I want to know why we, humans, age. People, in general, want to know why they age. The goal of biomedical research is to improve the human condition and so the study of aging in model organisms should be more than curiosity-driven. In this essay, I present the different model systems used to study human aging and debate their strengths and pitfalls.
Keywords: ageing, biogerontology, insects, Homo sapiens, invertebrates, life span, Mus musculus, Pan troglodytes, primates, Rattus norvegicus, vertebrates
Studying Human Aging in Humans
One major difficulty in studying human aging is its duration, particularly because researchers themselves are aging and have a limited lifespan. In order to learn more about the biology of aging, it is crucial to have adequate models. Since the human aging process takes decades to develop, however, it is almost impossible to study it in vivo. Researchers can describe human aging and investigate age-related pathologies, as mentioned before. There are two types of studies: longitudinal studies, which follow individuals throughout their lives, and cross-sectional studies, which compare young and old individuals. Both types of studies are observational, not mechanistic. There are some genetic studies of longevity in humans (Puca et al., 2001; Perls et al., 2002), but longevity is not aging and the true relevance of these studies remains to be established. Researchers cannot, however, conduct experiments in humans in the same way drugs aimed at cancer or AIDS can be tested in clinical trials. Therefore, most scientists resort to model systems and then extrapolate data from these different models into human aging. The choice of models is, however, diverse and highly controversial (Gershon and Gershon, 2000b). Unfortunately, the employment of inadequate models for the study of human aging can be catastrophic for research since it can shift the focus of gerontology to pathways that, though relevant in a certain model, may be irrelevant in humans.
The major model systems used to study human aging are: 1) human cells; 2) unicellular organisms such as the yeast Saccharomyces cerevisiae; 3) the roundworm Caenorhabditis elegans 4) the fruit fly Drosophila melanogaster 5) rodents such as mice (Mus musculus) and rats (Rattus norvegicus). The small size and short life cycles of these organisms--even mice do not commonly live more than 4 years--make them inexpensive subjects of aging studies, and the ability to genetically manipulate them gives researchers ample opportunities to test their theories.
One major model system of human aging are human cells, that have as major advantage the fact that researchers can concentrate on human biology. It is reasonable to assume that human aging has a cellular basis (de Magalhaes, 2004). Nonetheless, cellular models and the methods used to study them have a series of flaws, and so in vitro results may not be representative of what happens in vivo (Mondello et al., 1999). Succinctly, the major argument against cellular models is that most cellular models of aging, such as replicative senescence, are based on measurements of cell proliferation which are not necessarily a measurement of vitality (Cristofalo, 2001). Cancer, for instance, is derived from rapid, uncontrolled cellular proliferation. Other methods exist to measure aging in cells, such as stress resistance, but the relevance of these methods to organismal aging remains to be demonstrated (de Magalhaes, 2004). Cellular models of aging will not be covered in detail here as they are further described elsewhere.
Studying Human Aging in Model Organisms
Of course human studies should always be preferred, but model organisms are simply unavoidable in gerontology. Much of what we know about aging today derives from organisms like yeast, mice, rats, fruit flies, and roundworms (Fig. 1). Of course, it is nearly impossible to tell whether an organism is representative of human aging or not. It has been argued that similar mechanisms operate across many species (Longo, 1999; Longo and Fabrizio, 2002), while others have proposed that some aging mechanisms are common to all species while others are unique (Martin et al., 1996). Since the basic blocks of life are common to most known species, common pathways might be involved in aging across phylogeny (Tissenbaum and Guarente, 2002). Could it be that the weakest pathway succumbing to senescence is the same in all organisms? Such hypothesis is hard to believe based on the huge diversity of aging phenotypes found in nature, and certain animals appear to age for different causes than us. For example, the male of the Australian mice (Antechinus stuartii) has a bizarre aging phenotype, as mentioned elsewhere. Although this process leads to death, it is much different than the gradual waning of humans and so Antechinus do not appear good models of human aging. The question is: are the other models accurate paradigms of human aging?
Figure 1: Major model organisms of aging: yeast (top left), roundworms (top right), fruit flies (bottom left), and mice (bottom, right). The picture of C. elegans is used with permission from the copyright holders Juergen Berger and Ralf Sommer, Max-Planck-Institute for Developmental Biology, Tübingen, Germany. The picture of a fruit fly was taken by André Karwath and the picture of S. cerevisiae was taken by Maxim Zakhartsev and Doris Petroi, International University Bremen, Germany.
Even in animals that age gradually, such as mice, there is no a priori reason to expect them to age for the same causes and mechanisms as humans (Gershon and Gershon, 2000a). One problem is that all models organisms are considerably shorter-lived than humans and were developed for laboratory research based on their high fertility. Not only this means that there are different evolutionary processes acting on these organisms and on humans (see Austad, 1997b for arguments), but selection for fertility may have also selected for short lifespans in laboratory strains that generate bias in aging studies. In other words, the life-extending alleles found in these organisms may actually be simply restoring lifespan to what is normally found in the wild (Spencer and Promislow, 2002). The fact that wild-derived mouse strains take longer to reach sexual maturity and live significantly longer than common laboratory strains supports this view (Miller et al., 2002b).
Human physiology can be much different than that of model organisms. Clearly, the phenotypes of aging in yeast and humans are totally unalike (Gershon and Gershon, 2000b). Not even researchers working on yeast expect yeast aging to be a perfect mirror of human aging (Sinclair, 2002; Jazwinski, 2005), and some of the same criticisms aimed above at human cells can be extrapolated to yeast. Drosophila and C. elegans are mostly composed of post-mitotic cells, which means that not only they do not have cancer or many other age-related diseases, but it raises doubts on how valid results obtained in these animals are when extrapolated to humans. Maybe some general pathways of aging are conserved between all organisms. Certainly, not all age-related changes overlap. At present, it is impossible to tell for sure if a given model organism is accurate or how accurate it is. It does appear reasonable to assume that species evolutionary closer to humans have higher chances of being representative of human biology than distant species.
It can be argued that even if the aging process is not the same in distant organisms and humans, studies in lower life forms can help us understand the dynamics and structure of human aging. If aging is the corruption of life, then understanding how life itself works may help us understand aging. Much of what we know about the biochemistry of life--e.g., DNA replication and repair--came from studies in lower life forms such as bacteria and yeast. Many genes that modulate aging have been identified in model organisms such as yeast (Jazwinski, 2001), C. elegans (Johnson, 2002), Drosophila (Tower, 2000), and mice (Liang et al., 2003; Hasty and Vijg, 2004). These findings can serve as the basis for research into mammals and humans (Sinclair, 2002; Tissenbaum and Guarente, 2002; Butler et al., 2003; Warner, 2003). Some of these findings, such as CR and the insulin-signalling pathway (Longo and Fabrizio, 2002; Butler et al., 2003), appear to be conserved between different species while others have not been demonstrated in mammals (see below). Therefore, some mechanisms of aging found in model organisms may turn out to be relevant to humans, though studies on the mechanisms of aging in lower life forms should be corroborated in mammalian models before extrapolating into human aging. Importantly, explaining human aging based on research in model organisms, even mice, is problematic.
The telomeres, described in more detail elsewhere, are the perfect example of the limitations of model systems in aging research. Clearly, they are major players in cellular senescence. Telomere dysfunction in S. cerevisiae due to mutations in telomerase, an enzyme critical for telomere maintenance, leads to senescence (Lundblad and Szostak, 1989; Lowell and Pillus, 1998). In C. elegans, telomerase defects appear to result in sterility after a certain number of generations (Ahmed and Hodgkin, 2000), but a role of telomeres in its aging process have not been established. In Drosophila, telomere maintenance does not involve telomerase, though other proteins involved in telomere maintenance may overlap with those of humans (Cenci et al., 2005). Telomerase-deficient mice are normal up to four generations and then show some signs of accelerated aging (Blasco et al., 1997; Rudolph et al., 1999), but telomerase overexpression does not alter aging in mice (Artandi et al., 2002). On the other hand, telomerase dysfunction in humans causes dyskeratosis congenita, which shares some features with the sixth generation telomerase-deficient mice (Marrone and Mason, 2003). It is therefore nearly impossible to determine the impact of the telomeres and telomerase in human aging based on model systems. Even between mice and humans, there are similarities but also differences in the biological outcomes of telomerase deficiency.
Although aging in different mammals is often phenotypically similar, even eutherians may have different mechanisms of aging. Like mentioned above, the bulk of research in mammals is based in short-lived animals like mice and rats whose evolutionary forces acting on aging may have been different from those acting in humans (Austad, 1997b). Besides, there are numerous examples of research in animals, including mammals, being inadequate to humans (Pound et al., 2004). The phenotypic differences mentioned above between mice and humans due to telomerase deficiency are a perfect example. As proven time and time again in other biomedical fields, what occurs in the aging process of other mammals may not be representative of human biology (reviewed in Davenport, 2003). Therefore, if we base our understanding of human aging on model organisms, even mammals, we must be careful about extrapolating findings into humans. One of the reasons why the mechanisms responsible for human aging remain largely a mystery is the lack of appropriate models where scientists can test their hypotheses and the controversy relating to the interpretation of findings in those organisms.
Underrated Models of Aging
One of the problems of research on aging is that it is based on only a handful of models. Definitely, more models of aging would be helpful to gerontology, particularly models biologically closer to humans and long-lived animals. For example, employing other primate models in the study of aging could open new opportunities for research on aging because we are biologically closer to them and some species have been shown to age considerably faster than humans (Austad, 1997c). So far, research on aging is based on a handful of species. A bigger diversification of models of aging would be extremely beneficial to the field but so far it has been hindered by costs.
Previously, I argued that reptiles, in general, age slower than mammals. Not only reptiles age slower than size-equivalent mammals, but several reptilian families feature apparently non-aging animals with traits such as continuous tooth replacement and often female reptiles feature oocyte regeneration. Of course not all reptiles age slower than all mammals for that would be unrealistic given the flexibility demonstrated by natural selection in modulating longevity and aging (Cutler, 1979; de Magalhaes, 2003 for arguments). Still, maybe mammals lack certain anti-aging mechanisms that are present in some or all reptiles (de Magalhaes and Toussaint, 2002). Pathways unique to reptiles have already been identified that could contribute to the delayed reptilian aging (see Lutz et al., 2003). For instance, neurogenesis is predominant in reptiles (Font et al., 2001). Other studies found unique traits in reptiles that could be useful to humans: crocodiles have been shown to possess novel antimicrobial peptides (Shaharabany et al., 1999). Clearly, long-lived reptiles are an underestimated model for the study of aging and more attention should be given to study reptilian aging or the apparent absence of aging of some species.
Other long-lived animals could be potential models of aging not so much to discover what causes aging but to investigate how we can fight it. As mentioned before, some amphibians and fishes also feature negligible senescence (reviewed in Finch, 1990; Cailliet et al., 2001). Since amphibians and fishes are evolutionary further from us than reptiles, they are not, a priori, better models but can still prove useful. For example, amphibians can regenerate entire limbs while mammalian tissues, such as muscle, can only regenerate as isolated entities (reviewed in Brockes et al., 2001; Carlson, 2003). Lastly, birds too have been proposed as potentially useful models for understanding human aging due to their slow aging rates when compared to size-equivalent mammals (Holmes and Austad, 1995; Holmes et al., 2001).
It may be asked: why learn from species that are behind us in the race for immortality? It has been proposed that species without detectable senescence can "teach" us much more than species with short lifespans (Strehler, 1986). Even in species such as whales or elephants their evolution of longevity might have followed different pathways than in humans; studies in these species can lead to the discovery of new methods in the combat against the only disease we all possess. Research on several of these species can lead to creating transgenics--e.g., mice or even primates--with increased lifespans that if successful can then be extrapolated to humans. With the emerging age of genomics, employing these long-lived species in studies of aging is becoming a reality (de Magalhaes and Toussaint, 2004b).
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