Why A Low-Calorie Diet Extends Lifespans: Critical Enzyme Pair Identified
Experiment after experiment confirms that a diet on the brink of starvation expands lifespan in mice and many other species. But the molecular mechanism that links nutrition and survival is still poorly understood. Now, researchers at the Salk Institute for Biological Studies have identified a pivotal role for two enzymes that work together to determine the health benefits of diet restriction.
When lacking one enzyme or the other, roundworms kept on a severely calorie-restricted diet no longer live past their normal lifespan, they report in the June 24, 2009, advance online edition of the journal Nature.
“The only other known factor regulating longevity in response to diet restriction operates at the very end of the signaling cascade,” said Howard Hughes Medical Investigator and senior author Andrew Dillin, Ph.D., an associate professor in the Molecular and Cell Biology Laboratory. “These two enzymes are further up the ladder, bringing us closer to the receptor that receives the signal for throwing the switch to promote a healthy lifespan.”
Identifying the receptor may allow researchers to design drugs that mimic the signal and could lead to new treatments for age-related diseases. This could enable us to reap the health benefits of calorie restriction without adhering to extreme diets in which the satisfying feel of a full stomach is strictly off limits.
Although lifestyle factors such as obesity clearly influence life expectancy, genetic factors are considered central to the process of aging. To date, there are only three known genetic networks that ensure youthfulness when manipulated. One centers on the insulin/insulin growth factor-1, which regulates metabolism and growth; the second is driven by mitochondria, the cell’s power plants; and the third is linked to diet restriction.
But first author Andrea C. Carrano, Ph.D., a postdoctoral researcher in American Cancer Society Professor Tony Hunter’s laboratory, hadn’t set out to unravel the molecular connection between dietary restriction and increased lifespan when she started to investigate the role of the mammalian enzyme WWP-1. “I only knew that WWP-1 was a ubiquitin ligase and that mammalian cells contain three copies, which would make it difficult to study its function.”
Ubiquitin ligases work in tandem with so called ubiquitin-conjugating enzymes to attach a chain of ubiquitin molecules to other proteins. This process, called ubiquitination, flags protein substrates for destruction but can also serve as a regulatory signal.
Since the laboratory roundworm Caenorhabditis elegans only contains one copy, Carrano teamed up with Salk researcher Dillin, who studies aging and longevity in C. elegans. Initial experiments revealed that worms without the WWP-1 gene seemed normal but were more susceptible to various forms of stress. “This finding was the first hint that WWP-1 might play a role in the aging process since mutations that affect stress very often correlate with longevity,” she says.
Prompted by the findings, Carrano’s next set of experiments focused on WWP-1’s potential role in the regulation of lifespan. When she genetically engineered worms to overexpress WWP-1, well-fed worms lived on average 20 percent longer. Deleting PHA-4, which was discovered in Dillin’s lab and so far is the only gene known to be essential for lifespan extension in response to diet restriction, abolished the life-extending effects of additional WWP-1 placing the ubiquitin ligase as a central rung on the same genetic ladder as PHA-4. Without WWP-1, cutting down on calories no longer staved off death.
When a study by others found that UBC-18 interacts with WWP-1, Carrano wondered whether it could play a role in diet-restriction-induced longevity as well. She first confirmed that the UBC-18 functions as an ubiquitin-conjugating enzyme and gives WWP-1 a hand. She then tested whether it played a role in lifespan regulation. “Overexpression of UBC-18 was not enough to extend the lifespan of worms but depleting it negated the effects of caloric restriction,” says Carrano, who is busy looking for potential substrates of the UBC-18-WWP-1 ubiquitination complex.
“The WWP-1 pathway is highly conserved between worms and mammals and could play a role in the human aging process,” says senior author Tony Hunter, Ph.D., a professor in the Molecular and Cell Biology Laboratory. “We didn’t expect that this protein would be involved in the regulation of lifespan but it is very exciting when experiments lead you in a surprising direction.”
This work was supported by the National Institutes of Health, the Ellison Medical and Glenn Medical Foundations, the American Cancer Society and the Rossi Endowment.
ScienceDaily (June 28, 2009)
Breaking News Celebrity Death
Breaking News Celebrity Death
Current Grades
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Pandemic… Killer Pigs!
Seriously, if you play god, god will play in return!
ICD-9
Pseudorabies Virus = 078.89
Influenza Epidemic = 487.1
Influence Due to Identified Avian Influenza Virus = 488
Terrorism Involving Biological Weapons = E979.6
Swine influenza is a respiratory disease normally found in pigs but human cases can and do happen.
The current human cases were first reported in Southern California and Texas. Cases of swine influenza have now been confirmed in several countries including Mexico, US, Canada, Spain and the United Kingdom.
This strain of swine influenza contains a combination of genetic material typical to avian, swine and human flu viruses. Transmission of this new swine influenza virus is thought to occur in the same way as seasonal flu. Antiviral drugs are available which can effectively prevent and treat the infection, most reported cases of this infection outside of Mexico have recovered fully without the need for medical attention or antivirals.
~HPA
As Swine Flu Scare Unfolds, Virologist Underscores Need For Research On Animal Pathogens
ScienceDaily (Apr. 27, 2009) — The rapidly developing swine flu scare has activated a global response from the public health community and alarmed hundreds of millions of people, but there are a number of reasons why people should remain realistic and calm concerning the scope of the problem, according to Dr. X. J. Meng, a virologist who is on faculty in the Virginia-Maryland Regional College of Veterinary Medicine at Virginia Tech.
For one thing, according to Meng, who is considered one of the world’s leading experts on swine viruses, the Centers for Disease Control in Atlanta and the World Health Organization in Geneva have spent the past several years creating management protocols designed to deal with a global pandemic that might be caused by Avian Influenza H5N1, or “Bird Flu.” Pharmaceuticals have been stockpiled, and outbreak management and risk communication plans have been developed to minimize transmission patterns and contain the scope of a potential outbreak.
“Mortality from flu is generally not considered very high considering the high number of people who are being infected every year,” said Meng, although he does believe that it could spread quickly since it appears to be a novel virus and human-to-human transmission is occurring. “But it does look like one of those bugs that has the potential of leading to a pandemic.”
Meng suggested that possible reasons for the increased mortality rate associated with the Mexican cases as opposed to the American cases could be attributed to differences in the sophistication of the two healthcare systems, it could be the result of “other co-infecting or underlying diseases” that remain unclear at this time or it could be due to the very small number of cases that have been currently diagnosed in the United States.
“We have much to learn about this specific virus,” said Meng, who has a medical doctorate and a Ph.D virologist who frequently works with the National Institutes of Health and other organizations on infectious disease research and containment programs. “But then again, we have much to learn about many other zoonotic disease viruses.”
From SARS to Bird Flu, most of the emerging diseases affecting people today come from pathogens most often associated with animals, according to Meng, who is among a growing legion of scientists trying to convince the federal government to invest more money in studying animal pathogens as part of an overall effort to protect humans from disease. According to a recent article published in Science, Meng said, only $32 million of the $88 billion U.S. Department of Agriculture 2007 budget was allocated for farm animal disease research.
“If we can understand more about these viruses, their transmission behavior, and the mechanism of cross-species infection among animal and human populations, then we can better prepare ourselves for protecting human populations,” said Meng, who recently participated in a National Institutes of Health sponsored expert workshop entitled “Cross Species Infection Workshop” in Washington D.C. that summarized the dangers and called for the need to study the animal viruses in animals such as pigs before they jump species and infect humans.
“It will likely be several days before the virus is fully characterized in the laboratory,” he said. “Once that work is finished, we’ll know a lot more about how to proceed with the management of this situation.”
Meng said that one of the major factors that might minimize the scope of the outbreak and the spread of the virus could be related to the timing of this outbreak. Influenza viruses are “envelope viruses” that can be more efficiently transmitted in cold winter conditions that facilitate the survival of the virus, Meng said, and they typically do not do well in hot summer temperatures. “That is something that may limit the spread of this new virus,” he said.
The strain of swine virus H1N1 responsible for the emerging epidemic does not normally infect people and there are only a few cases of swine flu infections in humans each year in the United States, according to Meng. Because pigs have receptors for human, avian and pig viruses, they serve as a “mixing vessel” for new viruses, he said. This particular strain is believed to include components from pig, bird and human viruses that have been combined through a process known as genetic re-assortment. Humans are likely immunologically naïve to the new virus that has been created, which is why the danger for a potential global pandemic does exist.
~ScienceDaily.com
A Relationship With Self
The most important relationship we have in our lives is with our selves. And even though we are the only ones who are present at every moment of our lives—from birth onward—this relationship can be the most difficult one to cultivate. This may be because society places such emphasis on the importance of being in a romantic partnership, even teaching us to set aside our own needs for the needs of another. Until we know ourselves, however, we cannot possibly choose the right relationship to support our mutual growth toward our highest potential. By allowing ourselves to be comfortable with being alone, we can become the people with whom we want to have a relationship.
Perhaps at no other time in history has it been possible for people to survive, and even thrive, while living alone. We can now support ourselves financially, socially, and emotionally without needing a spouse for survival in any of these realms. With this freedom, we can pursue our own interests and create fulfilling partnerships with friends, business partners, creative cohorts, and neighbors. Once we’ve satisfied our needs and created our support system, a mate then becomes someone with whom we can share the bounty of all we’ve created and the beauty we’ve discovered within ourselves.
As we move away from tradition and fall into more natural cycles of being in the world today, we may find that there are times where being alone nourishes us and other periods in which a partnership is best for our growth. We may need to learn to create spaces to be alone within relationships. When we can shift our expectations of our relationships with ourselves and others to opportunities for discovery, we open ourselves to forge new paths and encounter uncharted territory. Being willing to know and love ourselves, and to find what truly makes us feel deeply and strongly, gives us the advantage of being able to attract and choose the right people with whom to share ourselves, whether those relationships fall into recognizable roles or not. Choosing to enjoy being alone allows us to fully explore our most important relationship—the one with our true selves.
