The so-called accelerated aging conditions, fortunately rare, are better thought of as DNA repair deficiency disorders, caused by specific inherited or spontaneous mutations that interfere with normally very efficient DNA repair processes. The results don't encompass all of the symptoms of aging, even if the outcome appears superficially similar to the late stages of normal aging, characterized by declining stem cell activity, faltering tissue maintenance, and the resulting failure of vital organs. This is perhaps best illustrated by the fact that it is not possible to just turn the situation around and generate enhanced healthy longevity via gene therapies that aim to boost the operation of DNA repair processes. This is demonstrated by the authors of the open access paper quoted below; they tested a variety of genes associated with different parts of the DNA repair infrastructure present in cells, and obtained quite mixed results on life span.
Engineering greater longevity in animal studies should be the first choice for a minimum standard of proof for the relevance of any particular cellular mechanism to aging, with other minimum standards involving many more mutually supporting lines of evidence for those cases where the life extension studies cannot yet be carried out for technical reasons. There are all too many papers out there in which researchers claim importance in aging on the basis of breaking a mechanism and observing reduced life span as a result. This isn't good enough, as the much more likely explanation in most cases is that breakage causes damage and dysfunction of forms that are irrelevant in normal aging, but which nonetheless raise mortality risk and shorten life. To create an exaggerated example, if you disable the operation of someone's liver, their life expectancy falls dramatically, but that doesn't put the liver at the center of the aging process, and nor does it mean that adding an extra liver to a healthy individual is going to significantly extend life.
This study of mixed results from attempts at DNA repair enhancement is interesting in that it is a step forward, but nonetheless fails to add clarity to the debate over the degree to which stochastic nuclear DNA damage is a meaningful cause of aging. The damage certainly grows with age and certainly increases cancer risk, but does it do more than this? Some researchers think that it dysregulates cellular metabolism to a large enough degree to matter, some do not. The research community is still in search of a definitive study that tips the evidence one way or another, but as this work shows that is likely to prove a complex undertaking:
Aging is a complex process that is far from being fully understood. Of the many factors that contribute to aging and the multiple changes on many levels that take place, one in need of further study at this time is the role of DNA repair. Because DNA damage does accumulate with age and appears to be associated with some of the detrimental aspects of aging, including neurodegeneration, boosting DNA repair mechanisms may be one approach to intervention.
Here, we investigated the potential life-extending effects of increasing the expression of genes known to be involved in DNA repair in Drosophila. We compared the overexpression of these genes throughout the body versus in the nervous system alone and throughout the lifespan versus in adulthood alone. We also included three known stressors. We found both positive and negative effects on lifespan, with many important variables, including gene, sex, stress exposure, extent of overexpression, developmental stage, and distribution of overexpression in the body.
The most pronounced effects of overexpression on lifespan occurred with Hus1, mnk, mei-9, mus210, spn-B, and WRNexo, which control the processes of DNA damage recognition and repair. Lifespan and stress resistance were interrelated, moreso in males than females, in that increased lifespan was associated with increased resistance to hyperthermia and oxidative stress, while decreased lifespan was associated with decreased resistance to all three stressors tested. Overexpression of DNA repair genes throughout development leads to opposite effects on lifespan when compared to adult-specific overexpression, and the direction of this dichotomy depends on whether the overexpression was ubiquitous or limited to the nervous system.
It is difficult to explain these effects on the basis of the available experimental or published data. Aging research is still in need of basic studies to address a wide variety of unanswered questions. This study presents a valuable set of preliminary data on the role of DNA repair in aging and points to a promising set of DNA repair genes and experimental conditions to pursue in greater detail in future studies that incorporate both transcription-level and protein-level effects on a wider variety of lifespan- and aging-related parameters.