Fight Aging!

Cells use the bloodstream as a way to communicate with one another, and blood in an old individual has many differences when compared to that of a young individual. The amounts of numerous important signal molecules are different, for example. By the evidence to date, obtained from parabiosis studies in which the circulatory systems of an old and a young individual are linked, this appears to be connected to the age-related decline in stem cell activity, and probably to many other systems as well. These signal molecules are just one class of change in the blood over the course of aging, however. Here is another: fragments of DNA sequences, the nucleic acids that make up DNA, are another type of molecule found in the bloodstream in greater amounts in old individuals. Researchers are presently debating whether and how this molecular debris might cause harm.

These circulating nucleic acids are thought to arise from the destruction of cells, though given that cells are capable of creating and releasing quite complex structures into the surrounding tissues - consider extracellular vesicles for example - it is perhaps plausible that dysfunctional cells could be exporting nucleic acids while still intact. The theorized problem caused by extracellular nucleic acids is that cells will take them up and integrate them into their DNA, and that this could be a significant source of stochastic mutational damage.

This might be considered a part of the broader argument as to whether nuclear DNA damage is significant in aging over a normal human life span in any way other than generating an increased risk of cancer. It is indisputably the case that mutational damage occurs, and is a distinguishing feature of old tissues, each cell with its own unique pattern of damage. What is hard to prove is that this actually causes significant problems in and of itself, absent any of the other changes of aging. A large enough level of mutation will definitely change the behavior of cells in ways that degrade tissue function, but is the present mutation rate in aging anywhere near high enough to get to that point? The studies needed to definitively answer that question have yet to take place.

The dark side of circulating nucleic acids

Billions of cells in the adult human body are eliminated daily through cell death processes, such as apoptosis and necrosis; especially necrotic cells, which unlike apoptotic cells are not generally removed cleanly by phagocytosis, are thought to be a source of degraded DNA fragments released to the blood plasma or serum as cell-free DNA or circulating free DNA (cfDNA). Some aspects of the biology of cfDNA are still unexplored and several key questions remain. One question with high relevance to aging is whether or not cfDNA fragments can behave as mobile genetic elements, illegitimately integrating in the chromosomal DNA of healthy cells in its own host, thereby contributing to genome instability and possibly causing age-related functional decline and age-related pathophysiological processes.

Recently evidence was provided that the integration of cell-free nucleic acid with host cells occurs in vivo as well as in vitro. Mice were injected intravenously with human cfDNA and Cfs and analysis of heart, lung, liver, and brain of the mice sacrificed 7 days after injection revealed genomic localization of nucleic acids, with Cfs localizing more efficiently than cfDNA. Of note, genomic integration of Cfs in the mouse brain indicated that chromatin particles are able to cross the blood-brain barrier. This recent work offers a fascinating new mechanism of age-related mutagenesis, highlighting the fate and effects of free nucleic acids within our body. However, many questions remain. Probably the most interesting question is whether cfDNA truly behaves as mobile genetic elements under normal conditions. That is, rather than extracting concentrated cfDNA from heterogenic serum samples and intravenously injecting that in the mouse, integration of its own cfDNA should be studied, for example, as a function of age. Because integrated DNA fragments can then no longer be uniquely aligned as foreign DNA to a reference sequence, single cells or clones should be studied for insertion events as compared to the germline sequence, which is considerably more difficult than screening for reads containing human sequences.

While still lacking in important details, this recent work opens up the intriguing prospect of a new, endogenous source of genome instability that could well contribute to increased genome mosaicism with age. In this respect, cfDNA could act similarly to the previously described age-related derepression of endogenous retrotransposons in the somatic genome during aging. In this respect, there is evidence that cfDNA becomes increasingly frequent in the circulation as a function of age, for example, due to increased vulnerability of aged and damaged cells to cell death. Its activation of the DNA damage response could increase the level of genome instability considerably, contributing to aging-related degenerative processes, such as cellular senescence, cancer, and inflammation. Further research on the biological and pathological roles of cell-free nucleic acids will help to elucidate its importance as an intrinsic mechanism of aging.