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Lead Section: As an organism ages, the likelihood of DNA damage accumulation increases. Additionally, the protective mechanisms that correct the damages become less efficient. The combined result of these two factors gives rise to a higher rate of DNA damage accumulation as time goes on, which then causes several of the phenotypes associated with aging.

After Frederick Sanger developed techniques to rapidly sequence DNA in the 1970's, scientists were able to determine the causes of many health conditions and diseases that were previously unknown. Huntington's disease was one of the first genetic diseases to be mapped out and studied. The application of similar experimental techniques for other conditions/diseases revealed that the accumulation of DNA damage was common in biologically older organisms or organisms that demonstrated certain forms of accelerated aging. This damage can take many forms as a result of extrinsic or intrinsic factors. DNA damage that results in aging in multicellular organisms can be categorized into two groups based on the location of the DNA molecules- Nuclear DNA damage (located in the nucleus) and mitochondrial DNA (mtDNA) damage (located in the mitochondria). The Hallmark of Aging review paper identifies both forms of DNA damage as factors which accelerate aging. The paper groups these two forms of DNA damage under the sub-category of the "Genomic instability" hallmark. It is to be noted that, while both DNA and mtDNA are the same structurally, they have different repair mechanisms and are subjected to very different stressors. Nuclear DNA, in general, is considered better protected than its mitochondrial counterpart. The nucleus itself serves as a barrier between the stressors in the cellular environment and the DNA molecule. The nuclear DNA also has telomeres to protect its ends from degradation. Cells have evolved to have very efficient and damage specific DNA repair machineries, which are always employed in preserving the integrity of the DNA. Despite all these protective mechanisms, one of the greatest threats to nuclear DNA is aneuploides, (abnormal number of chromosomes) which is a product of miscommunication during the cell cycle. The presence of an irregular number of chromosomes can impact the competency of the Stem cells. Without functional stem cells, tissue renewal becomes hindered in the organism. Mitochondrial DNA lacks  the different safety features which nuclear DNA has. It has not evolved efficient DNA repair mechanisms either. Additionally, the mtDNA molecule is constantly exposed to ROS, a byproduct of cellular respiration; this increases its likelihood of accumulating mutations. There is some debate over mtDNA mutations role in aging  as mtDNA molecules demonstrate heteroplasmy. However, various studies have shown that individual aging cells have higher amounts of mtDNA mutation load and can even demonstrate heteroplasmy. At the time of publication of the review article, there was no research showing that a reduction in mtDNA mutation load can help extend lifespan.

Research done since the review publication:

Since the publishing of “The Hallmark of Aging” review in 2013, many papers have been published on the subject, providing research which further elaborates on the role of the different hallmarks. With the recent advancement in bio-engineering tools and techniques, the field of genetics has especially progressed. This has provided us with a great deal of insightful and interesting information on the genomic instability hallmark.  

Previously, there was no reliable simple invertebrate model organism that could be used to study the mtDNA mutation. However, in 2014, Leslie et al. published a paper showing that Drosophila melanogaster can serve as an effective model. The study also demonstrated that Reactive oxygen species are not responsible for the majority of the mtDNA mutations that translate into aging and aging related diseases.While their results are preliminary, and reproducibility of the data must be confirmed, it is definitely promising.

The recent technological progress has also provided scientists with the privilege of working with stem cells. This has furthered our understanding of inheritable diseases that are the result of germline mtDNA mutations. It was found that germline mtDNA mutations that lead to respiratory chain (RC) deficiencies are the products of downregulation in the transcription in mtRNAsas well as a reduction in the mtRNAs half life.

It was already known that mtDNA with extensive mutations will often undergo mitophagy; this is obstructed by proteins from the kinase family. Cells with inhibited rapamycin (mTOR) kinase activity supported this hypothesis by demonstrating a reduction in the number of mtDNA mutations, as well as production of more ATP.

Many neurodegenerative diseases are the result of mtDNA mutations. A great deal of research has been done to see how mtDNA mutations cause these conditions and what can we do reduce/diminish their effects. Some rare cases of Alzheimer's disease(AD) and Parkinson's disease (PD) are caused by mtDNA mutations. In general it was found that mtDNA mutation numbers increase,in the brain, in cases of both AD and PD( as well as Down Syndrome and Dementia).  It was also found that patients with these conditions have reduced mtDNA mRNA levels, altered mtDNA copy number, and abnormal Aβ metabolism (aka Beta oxidation) in their brain tissues. Discovery of these common variables between the different diseases allows for “common  genetic and pathophysiology explanation”, which can then be used to create for efficient treatments.

Dietary restriction is often used to reduce the effects of aging and related diseases. Research was done to examine the impact of dietary restriction on mice with Progeria (resulting in the accumulation of mtDNA mutations). For this, mutant mice were subjected to varying degrees of dietary restriction. It was seen that median and maximum lifespan increased by ~ 200%. Therefore, dietary restriction can aid in counteracting effects mtDNA damage related conditions.

The other theme that is constantly observed as our understanding of the different hallmarks increases, is that, these hall marks are often linked to one another and rarely exist as individuals. Telomere length and mtDNA instability are usually considered independent of one another. But recent research has demonstrated that telomerase, an enzyme that maintains of telomere length, is also responsible for responsible for responding to ROS related stress. In Tyrka et al. the scientists have demonstrated that mitochondrial proliferation and function declined in various tissues of mutant mice with severe telomere damage. The telomere dysfunction in some cases can turn on the p53 pathway.