One of the most interesting areas of research into aging at the moment is the question of whether detrimental epigenetic changes that occur in cells throughout the body with age, altering cell behavior for the worse, are caused by the operation of DNA repair processes in response to stochastic damage to nuclear DNA. The concept and animal study evidence are recent enough that it should be considered speculative, and any of the details published to date subject to revision.
If true, however, this relationship in which DNA repair causes epigenetic aging would neatly resolve a range of challenges in the understanding of the role of nuclear DNA damage in aging. For example that mutational damage to nuclear DNA doesn't appear to cause enough harm to cell function to explain the major changes that occur with age. Most nuclear DNA damage occurs in somatic cells with few cell divisions remaining, limiting the spread of the mutation, and occurs in gene sequences that don't much matter or are not even used.
Somatic mosiacism, the spread of mutations over time from stem cell populations out into the tissues they support via the vector of daughter somatic cells, can somewhat salvage this situation by amplifying a tiny number of mutations into widespread existence. However, present investigations of the role of clonal hematopoiesis of indeterminate potential, the name given to somatic mosaicism in hematopoietic cells and the immune system, suggest that it isn't harmful enough to explain very much of aging. It raises risks, it isn't driving degeneration.
Today's open access paper is a recent exploration of epigenetic change induced by DNA damage, employing a mouse model generated a few years ago. Here, this model is crossbred with an Alzheimer's disease model in order to look at relevance to that condition. Cynically, one should assume that this choice of direction in research is driven as much by the funding incentives as the reasonable scientific rationale for the relevance of a mechanism of aging to any specific age-related condition, as work on Alzheimer's disease represents a sizable fraction of all public funding for aging research. Still, all significant new work on this issue of DNA repair and epigenetic change is welcome.
The dramatic increase in human longevity over recent decades has contributed to a rising prevalence of age-related diseases, including neurodegenerative disorders such as Alzheimer's disease (AD). While accumulating evidence implicates DNA damage and epigenetic alterations in the pathogenesis of AD, their precise mechanistic role remains unclear. To address this, we developed a novel mouse model, DICE (Dementia from Inducible Changes to the Epigenome), by crossing the APP/PSEN1 (APP/PS1) transgenic AD model with the ICE (Inducible Changes to the Epigenome) model, which allows for the controlled induction of double-strand DNA breaks (DSBs) to stimulate aging-related epigenetic drift.
We hypothesized that DNA damage induced epigenetic alterations could influence the onset and progression of AD pathology. After experiencing DNA damage for four weeks, DICE mice, together with control, ICE, and APP/PS1 mice, were allowed to recover for six weeks before undergoing a battery of behavioral assessments including the open-field test, light/dark preference test, elevated plus maze, Y-maze, Barnes maze, social interaction, acoustic startle, and pre-pulse inhibition (PPI). Molecular and histological analyses were then performed to assess amyloid-β pathology and neuroinflammatory markers.
Our findings reveal that DNA damage-induced epigenetic changes significantly affect cognitive behavior and alters amyloid-β plaque morphology and neuroinflammation as early as six months of age. These results provide the first direct evidence that DNA damage can modulate amyloid pathology in a genetically susceptible AD model. Future studies will be aimed at investigating DNA damage-induced epigenetic remodeling across additional models of AD and neurodegeneration to further elucidate its role in brain aging and disease progression.
View the full article at FightAging
