The goal of aging research should, in a perfect world, be to repair the causes of age-related degeneration, frailty, and disease. Forms of damage to cells and tissue accumulate as a side-effect of the normal operation of metabolism, and that leads to a chain of consequences that is eventually fatal. Think of rust or wear on toothed gears and the consequences of that; aging is much the same thing, only far more complex because we are very complex, self-repairing machines. The best therapies for aging will be those that revert damage and rescue us from the consequences of that damage.
Researchers often work with animals whose biochemistry has been deliberately altered to malfunction. Accelerated aging through DNA repair deficiency, for example. This is done because animal studies are enormously expensive, but if there is a way to compress the time needed to evaluate specific aspects of biology, then that will be done. In the future this will be replaced with simulation and engineered tissue rather than whole animals, but for now there are many lineages of mice and other species engineered to age more rapidly. Except that they are not in fact aging more rapidly: their biology is broken in a fundamental way that happens to produce more of certain types of cellular and tissue damage. That in the end produces consequences that somewhat resemble aging, but it isn't the same. Think of the difference between progeria and normal aging in humans: at the high level there are apparent similarities, but at the level of cells and tissues it is very different.
Researchers interested in aging have engineered lineages of mice in which metabolism is broken in some fundamental way, and then gone on to restore some of the harm done via a prospective treatment. At the high level you might think that this looks very similar to the description of the best path towards the treatment of aging: there is damage, and that damage is restored or worked around. Yet it is a very different situation. It is very rarely the case that researchers can make any useful claim related to normal aging based on rescue of a pathologically dysfunctional metabolism through treatment. Such studies are a starting point only, a comparatively low cost way to carry out a preliminary proof of concept for the mechanisms involved, or to investigate specific biochemical processes by creating a situation in which they function in a different way. It is a way to make sure that the actual mechanics of the potential therapy are in fact doing what they are supposed to be doing. Then research can move on to tests in normal animals.
This is exactly what happened for senescent cell clearance as a treatment for aging over the past few years: the initial proof of concept was carried out in an accelerated aging mouse lineage, and while this was one of the rare cases where being excited about the outcome (a slowing of dysfunction) was actually merited, it was still the case that only a demonstration in normal mice would seal the deal. That happened this year, and the fact that it was a mere four years between the two research reports is noteworthy: that is rapid indeed in the world of life science research.
Given all of this, when reading about the research quoted below bear in mind that this is really only a demonstration to show that the relevant mechanism probably work as expected in mammals. It says little about whether or not the treatment will prove to be in any way useful in normal animals rather than those with an artificial accelerated aging condition produced by genetic damage of DNA repair mechanisms. It is interesting to speculate given the details regarding increased resilience in the face of certain types of DNA damage, but until it is tried in healthy, normal animals that will remain speculation.
Mice with low levels of the ATR protein, essential for the repair of damaged DNA, age faster than normal. Researchers have established a method to rescue the premature aging in these mice, doubling their life span. The strategy: to introduce a mutation capable of increasing the body's capacity to produce nucleotides - the building blocks of DNA - available in the cells. Together with the original mutation in ATR that caused the premature aging, the animals contained multiple copies of Rrm2, the key gene for the synthesis of nucleotides. The results showed how the accelerated aging was significantly alleviated in these mice, namely increasing their survival from an average of 24 weeks to 50 weeks.
The genome of every living being contains certain fragile areas. These are defined due to their tendency to break spontaneously, and they have been shown to be involved in human diseases, including cancer. The studies described in this research paper showed that those mice with additional copies of Rrm2 suffered less DNA breaks in these fragile areas, this being the first mammal described to present a genome which is less fragile than that of a normal mouse.
Whether these results are relevant with respect to normal - rather than premature - aging remains to be discovered. Whatever the case, the authors point out that standard medical practice includes prescribing folic acid (or vitamin B12) supplements to the elderly to delay or lessen the degenerative symptoms associated with advanced age. Bearing in mind that folic acid is, among other things, a precursor molecule in the synthesis of nucleotides, these results might indicate that a scarcity of nucleotides could contribute towards the aging process in humans. "The question we are asking ourselves now is whether an increase in the capacity to produce nucleotides could also lengthen life expectancy in normal animals without premature aging."
In Saccharomyces cerevisiae, absence of the checkpoint kinase Mec1 (ATR) is viable upon mutations that increase the activity of the ribonucleotide reductase (RNR) complex. Whether this pathway is conserved in mammals remains unknown. Here we show that cells from mice carrying extra alleles of the RNR regulatory subunit RRM2 (Rrm2TG) present supraphysiological RNR activity and reduced chromosomal breakage at fragile sites. Moreover, increased Rrm2 gene dosage significantly extends the life span of ATR mutant mice. Our study reveals the first genetic condition in mammals that reduces fragile site expression and alleviates the severity of a progeroid disease by increasing RNR activity.