Old Stem Cells Will be Directed to Act Young by Blood

Even with advancing age, blood stem cells keep churning out your blood cells, but the mix of blood cell types goes awry, making you more prone to disease.

Joslin Diabetes Center scientists now have demonstrated that in old mice exposed to certain proteins that are present in blood from young mice, old blood stem cells begin to act like young ones-and this process is driven by signals from another type of cell nearby in the bone.

Published in a paper in Nature on January 28, the findings from researchers in the lab of Joslin Principal Investigator Amy J. Wagers, Ph.D., advance our understanding of aging of the blood-forming ("hematopoietic") system and point toward ways to treat age-related ailments via the blood.

Previous work by many labs gave evidence that the decline in blood stem cell function that comes with age is partly intrinsic to the cells themselves. However, these cells also are affected by signals from other cells in the local bone marrow microenvironment or "niche".

An earlier study led by Shane Mayack, Ph.D., a postdoctoral fellow in the Wagers lab, pinpointed bone-forming cells known as osteoblasts as key players in this signaling from the niche, and showed that osteoblasts play a particular role in blood stem cell maintenance and regeneration.

For the latest paper, Mayack and her colleagues studied the blood stem cell aging process in young and old mice. The researchers found that as osteoblasts age, they change the signals that they send to stem cells, and that this change makes those cells less able to produce the right mixture of blood cells.

More dramatically, in a series of tests in which two mice shared a common blood circulation, the scientists revealed that this aging mechanism could be reversed. In old mice paired with young mice, the existing populations of osteoblasts showed signs of rejuvenation. Remarkably, this rejuvenation was communicated to the stem cells as well, such that the blood-forming abilities of these aged mice took on much more "youthful" characteristics.

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"What''s most exciting is that the changes that occur in blood stem cells during aging are reversible, through signals carried by the blood itself," says Wagers, who is also an Associate Professor at Harvard University. "This means that the blood system offers a potential therapeutic avenue for age-related stem cell dysfunction."

"These findings open up exciting new avenues of research, including the potential for studying other types of tissues that aren''t as well understood, in which aging may be regulated by stem-niche cell interactions in a similar way," adds Mayack. "Over time, these findings may also influence the way blood disorders are treated."

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As a next step, investigators will hone in on how signals sent to and from osteoblasts are altered as the cells age.

The Joslin team has begun by examining the role of IGF-1 (insulin-like growth factor-1), a protein that other studies have shown can aid in regenerating skeletal muscle. To their surprise, they found that they could partially correct aging defects in osteoblasts by suppressing IGF-1, rather than enhancing it. "This difference highlights the complexity of the controls that are involved in cell regeneration," Wagers comments.

While the work does not directly address diabetes mechanisms, Wagers notes that "there''s more and more evidence of an overlap in the regulatory pathways that are implicated in aging and in type 2 diabetes."

Jennifer L. Shadrach and Francis S. Kim, both of Joslin, also contributed to the project. The work was supported by the National Institutes of Health, the Burroughs Wellcome Fund, the Glen Foundation, the Iacocca Foundation and the W.M. Keck Foundation.

Joslin Diabetes Center is the world''s preeminent diabetes research and clinical care organization. Joslin is dedicated to ensuring people with diabetes live long, healthy lives and offers real hope and progress toward diabetes prevention and a cure for the disease. Founded in 1898 by Elliott P. Joslin, M.D., Joslin is an independent nonprofit institution affiliated with Harvard Medical School.

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