HSCI/MGH researchers identify gene product involved in stem cell aging and death

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Finding could have broader implications involving tissue aging and repair

A multi-institutional team of Harvard researchers may have advanced our understanding of physiological aging with a new study in which they greatly reduced the impact of aging on blood stem cells. A report on their findings appears in the latest edition of the journal Nature along with similar but independent findings from research teams at the universities of North Carolina and Michigan.

The Harvard team, led by David T. Scadden, has demonstrated that reducing the accumulation of the cyclin-dependent kinase inhibitor p16INK4a, a gene product previously noted to increase in aging cells, may reduce the physiological impact of aging on adult stem cells, and may improve the ability of aged tissues to repair themselves. Scadden is co-director of the Harvard Stem Cell Institute (HSCI) and director of the Center for Regenerative Medicine at Massachusetts General Hospital (MGH).

The researchers found that reducing the accumulation of p16INK4a in haematopoietic stem cells (blood stem cells) reduces cell death as well as defects in the ability of the cells to repopulate.

“There are two things about this that are important,” Scadden said. “It shows that specific properties of aging stem cells directly contribute to the reduced healing that occurs with aging; and it indicates that one might be able to modify a single gene product and improve the function of aging stem cells and repair of aging tissue – and that is very encouraging. This may mean that there are opportunities to target this gene product with medication and potentially decrease the impact of aging.

“However,” Scadden noted, “p16INK4a is also known to suppress tumor formation, so a judicious balance must be struck between reduced p16INK4a when needed for repair and sufficient p16INK4a to prevent emergence of malignant stem cells.”

The findings by the teams at Harvard, Michigan, and UNC indicate that they may have discovered a generalized mechanism by which various types of tissues have altered healing with age. Thus, discovering ways to suppress p16INK4a could potentially have an ameliorating effect on age-related cell death and repair of tissue damage throughout the body.

The Scadden team includes Viktor Janzen, Randolf Forkert, Heather E. Fleming, and Yoriko Saito, of HSCI and MGH; Michael T. Waring and David M. Dombkowski of MGH; Ronald A. DePinho of the Dana-Farber Cancer Institute and Harvard Medical School; and Norman E. Sharpless of the Lineberger Comprehensive Cancer Center at the University of North Carolina School of Medicine.