A biochemical pathway that helps keep cells alive when oxygen is low also plays a role in longevity and resistance against some diseases of old age, according to a report to be published April 16 in the journal Science.
A cell's protective reaction to a drop in oxygen is called the hypoxic response. Researchers at the University of Washington (UW) have found that nematode worms live longer if their genetic make-up permits their cells to turn on the hypoxic response under normal oxygen conditions.Not only do these worms live longer, the researchers noted, their cells are relatively free from the toxic proteins that accumulate and clump together as an animal ages.
The co-lead authors, Dr. Ranjana Mehta and Dr. Katy Steinkraus, uncovered the life-extending role of the hypoxic response while studying the mechanism by which dietary restriction slows aging in nematodes. Dietary restriction has been shown to increase life span in many different organisms, including worms, flies and mice. Kaeberlein's group had previously found that dietary restriction also protects against toxic protein aggregation in nematode models of Huntington's and Alzheimer's diseases. To their surprise, however, genetic experiments mapped the hypoxic response to a previously unknown longevity pathway, different from dietary restriction.
"The research findings suggest that the hypoxic response promotes longevity and reduces the accumulation of toxic proteins by a mechanism that is distinct from both dietary restriction and insulin-like signaling. It appears to be an alternative pathway," Kaeberlein said. "However, we don't know if future studies might reveal that all of these different genetic pathways converge somewhere down the line into a common mechanism for delaying the effects of age."
The key factor that controls the hypoxic response is called HIF. HIF is regulated by another protein called VHL-1, which tags HIF to be destroyed by a cellular machine called the proteasome. Destruction of HIF by VHL-1 keeps the hypoxic response "off" when oxygen is present. The UW researchers bred worms that could not produce VHL-1, leading to persistence of HIF even in the presence of high oxygen levels. They found that these worms, which were able to turn on the hypoxic response under normal oxygen conditions, lived about 30 percent longer than worms whose cells made VHL-1.
They also found that animals lacking VHL-1 were resistant to the toxic proteins known to cause Alzheimer's and Huntington's diseases, and that their cells accumulated less of an age-pigment called lipofuscin. Lipofuscin is thought to be one indicator of an animal's health during aging. According to Kaeberlein, "These observations may suggest that the hypoxic response not only increases life span, but also lengthens health span and protects against the molecular processes that lead to neurodegenerative diseases in people." Health span refers to the period of an organism's life that is relatively free of disease.
The authors note that the hypoxic response, including HIF and VHL-1, is very well conserved in organisms from nematodes to humans, raising the possibility that modulating HIF activity may be useful for treating some age-associated diseases, and perhaps even slowing aging, in people. Kaeberlein cautions, however, that "mutation of VHL-1 is associated with a variety of tumors, and any therapies targeted toward activation of HIF would most likely need to be specific for cells that are not rapidly dividing, such as brain cells or muscle cells."
"What we're focused on now," says Mehta, "is figuring out how HIF is protecting the animals from aging." In both worms and people, HIF regulates the activity of several factors involved in growth and resistance to stress. "One or more of these factors must be the key."
Kaeberlein agrees. "This is a completely new pathway for aging and age-associated disease. If we can understand at a very detailed level how HIF is slowing aging, we may be able to use that information to develop effective therapies for treating age-associated diseases in people."
The researchers on the study entitled "Proteasomal Regulation of the Hypoxic Response Modulates Aging in C. elegans," in addition to Kaeberlein, Mehta, and Steinkraus, were George Sutphin, Fresnida J. Ramos, Lara S. Shmieh, Alexander Huh, Christina Davis, and Devon Chandler-Brown, all from the UW Department of Pathology or the UW Molecular and Cellular Biology Program.
The research was supported by the Alzheimer's Association, the Glenn Foundation, the American Federation for Aging Research, the National Institutes of Health, and the Hereditary Disease Foundation. Kaeberlein is an Ellison Medical Foundation New Scholar in Aging.
Leila Gray | EurekAlert!
Scientists uncover the role of a protein in production & survival of myelin-forming cells
19.07.2018 | Advanced Science Research Center, GC/CUNY
NYSCF researchers develop novel bioengineering technique for personalized bone grafts
18.07.2018 | New York Stem Cell Foundation
A new manufacturing technique uses a process similar to newspaper printing to form smoother and more flexible metals for making ultrafast electronic devices.
The low-cost process, developed by Purdue University researchers, combines tools already used in industry for manufacturing metals on a large scale, but uses...
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
20.07.2018 | Power and Electrical Engineering
20.07.2018 | Information Technology
20.07.2018 | Materials Sciences