BRASTO Mice, an Example of Calorie Restriction Mimetic Research

A common path for metabolic - and now aging - research is as follows: firstly specific gene variants or changes in gene expression are identified in laboratory animals as the likely cause of a particular characteristic. Extended longevity, say, or enhanced regenerative ability. Some of these discoveries are fortunate accidents, and some are the result of deliberate test programs aimed at verifying a specific theory, but either way the next step is the production of genetically altered animals for further study. Genetic discoveries are rarely as clean-cut as researchers would like, in the initial stages at least. But gene engineering of laboratory animals - usually mice in the later stages of investigation - allows study of specific genes or metabolic processes under more controlled and useful circumstances that those of the original discovery. Pieces of the biochemical puzzle can be changed, moved around, or removed, and the resulting changes observed and incorporated into a growing understanding of the processes involved.

With genetically altered mice in hand - and at least a basic understanding as to why these genetic alterations produce observed changes in the mice - researchers can then proceed to design or screen for compounds that reproduce some of the effects of this specific gene engineering project. Recall that genes are blueprints for proteins, the cogs, switches, dials, and screws in the machinery of cells. The process by which proteins are produced from genes is complicated, full of feedback loops, and very open to manipulation in this age of biotechnology. Levels of a specific protein can be dialed up or down by the introduction of a suitable drug - though rarely without all sorts of other cascading side-effects. More precise are new tools that use RNA to very precisely target a single protein; there the side-effects stem from the fact that few proteins are involved in only one process in the body. Evolution loves reuse, and it is very challenging to turn just one dial at a time in our biochemistry.

In any case, from this point on in the path is the traditional one of drug development: discovery, testing, trials, high costs, and ridiculous regulatory barriers.

Here is an example of metabolic longevity research still in the gene engineered mouse stage, another spin-off from past years of investigation into sirtuins and the biochemistry of calorie restriction:

Aging and Longevity Tied to Specific Brain Region in Mice

At the start of the research project, the study's lead author Akiko Satoh, PhD, a postdoctoral research associate in developmental biology, saw that mice on low-calorie diets had increased amounts of SIRT1 in specific regions of the hypothalamus and that neurons in the same regions were activated.

So the research team developed mice that continually produced higher amounts of SIRT1 in their brains to see what the effect would be. That's when Satoh observed the mice's unusual level of activity under fasting conditions. "This is the first time that it has been demonstrated that SIRT1 is a central mediator for behavior adaptation to low-calorie conditions," Satoh says.

Interestingly, these mice, called BRASTO (brain-specific SIRT1-overexpressing) mice, also maintained higher body temperatures after a 48-hour fast than ordinary mice, which experience a drop in body temperature during fasting.

"The BRASTO mice have a better capability to come up with energy to achieve a higher body temperature and increased activity level when food is restricted," says Imai, associate professor of developmental biology and of medicine.


The scientists are continuing to study the BRASTO mice to see if they live longer than ordinary mice.

One of the things that this work underscores is that despite the vast sums of money devoted to understanding sirtuins over the past five years, there is still remains great deal yet to be accomplished. Further, consider that these are just a few out of thousands of potentially relevant proteins in the biochemistry of mammals, of interest to attempts to slow down aging. Manipulation of metabolism is the slow boat in this race: there are better strategies to extend the healthy human life span.


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