Pathways that extend lifespan by 500 percent identified

Caenorhabditis elegans (stock image).

Scientists at the MDI Biological Laboratory, in collaboration with scientists from the Buck Institute for Research on Aging in Novato, Calif., and Nanjing University in China, have identified synergistic cellular pathways for longevity that amplify lifespan fivefold in C. elegans, a nematode worm used as a model in aging research.

The increase in lifespan would be the equivalent of a human living for 400 or 500 years, according to one of the scientists.

The research draws on the discovery of two major pathways governing aging in C. elegans, which is a popular model in aging research because it shares many of its genes with humans and because its short lifespan of only three to four weeks allows scientists to quickly assess the effects of genetic and environmental interventions to extend healthy lifespan.

Because these pathways are "conserved," meaning that they have been passed down to humans through evolution, they have been the subject of intensive research. A number of drugs that extend healthy lifespan by altering these pathways are now under development. The discovery of the synergistic effect opens the door to even more effective anti-aging therapies.

The new research uses a double mutant in which the insulin signaling (IIS) and TOR pathways have been genetically altered. Because alteration of the IIS pathways yields a 100 percent increase in lifespan and alteration of the TOR pathway yields a 30 percent increase, the double mutant would be expected to live 130 percent longer. But instead, its lifespan was amplified by 500 percent.

"Despite the discovery in C. elegans of cellular pathways that govern aging, it hasn't been clear how these pathways interact," said Hermann Haller, M.D., president of the MDI Biological Laboratory. "By helping to characterize these interactions, our scientists are paving the way for much-needed therapies to increase healthy lifespan for a rapidly aging population."

The elucidation of the cellular mechanisms controlling the synergistic response is the subject of a recent paper in the online journal Cell Reports entitled "Translational Regulation of Non-autonomous Mitochondrial Stress Response Promotes Longevity." The authors include Jarod A. Rollins, Ph.D., and Aric N. Rogers, Ph.D., of the MDI Biological Laboratory.

"The synergistic extension is really wild," said Rollins, who is the lead author with Jianfeng Lan, Ph.D., of Nanjing University. "The effect isn't one plus one equals two, it's one plus one equals five. Our findings demonstrate that nothing in nature exists in a vacuum; in order to develop the most effective anti-aging treatments we have to look at longevity networks rather than individual pathways."

The discovery of the synergistic interaction could lead to the use of combination therapies, each affecting a different pathway, to extend healthy human lifespan in the same way that combination therapies are used to treat cancer and HIV, Pankaj Kapahi, Ph.D., of the Buck Institute, has said. Kapahi is a corresponding author of the paper with Rogers and Di Chen, Ph.D., of Nanjing University.

The synergistic interaction may also may explain why scientists have been unable to identify a single gene responsible for the ability of some people to live to extraordinary old ages free of major age-related diseases until shortly before their deaths.

The paper focuses on how longevity is regulated in the mitochondria, which are the organelles in the cell responsible for energy homeostasis. Over the last decade, accumulating evidence has suggested a causative link between mitochondrial dysregulation and aging. Rollins' future research will focus on the further elucidation of the role of mitochondria in aging, he said.

The research was conducted at the MDI Biological Laboratory and Nanjing University using information from double mutants developed by Kapahi. Rollins' and Rogers' work was supported by the National Institutes of Health (AG056743), the Morris Scientific Discovery Fund and the National Institute of General Medical Sciences (P20GM103423 and P20GM104318).

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Materials provided by Mount Desert Island Biological Laboratory. Note: Content may be edited for style and length.

Pathways that extend lifespan by 500 percent identified

Caenorhabditis elegans (stock image).

Scientists at the MDI Biological Laboratory, in collaboration with scientists from the Buck Institute for Research on Aging in Novato, Calif., and Nanjing University in China, have identified synergistic cellular pathways for longevity that amplify lifespan fivefold in C. elegans, a nematode worm used as a model in aging research.

The increase in lifespan would be the equivalent of a human living for 400 or 500 years, according to one of the scientists.

The research draws on the discovery of two major pathways governing aging in C. elegans, which is a popular model in aging research because it shares many of its genes with humans and because its short lifespan of only three to four weeks allows scientists to quickly assess the effects of genetic and environmental interventions to extend healthy lifespan.

Because these pathways are "conserved," meaning that they have been passed down to humans through evolution, they have been the subject of intensive research. A number of drugs that extend healthy lifespan by altering these pathways are now under development. The discovery of the synergistic effect opens the door to even more effective anti-aging therapies.

The new research uses a double mutant in which the insulin signaling (IIS) and TOR pathways have been genetically altered. Because alteration of the IIS pathways yields a 100 percent increase in lifespan and alteration of the TOR pathway yields a 30 percent increase, the double mutant would be expected to live 130 percent longer. But instead, its lifespan was amplified by 500 percent.

"Despite the discovery in C. elegans of cellular pathways that govern aging, it hasn't been clear how these pathways interact," said Hermann Haller, M.D., president of the MDI Biological Laboratory. "By helping to characterize these interactions, our scientists are paving the way for much-needed therapies to increase healthy lifespan for a rapidly aging population."

The elucidation of the cellular mechanisms controlling the synergistic response is the subject of a recent paper in the online journal Cell Reports entitled "Translational Regulation of Non-autonomous Mitochondrial Stress Response Promotes Longevity." The authors include Jarod A. Rollins, Ph.D., and Aric N. Rogers, Ph.D., of the MDI Biological Laboratory.

"The synergistic extension is really wild," said Rollins, who is the lead author with Jianfeng Lan, Ph.D., of Nanjing University. "The effect isn't one plus one equals two, it's one plus one equals five. Our findings demonstrate that nothing in nature exists in a vacuum; in order to develop the most effective anti-aging treatments we have to look at longevity networks rather than individual pathways."

The discovery of the synergistic interaction could lead to the use of combination therapies, each affecting a different pathway, to extend healthy human lifespan in the same way that combination therapies are used to treat cancer and HIV, Pankaj Kapahi, Ph.D., of the Buck Institute, has said. Kapahi is a corresponding author of the paper with Rogers and Di Chen, Ph.D., of Nanjing University.

The synergistic interaction may also may explain why scientists have been unable to identify a single gene responsible for the ability of some people to live to extraordinary old ages free of major age-related diseases until shortly before their deaths.

The paper focuses on how longevity is regulated in the mitochondria, which are the organelles in the cell responsible for energy homeostasis. Over the last decade, accumulating evidence has suggested a causative link between mitochondrial dysregulation and aging. Rollins' future research will focus on the further elucidation of the role of mitochondria in aging, he said.

The research was conducted at the MDI Biological Laboratory and Nanjing University using information from double mutants developed by Kapahi. Rollins' and Rogers' work was supported by the National Institutes of Health (AG056743), the Morris Scientific Discovery Fund and the National Institute of General Medical Sciences (P20GM103423 and P20GM104318).

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Materials provided by Mount Desert Island Biological Laboratory. Note: Content may be edited for style and length.

Some stress in early life extends lifespan, research in roundworms shows

Caenorhabditis elegans 

Some stress at a young age could actually lead to a longer life, new research shows.

University of Michigan researchers have discovered that oxidative stress experienced early in life increases subsequent stress resistance later in life.

Oxidative stress happens when cells produce more oxidants and free radicals than they can deal with. It's part of the aging process, but can also arise from stressful conditions such as exercise and calorie restriction.

Examining a type of roundworm called Caenorhabditis elegans, U-M scientists Ursula Jakob and Daphne Bazopoulou found that worms that produced more oxidants during development lived longer than worms that produced fewer oxidants. Their results are published in the journal Nature.

Researchers have long wondered what determines variability in lifespan, says Jakob, a professor of molecular, cellular and developmental biology. One part of that is genetics: If your parents are long-lived, you have a good chance for living longer as well. Environment is another part.

That other stochastic -- or random -- factors might be involved becomes clear in the case of C. elegans. These short-lived organisms are a popular model system among aging researchers in part because every hermaphroditic mother produces hundreds of genetically identical offspring. However, even if kept in the same environment, the lifespan of these offspring varies to a surprising extent, Jakob says.

"If lifespan was determined solely by genes and environment, we would expect that genetically identical worms grown on the same petri dish would all drop dead at about the same time, but this is not at all what happens. Some worms live only three days while others are still happily moving around after 20 days," Jakob said. "The question then is, what is it, apart from genetics and environment, that is causing this big difference in lifespan?"

Jakob and Bazopoulou, a postdoctoral researcher and lead author of the paper, found one part of the answer when they discovered that during development, C. elegans worms varied substantially in the amount of reactive oxygen species they produce.

Reactive oxygen species, or ROS, are oxidants that every air-breathing organism produces. ROS are closely associated with aging: the oxidative damage they elicit are what many anti-aging creams claim to combat. Bazopoulou and Jakob discovered that instead of having a shorter lifespan, worms that produced more ROS during development actually lived longer.

"Experiencing stress at this early point in life may make you better able to fight stress you might encounter later in life," Bazopoulou said.

When the researchers exposed the whole population of juvenile worms to external ROS during development, the average lifespan of the entire population increased. Though the researchers don't know yet what triggers the oxidative stress event during development, they were able to determine what processes enhanced the lifespan of these worms.

To do this, Bazopoulou sorted thousands of C. elegans larvae according to the oxidative stress levels they have during development. By separating worms that produced large amounts of ROS from those that produced little amounts of ROS, she showed that the main difference between the two groups was a histone modifier, whose activity is sensitive to oxidative stress conditions.

The researchers found that the temporary production of ROS during development caused changes in the histone modifier early in the worm's life. How these changes persist throughout life and how they ultimately affect and extend lifespan is still unknown. What is known, however, is that this specific histone modifier is also sensitive to oxidative stress sensitive in mammalian cells. Additionally, early-life interventions have been shown to extend lifespans in mammalian model systems such as mice.

"The general idea that early life events have such profound, positive effects later in life is truly fascinating. Given the strong connection between stress, aging and age-related diseases, it is possible that early events in life might also affect the predisposition for age-associated diseases, such as dementia and Alzheimer's disease," Jakob said.

Next, the researchers want to figure out what key changes are triggered by these early-life events. Understanding this might allow scientists to develop lifespan-extending interventions that work at later stages in life.

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Materials provided by University of Michigan. Note: Content may be edited for style and length.