Reaction to DNA damage and aging
Review of research articles published in 2009 that have made or will make a significant contribution to the study of aging – Part 2.
In 2009, it was demonstrated that a persistent reaction to DNA damage developing in cells in the phase of physiological aging is necessary to maintain their ability to express and secrete inflammatory cytokines [8]. IL-1-alpha bound to the cell surface is necessary for the secretion of IL-6 and IL-8 associated with physiological aging, two pro–inflammatory cytokines that aggravate the phenotype of physiological aging [9].
Both for the initiation and maintenance of cytokine secretion, ATM, NBS1 and CHK2 proteins involved in the development of the reaction to DNA damage are required, but not the p53 protein. ATM is also necessary for the secretion of IL-6 during physiological aging induced by oncogene activation, as well as in damaged cells undergoing physiological aging. It has been suggested that such activity of proteins reacting to DNA damage allows cells in the phase of physiological aging to inform the cells of surrounding tissues about their abnormal state [8]. In addition, a reaction to DNA damage can develop in cells in the phase of physiological aging, even in the absence of recorded DNA damage [10]. This pseudo-reaction to DNA damage is a marker of cell hyperactivation and is suppressed by rapamycin [10], a drug that slows down the physiological aging of cells and has been approved for clinical use [11]. Thus, a stable reaction to DNA damage, regardless of the presence of DNA damage, can be a component of the phenotype of physiological aging.
It has been demonstrated that longevity–associated mutations of the yeast gene SCH9 - the yeast homologue of the conserved (preserved in almost unchanged form during evolution) gene S6K (ribosomal S6 kinase) – cause a significant decrease in the number of age-related DNA damage by suppressing the activity of error-prone genes responsible for repairing DNA damage [12].
In addition, the age-related deterioration of the nuclear pore complexes leads to an increase in the permeability of the nuclear envelope and the penetration of cytoplasmic proteins into the nuclei of postmitotic cells [13]. The ability to respond to stress decreases with age. Transcription-regulating factors that ensure the development of a stress response can have an impact on life expectancy. In 2009, Westerheide et al. demonstrated that stress-induced regulation of heat shock factor-1 (HSF-1), carried out by SIRT1 deacetylase (sirtuin-1), can play a role in regulating life expectancy [14]. Identification of sirtuin targets may help to understand the importance of transcriptional regulation of age-related diseases.
A very interesting assumption is that the reaction of cells to certain types of DNA damage (for example, DNA breaks) leads to epigenetic changes that change gene expression [15]. Such changes do occur in mammalian cells. It would be interesting to find out whether the epigenetic changes that occur in response to DNA damage are the consequences of aging, or may be its direct cause.
Continuation: Mitochondria, oxidative stress and aging.
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