A Small Step Towards Determining the Relevance of Nuclear DNA Damage to Normal Aging
Researchers recently reported the development of a system to generate a form of damage to nuclear DNA in a sizable number of discrete locations in a controlled, isolated way, and use it to test a limited hypotheses regarding the contribution of DNA damage to age-related epigenetic changes. This is a small step forward towards determining whether or not nuclear DNA damage is a meaningful cause of aging. This damage occurs constantly and randomly, most of it repaired, but the few mutations that slip through accumulate in tissues across a lifespan. You have more of this damage if you are old, and this is one of the reasons that cancer is an age-related disease: the more mutations, the more likely it is that the right combination to spark a cancer occurs. But beyond cancer, is this random nuclear DNA damage, different in every cell, a significant cause of aging over the present human life span? The consensus is yes, and the thinking is that these mutations cause enough dysregulation of cellular activities to be harmful, but this consensus is disputed.
What is needed is a way to either create or repair random nuclear DNA damage in isolation of other cellular processes. There are plenty of interventions to slow aging in laboratory animals that happen to slow the rate at which nuclear DNA damage occurs, but these interventions also alter vast swathes of the operating details of cellular metabolism. There is no way to pin down the relevance of nuclear DNA damage on its own in that situation. The methodology reported in the open access paper linked here is a small step towards the sort of biotechnology needed to reproduce random nuclear DNA damage in much the same way as it occurs naturally, and thus run a study on whether or not it is a cause of aging. There is still a way to go towards that end result, however:
The accumulation of DNA damage is a conserved hallmark of cancer and aging. Of all DNA lesions, DNA double-strand breaks (DSBs) are arguably the most harmful. Defects in DSB repair can result in cell cycle arrest, apoptosis or genomic aberrations and have been linked to both disease progression and a premature onset of aging phenotypes. Consistent with the latter, DSB induction was found to be sufficient to promote a subset of age-related pathologies in mice. In addition to the often detrimental effects of mutations and chromosomal abnormalities, DSBs cause significant changes in the chromatin environment both at and beyond the break site, raising the intriguing possibility that DSB repair contributes to (persistent) epigenetic defects that may eventually alter cell function. It is of note that epigenetic dysfunction in a small subset of cells may be sufficient to affect entire tissues, and possibly organismal aging.The distinction between cell-intrinsic and systemic consequences of DSB induction is, thus, critical to advance our understanding of the role of DSBs in age-associated functional decline. However, despite numerous cell-based reporter systems for DSB induction, there is a scarcity of tools to follow the consequences of DSBs for cell and tissue function in higher organisms. Here, we describe a mouse model that allows for both tissue-specific and temporally controlled DSB formation at ∼140 defined genomic loci. Using this model, we show that DSBs promote a DNA damage signaling-dependent decrease in gene expression in primary cells specifically at break-bearing genes, which is reversed upon DSB repair. Importantly, we demonstrate that restoration of gene expression can occur independently of cell cycle progression, underlining its relevance for normal tissue maintenance. Consistent with this, we observe no evidence for persistent transcriptional repression in response to a multi-day course of continuous DSB formation and repair in mouse lymphocytes in vivo. Together, our findings reveal an unexpected capacity of primary cells to maintain transcriptome integrity in response to DSBs, pointing to a limited role for DNA damage as a mediator of cell-autonomous epigenetic dysfunction.