If evolution works by selecting for the most advantageous genes, it begs the question: why haven't we evolved immortality? According to a decades-old hypothesis, certain genes that promote reproductive success also promote aging later in life, and now a study from Johannes Gutenberg University has identified some of these genes. The team also found that switching off those genes dramatically extended the lifespan of worms.
Getting old and dying is a natural part of life, but that doesn't mean we aren't interested in slowing or stopping it. There's a huge body of science dedicated to fighting aging at the genetic level, to find ways to extend not just our lifespan but our "healthspan" – the percentage of our lives in which we enjoy good health. There's not much point living to 110 if we spend our last 30 years completely bedridden.
But why hasn't evolution already done the heavy lifting for us? Individuals with traits that help them live longer are more likely to pass on their genes, so in theory, aging should have been entirely weeded out by now. To explain this apparent contradiction, in the 1950s biologist George Williams proposed the theory of antagonistic pleiotropy (AP), which operates on the principle of "benefit now, pay later." Essentially, the idea goes that evolution would select for genes that improve an individual's reproductive success in youth, and ignore any negative repercussions later in life because the genes have already been passed onto the next generation.
Williams' theory has since been backed up mathematically, and its effects can be seen in nature, but direct evidence had proven elusive. To test the idea, the Johannes Gutenberg team screened the genes of a worm species called C. elegans, and identified 30 genes that seem to fit the AP bill, helping in youth but turning against the animals in old age.
"The evolutionary theory of aging just explains everything so nicely but it lacked real evidence that it was happening in nature," says Jonathan Byrne, co-lead author of the study. "Evolution becomes blind to the effects of mutations that promote aging as long as those effects only kick in after reproduction has started. Really, aging is an evolutionary oversight.
"From a relatively small screen, we found a surprisingly large number of genes that seem to operate in an antagonistic fashion. Considering we tested only 0.05% of all the genes in a worm this suggests there could be many more of these genes out there to find."
To the team's surprise, many of the identified genes have a particular function in common: they regulate a vital process called autophagy. This is the recycling mechanism of cells, where they degrade to clear out the "cellular garbage" before it piles up and damages the cells. Autophagy works well in young organisms but is known to slow down and cause chaos later in life, so switching it off at a certain age could help improve both healthspan and lifespan.
"This could force us to rethink our ideas about one of the most fundamental processes that exist in a cell," says Holger Richly, principal investigator of the study. "Autophagy is nearly always thought of as beneficial even if it's barely working. We instead show that there are severe negative consequences when it breaks down and then you are better off bypassing it all together. It's classic AP. In young worms, autophagy is working properly and is essential to reach maturity but after reproduction, it starts to malfunction causing the worms to age."
The researchers found that by inactivating autophagy in the C. elegans' neurons, the worms stayed healthier for longer and their lifespan increased by an extra 50 percent. The researchers aren't yet sure of the mechanism behind the healthier neurons, but if the research can be applied to humans, it could not only improve our health- and lifespan, but combat neurodegenerative diseases like Alzheimer's, Parkinson's and Huntington's.
"Imagine reaching the halfway point in your life and getting a drug that leaves you as fit and mobile as someone half your age who you then live longer than, that's what it's like for the worms," says Thomas Wilhelm. "We turn autophagy off only in one tissue and the whole animal gets a boost. The neurons are much healthier in the treated worms and we think this is what keeps the muscles and the rest of the body in good shape."
The research was published in the journal Genes & Development.
Source: Johannes Gutenberg University
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