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DNA damage metabolism and aging
E Mullaart1, P H Lohman, F Berends
1Department of Molecular Biology, TNO Institute for Experimental Gerontology, Rijswijk, The Netherlands.
Abstract:
As a result of permanent exposure to low levels of various endogenous and exogenous genotoxic agents, large numbers of lesions are continuously induced in the DNA of cells of living organisms. Such lesions could lead to dysfunction of cells and tissues, and they might well be the underlying cause of the age-related reduction of homeostatic capacity and the increased incidence of cancer and other diseases of old age. The rate of damage induction as well as the persistence of the lesions depends on the activity, efficiency and reliability of a wide variety of molecular defense systems. However, a certain degree of imperfection seems to be a general characteristic of most of these defense systems and this could lead to a gradual accumulation of DNA alterations during aging. Even when the original lesions are quickly removed, they can still lead to secondary changes in the DNA, such as DNA-sequence changes and changes in gene expression. This process would be accelerated in case of the occurrence of an age-related decline in the efficiency of these molecular defense systems. This review deals with the present knowledge on the occurrence of 'spontaneous' DNA damage in aging organisms, its potential sources, the influence of preventive and processive cellular defense mechanisms and its consequences in terms of DNA-sequence changes, DNA conformational and configurational changes and changes in gene expression. In general, it can be concluded from the data discussed here that, in spite of a number of discrepancies and conflicting results, an age-related accumulation of DNA alterations occurs at all levels, e.g., chemical structure, DNA-sequence organization and gene expression.
Insights
DNA damage accumulates with age due to imperfect cellular defense mechanisms. This accumulation of DNA alterations contributes to age-related decline and increased disease risk.
Area of Science:
- Molecular Biology
- Genetics
- Aging Research
Background:
- Cells constantly face DNA damage from internal and external genotoxic agents.
- Accumulated DNA damage is linked to reduced cellular function, aging, and increased disease incidence.
Purpose of the Study:
- To review current knowledge on spontaneous DNA damage in aging organisms.
- To explore sources of DNA damage, cellular defense mechanisms, and consequences.
- To understand the link between DNA alterations and aging.
Main Methods:
- Literature review of studies on DNA damage and aging.
- Analysis of cellular defense systems and their efficiency.
- Examination of consequences including DNA sequence and gene expression changes.
Main Results:
- Imperfect cellular defense systems lead to gradual DNA alteration accumulation during aging.
- Even repaired DNA damage can cause secondary changes in DNA sequence and gene expression.
- Age-related decline in defense mechanisms accelerates DNA alteration accumulation.
Conclusions:
- An age-related accumulation of DNA alterations occurs across chemical structure, DNA sequence, and gene expression.
- Despite conflicting results, the link between DNA damage and aging is evident.
- Understanding these processes is crucial for addressing age-related diseases.