$54,000
$15,970

Clonal Expansion of Stochastic Nuclear DNA Damage as a Contributing Cause of Aging

Damage to the nuclear DNA in our cells is constant and ongoing, either due to reactive molecules, or errors during replication of DNA. Near all of this damage is rapidly and successfully repaired by a panoply of highly efficient maintenance processes. Nonetheless, damage slips through to accumulate over a lifetime, particularly in long-lived cell populations. The most obvious consequence of this damage is cancer, resulting when the blueprint driving cellular operations changes in ways that allow unfettered and uncontrolled replication. Other than cancer, however, does this random damage to cells in fact contribute meaningfully to aging, through disarray in normal cellular metabolism? The consensus is that it does, but there are dissenters from that view, as well as evidence to cast doubt on a necessary causal connection between high levels of stochastic DNA damage and age-related disease and mortality.

The authors of the open access paper noted here consider that the more important aspect of stochastic DNA damage is not its occurrence, but the degree to which it is then replicated: that some DNA damage does result in significant replication of cells containing that damage, even in the absence of cancer. This is a somewhat more plausible argument for a connection to tissue dysfunction than is stochastic DNA damage on its own. It would require far fewer persistent mutations in individual cells in order to produce resulting changes in tissue or organ function, and it dovetails fairly well with what is observed in the DNA of old tissues with more modern genetic technologies.

DNA encodes the basic instructions to construct an organism during its development, and its stability is essential to life. However, DNA mutations are also necessary for evolution because they provide the requisite genetic variation for natural selection. Thus, opposing forces act on DNA maintenance: stability to preserve the quality of the genetic information within individuals and instability to warrant intergenerational genetic diversity.

For new genetic information to have its phenotypic effect, the zygote must divide and clonally expand during embryonic development. While the cells that make up the resulting organism may differ in morphology and physiology, their underlying genetic code should be, in principle, identical. However, much like how genetic variation drives selection within organismal populations, genetic variation arising within a single individual enables selection for or against somatic cells. The stochastic nature of mutagenesis, the sparse gene content of the human genome, and the limited degeneracy of the genetic code imply that most mutations have neutral or deleterious consequences. Occasionally, however, mutations provide a selective advantage that leads to the expansion of the mutant cell into a clone. This process can be influenced by the timing of mutations during an organism's lifecycle, their frequency, and their functional consequence to a cell's physiology. The result is genetically distinct populations of cells within an individual, a phenomenon known as somatic mosaicism.

The existence of somatic mosaicism is well documented. However, the occurrence of somatic mosaicism is not limited to development and has been recognized as an aging phenotype for decades. An increase of somatic mutations with age has been reported for a variety of target genes. Similarly, age-associated accumulation of chromosomal alterations has been documented. These early findings appear to be only the tip of an iceberg in terms of somatic mutations in normal tissue. The advent of Next Generation Sequencing (NGS) technologies has led to the striking revelation that older individuals not only accumulate chromosomal alterations but also abundant mutations in cancer driver genes. As error-correction NGS (ecNGS) technologies have improved the limit for mutation detection, the prevalence of cancer-associated mutations in adults now appears close to 100%.

Furthermore, recent single-cell studies point to the possibility that essentially all cells have unshared mutations in their genomes. In view of this extensive genetic diversity, it is perhaps not surprising that mutations that confer a proliferative advantage are readily detected as clonal populations of increasing abundance and size in the elderly. These clonal populations might lead to loss of organismal health through the functional decline of tissue and/or the promotion of disease processes, such as cancer. In this review, we summarize recent research that supports the notion that aberrant clonal expansion (ACE) resulting from cancer-associated mutations are common in noncancerous tissue and accumulate with age. We propose ACE to be a previously underappreciated aging phenotype that is universal in most organisms, affects multiple tissues, and likely helps explain why aging is the biggest risk factor for cancer.

Link: https://doi.org/10.1371/journal.pgen.1007108

Comments

After a fast reading of the paper, it seems that they only have indirect evidence that natural selection is acting in the clones. Anyway, it's very interesting.

Posted by: Antonio at January 8th, 2018 7:36 AM

Extremely interesting. Thought I dont understand everything: "he stochastic nature of mutagenesis, the sparse gene content of the human genome, and the limited degeneracy of the genetic code imply that most mutations have neutral or deleterious consequences. Occasionally, however, mutations provide a selective advantage that leads to the expansion of the mutant cell into a clone. This process can be influenced by the timing of mutations during an organism's lifecycle, their frequency, and their functional consequence to a cell's physiology. The result is genetically distinct populations of cells within an individual, a phenomenon known as somatic mosaicism."

Can anyone explain if it has something with mosaicism with T21 inside to do or is that the reason mosaicism forms?

Posted by: Norse at January 8th, 2018 3:50 PM

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.