C. elegans for aging studies
C.elegans (Caenorhabditis elegans) is a free-living, transparent nematode (roundworm), about 1 mm in length, which naturally lives in temperate soil environments. C. elegans is a self-fertilizing hermaphrodite that has a temperature sensitive life span. They are also inexpensive to maintain and can be grown in vast quantities in the lab. Due to these characteristics, C. elegans has emerged as one of the premiere model systems for aging research.
Here, we have assembled a collection of manuscripts published in npj Aging and Mechanisms of Disease that utilized the compelling model system, C. elegans.
Selected Research and Reviews
A new study pinpoints a consistent set of genes and pathways underlying variations in yeast lifespan. Vadim Gladyshev at Harvard Medical School and co-workers analyzed 22 Saccharomyces cerevisiae yeast strains with diverse lifespans and habitats, looking to identify genomic signatures associated with natural variations in longevity. They observed a number of factors that characterized the longest-lived strains, including the upregulation of aerobic respiration, and found that interactions between genes and the environment were key. They also showed that factors associated with increased longevity in yeast strains do not necessarily degrade the fitness of those strains in the wild, and that longevity can be influenced through diet. The study thus paints a more complete picture of how environmental factors trigger changes—some hard–wired in the genome—that have real consequences on aging and longevity.
Morphological remodeling of C. elegans neurons during aging is modified by compromised protein homeostasis
Misfolded proteins and disrupted protein maintenance can lead to aging-related changes in neuron shape. Elena Vayndorf from the University of Alaska Fairbanks and colleagues in the US, Canada and France studied a strain of nematode Caenorhabditis elegans in which selected neurons express part of the human gene responsible for Huntington’s disease, which is an aging-related, neurodegenerative disorder. The researchers also blocked expression of genes involved in protein manufacture, folding, trafficking and degradation in healthy neurons. With both experimental manipulations, they observed changes in the morphology of the animal’s neurons that normally occur during aging. Given the similarities between C. elegans and human neurons, the authors propose that drugs targeting the cellular pathways that guide protein maintenance could help retain brain function in age-associated neurological diseases like Huntington’s.
Metformin decreases progerin expression and alleviates pathological defects of Hutchinson–Gilford progeria syndrome cells
A diabetes drug with a proven track record in the clinic may also offer an alternative treatment for a rare 'premature aging' disorder. A genetic mutation in patients with Hutchinson-Gilford progeria syndrome (HGPS) produces a defective protein called progerin, which causes children to develop skeletal, cardiovascular and other symptoms normally seen in the elderly. Researchers led by Xavier Nissan at I-Stem in France have demonstrated that metformin triggers a biochemical 'switch' that causes cells to decrease their production of progerin, and instead generate an alternative, non-toxic protein. Relative to untreated cells, metformin-treated cells were less prone to develop structural abnormalities or undergo premature maturation. Importantly, doctors have used metformin for over 20 years, suggesting that such a treatment approach should be safe for HGPS patients.
Increased activity of a single gene improves healthy lifespan of mice and flies, highlighting a new cellular pathway involved in aging. An international team of researchers led by Rafael de Cabo at the National Institutes of Health in Baltimore studied aging and disease progression in flies and mice genetically modified to overexpress antioxidant protein called cytochrome b5 reductase (CYB5R). These animals had modest improvements in lifespan, and mice had delayed tumor growth compared to controls in a model of liver cancer. Interestingly, the data suggest that this lifespan improvement was mediated by different biochemical pathways activated by calorie restriction, a well-studied longevity technique. Treatments or techniques that increase activity of the CYB5R pathway could thus be a viable alternative approach to lengthening healthy lifespan.
The main cause of disease worldwide is aging, a process long suspected to result from damage accumulation. However, new work from a team led by David Gems at University College London describes a different type of cause: quasi-programs, or the futile run-on biological programs in later life, supporting a recently proposed, alternative theory about aging. The study focuses on the short-lived worm C. elegans, which during aging develop very large tumors in the uterus. The authors show how such tumors develop due to futile attempts by unfertilized eggs to develop by switching on programs of embryogenesis. In mammals, similar runaway programs cause teratomas, a type of benign tumor of grotesque appearance. This work provides new insights about the nature of aging as a disease process, suggesting that it is to an extent teratoma-like.