How Old Can We Get? It Might Be Written in Stem Cells

No clock, no crystal ball, but lots of excitement — and ambition — among Harvard scientists

stem cell
Human heart cells developed from human skin cells, beating in a dish. Courtesy of Richard T. Lee laboratory.

Third in an occasional series on how Harvard researchers are tackling the problematic issues of aging.

“If only,” wrote an ancient Japanese poet, “when one heard that Old Age was coming one could bolt the door….”

Science is working on it.

Aging is as much about the physical processes of repair and regeneration — and their slow-motion failure — as it is the passage of time. And scientists studying stem cell and regenerative biology are making progress understanding those processes, developing treatments for the many diseases whose risks increase as we get older, while at times seeming to draw close to a broader anti-aging breakthrough.

If stem cells offer potential solutions, they’re also part of the problem. Stem cells, which can differentiate into many cell types, are important parts of the body’s repair system, but lose regenerative potency as we age. In addition, their self-renewing ability allows the mutations that affect every cell to accumulate across cellular generations, and some of those mutations lead to disease.

“We do think that stem cells are a key player in at least some of the manifestations of age,” said Professor of Stem Cell and Regenerative Biology David Scadden, co-director of the Harvard Stem Cell Institute. “The hypothesis is that stem cell function deteriorates with age, driving events we know occur with aging, like our limited ability to fully repair or regenerate healthy tissue following injury.”

When it comes to aging, certain tissue types seem to lead the charge, according to Professor of Stem Cell and Regenerative Biology Lee Rubin, who directs the Harvard Stem Cell Institute’s Therapeutic Screening Center. Particular tissues — nerve cells appear to be one — somehow signal to others that it’s time to age. This raises the prospect, Rubin said, that aging might be reversed by treating these key tissue categories, rather than designing individual treatments for the myriad tissue types that make up the body.

“The process of aging involves all tissues in your body and, while different things go wrong in each tissue, they go wrong at basically the same rate,” Rubin said. “We can think of it as a process that is somehow coordinated, or there are fundamental processes in each tissue that play out.”

In addition to key tissues, certain chemical pathways — like insulin signaling —seem to be able to control aging, said Rubin, whose work has received backing from the National Institute of Neurological Disorders and Stroke, as well as private foundations. The insulin signaling pathway is a chemical chain reaction in which the hormone insulin helps the body metabolize glucose. Reducing it has been shown to greatly extend life span in flies and worms, Rubin said. Also, signaling doesn’t have to be reduced in all tissues.

“If you just reduce it in neurons, the whole fly or worm lives longer,” Rubin said. “Certain key tissues in those organisms, if you selectively manipulate those tissues, have a positive effect on a number of processes in other tissues.”

Because it circulates throughout the body, blood is an obvious place to look for controlling or signaling molecules that prompt or coordinate aging. A key carrier of oxygen and nutrients, blood is also rich with other compounds, some of which appear to play a role in decline linked to age.

Scadden described recent work done separately by Ben Ebert, a professor of medicine working at Harvard-affiliated Brigham and Women’s Hospital, and Steve McCarroll, the Dorothy and Milton Flier Associate Professor of Biomedical Science and Genetics, that identified age-related changes in the blood that can increase the risk of diseases we don’t typically think of as blood diseases.

Another tantalizing study, published in 2013, used the blood of a young mouse to rejuvenate the organs of an older one. In these “parabiotic” experiments, conducted by Professor of Stem Cell and Regenerative Biology Richard Lee and Forst Family Professor of Stem Cell and Regenerative Biology Amy Wagers, the circulatory systems of the two mice were joined, allowing the blood of the young to flow through the older one’s body. The older mouse showed improvements in muscle tone and heart function. Later, similar experiments done by Rubin also showed improvements in neuronal health and brain functioning.

The young mouse’s fate depended on the age of the older mouse, Rubin said. If the latter was middle-aged, the young mouse appeared to be fine. If the older mouse was very old, however, the young mouse did worse.

Rubin said the experiments suggest that blood contains both positive and negative factors that influence aging. It may be, he said, that both are always present, but that positive factors outweigh negative in the young and that negative factors increase as we age.

“The process of aging involves all tissues in your body and … different things go wrong in each tissue,” says Lee Rubin. “[I]f you selectively manipulate those tissues, [it can] have a positive effect on a number of processes in other tissues.” Kris Snibbe/Harvard Staff Photographer

Researchers have identified but not yet confirmed candidate blood factors for the rejuvenating effects. What seems not in doubt is the overall effect of the young blood on the old mouse. Interest is intense enough that a California company, Alkahest, has begun experiments giving Alzheimer’s patients plasma from young blood in hopes of improving cognition and brain function.

Even if that approach works, Rubin said, there would be practical hurdles to the widespread administration of young people’s blood plasma to older patients. But with an active compound identified, a drug could be made available to restore at least some cognitive function in Alzheimer’s patients.

In addition to the overall process of aging, researchers at the Harvard Stem Cell Institute, as well as across the University and its affiliated institutions, are investigating an array of diseases whose incidence increases — sometimes dramatically — with age.

The list includes several of the country’s top causes of death — heart disease, stroke, diabetes, and cancer — as well as rarer conditions such as the lethal neurodegenerative disorder amyotrophic lateral sclerosis (ALS).

Two decades ago, when stem cell research hit mainstream consciousness, many thought its greatest promise would be in stem cells’ ability to grow replacement parts: organs and tissues for damage caused by trauma or disease.

The stem cell revolution is still developing, Scadden said, but so far has taken a different form than many expected. The dream of harnessing stem cells to grow replacement hearts, livers, and kidneys remains, but potentially powerful uses have emerged in modeling disease for drug discovery and in targeting treatment for personalized medicine.

“We thought stem cells would provide mostly replacement parts. I think that’s clearly changed very dramatically. Now we think of them as contributing to our ability to make disease models for drug discovery.”

— David Scadden

Researchers have taken from the sick easily accessible cells, such as skin or blood, and reprogrammed them into the affected tissue type — nerve cells in the case of ALS, which most commonly strikes between 55 and 75, according to the National Institutes of Health (NIH).

These tissues are used as models to study the disease and test interventions. Work on ALS in the lab of Professor of Stem Cell and Regenerative Biology Kevin Egganhas identified a drug approved for epilepsy that might be effective against ALS. This application is now entering clinical trials, in collaboration with Harvard-affiliatedMassachusetts General Hospital.

In the end, stem cells might have their greatest impact as a drug-discovery tool, Scadden said.

“Much of stem cell medicine is ultimately going to be ‘medicine,’” he said. “Even here, we thought stem cells would provide mostly replacement parts. I think that’s clearly changed very dramatically. Now we think of them as contributing to our ability to make disease models for drug discovery.”

Also evolving is knowledge of stem cell biology. Our previous understanding was that once embryonic stem cells differentiated into stem cells for muscle, blood, skin, and other tissue, those stem cells remained flexible enough to further develop into an array of different cells within the tissue, whenever needed.

Recent work on blood stem cells, however, indicates that this plasticity within a particular tissue type may be more limited than previously thought, Scadden said. Instead of armies of similarly plastic stem cells, it appears there is diversity within populations, with different stem cells having different capabilities.

If that’s the case, Scadden said, problems might arise in part from the loss of some of these stem cell subpopulations, a scenario that could explain individual variation in aging. Getting old may be something like the endgame in chess, he said, when players are down to just a few pieces that dictate their ability to defend and attack.