There are a range of mouse laboratory species genetically engineered to age more rapidly than usual. Reduction in the cost and time taken for studies is the impetus in some cases, a bet that the economic benefits will outweigh any uncertainty introduced by differences in these species. Other accelerated aging species were created to study processes of aging, DNA repair, or other important mechanisms.
One of these species is the BubR1 mutant, noted here at Fight Aging! back in 2004. Interestingly, this was the species used in last year's demonstration that (accelerated) aging can be slowed by removal of senescent cells. There are the usual cautions about extrapolating from work in accelerated aging mice, but at this point people expect to see much the same result in mice that age normally: better health, extended life.
But back to BubR1. If there is too little of it, accelerated aging results, as described in 2004. Researchers have now shown that boosting levels of BubR1 seems to slow aging, placing it into a small and select category of genetic or metabolic alterations that can be reversed to either speed or slow aging. Here's an article and the release:
Biologists report that genetically engineered mice that make extra BubR1 are less prone to cancer. For example, they found that when they exposed normal mice to a chemical that causes lung and skin tumors, all of them got cancer. But only 33% of those overexpressing BubR1 at high levels did. They also found that these animals developed fatal cancers much later than normal mice - after about 2 years, only 15% of the engineered mice had died of cancer, compared with roughly 40% of normal mice.
The animals that overexpressed BubR1 at high levels also lived 15% longer than controls, on average. And the mice looked veritably Olympian on a treadmill, running about twice as far - 200 meters rather than 100 meters - as control animals. All of this left [researchers] thinking that BuBR1's life-extending effects aren't due to only its ability to prevent cancer, although that's not yet certain.
"We've known for some time that reduced levels of BubR1 are a hallmark of aging and correspond to age-related conditions, including muscle weakness, cataract formation and tumor growth. Here we've shown that a high abundance of BubR1, a regulator of chromosome segregation during mitosis, preserves genomic integrity and reduces tumors, even in the face of some genetic alterations that promote inaccurate cell division. Our findings suggest that controlling levels of this regulator provides a unique opportunity to extend healthy life span."
Researchers studied two lines of transgenic mice, one with moderate expression of BubR1 and the other with high expression. Outcomes of a series of experiments showed that mice with high expression of the gene were dramatically effective in preventing or limiting age-related disease compared to those with moderate expression and especially to wild type mice.
The findings were significant. Only 33 percent of these high expressing mice developed lung and skin tumors compared to 100 percent of the control group. BubR1 overexpression markedly reduced aneuploidy (a state of having an abnormal number of chromosomes), which causes birth defects. Other results showed these mice were protected from muscle fiber deterioration, that they were better performers in treadmill tests, that they had much reduced levels of renal sclerosis, intestinal fibrosis and tubular atrophy - all signs of aging. They also showed higher cardiac-stress tolerance and resistance to age-related retinal atrophy.
Mice, it should be recalled, are little tumor factories. Anything that can reduce cancer rates will likely extend their lives somewhat - but these results have a slew of other measures to go with that, making the effect look more general than just cancer resistance. I'd say it's all fuel for the debate over the degree to which DNA damage is a significant cause of aging versus just a significant cause of cancer.
The published paper for this BubR1 work is available online if you wish to dig deeper, but sadly not open access.