Too tired to fix it: Declining DNA repair deficiency and energy budget in aging cells

Last week, we learned that DNA damage accumulates in aging hematopoietic stem cells (hSCs; see our earlier article, Sucking the life out of marrow), and that this buildup of genetic lesions is likely responsible for decreased proliferative and regenerative capacity in these cells.

Why would DNA damage accumulate in aging cells? The trivial explanation is, simply, time passing: Unless repair mechanisms are 100% efficient, the passage of time will result in a slow, steady buildup of damage.

Another possibility is that DNA repair itself becomes less efficient with age, causing damage to accumulate with increasing speed over time. This is the conclusion of Meyer et al., working not in hSCs but in intact C. elegans. They found, in both genomic and mitochondrial DNA, that aged worms repair their DNA more slowly than young worms:

Decline of nucleotide excision repair capacity in aging Caenorhabditis elegans


Caenorhabditis elegans is an important model for the study of DNA damage and repair related processes such as aging, neurodegeneration, and carcinogenesis. However, DNA repair is poorly characterized in this organism. We adapted a quantitative polymerase chain reaction assay to characterize repair of DNA damage induced by ultraviolet type C (UVC) radiation in C. elegans, and then tested whether DNA repair rates were affected by age in adults.


UVC radiation induced lesions in young adult C. elegans, with a slope of 0.4 to 0.5 lesions per 10 kilobases of DNA per 100 J/m2, in both nuclear and mitochondrial targets. L1 and dauer larvae were more than fivefold more sensitive to lesion formation than were young adults. Nuclear repair kinetics in a well expressed nuclear gene were biphasic in nongravid adult nematodes: a faster, first order (half-life about 16 hours) phase lasting approximately 24 hours and resulting in removal of about 60% of the photoproducts was followed by a much slower phase. Repair in ten nuclear DNA regions was 15% and 50% higher in more actively transcribed regions in young and aging adults, respectively. Finally, repair was reduced by 30% to 50% in each of the ten nuclear regions in aging adults. However, this decrease in repair could not be explained by a reduction in expression of nucleotide excision repair genes, and we present a plausible mechanism, based on gene expression data, to account for this decrease.


Repair of UVC-induced DNA damage in C. elegans is similar kinetically and genetically to repair in humans. Furthermore, this important repair process slows significantly in aging C. elegans, the first whole organism in which this question has been addressed.

The authors do not specify the mechanism by which DNA repair becomes less efficient, but they do make some intriguing observations: The transcription of nucleotide excision repair (NER) genes does not differ significantly between old and young adult worms — indeed, they find that no DNA repair gene is transcribed at lower levels in aged animals. Therefore, the expression level of NER machinery remains constant, and we must look elsewhere to explain the decreased efficiency of repair.

The authors propose two speculative causes, the first of which is specific to mitochondrial DNA. Mitochondrial protein targeting and transport become less efficient in aged cells, so even if old cells are synthesizing nuclear-encoded repair enzymes at the same levels as in young cells, these proteins might not make it to their destination, resulting in a decrease in repair activity within the mitochondria.

The second hypothetical cause is more general: While the authors observed no significant decrease in DNA repair gene expression, they did see a broad decline in energy production and other systems involved in cellular homeostasis. They speculate that these basis cellular functions are play a necessary supporting role in repair:

A related possibility that might be detectable by gene expression analysis is that DNA repair rates decreased in aging adults because cellular functions necessary to support repair were impaired. Analysis of Gene Ontologies that were altered in aging vs young nematodes revealed several intriguing differences…. Our results suggest a decrease in many processes that are fundamental to homeostasis, including ion transport, catalytic activity, and energy production.

In other words, old cells might lack the energy to perform repair function at maximum efficiency: if ATP is limiting, then simply staying alive will require an increasing proportion of the available energy budget, and the DNA might be allowed to fall into disrepair.

One comment

  1. Very interesting paper and thank you for reviewing it because I had a hard time deciphering it. If only scientists were better writers… Especially me. At any rate, I think this is going to be a hot topic because I’m working on the same sort of thing 🙂

Comments are closed.