Researchers find key to 'tired' blood and immune systems

March 3, 2017 by Jeff Norris, University of California, San Francisco

A molecular key to aging of the blood and immune system has been discovered in new research conducted at UC San Francisco, raising hope that it may be possible to find a way to slow or reverse the growing risk for aging-associated chronic inflammatory diseases, anemia, blood cancers, and life-threatening infections.

The key is a link between the health of a rare population of adult that arise early in development and are responsible for replenishing all cell types throughout a lifetime, and a newly identified role for autophagy, an important cellular cleanup and recycling process that was the focus of the 2016 Nobel Prize in Physiology or Medicine.

In their new study, published online March 1 in Nature, the UCSF team discovered that in addition to its normal role in cellular waste-processing, autophagy also is needed for the orderly maintenance of blood-forming (HSCs), the that give rise to red , which carry oxygen, and to platelets, which prevent bleeding, as well as the entire immune system, which fights infections and disposes of pathogens.

The researchers found that autophagy keeps HSCs in check by allowing metabolically active HSCs to return to a resting, quiescent state akin to hibernation. This is the default state of adult HSCs, allowing their maintenance for a lifetime.

According to Emmanuelle Passegué, PhD, the senior scientist for the study, "This is a previously unknown role for autophagy in ." 

Failure to activate autophagy has profound impacts on the , Passegué's team found, leading to the unbalanced production of certain types of blood cells. Defective autophagy also diminished the ability of HSCs to regenerate the entire blood system when they were transplanted into irradiated mice, a procedure similar to bone marrow transplantation.

The researchers determined that 70 percent of HSCs from old mice were not undergoing autophagy, and these cells exhibited the dysfunctional features common among old HSCs. However, the 30 percent of old HSCs that did undergo autophagy looked and acted like HSCs from younger mice.

Passegué led the study while she was a professor of medicine with the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at UCSF. In January she became an Alumni Professor in the Department of Genetics & Development and the director of the Columbia Stem Cell Initiative at Columbia University Medical Center.

Therapies for Rejuvenating Aging Blood and Immune Systems
Scientists have identified many different tissue-specific stem cells, all of whose performance declines with age, Passegué said. Finding out how this occurs has been an active area of research, and a focus of her laboratory group in recent years. 

In a large series of experiments and analyses, many conducted by the study's first author, Theodore Ho, a UCSF graduate student, the scientists compared characteristics of HSCs from old mice with those of HSCs from younger mice that had been genetically programmed so that they could not undergo autophagy. They found that loss of autophagy in young mice was sufficient to drive many of the defects that arise naturally in the blood of old mice, including changes in the cellular appearance of HSCs and a disruption in the normal proportions of the various types of blood cells, characteristics of old age.

Previous research had shown that autophagy causes the formation of "sacs" within cells that can engulf and enzymatically digest molecules and even major cellular structures, including mitochondria, the cell's biochemical power plants. But in the new study, the researchers found that genetically programmed loss of autophagy resulted in the accumulation of activated mitochondria with increased oxidative metabolism that triggered chemical modifications of DNA in HSCs.

These "epigenetic" DNA modifications altered the activities of genes in a way that changed the developmental fate of HSCs. They triggered disproportionate production of certain blood cells and reduced the ability of HSCs to regenerate the entire blood system when transplanted. This result was similar to what the researchers observed in the majority of old HSCs that failed to activate autophagy.

In contrast, the minority of old HSCs that still exhibited significant levels of autophagy were able to keep their mitochondria and metabolism in check, and could re-establish a healthy blood system following transplantation, similar to HSCs from young mice.

However, in a hopeful sign for potential future therapies to rejuvenate , the researchers succeeded in restoring autophagy to old HSCs by treating them with pharmacological agents in a lab dish.

"This discovery might provide an interesting therapeutic angle to use in re-activating in all of the old HSCs, to slow the aging of the blood system and to improve engraftment during bone marrow or HSC transplantation," Passegué said. "It is our hope that the end point will be a way to really improve the fitness of stem cells and to use that capability to help the elderly by preventing the development of blood cancers and providing them with better immune systems to fight infections."

Explore further: Scientists wage fight against aging bone marrow stem cell niche

More information: Theodore T. Ho et al. Autophagy maintains the metabolism and function of young and old stem cells, Nature (2017). DOI: 10.1038/nature21388

Related Stories

Scientists wage fight against aging bone marrow stem cell niche

March 2, 2017
As people get older so do the hematopoietic stem cells (HSCs) that form their blood, creating an increased risk for compromised immunity and certain blood cancers. Now researchers are reporting in the scientific journal EMBO ...

Changing the environment within bone marrow alters blood cell development

February 22, 2017
Researchers at the University of Illinois report they can alter blood cell development through the use of biomaterials designed to mimic characteristics of the bone marrow.

Dose of transplanted blood-forming stem cells affects their behavior

May 25, 2016
Unlike aspirin, bone marrow doesn't come with a neatly printed label with dosage instructions. However, a new study published in Cell Reports provides clues about how the dose of transplanted bone marrow might affect patients ...

Scientists identify progenitor cells for blood and immune system

June 18, 2015
University of California San Francisco scientists have identified characteristics of a family of daughter cells, called MPPs, which are the first to arise from stem cells within bone marrow that generate the entire blood ...

Blood stem cells study could pave the way for new cancer therapy

March 10, 2016
People with leukaemia could be helped by new research that sheds light on how the body produces its blood supply.

Stem cell survival strategy key to blood and immune system health

February 14, 2013
Stem cells of the aging bone marrow recycle their own molecules to survive and keep replenishing the blood and immune systems as the body ages, researchers at UC San Francisco (UCSF) have discovered.

Recommended for you

Everything big data claims to know about you could be wrong

June 19, 2018
When it comes to understanding what makes people tick—and get sick—medical science has long assumed that the bigger the sample of human subjects, the better. But new research led by UC Berkeley suggests this big-data ...

Are you sticking to your diet? Scientists may be able to tell from a blood sample

June 19, 2018
An analysis of small molecules called "metabolites" in a blood sample may be used to determine whether a person is following a prescribed diet, scientists at Johns Hopkins Bloomberg School of Public Health have shown.

Diagnosing and treating disorders of early sex development

June 19, 2018
Diagnosing, advising on and treating disorders of early sex development represent a huge medical challenge, both for those affected and for treating physicians. In contrast to the earlier view, DSD (Difference of Sex Development) ...

BPA can induce multigenerational effects on ability to communicate

June 18, 2018
Past studies have shown that biparental care of offspring can be affected negatively when females and males are exposed to bisphenol A (BPA); however, previous studies have not characterized how long-term effects of BPA exposure ...

New compound shown to be as effective as FDA-approved drugs against life-threatening infections

June 15, 2018
Purdue University researchers have identified  a new compound that in preliminary testing has shown itself to be as effective as antibiotics approved by the Food and Drug Administration to treat life-threatening infections ...

Foods combining fats and carbohydrates more rewarding than foods with just fats or carbs

June 14, 2018
Researchers show that the reward center of the brain values foods high in both fat and carbohydrates—i.e., many processed foods—more than foods containing only fat or only carbs. A study of 206 adults, to appear June ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.