Fight Aging!

The gene BubR1 is of interest to cancer researchers involved in the study of various forms of nuclear DNA damage, the intricate but usually very reliable DNA repair mechanisms that strive to revert that damage, dysfunction in those repair mechanisms, and how these items relate to cancer and aging. Cancer is quite clearly a condition spawned by damage to the DNA in the cell nucleus; the more of that damage you suffer, the more likely it is that one of your cells will undergo the right combination of mutations to turn it into an unfettered, self-replicating cancer seed - something that looks and acts a lot like a stem cell, spawning copies of itself and a legion of descendants prone to further mutation and causing havoc.

For those of us who follow longevity science, the gene BubR1 is of interest because altering its gene expression level is one of the few simple mechanisms than can both shorten and extend life in mice. Less BubR1 produces an accelerated aging condition, while more of it appears to slow aging, reducing the incidence of various common age-related conditions in the mice that have this gene therapy applied to them.

It is important to note that accelerated aging conditions are generally classed as DNA repair dysfunctions. The worse the dysfunction, the faster that the individual suffers what looks a lot like accelerated aging - but there is some debate in the research community as to whether what is happened should be described as accelerated aging. From the perspective of those of us interested in ways to extend healthy life, research results involving laboratory animals suffering from artificially induced forms of accelerated aging have to be viewed carefully, because they are rarely straightforwardly applicable to normal aging. When you alter genes in a way that causes accelerating aging, such as by reducing the efficiency of some crucial part of DNA repair, this is analogous to breaking a part of a machine - you shouldn't be surprised to find that it fails sooner and more readily than its unbroken peers. That doesn't necessarily say anything about how you might extend the working life of that type of machinery, however.

So you really have to look at each research result on a case by case basis; the ones that are interesting and do have something to say about normal aging are almost always those in which the mechanism causing accelerating aging can be turned around to extend life, as is the case for BubR1 levels.

As it so happens, this all ties in to cellular senescence, another topic of interest to those of us who follow developments in longevity science. Senescent cells are those that have left the cell cycle due to age or damage - such as damage to their nuclear DNA - and really should be destroyed, either by their own programmed cell death processes or by the immune system. Cellular senescence might be thought of as a part of the evolved balance between cancer risk and the need for cells to work and maintain tissues; the more damage there is in the cellular environment, the more cells become senescent, an adaptation that lowers the risk of cancer by preventing damaged cells from undertaking their normal range of activities.

Unfortunately senescent cells are still harmful in and of themselves, as they secrete all sorts of unwanted signals and remodel their local environment. The more of them there are, the more their presence damages the surrounding tissue. The growth in senescent cells with age is one of the root causes of degenerative aging, and getting rid of them on a regular basis is one of the proposed rejuvenation therapies in the SENS vision for reversing the course of aging.

A demonstration of improved health measures in mice through destruction of senescent cells was carried out two years ago. The study used BubR1 mutants suffering from accelerated aging - and thus a faster accumulation of DNA damage and senescent cells. Researchers often use accelerated aging as a way to enable studies to conclude more rapidly, and thus be conducted at an affordable cost; there is an enormous difference in cost between a study that runs a few months and one that runs a few years. Here, however, it is the case that the researchers involved are as much interested in cancer and DNA damage as they are in aging, and the BubR1 mice are their main object of study for many reasons. That they are producing results of interest to longevity science on the matter of cellular senescence is a side-effect of the main thrust of their research, and a consequence of the overlapping mechanisms involved: DNA damage, DNA repair, cancer, aging, accelerated aging, and cellular senescence.

So that all said, let me point you to the latest research publication from this group, which pleasantly enough is open access. You might want to try the summary first, which explains their conjecture that cellular senescence resulting from DNA damage falls most heavily on the stem-like cells responsible for tissue maintenance:

Mayo Clinic researchers discover that stem cell senescence drives aging

BubR1 is an essential part of the mitotic checkpoint, the mechanism controlling proper cell division or mitosis. Without sufficient levels of BubR1, chromosomal imbalance will occur, leading to premature aging and cancer. Using mutant mice that expressed low levels of BubR1, the researchers found development of dysfunctional tissue with impaired cell regeneration. In analyzing the progenitor populations in skeletal muscle and fat, they found that a subset of progenitors was senescent.

"Earlier we discovered that senescent cells accumulate in tissues with aging and that removal of these cells delays age-related functional decline in these tissues. The key advance of the current study is that the progenitor cell populations are most sensitive for senescence, thereby interfering with the innate capacity of the tissue to counteract degeneration."

As to the open access paper itself, I should mention it is largely concerned with one specific fairly drastic form of DNA damage, the class of chromosome abnormalities known as aneuploidy, and the relationships between aneuploidy, cancer and aging, but touches on much of what was discussed above.

Aneuploidy in health, disease, and aging

The link between BubR1 and early aging raises the question as to whether BubR1 is implicated in natural aging. One observation consistent with such a role is that BubR1 levels decline in various tissues with chronological aging, at least in mice. The underlying mechanisms are poorly understood: [BubR1] expression could simply decline as a result of reduced cell proliferation with aging, but a study on transgenic mice that constitutively overexpress BubR1 and are not subject to an age-related drop in BubR1 seem to argue against this. BubR1 transgenic mice live longer than normal mice and have an increased healthspan (the period during which an organism is free from serious or chronic disease, including cancer) characterized by attenuated muscle and renal atrophy, glomerulosclerosis, and increased cardiac function.

These studies further uncovered that aneuploidization is a hallmark of aging, raising the possibility that age-related aneuploidy contributes to tissue dysfunction. Consistent with this idea, reduced senescence and tissue deterioration in BubR1 transgenic mice tightly correlated with attenuated age-related aneuploidy. How BubR1 overexpression counteracts chromosome missegregation remains under investigation, with early evidence suggesting that defects in mitotic checkpoint control and microtubule-kinetochore attachment are ameliorated. This would imply that both these mitotic processes are subject to age-related decline and at least partially responsible for age-related aneuploidy.

As you can see, this also relates to the debate regarding the degree to which nuclear DNA damage is a cause of degenerative aging versus merely a marker of advancing age and a determinant of cancer risk. There are of course many different forms of DNA damage, and some arguments revolve around one type or another (such as double-strand breaks) being important in aging.