Writing in a February issue of Genes & Development, researchers from Harvard Medical School (HMS) in the US describe how feeding omega-6 fatty acids to Caenorhabditis elegans roundworms or adding them to cultured human cells activates autophagy, a natural, self-digestion form of renewal by which cells break down and recycle their own defective or worn-out components and molecules.
Response to Nutrient Shortage and Lifespan Regulation May Share Same Molecular MachineryConditions of metabolic stress, such as when nutrients are scarce, triggers changes in gene expression, and activates metabolic programs like autophagy that promote survival by making more efficient use of internal energy reserves.
First author Eyleen O'Rourke, research fellow in genetics at Massachusetts General Hospital, the primary teaching hospital of Harvard Medical School, says in a statement:
"It has been suggested that autophagy can extend lifespan by maintaining cellular function, and in humans a breakdown in autophagic function may be involved in diseases including inflammatory bowel disease, Parkinson's disease, and, in a more complex way, in cancer and metabolic syndrome."
Even when food is abundant, activation of metabolic programs like autophagy can extend lifespan, but we know little about the underlying metabolic and molecular changes involved, O'Rourke and colleagues note in their study background.
The study took place in the lab of corresponding author Gary Ruvkun, HMS professor of genetics, whose team studies the development, longevity and metabolism of C. elegans.
Previous work in the lab has already established that certain gene variants can double or triple the roundworm's lifespan, and that mutations in corresponding genetic pathways in mammals have a similar effect.
Some of these gene variants also help mammals survive starvation, leading researchers to believe response to nutrient deprivation and regulation of lifespan share the same underlying molecular machinery.
Genomic Search Leads to Discovery of Omega Fatty Acids as Trigger for AutophagyTo find out more about the molecular machinery, O'Rourke scanned genomic databases of all sorts of animals looking for genes that change their expression in response to fasting.
The search revealed that in C. elegans, expression of the gene lipl-4 increases seven-fold when the roundworm is starved of nutrients.
The researchers found that an engineered strain of the roundworm that constantly expresses high levels of the gene, even when nutrients are plentiful, also had higher levels of an omega-6 fatty acid called arachidonic acid (AA), and an omega-3 fatty acid called eicosapentanoic acid (EPA).
Having discovered that omega fatty acids appear to be involved in starvation resistance, the researchers then fed AA and another omega-6 fatty acid, but not EPA, to normal strains of the roundworm (ie not engineered to constantly express lipl-4), with full access to nutrients, and found this triggered autophagy.
They also found when they fed the roundworms a normal diet supplemented with omega-6 fatty acids, they lived 20 to 25% longer than usual.
Testing Effect in Human CellsThere is evidence that taking omega-3 and omega-6 fatty acid supplements can prevent some illnesses and improve health in humans, so the researchers decided to test their findings in cultured human cells.
They found similar results as in the roundworms: omega-6 acids (but not EPA) activated autophagy in cultured human cells.
O'Rourke and colleagues conclude this result suggests omega-6 fatty acids likely trigger autophagy in all multicellular animals.
Omega-6 Fatty Acids May Provide Benefits of Caloric Restriction without Limiting Food IntakeThe researchers also found that the omega-6 fatty acids only extended lifespan in the roundworms when certain genes required for autophagy were present.
O'Rourke explains that nearly all the mechanisms we know of that extend lifespan, such as sterility, insulin insensitivity and caloric restriction, depend on triggering autophagy.
Discovering that supplementation with omega-6 fatty acids can trigger autophagy, the cellular response to fasting, in roundworms, even when they are eating normally with a plentiful food supply, suggests adding omega-6 fatty acids to a diet may provide the benefit of caloric restriction without having to limit food intake.
"It also suggests that the reported benefits of omega-6 acids could depend in part on activation of an evolutionarily ancient program for surviving food deprivation," says O'Rourke.
The authors note that many researchers and doctors believe omega-6 fatty acids, usually present in vegetable oils, poultry and meat, can raise the risk of cardiovascular disease, despite evidence to the contrary.
"We hope that our findings - made by investigating the cellular responses of a 1-millimeter roundworm - will lead the scientific and medical community to look back at all the epidemiologic, basic and clinical research data and to study the effects of omega-6 fatty acids on multiple types of human cells and live animals in order to gain better knowledge on how balanced intake of these nutrients benefits human health," urges O'Rourke.
Grants from the National Institutes of Health funded the study.
In August 2012, scientists at the Ludwig Institute for Cancer Research in Oxford, UK, reported the discovery of a critical molecular switch that regulates autophagy that appears to be disabled in cancer.