A Brief Introduction to Model Organisms in Aging Research

The varied approaches to research developed over past decades by the aging research community are driven by two things: firstly that we live for a long time, and secondly the absence of a way to accurately determine an individual's biological age. The only way to measure the effects of potential treatments is to carry out life span studies, and in humans that is impractical to say the least. Thus research into aging and longevity starts with short-lived animals such as nematode worms and flies: exploration and experimentation takes place using these species because life span studies can be carried out in a suitably short period of time to make progress. Promising work moves to mice, where life span studies can last for five years and cost millions. Only later do potential treatments make it to human clinical trials, if at all. This is all much the same as most modern medical research; the process of discovery and development moves incrementally from a state of being far from human biology and cheap to work on to a state of being close to human biology and very expensive to work on.

To a surprising degree the fundamental biology of cells, regulation of metabolism, and mechanisms of aging are similar in even very widely separated species. Aging and many of its interesting epicycles such as the calorie restriction response appeared very early in evolutionary history, a long way down in the tree of life. Thus research in lower animals can still be relevant to human cellular biochemistry, and provide insight into human aging. Nonetheless, worms are not mice and mice are not people. The cost of investigative research that starts with other species is that there is a fair degree of failure when translating promising work over to mammals, and yet more failure when moving from short-lived mammals such as mice to long-lived mammals such as humans. That is acceptable given that the alternative is no research at all, as all studies would be prohibitively expensive to carry out.

Another aspect of research into aging and its associated medical conditions is that genetically altered lineages of laboratory animals are frequently employed. The reasons for this are again economic at root. If you want to study a specific condition, such as old age for example, it is more cost-effective to work with mice that suffer from a DNA repair deficiency that mimics some aspects of accelerated aging than it is to work with normal mice. More research can be carried out more rapidly with accelerated aging mice, even when accounting for the fact that a significantly greater fraction of the results will be irrelevant to normal aging. The same applies to the many different animal models of specific age-related diseases: these are all loose replicas intended to share some characteristics of the disease as it occurs in humans, but under the hood they are not the same thing at all. Animal models are a way to make progress in a cost-effective manner, not an accurate rendition. These things are always worth bearing in mind when reading research results based on animal studies.

Do Model Animals Tell Us Anything about Human Aging?

Using model animals in gerontological studies has yielded an enormous wealth of useful information about the mechanisms of human aging and longevity. Animal models were crucial in identifying the conserved pathways that regulate human aging. Model organisms are fundamental for aging research, because there are serious limitations of using human subjects, such as the length of lifespan, genetic heterogeneity and vast differences in environmental influences. The shape of survival curves represents the health of the organism over time. Model organisms display significantly different lifespans, however the survival curves resemble those of humans quite remarkably.

Yeast S.cerevisiae

Yeasts have been instrumental in identifying the major conserved aging pathways shared among a large variety of species. Despite the fact that yeast is a unicellular organism that has significant differences in its genetic pathways with humans, the advantages of using yeast as an aging model include their fast growth, low cost and easy storage and maintenances of organism strains. Over the years researchers have developed a broad variety of genetic manipulations that make yeast a powerful tool in the hands of an aging biologist.

Nematode C.elegans

The roundworm Caenorhabditis elegans is a powerful model for studying aging due to its short lifespan. It is easy to culture and maintain strains because nematodes can be kept frozen and suffer no apparent damage upon thawing. The animals are optically transparent and can be used in high-throughput automated experiments, which makes them a perfect tool for answering the most pressing questions in biology of aging. However, there are obvious drawbacks of using C. elegans as a model for human aging. They are evolutionary distant from humans, lack tissues like brain, blood, they don't have internal organs and are post-mitotic, meaning that nematodes lack the ability to regenerate their tissues and are limited in serving as a model of aging of highly proliferative tissues.

Fruit fly D.melanogaster

Fruit flies have many advantages as a model system for aging studies. They have a relatively short lifespan of 60-80 days, which is more than that of a nematode, but compared to them drosophila have more distinct tissues and organs including the brain, eyes, kidney, liver and heart. Fruit flies have proliferating stem cell populations in their guts. Flies share about 60% of disease-related genes with humans, which makes them a desirable model also given their low cost and easy handling. However, maintaining a transgenic strain is more costly and labor-heavy, since whole flies cannot be frozen and thawed without damage.

Hydra

Hydra is definitely not the most popular model organism, but it might be overlooked quite groundlessly. Hydras are notorious for their negligible senescence. This very fact makes them a very desirable system to study. In fact, there is no apparent senescence in asexually reproducing hydras, yet the signs of aging can be seen after the organism reproduces sexually. Another overlooked fact is that hydras share 6071 genes with humans, whereas fruit flies have 5696 genes in common with humans, and nematodes - only 4751. Among the known human aging-related genes at least 80% are shared with hydra.

Fish

The most widely used fish model is the zebrafish D.rerio. It lives for about 2-3 years, which is not particularly beneficial, because its lifespan is similar of rodents, but it is more evolutionary distant from humans. Nonetheless, zebrafish has a remarkable ability to regenerate its tissues, which is an advantage for elucidating the mechanisms of tissue regeneration and longevity. Another fish may be a more promising laboratory model for aging - turquoise killifish Nothobranchius furzeri. Killifish is one of the shortest-lived vertebrate with a lifespan of only 13 weeks. Its small size and high fecundity offer a considerable advantage in terms of reducing laboratory costs on housing and maintenance.

Rodents

Mice are invaluable in aging research. There are approximately 99% of human orthologs in mice, which is a significant advantage compared to invertebrate models. Mouse lifespan is approximately 2-3 years depending on the strain, which makes them a more expensive tool in the arsenal of an aging biologist. Inbred mice have been studied very extensively and a large body of knowledge about aging mechanisms, age-related diseases and existing and potential therapies was created using this model. Using inbred lines is a double-edged sword: on one hand, genetic differences between animals are virtually non-existent, however this is not representative of human population and it is not clear to what extent the results can be transferred to humans.

Naked mole rats

Heterocephalus glaber, the naked mole rat, is the most long-lived rodent with a maximum life span of approximately 30 years. Naked mole rat exhibits negligible senescence, virtually no age-related increase in mortality and high reproduction levels until death. They have several signs of age-related pathology similar to humans, such as osteoarthritis and degeneration of the retina. Naked mole rats can provide clues to mechanisms of longevity and potential therapies in humans, and hence are an extremely valuable model animal. There are several disadvantages of using them as laboratory animals, however, including specific housing conditions like low light levels, high temperature and humidity. Very long lifespan poses an obvious limitation on the variety of experiments suitable for this model.

Primates

Rhesus macaques have been used in various types of research, however there are not too many studies of age-related mechanisms in primates. The main reasons for that are their long lifespan, which is more than 30 years, their size and weight, which complicate housing and maintenance and make this model an expensive and hard to handle. However, there are several distinct advantages of using non-human primates for studying age-related pathologies, such as Alzheimer's disease and other neurodegenerative diseases that can't be recapitulated in mouse models.

Comments

How long have people been studying Killifish for? It seems like the world only became aware of them in the last year?

Posted by: Jim at April 16th, 2015 6:57 PM

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