Research on nemotode worms is helping to illuminate ways to lengthen their lifetimes. The findings have yet to be replicated in vertebrates, including humans.
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In October 2009 Stanford University geneticist Anne Brunet was sitting in her office when graduate student Eric Greer came to her with a slightly heretical question. Brunet's lab had recently learned that they could lengthen a worm's lifetime by manipulating levels of an enzyme called SET2. "What if extending a worm's lifetime using SET2 can affect the life span of its descendants, even if the descendants have normal amounts of the enzyme?" he asked.
The question was unorthodox, Brunet says, "because it touches upon the Lamarckian idea that you can inherit acquired traits, which biologists have believed false for years." The biologist Jean-Baptiste Lamarck theorized in 1809 that the traits exhibited by an organism during its lifetime were augmented in its offspring; a giraffe that regularly stretched its neck to eat would father calves whose necks were longer. The idea was largely discredited by Darwin's theory of evolution, first published in 1859. More recently, scientists have begun to realize that an organism's behavior and environment may indeed influence the genes it passes to its offspring. The heritability of those acquired traits is not based on DNA, but on alterations in the molecular packaging that surrounds a gene. When Greer approached Brunet in 2009 with his question about worms and SET2, such "epigenetic" inheritance had only been discovered for simple traits such as eye color, flower symmetry and coat color.
Brunet and Greer went ahead with the experiment. The results, published October 19 in Nature, provide the first evidence that some aspects of longevity can be passed from parent to offspring, independent of DNA's direct influence. (Scientific American is part of Nature Publishing Group.)
"I think this is a fundamentally important finding," says Matt Kaeberlein of the University of Washington in Seattle, who studies molecular mechanisms of aging. "It demonstrates for the first time that aging can be influenced by epigenetic changes that occurred in prior generations."
The study used Caenorhabditis elegans worms with very low levels of SET2. The enzyme normally adds methyl molecules onto DNA's protein packaging material. In doing so, the enzyme opens up the packaging material, allowing the genes to be copied and expressed. Some of those genes appear to be pro-aging genes, Brunet says. Her team knocked out SET2 by removing genes that code for it. This had the effect of significantly lengthening the worms' life spans, presumably because those pro-aging genes were no longer expressed.
Next, the long-lived, enzyme-lacking worms mated with normal ones. The offspring had the regular genes for making SET2, and even expressed normal amounts of the enzyme, but they lived significantly longer than control worms whose parents both had regular life spans. The life-extending effect carried over into the third generation, but returned to normal by the fourth generation (in the great-grandchildren of the original mutant worms). For the first few generations, having a long-lived ancestor increased life expectancy from 20 days to 25, extending a worm's longevity by 25 to 30 percent on average.
Brunet and her team have not yet determined the exact mechanism for the lifetime extension, or which molecules are at work. This is one of the study's imperfections, says David Katz, who researches epigenetic transcriptional memory at Emory University. Regardless, "the effect is clearly epigenetic," he says, "and it's probably one of the most complicated traits that has been linked to epigenetic inheritance."
The knowledge that epigenetics can impact a complex trait like life span has scientists curious to find out what other kinds of traits—such as disease susceptibility, metabolism and developmental patterns—are epigenetically heritable. Because epigenetic effects can be modified by environmental stimuli, Kaeberlein points out, it is possible that some of these traits "could be determined, at least in part, by the environment and lifestyle choices of parents, grandparents or even great-grandparents."
The study’s results are also exciting because the genes that code for the life-lengthening SET2 enzyme exist in other species, including humans. Brunet says she wants see if the results can be replicated in vertebrates, such as fish and mammals. Those questions will not be answered for many years, because it is unknown whether the SET2 complex has the same function in other species, and because those species have longer generational time frames.
"Worms have very short lives," Brunet says. "Will the effect apply to mammals that live thousands of times longer? We are excited to find out."
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9 Comments
Add Comment"What if lengthening a worm's lifetime using SET-2 can affect the lifespan of its descendants, even if the descendants have normal amounts of the enzyme?" asked Eric Greer.
Reply | Report Abuse | Link to thisAn old quote: Inexperience is what allows a young man to do what an old man says is impossible.
This is a very interesting find. It will be interesting to see if any epigenetic inheritances are found to be permanent.
I would love to see some more articles like this, covering some of the other factors in adaptation than then gene sequence themselves. I am still so gray on understanding those other mechanisms.
Reply | Report Abuse | Link to thisI don't understand.
Reply | Report Abuse | Link to thisFrom the description, it seems the knockout worms mated to normal worms would still inherit one normal copy of the gene. If it's dominant, it would express in half the offspring, and not disappear by the fourth generation.
Can anybody explain to me why this isn't the case?
The key concept here is that the goal of the study is to consider epigenetic effects and rule out effects of genetic inheritance.
Reply | Report Abuse | Link to thisMax, you're right. The progeny of knockout worms mated to the normal worms inherit one normal copy of the gene -- this is confirmed by their SET2 levels were at "normal amounts."
But what's different about the progeny? One of the parents had no SET2. That parent's gametes had DNA that was not *methylated*.
"For the first few generations, having a long-lived ancestor increased life expectancy from 20 days to 25..." This means that any subsequent progeny that had an ancestor with DNA that wasn't *methylated* ended up living longer.
As you pointed out, since the SET2 gene is dominant, it would be expressed in EVERY generation -- EXCEPT for the knockout generation. What is remarkable is the epigenetic effects of having a great-grandparent with unmethylated DNA -- and the only generation that could have had gametes with unmethylated DNA was the knockout generation.
They selected for individuals who where homozygous for the wild type gene in the F2.
Reply | Report Abuse | Link to thisTheory of Carbon SIgnaling does not require inheritance of structural DNA determinants. However, closely interplays within the process of entangled matter carbon related states. Take it!
Reply | Report Abuse | Link to thisA similar phenom was described in water fleas several years ago. In that model the bugs were exposed to low concentration so formaldehyde to stimulate the production of a protective protein coat. The p1 generation was then placed in normal aquarium condition and the thickness of the protein coat was observed over subsequent generations. The increased thickness persisted into the 3rd generation but was back to normal in the forth. I anticipate that changes observed in this model come from products down stream in the SET2 cascade behaving similarly.
Reply | Report Abuse | Link to thisThis type of work should serve as a reminder to never completely dismiss the observations of past investigators. Regardless of the explanations proffered, these were very intelligent scientists that we can only hope to be as good as. Just because we have more explanatory power today is not a reason to throw them on the trash heap.
BTW: for you anti evolutionists, you should be after Lamark not Darwin. He was the one who gave the first systematic explanation of "evolution". Just because his mechanism did not work out is no reason to completely discredit him. Note Darwin professed ignorance as to exactly how survival of the fittest past to subsequent generations. He knew he could propose the theory without working out all the nuts a bolts. Had Lamark limited his comments to the observations and stayed away from the mechanics of the issue we may have had evolutionary theory 100 years sooner.
If an organism lived longer, say, twice normal, would it mature much later and reproduce in the normal reproductive episode?
Reply | Report Abuse | Link to thisSounds like a real can of worms....
There was another article a couple of weeks ago that identified a protein found in large quantity in aged humans that is found in very low quantity in children. Perhaps these worm researchers and this other group should get together and compare notes.
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