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PICTURED: C. elegans under a microscope. Photo credit: Zeiss Microscopy. CC 2.0

Back in 2013, researchers at the Buck Institute for Research on Aging published a remarkable finding after mutating two genes in C. elegans – tiny worms that share almost all of our DNA, and are a model species. Scientists often experiment with these worms because it’s cheaper than mouse studies and avoids human trial restrictions.

C. elegans live a few weeks, but when the researchers created a worm with mutations in the daf-2 gene, part of the insulin signaling pathway, they demonstrated 100% increased lifespan. Another mutation, in the rsks-1 gene that’s part of the TOR (Target of Rapamycin) pathway, which determines cell growth and proliferation, conferred 30% increased lifespan in C. elegans.

However in the 2013 paper after Professor Pankaj Kapahi created a worm with mutations in both the daf-2 and rsks-1 genes, which reside in the two different critical metabolic pathways associated with aging previously mentioned, the worms lived 454% longer than non-mutants, rather than the 130% that basic arithmetic would suggest.

The secret in the worms

These pathways, the insulin signaling pathway and TOR, are streams of genetic information that play a large role in cellular activity like growth, survival, protein synthesis, and more, but are particularly associated with age.

Now 7 years later the Buck researchers are building on the 2013 breakthrough that made headlines in the aging community and even made it into the monolog on the Tonight Show. Postdoc researchers who worked with Professor Kapahi and the Buck Institute but that now run their own labs are continuing this work and have discovered how these two mutations work synergistically to improve lifespan.

In the mutant worms, the activity of the two altered genes lead to an increased activity and expression of a gene called DAF-16, which in humans is known as the FOXO pathway. FOXO is another continuously- important pathway that’s involved in cell growth and longevity.

The increase in DAF-16 expression in the mutant worms led to them producing less and less of a protein called cytochrome-c. Reduced cytochrome-c resulted in signals being sent to the intestines of these worms that led to increases in other processes that promote mitochondrial health – one of the foundations of healthy and successful aging in mice and yeast cells, and very likely humans as well.

Concerning humans

The hope with this research is that once the mechanisms for why these genes cause such a generous increase in lifespan is discovered, and other cells and pathways that are affected by these changes are identified, scientists can determine whether this sort of intervention can be applied to mammals – and eventually even humans.

The difficulty here is that biological functions often have a give and take nature to them, and processes that benefit one aspect of the body might be detrimental to another. For example while TOR plays an important role in aging because it keeps cells strong and healthy, as well as replacing ones that die, it can also help conduct the growth and proliferation of cancer cells, as over-regulation of TOR can lead to malignant cells continuing to live beyond when the body would normally allow them to die.

Humans can live on for many decades, while C. elegans live merely weeks, so genetic interventions that affect worms are a good start, but must be advanced to mouse studies as any negative effect such interventions might have would have much greater consequences in mice than in worms.

Professor Kapahi is working now on information related to these mutant worms when placed in a calorie-restricted state – another repeatedly proven longevity intervention – to see if the 454% can become even higher.