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in the bone marrow
Scientists say they’ve identified a molecular pathway that is critical to hematopoietic stem cell (HSC) aging and can be manipulated to rejuvenate blood.
The researchers found that HSCs’ ability to repair damage caused by inappropriate protein folding in the mitochondria is essential for the cells’ survival and regenerative capacity.
The discovery has implications for research on reversing the signs of aging, a process thought to be caused by increased cellular stress and damage.
“Ultimately, a cell dies when it can’t deal well with stress,” said study author Danica Chen, PhD, of the University of California, Berkeley.
“We found that by slowing down the activity of mitochondria in the blood stem cells of mice, we were able to enhance their capacity to handle stress and rejuvenate old blood. This confirms the significance of this pathway in the aging process.”
Mitochondria host a multitude of proteins that must be folded properly to function correctly. When the folding goes awry, the mitochondrial unfolded-protein response (UPRmt) kicks in to boost the production of specific proteins to fix or remove the misfolded protein.
There has been little research on the UPRmt pathway, but studies in roundworms suggest its activity increases when there is a burst of mitochondrial growth.
Dr Chen and her colleagues noted that adult stem cells are normally in a quiescent state with little mitochondrial activity. They are activated only when needed to replenish tissue.
At that time, the mitochondrial activity increases, and stem cells proliferate and differentiate. When protein-folding problems occur, this fast growth could lead to more harm.
Dr Chen’s lab stumbled upon the importance of UPRmt in HSC aging while studying sirtuins, a class of proteins recognized as stress-resistance regulators.
The researchers noticed that levels of one particular sirtuin, SIRT7, increase as a way to help cells cope with stress from misfolded proteins in the mitochondria. But SIRT7 levels decline with age.
“We isolated blood stem cells from aged mice and found that when we increased the levels of SIRT7, we were able to reduce mitochondrial protein-folding stress,” Dr Chen said. “We then transplanted the blood stem cells back into mice, and SIRT7 improved the blood stem cells’ regenerative capacity.”
The researchers also found that HSCs deficient in SIRT7 proliferate more. This faster growth is due to increased protein production and increased activity of the mitochondria, and slowing things down appears to be a critical step in giving cells time to recover from stress.
Dr Chen likened this to an auto accident or stalled car stopping traffic on a freeway.
“When there’s a mitochondrial protein-folding problem, there is a traffic jam in the mitochondria,” she said. “If you prevent more proteins from being created and added to the mitochondria, you are helping to reduce the jam.”
Until this study, it was unclear which stress signals regulate HSCs’ transition to and from the quiescent state and how that related to tissue regeneration during aging.
“Identifying the role of this mitochondrial pathway in blood stem cells gives us a new target for controlling the aging process,” Dr Chen said.
She and her colleagues described this work in Science. 
in the bone marrow
Scientists say they’ve identified a molecular pathway that is critical to hematopoietic stem cell (HSC) aging and can be manipulated to rejuvenate blood.
The researchers found that HSCs’ ability to repair damage caused by inappropriate protein folding in the mitochondria is essential for the cells’ survival and regenerative capacity.
The discovery has implications for research on reversing the signs of aging, a process thought to be caused by increased cellular stress and damage.
“Ultimately, a cell dies when it can’t deal well with stress,” said study author Danica Chen, PhD, of the University of California, Berkeley.
“We found that by slowing down the activity of mitochondria in the blood stem cells of mice, we were able to enhance their capacity to handle stress and rejuvenate old blood. This confirms the significance of this pathway in the aging process.”
Mitochondria host a multitude of proteins that must be folded properly to function correctly. When the folding goes awry, the mitochondrial unfolded-protein response (UPRmt) kicks in to boost the production of specific proteins to fix or remove the misfolded protein.
There has been little research on the UPRmt pathway, but studies in roundworms suggest its activity increases when there is a burst of mitochondrial growth.
Dr Chen and her colleagues noted that adult stem cells are normally in a quiescent state with little mitochondrial activity. They are activated only when needed to replenish tissue.
At that time, the mitochondrial activity increases, and stem cells proliferate and differentiate. When protein-folding problems occur, this fast growth could lead to more harm.
Dr Chen’s lab stumbled upon the importance of UPRmt in HSC aging while studying sirtuins, a class of proteins recognized as stress-resistance regulators.
The researchers noticed that levels of one particular sirtuin, SIRT7, increase as a way to help cells cope with stress from misfolded proteins in the mitochondria. But SIRT7 levels decline with age.
“We isolated blood stem cells from aged mice and found that when we increased the levels of SIRT7, we were able to reduce mitochondrial protein-folding stress,” Dr Chen said. “We then transplanted the blood stem cells back into mice, and SIRT7 improved the blood stem cells’ regenerative capacity.”
The researchers also found that HSCs deficient in SIRT7 proliferate more. This faster growth is due to increased protein production and increased activity of the mitochondria, and slowing things down appears to be a critical step in giving cells time to recover from stress.
Dr Chen likened this to an auto accident or stalled car stopping traffic on a freeway.
“When there’s a mitochondrial protein-folding problem, there is a traffic jam in the mitochondria,” she said. “If you prevent more proteins from being created and added to the mitochondria, you are helping to reduce the jam.”
Until this study, it was unclear which stress signals regulate HSCs’ transition to and from the quiescent state and how that related to tissue regeneration during aging.
“Identifying the role of this mitochondrial pathway in blood stem cells gives us a new target for controlling the aging process,” Dr Chen said.
She and her colleagues described this work in Science.
in the bone marrow
Scientists say they’ve identified a molecular pathway that is critical to hematopoietic stem cell (HSC) aging and can be manipulated to rejuvenate blood.
The researchers found that HSCs’ ability to repair damage caused by inappropriate protein folding in the mitochondria is essential for the cells’ survival and regenerative capacity.
The discovery has implications for research on reversing the signs of aging, a process thought to be caused by increased cellular stress and damage.
“Ultimately, a cell dies when it can’t deal well with stress,” said study author Danica Chen, PhD, of the University of California, Berkeley.
“We found that by slowing down the activity of mitochondria in the blood stem cells of mice, we were able to enhance their capacity to handle stress and rejuvenate old blood. This confirms the significance of this pathway in the aging process.”
Mitochondria host a multitude of proteins that must be folded properly to function correctly. When the folding goes awry, the mitochondrial unfolded-protein response (UPRmt) kicks in to boost the production of specific proteins to fix or remove the misfolded protein.
There has been little research on the UPRmt pathway, but studies in roundworms suggest its activity increases when there is a burst of mitochondrial growth.
Dr Chen and her colleagues noted that adult stem cells are normally in a quiescent state with little mitochondrial activity. They are activated only when needed to replenish tissue.
At that time, the mitochondrial activity increases, and stem cells proliferate and differentiate. When protein-folding problems occur, this fast growth could lead to more harm.
Dr Chen’s lab stumbled upon the importance of UPRmt in HSC aging while studying sirtuins, a class of proteins recognized as stress-resistance regulators.
The researchers noticed that levels of one particular sirtuin, SIRT7, increase as a way to help cells cope with stress from misfolded proteins in the mitochondria. But SIRT7 levels decline with age.
“We isolated blood stem cells from aged mice and found that when we increased the levels of SIRT7, we were able to reduce mitochondrial protein-folding stress,” Dr Chen said. “We then transplanted the blood stem cells back into mice, and SIRT7 improved the blood stem cells’ regenerative capacity.”
The researchers also found that HSCs deficient in SIRT7 proliferate more. This faster growth is due to increased protein production and increased activity of the mitochondria, and slowing things down appears to be a critical step in giving cells time to recover from stress.
Dr Chen likened this to an auto accident or stalled car stopping traffic on a freeway.
“When there’s a mitochondrial protein-folding problem, there is a traffic jam in the mitochondria,” she said. “If you prevent more proteins from being created and added to the mitochondria, you are helping to reduce the jam.”
Until this study, it was unclear which stress signals regulate HSCs’ transition to and from the quiescent state and how that related to tissue regeneration during aging.
“Identifying the role of this mitochondrial pathway in blood stem cells gives us a new target for controlling the aging process,” Dr Chen said.
She and her colleagues described this work in Science.