of nDNA single-strand breaks in hippocampal pyramidal and granule cells as well as in cerebellar granule cells but not in cerebellar Purkinje cells. The reverse pattern was found for age-related reductions in total numbers of neurons. Only the total number of cerebellar Purkinje cells was significantly reduced during aging whereas the total numbers of hippocampal pyramidal and granule cells as well as of cerebellar granule cells were not. This formerly unknown inverse relation between age-related accumulation of nDNA damage and age-related loss of neurons may reflect a fundamental process of aging in the central nervous system.

Source: Bart P.F. Rutten, Christoph Schmitz, Oliver H.H. Gerlach, Hans M. Oyena, Emmily Bueno de Mesquita, Harry W.M. Steinbusch, Hubert Korr; The aging brain: Accumulation of DNA damage or neuron loss? Neurobiology of Aging 2005.
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