Killifish as a Platform for the Study of the Biochemistry of Aging

There are many trade-offs to be made in aging research, and most of them involve the balance between expended resources and time on the one hand and the expectation value of knowledge gained on the other. The challenge inherent in the present study of aging is that in terms of quality and usefulness of data there is still little that beats waiting and watching - sitting back and following the entire life span of your subjects, taking measurements as you go. This is wildly impractical for human aging, enormously expensive and unlikely to happen again any time soon for other longer-lived primates, given the debates over the structure and results of two presently running calorie restriction life span studies in rhesus macaques, and merely painfully expensive to arrange for mice. Things start to look up once you head on past mice to very short-lived species such as flies and nematode worms: the cost falls and studies of aging that produce quality data for that species become affordable, as well as being something that can be carried over the course of a few months.

What is the value of good quality data for nematode aging, under the influence of a variety of genetic alterations, environmental circumstances, and other treatments, however? Far less than if we magically had access to similar data for humans, that is certain, but to a surprising degree many aspects of the cellular biochemistry of aging are shared between very diverse species, even those as distant as humans and nematodes. The insights that can be obtained, while rarely if ever directly applicable across such a large gulf, are well worth the cost. They serve to steer much more expensive research in mammals, guiding the larger expenditures to the lines of work more likely to produce results. In turn work in mice serves to steer the again much more expensive process of producing applications of research for human use.

So short-lived animals whose biochemistry is well understood serve an important role in exploratory research. Starting there, even though far removed from human biology, ultimately reduces costs and rules out dead ends in the process of medical development and aging research considered as a whole. Further, a diversity of short-lived species to study is a good thing: comparisons between them can help to more efficiently identify initially promising findings that turn out to be peculiar to one species, which is a lot better than figuring that out only later, after five years of further mouse studies. Here is an example of scientists working to develop the infrastructure and understanding needed for a comparatively new addition to the species employed in the laboratory for aging research:

Tiny fish makes big splash in aging research at Stanford

"Live fast, die old" maybe isn't the catchiest motto. But, for the African turquoise killifish, it's apt. The killifish is one of the world's shortest-lived vertebrates, with some varieties living only four months. Old killifish display many characteristics of aging humans: declining fertility and cognitive function, a loss of muscle mass and an increasing likelihood to develop cancerous tumors. The fact that the fish shares many biological characteristics with humans makes it a promising candidate for the study of aging and longevity. But until now, scientists didn't have the necessary tools and information with which to conduct genetic studies.

Now, researchers have mapped the location of specific genes involved in aging and age-related diseases along the killifish's chromosomes. They've studied patterns of gene expression in its various tissues, and used genome-editing technology to mutate 13 genes thought to be associated with the aging process. This new biological tool kit, which the researchers have made publicly available, will make it possible to trace the effect of specific genetic changes on aging and the diseases that accompany it.

A short life span allows researchers to quickly assess the effect of genetic variations among different strains of fish. It also allows them to breed and raise hundreds of progeny for study within the span of months, rather than the many years required to conduct similar experiments in other vertebrates. "The life span of a mouse can be as long as three to four years. This is close to the average length of a postdoctoral or graduate student position. This means that it would be very difficult for a researcher to conduct a meaningful analysis of aging in the mouse within a reasonable time period."

The killifish's rapid life cycle meant that researchers were able to generate fish carrying the mutations within 30-40 days, and stable lines - that is, fish with the mutation stably integrated into all their cells, which they will then pass on to all their progeny - within about two to three months. In contrast to laboratory mice, the length of killifish telomeres, which average around 6,000-8,000 nucleotides, is similar to that of humans. As a result, researchers were able to quickly see the effect of a telomerase-disabling mutation in the fish. Interestingly, fish in which telomerase activity was disabled displayed a variety of traits that are similar to those seen in humans with a disorder called dyskeratosis congenita, which is also due to a mutation in telomerase. The researchers conclude that the killifish is currently the fastest way to study diseases of telomere shortening in vertebrates. They are hopeful that the other mutant strains will be equally useful in their lab and in other labs worldwide.

Comments

probably one of the more major breakthroughs as of recent. If killfish serve as useful as mice, that would amplify the speed in conducting research tremendously

Posted by: thatoneperson at February 12th, 2015 11:02 PM

I would be interested to hear if SENS would consider using the fish for studies? But it does allow for a high throughput animal model to test aging therapies on.

Posted by: Steve H at February 13th, 2015 10:31 AM

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