DNA is a precious molecule. It encodes vital information about cellular content and function. There are only two copies of each chromosome in the cell, and once the sequence is lost no replacement is possible. The irreplaceable nature of the DNA sets it apart from other cellular molecules, and makes it a critical target for age-related deterioration.
To prevent DNA damage cells have evolved elaborate DNA repair machinery. Paradoxically, DNA repair can itself be subject to age-related changes and deterioration.
The changes in efficiency of mismatch repair (MMR), base excision repair (BER), nucleotide excision repair (NER) and double-strand break (DSB) repair systems during aging, and potential changes in DSB repair pathway usage that occur with age.
Mutations in DNA repair genes and premature aging phenotypes they cause have been reviewed extensively elsewhere, therefore the focus of this review is on the comparison of DNA repair mechanisms in young versus old.
The prevailing view regarding causes of aging is that aging results from accumulation of somatic damage. Damage to DNA can lead to cell cycle arrest, cell death or mutation. The majority of mutations do not kill the cell, but when accumulated in sufficient numbers may lead to deregulation of transcription patterns, reduced fitness and ultimately the aging phenotype.
DNA repair is essential for cell vitality, cell survival, and cancer prevention, yet cells’ ability to patch up damaged DNA declines with age for reasons not fully understood.
Now, research led by scientists at Harvard Medical School (HMS) reveals a critical step in a molecular chain of events that allows cells to mend their broken DNA.
The findings, to be published March 24 in Science, offer a critical insight into how and why the body’s ability to fix DNA dwindles over time and point to a previously unknown role for the signaling molecule NAD as a key regulator of protein-to-protein interactions in DNA repair. NAD, identified a century ago, is already known for its role as a controller of cell-damaging oxidation.
Additionally, experiments conducted in mice show that treatment with the NAD precursor NMN mitigates age-related DNA damage and wards off DNA damage from radiation exposure.
Credit: US National Library of Medicine
Harvard Medical School