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C.Elegans as a Model for Aging Research
Posted on: May 28, 2003

When the nematode worm Caenorhabditis elegans was first considered as a model for the study of ageing, few foresaw how valuable it would prove to be. More than 50 genes that extend lifespan have now been described. Some of these genes regulate a key developmental switch, while the others control core processes, such as the overall rate of metabolism. These are exactly the kinds of processes predicted to be important to longevity by the evolutionary theories of ageing, which suggests that competition of metabolic resources between processes such as growth, reproduction and cellular maintenance lies at the heart of the ageing process.

Now the major cellular changes that accompany ageing in a number of important cell types are characterized. Intriguingly, was found that worms are perhaps not so very different from humans, at least in the sense that important aspects of their decline into senescence is the progressive deterioration of muscle, known as sarcopenia. By contrast, the worm nervous system appears remarkably well preserved. Here we present an overview of deterioration events encountered in ageing process.

The behavioral study of ageing nematodes showed significant decrease in mobility. Age-associated locomotory defects increase progressively in severity over time. Age-related behavioral changes occur with different times of onset and progress at different rates of decline in individual animals. The individual time of onset and the rate of behavioral decline are widely variable among isogenic members of same-age population reared under the same environmental conditions. It indicates that at least one major factor in behavioral ageing of C.elegansi is stochastic.


Fig. 1

Maintenance of nervous system integrity in animal ageing

Initially was sought that age-related neurodegeneration in C.elegans because diminished locomotory responses could result from neuronal structural deterioration or cell death and because the vacuolar structures in ageing nematodes superficially resemble necrotic-like neuronal cell death. Surprisingly, detailed examination of representative sensory ant motor neurons failed to indicate any signs of neuronal degeneration associated with either advanced C.elegans age or extensive behavioral decline. The study of C.elegans nervous system indicates that there is little if any neuronal cell death during the lifespan, even in severely compromised animals. There is no large-scale age-associated loss or restructuring of neurites or nuclei. Although it cannot be ruled out the significant changes in biophysical properties (nerve conduction, synaptic transmission), it is clear that at the cellular level the nervous system is well maintained in senescing C.elegans. If old worms wriggle less, it is not, it seems, because they have forgotten to do so.

Previous analyses of ageing in other nematodes also failed to note significant neuronal deterioration with age. Neuronal counts in fly eye and antenna provided no evidence for neuronal loss as a significant component of Drosophila ageing. There is little neuronal loss associated with normal ageing in specific human brain regions studied, challenging long-held notions about significant loss of mammalian brain neurons with age. The basic maintenance of the cellular integrity of nervous systems might be a common feature of metazoan ageing, although given documented differences in neuronal integrity among various ageing rodent inbred strains, it is clear that genetic factors can influence neuronal health and function in aged animals.

Because extensive neuronal loss seems less of a significant factor in age-related cognitive and motor deficits in humans, experimental attention has turned to the evaluation of synaptic function in higher organisms. A higher resolution examination of synaptic function in nematodes (quantification of synaptic proteins in synapses, characterization of neuronal transcripts and synaptic integrity in specific behavioral classes over time) will be required to identify molecular and subcellular changes that accompany neuronal ageing in C.elegans.

Like humans, C.elegans experience sarcopenia

Progressive locomotory impairment during C.elegans ageing could be the consequence of a decline in muscle function. The age-related muscle deterioration was examined by monitoring of body wall muscle nuclei or sarcomeres. The apparent decrease, beginning in mid-life, in number of nuclei was observed. Nucleus and nucleolus begin losing circularity and becoming more misshapen. Nucleolar size seems to increase relative to nuclear size with age (at day 7 the rations of nucleolar size to nuclear was 0.16±0.01 while in the late-life time - 0.30±0.02). Nuclear changes in different muscle cells in age-related animals were variable, indicating that stochastic factors might influence this process.

In young animals, sarcomeres are organized in tight parallel symmetric rows. Sarcomeres in older animals seem progressively disorganized with less dense packing and irregular orientation. In some individual muscles marked changes in sarcomere orientation or fraying individual sarcomeres into thinner, misdirect strands, were observed. However, muscles do not fully disintegrate during C.elegans ageing. Sarcomeres become clearly more disorganized in old muscles and include significantly fewer myosin thick filaments per sarcomere unit. A sticking and prevalent shrinkage of the muscle cells, due to a progressive cytoplasmic loss, was observed. The plasma membrane becomes highly invaginated.

Muscle deterioration in ageing animals is not limited to body wall muscle. With increasing age the pharynx looses its smooth, rounded shape as well as myofibrils in individual pharyngeal muscles are lost over time.

C.elegans body wall muscle is considered to be analogous to human skeletal muscle. In humans, loss of muscle mass is associated with shrinkage in the sizes of the fused muscle cells, thought to be due to a decrease in the cytoplasmic volume of the cell. In rats, sarcomere integrity is progressively compromised with age such that the packing geometry of the sarcomere fibres is generally loosened, and fraying and loss of direction of individual muscle fibres occur. Drosophila flight muscle also exhibits signs of age-related deterioration.


Fig. 2

Many additional cell types (such as hypodermis and intestine), but not all (the kidney-like canal cell and some oocytes), exhibit age-related deterioration. A decline in these cell types seems to be stochastic, much as muscle decline does. Ageing affects different cell types at different rates in C.elegans, thus stochastic events are factors in the age-related decline of multiple tissue types. It might be noteworthy that hypodermis and intestine often suffer random but extreme local crises, apparently associated with plasma membrane disruption, which might contribute to the death of the animal in advanced age.

Unregulated biosynthesis in post-reproductive C.elegans

Several examples indicate unregulated biosynthesis late in life. Marked accumulation of lipid inclusions in intestine and hypodermis was detected as well as marked thickening of C.elegans cuticle during ageing. Increases in cuticle thickness can reach 10-fold than in young adults in some locales, indicating that hypodermal cells continue collagen synthesis well into adulthood. The accumulation of body-wide electron-dense lipid-like material similar to previously identified as yolk protein. In young animals, the yolk protein is found almost exclusively in the intestine (where it is synthesized) as well as in the late-stage oocytes (which accumulate it) and embryos. But as animals enter post-reproductive period, the yolk protein is found in the body cavity of the animal. Thus, yolk protein production continues in the absence of oogenesis in post-reproductive nematodes. The extensive accumulation of macromolecules, such as yolk proteins, cuticle proteins and lipids, suggests that in post-reproductive animals biosynthesis/protein turnover is not tightly regulated.

Biomarkers of ageing

The gene age-1 encodes a phosphatidyl-inositol-3-OH kinase (PI(3) kinase) that acts downstream in the DAF-2 insulin-like receptor signaling to influence lifespan. The mutation of age-1 prolongs lifespan to 60-100% by enhancing locomotory activity in ageing populations and thus delaying the onset of age-related muscle nuclear changes. age-1 PI(3) kinase might exert its effects on health span and longevity in part by prolonging muscle integrity. PI(3) kinase is the first genetic factor influencing nematode sarcopenia and is a candidate for a similar role in human sarcopenia. Interestingly, an age-1 mutant effect on the muscle nuclei is first evident in mid-life, beginning near the post-reproductive transition. Thus, the idea that mid-life events might have a significant impact on health span and longevity could be reinforced.

A strong stochastic component for age-related decline

A dramatic feature of the changes described in the aged worms is the seemingly random nature of the large variations between individuals; in other words, the changes appear to be highly stochastic. The cellular changes in ageing C.elegans revealed several remarkable aspects of nematode senescence. Key findings that are stochastic factors make a significant contribution to senescence decline and that different cell types deteriorate at markedly different rates, with the nervous system being spared extensive cellular decline while muscle undergoes a profound and progressive deterioration with the mid-life onset.

The striking aspect of the biology of the ageing C.elegans is the wide variability in both the time of onset and the rate of apparent deterioration within an isogenic population reared under uniform environmental conditions. Although factors in the microenvironment or life histories of individuals could profoundly affect ageing rates, repeatedly was observed stochastic occurrence of cellular demise within the same cell types of individual animals. The marked variation in cellular decline is probably attributed to random damage or failures. In providing evidence for significant stochastic influences on both the overall senescent decline of the organism and the degeneration of individual cells within C.elegans, the data support a key premise of the "disposable soma" theory of ageing, which postulates that damage caused by chance events is a major contributor to ageing soma. Genes that influence ageing and lifespan should primarily be involved in maintenance and repair of the soma.

Nematode strains have exceptional genetic uniformity (arising from the fact that they are self-fertilizing hermaphrodites), they are cultured in uniform environmental conditions and they have a developmental process of almost clockwork precision. We know that in humans one of the hallmarks of the ageing process is an increase in variability. Indeed, it has been said of humans that we are all born copies but die originals. This variability in human populations can be readily attributed to the uniqueness of our individual combinations of nature and nurture, but such as explanation does not work for worms.

Lest we imagine that aged worms can now be taken for a complete model of old people, we must remember that the adult worm is post-mitotic; it has no dividing cells apart from those in its gonads. Thus, C.elegans can never be a model for the important contributions to human ageing that comes from impaired cell proliferation in the many mammalian tissues and organs that maintain themselves by cell renewal.

Figures from: http://www.u.arizona.edu/~acutter/organism.htm
Source: 1. T. B. L. Kirkwood and C. E. Finch. The old worm turn more slowly. Nature, vol.419, 2002 10 24;
2. L. A. Herndon, P. J. Schmeissner, J. M. Dudaronek, P. A. Brown, K. M. Listner, Yuko Sakano, M. C. Paupard, D. H. Hall and M. Driscoll. Stochastic and genetic factors influence tissue-specific decline in ageing C.elegans. Nature, vol.419, 2002 10 24.
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