Science Spotlight

Only the (insensitive worms) die young

From the Brent Laboratory (Basic Sciences Division)

Different species of organisms vary extensively in their lifespan.  Dogs live for 5-20 years, fruit flies live for about a month, and giant tortoises can live for 150 years.  But what about variation in life expectancy within one species?  Obviously, there are many contributing environmental factors, such as the availability of food and shelter, the frequency of encountering predators, and catastrophic situations like flood or drought. Also contributing is the genetic make-up of each individual, called the genome, which affects metabolism, response to environmental stress, and lifespan. Scientists have made observations which suggest there migh tbe a third factor at play; research from the Brent Laboratory (Basic Sciences Division) has described differences in gene expression among genetically identical populations of budding yeast grown under constant environmental conditions1.  Their work showed that the amount of this inter-individual variation was under genetic control.  

Scientists have observed this phenomenon in multicellular organisms as well; genetically identical mice that are raised under constant conditions vary widely in their overall body weight2.  They have also observed differing levels of gene expression between genetically identical microscopic roundworms, C. elegans, kept on the same petri dish at constant temperature. Currently, the cause of this non-genetic, non-environmental inter-individual variation is unclear. It is possible that epigenetic differences, meaning the way the genome is structured by proteins that are inherited directly from ancestor cells, might account for the variation.  Alternatively and in line with previous research in the Brent Laboratory, it is possible that the amount of inter-individual variation that exists in one population versus another might be influenced by specific genes that either limit or broaden the amount of variation possible. C. elegans is a good model multicellular organism for studying inter-individual variation because they require minimal upkeep, they have a relatively short lifespan (2-3 weeks, reproducing on average every 4 days), and genetic mutations can be made easily.  

C. elegans. (Wood, W. B. (Ed.). (1988). The Nematode Caenorhabditis elegans. N.Y.: Cold Spring Harbor Labortory Press.)

Previously, researchers found that a higher level of expression of heat shock inducible genes in young adult C. elegans correlated with longer lifespan3. Later, scientists in the Brent Laboratory (Basic Sciences Division) found that genetically distinct populations of C. elegans with vastly different amounts of expression of the same heat shock gene actually all shared a common "coefficient of variation". This was surprising because strains (populations) with a lower expression level might be expected to have higher variation in expression due to stochastic noise in transcription and translation. Therefore, rather than "biochemical noise" in gene expression accounting for non-genetic, non-environmental variation between individuals, Alex Mendenhall, then a postdoctoral fellow and now a faculty member at University of Washington, and Basic Sciences member Roger Brent hypothesized that there may be molecular mechanisms which actively promoted or prevented inter-individual variation in worms as well as yeast.  Put simply, there may be mechanisms that increase or decrease the overall possible range of expression of specific genes.  Such variation may be beneficial for the survival of a population; for example, it might be adaptive to vary to a certain, constrained degree in the response to heat shock.  

In their latest publication in the Journals of Gerontology: Biological Sciences, Mendenhall, Brent, and their colleagues report that thermosensory neural signaling in C. elegans increases inter-individual variation while insulin-like signaling decreases inter-individual variation in expression of heat-shock responsive genes. They measured the coefficient of variation in normal, wild-type worms with that in a population of worms with non-functional thermosensory neurons, created through an inserted genetic mutation.  Signaling by these neurons is important for a proper response to heat shock stress.  Interestingly, variation in gene expression was lower among worms with non-functional thermosensory neurons.  This suggests that normally thermosensory neuron signaling works to increase inter-individual variation in heat shock responsive gene expression.  Next, they investigated another pathway known to control the expression of heat shock responsive genes, the insulin-like signaling pathway.  They compared variation in populations in which the insulin-like signaling pathway was turned up or down via genetic mutations. They found that worms with mutations that hyper-activate insulin-like signaling had a narrowed range of inter-individual expression while worms with mutations that decrease insulin-like signaling had a widened range of expression.  They concluded that insulin-like signaling limits inter-individual variation in expression of heat shock proteins.  

Mendenhall and Brent do not know the significance of the correlation between variation in expression of these heat shock responsive genes and the variation in lifespan. However, they point out that understanding mechanisms that control cell-to-cell and individual-to-individual variation may be important for human health.  For example, cells that only express a low level of proteins that suppress tumor development may be more prone to develop into cancer cells. Ongoing work will help better our understanding of the molecular basis and consequences of variation in gene expression in populations of yeast, C. elegans, and cells in vertebrate tissues.  

Mendenhall A, Crane MM, Tedesco PM, Johnson TE, Brent R.  2017.  "Caenorhabditis elegans genes affecting interindividual variation in life-span biomarker gene expression."  Journals of Gerontology: Biological Sciences.  Vol. 00, No. 00, 1-6.  

This research was funded by the National Institutes of Health.  

Additional citations:

1.  Colman-Lerner, A., Gordon, A., Serra, E., Chin, T., Resnekov, O., Endy, D., Pesce, G. and Brent, R. 2005.  "Regulated cell-to-cell variation in a cell fate decision system." Nature. 437, 699-706

2.  Gartner K.  1990.  "A third component causing random variability beside environment and genotype.  A reason for the limited success of a 30 year long effort to standardize laboratory animals?"  Lab Anim.  24:71-77.

3.  Rea SL, Wu D, Cypser JR, Vaupel JW, Johnson TE.  2005.  "A stress-sensitive reporter predicts longevity in isogenic populations of Caenorhabditis elegans."  Nat Genet. 37(8):894-8.