New work from Emmanuelle Passegué reveals how they age and how they may be rejuvenated.
Hippocrates theorized that in old age, the balance of the body’s four “humors” is disturbed: blood and yellow bile are lacking, while phlegm and black bile are abundant. Although the ancient Greek physician’s notion of bodily humors and their role in aging eventually faded into obscurity, he wasn’t entirely wrong.

Though older people do not have less blood than their younger counterparts, something in old blood is indeed lacking, according to Emmanuelle Passegué, PhD, the new director of the Columbia Stem Cell Initiative (CSCI) and one of the nation’s foremost authorities on hematopoietic stem cells (HSCs), blood–forming stem cells that originate in the bone marrow.

Throughout our lives, HSCs give rise to oxygen–carrying red blood cells, infection–fighting white blood cells, and clot–forming platelets. When things wrong with HSCs – as they often do with aging – many parts of the body are bound to suffer.

“Humans weren’t meant to reach old age,” says Dr. Passegué, who is also Alumni Professor of Genetics & Development (in rehabilitation & regenerative medicine) at Columbia. “Our bodies evolved to work at peak efficiency during our reproductive years. After that, tissues and stem cells begin to deteriorate, and there’s no selection process to get rid of old or mutated stem cells.”

Exactly how blood–forming stem cells age is now coming into focus. In a recent mouse study, published in the journal Nature, Dr. Passegué’s team found that about two–thirds of aged HSCs failed to activate autophagy, a critical mechanism for recycling cellular waste, and discard cellular structures such as mitochondria, the cell’s energy–producing engines. Accumulation of mitochondria in aged HSCs that cannot engage autophagy results in an overactive metabolism, which leads to an imbalance in blood cell production and impaired self–renewal of stem cells – all features of a dysfunctional aged blood system. “This is a previously unknown role for autophagy in stem cell biology,” says Dr. Passegué.

But not all HSCs changed with age. The remaining third of HSCs remained relatively youthful and were still able to activate autophagy. This sustained the cells in a relatively quiescent state, which is necessary for maintaining the HSC population over a lifetime and for properly responding to the body’s ever–changing demand for new blood cells.

“The question now is whether we can find therapies that keep the good aged HSCs and get rid of the bad ones,” she says. In theory, such remedies would support healthy aging and help the elderly mount a more robust response to infections, inflammation, and blood cancers. In an encouraging sign, the Passegué team was able to restore autophagy in aged HSCs in tissue culture by treating them with chemical compounds.