Loss of Ribosomal DNA is Associated with Aging in Flies

Researchers here make an interesting discovery in the genetics of fly aging. Old flies lose repeated DNA sequences in the genome that encode for RNA related to the ribosome, a cellular structure important in the intricate, multi-stage process by which proteins are created from their genetic blueprints. Protein creation changes in numerous ways in later life, better ribosomal function is associated with greater species longevity, and it is known that ribosomal RNA genes acquire epigenetic markers in a characteristic way with age. How exactly this all links together is yet to be determined in detail.

The more interesting part of the report here is that young flies regain lost ribosomal DNA, if they were the offspring of old parents and thus inherited a genome with few repeats of ribosomal DNA. This suggests that, whatever is going under the hood, the loss of ribosomal RNA genes is a secondary aspect of aging, driven by some other process. We might ask whether this observation in flies is relevant to mammals. It may not be, judging from the results of an older study in aged mice that examined this part of the genome and found no great losses - but that was sufficiently long ago that revisiting the topic is certainly on the agenda.

Studies in fruit flies have shown how cells in the offspring of older fathers can replace copies of genes that have been lost due to aging. The findings provide clues as to how some cells could overcome genomic shrinkage that appears to occur as an organism ages. If the same results can be confirmed in humans, they could offer a new level of understanding about how cells deteriorate with time.

The team looked specifically at ribosomal DNA (rDNA) loci that contain the genes for ribosomal RNA (rRNA). These loci are repeated at multiple sites on different chromosomes. For example, five human chromosomes contain regions in which rDNA genes are repeated hundreds of times. However rDNA is very unstable. "rDNA loci, composed of hundreds of tandemly duplicated arrays of rRNA genes, are known to be among the most unstable genetic elements due to their repetitive nature. The end result is that some copies are lost every cycle. They are popping out of the chromosome."

Studies have confirmed that in yeast cells, at least, this rDNA instability and gene copy loss underlies aging, via a process known as replicative senescence. What isn't yet known, however, is whether rDNA instability contributes to aging in multicellular organisms. To investigate this further, the researchers turned to the fruit fly, Drosophila melanogaster. Their studies looks more closely at the dynamics of rDNA loci and rDNA loss during aging in male Drosophila germline stem cells (GSCs), which continue to divide throughout adulthood. The results of their cell analyses showed that in comparison with younger male fruit flies, older males had fewer copies of the rDNA genes on the Y chromosome in their GSCs-in effect their Y chromosomes had shrunk. These older fathers then passed the reduced amount of rDNA on to their male offspring.

However, rather make do with fewer rDNA genes, the offspring were able to rebuild the number of rDNA copies in the Y chromosomes of their GSCs. By the time they had reached about 10 days of age, the sons of aged fathers had comparable amounts of rDNA to those male offspring of younger fathers that had passed on less depleted Y chromosomal rDNA. Interestingly, recovery of of rDNA copy number was limited to young adults, suggesting that the mechanisms at work might only occur under certain conditions. The results indicate that rejuvenation of rDNA in sons plays a key role in the persistence of stem cells from father to son. What isn't known yet is whether the same rebuilding of lost rDNA can also occur in female stem cells in the ovary.

Further analysis indicated that the process of rDNA copy number recovery uses the same factors that are needed for a phenomenon known as rDNA magnification, in which DNA copy number is rapidly expanded in the male germline of animals that are deficient in rDNA due to large rDNA deletions. "Our study also indicates that the phenomenon classically regarded as 'rDNA magnification' might be a manifestation of a general 'maintenance' mechanism that operates in the population that experiences normal fluctuations in rDNA copy number." The researchers suspect that mechanisms allowing cells to reset gene copy number may also be present in some types of human cells, but this has yet to be demonstrated.

Link: https://www.genengnews.com/gen-news-highlights/aging-clues-found-in-stem-cell-ribosomal-dna/81255490

Comments

"The more interesting part of the report here is that young flies regain lost ribosomal DNA, if they were the offspring of old parents and thus inherited a genome with few repeats of ribosomal DNA. This suggests that, whatever is going under the hood, the loss of ribosomal RNA genes is a secondary aspect of aging, driven by some other process."

Is this loss of DNA secondary damage or primary damage? Just because young males can recover this DNA, doesn't mean that it is not primary damage that drives aging. After all, there is no evolutionary pressure to maintain systems after the reproductive age of an organism.

https://www.genengnews.com/gen-news-highlights/aging-clues-found-in-stem-cell-ribosomal-dna/81255490?q=fruit

"The results of their cell analyses showed that in comparison with younger male fruit flies, older males had fewer copies of the rDNA genes on the Y chromosome in their GSCs-in effect their Y chromosomes had shrunk. These older fathers then passed the reduced amount of rDNA on to their male offspring.

However, rather make do with fewer rDNA genes, the offspring were able to rebuild the number of rDNA copies in the Y chromosomes of their GSCs. By the time they had reached about 10 days of age, the sons of aged fathers had comparable amounts of rDNA to those male offspring of younger fathers that had passed on less depleted Y chromosomal rDNA. "Strikingly, we found that GSCs in the F1 generation are capable of recovering rDNA copy number in the early ages of adulthood, revealing the likely presence of a mechanism that maintains rDNA copy number through generations," the authors write. "This recovery was something we really didn't expect," Yamashita acknowledges.

Interestingly, recovery of of rDNA copy number was limited to young adults, suggesting that the mechanisms at work might only occur under certain conditions. "It remains unclear if such conditions are developmentally programmed or reflect the limitation of certain cell biological processes that underlie rDNA copy number recovery," the authors point out. The results do indicate that rejuvenation of rDNA in sons plays a key role in the persistence of stem cells from father to son. What isn't known yet is whether the same rebuilding of lost rDNA can also occur in female stem cells in the ovary."

Posted by: Jim at March 5th, 2018 7:02 AM

In yeast, isolates with experimentally reduced rDNA dosage experience a gradual return to original levels over time.
Rapid amplification of the locus has long been well documented in somatic tissues of fruitflies that inherit reduced rDNA arrays, and an upwards of 10,000-fold amplification of the rDNA has been well described in amphibians oocytes
See: Ribosomal DNA copy number is coupled with gene expression variation and mitochondrial abundance in humans. https://www.nature.com/articles/ncomms5850#f8

Posted by: Dmitry at March 6th, 2018 5:35 AM

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