Fly stem cells give insights into aging and longevity

Yesterday brought news about stem cells in older people. Today, there's news by CIRM grantees about how a single gene alteration in a stem cell can help keep an entire organ more youthful -- at least in flies.

The work was by a team of researchers at the University of California, Los Angeles, the Salk Institute for Biological Studies and the University of California, San Diego. It all started with a long-known observation: cutting calories in many laboratory animals can also dramatically extend the animal's life. This is true in common lab animals such as flies, worms, and mice, and also holds true in primates.

In addition to living longer, those hungry, long-lived animals have more of the energy-producing cellular structures called mitochondria. The researchers were curious if simply boosting the number of mitochondria without all that painful hunger would work the same trick. One known way of boosting mitochondria is to rev up a protein called PGC-1.

A press release from Salk describes the work of associate professor Leanne Jones' work like this:

"This chain of connections between the mitochondria and longevity inspired Jones and her colleague to investigate what happens when the PGC-1 gene is forced into overdrive. To do this, they used genetic engineering techniques to boost the activity of the fruit fly equivalent of the PGC-1 gene. The flies (known as Drosophila melanogaster) have a short lifespan, allowing the scientists to study aging and longevity in ways that aren't as feasible in longer-lived organisms such as mice or human."

The researchers specifically bumped up the PGC-1 gene in stem cells that line the fly intestine. They found two things: 1) those fly intestine stem cells had more mitochondria, and 2) the flies lived a lot longer than their unaltered lab-mates. All that, with no starvation.

Here, I should pause to say that if you think your intestine is so different from a fly's you'd be wrong. Their intestine is lined with stem cells not unlike our own, and those cells function in a very similar way using similar genes. That's not to say that all research in flies directly translates to humans, but it is a pretty good model for testing out ideas.

Jones, who has a New Faculty award from CIRM, had this to say in the press release about the findings:

"Slowing the aging of a single, important organ - in this case the intestine - could have a dramatic effect on overall health and longevity," Jones says. "In a disease that affects multiple tissues, for instance, you might focus on keeping one organ healthy, and to do that you might be able to utilize PGC-1."

This research is in the very preliminary stages and is far from being ready for an human use. However, it's this kind of basic discovery that continuously fuels new ideas for human therapies.

CIRM Funding: Leanne Jones (RN1-00544-1)
Cell Metabolism, November 1, 2011

- A.A.

Older stem cells returned to youth

We've written quite a bit about research by CIRM grantee Irina Conboy at the University if California Berkeley (blogged here), who has found that the muscle stem cells in older people don't respond as enthusiastically to repair muscle damage — much to the dismay of aging athletes. What they've also learned is that environment is key. Those same sluggish stem cells respond more rapidly when bathed in younger blood, at least in mice. Their work suggests that the muscle stem cells are still effective, it's the older surrounding cells that are the problem.

New research by a group at the University of Texas Health Science Center San Antonio has found something similar with stem cells that produce bone. They took mesenchymal stem cells from the bone marrow of mice. These cells are different than the blood-forming stem cells also found in bone marrow, which continuously form all cells of the blood system. The mesenchymal stem cells are bone marrow residents that can make bone, cartilage and fat, among other tissues.

The research, published in the FASEB Journal in May, showed that mesenchymal stem cells (MSCs) from old and young mice both multiplied four times more when grown in the lab on cells taken from younger mice versus older mice. What this means is that even though the tissue-specific stem cells might not be very active in an older body, those cells can be given a new lease on life in the lab. A press release from UT Health Science Center quotes the senior author on the work:

“The number and quality of those cells decline with age, that is very clear,” said Xiao-Dong Chen, M.D., Ph.D., a stem cell researcher at the UT Health Science Center. “And, using the patient’s own cells can impact results.”

This work was in mice, which means that it may or may not translate to humans. But this kind of research is important, given that many stem cell-based therapies that CIRM and others are funding address diseases that occur in older people with older stem cells. Knowing how to return those stem cells to a more youthful state could be important for developing effective therapies of aging.

- A.A.

Bakersfield residents learn about stem cell progress in aging, macular degeneration

This weekend CIRM hosted an educational event in Bakersfield to update people on the progress being made by CIRM grantees. The event featured a keynote address by board chair Jonathan Thomas plus talks by grantees working on age-related diseases including blindness.

Although CIRM holds board meetings throughout California, this is the first time people in Bakersfield have had a chance to hear directly from CIRM. If media attention in advance of the meeting is anything to judge by, the local community was excited about hosting us. The local radio station KERN spoke with CIRM patient advocate coordinator Chris Stiehl, who helped organize the event. You can listen to that interview here.

Among other things, Stiehl discussed the Geron spinal cord injury trial as one sign that the field of stem cell research is progressing.

"Geron Corporation is doing clinical trials with stem cells on people with spinal cord injuries. That's amazing. We never had anything for those people except wheelchairs and someday they may get out of their wheelchairs because of this."

The Bakerfield Californian also had a nice piece announcing the event.

As with all CIRM patient advocacy events, if you can't make the event you can follow the discussion on Twitter either by watching the stem cell conversation on #stemcells or by following the event's hash tag, which is listed on the agenda on the CIRM web site. There's another event coming up October 29 in Santa Rosa, which you can follow at #CIRMSantaRosa.

These types of public events featuring CIRM scientists and patient advocates are going to be ongoing throughout the state as a way of making sure the people of California get a chance to learn about progress being made by the institute.

You can get more information about all the awards CIRM has funded and which institutes have received funding on our website.

A.A.

On stem cells, sports injuries and aging

A headline today grabbed my attention: Can your own stem cells heal your running injuries?

The answer, in a word: Duh.

That's the whole point of tissue-specific stem cells like the ones lurking in muscles. These are the body's reservoir for repairing and rebuilding tissues. In fact, several CIRM grantees are studying what makes muscle stem cells tick, and what make them tick less effectively as we age. A bit of shameless self-promotion, but here's a story by yours truly from the Stanford School of Medicine magazine about work by Tom Rando, who was studying signals that direct muscle stem cells to heal injuries. His post-doctoral student Irina Conboy went on to found her own lab at the University of California, Berkeley, where she got a New Faculty Award to continue the work (we've blogged about her work here).

I suppose what's implied in the headline isn't whether stem cells normally heal injuries, which they do, but whether they can be used medically to heal injuries more effectively as in the case of the baseball pitcher Bartolo Colon.

To date, CIRM isn't funding work relating directly to, say, shin splints or plantar fasciatis. But a number of grantees are studying not only muscle stem cells but also another type of stem cell called a mesenchymal stem cell that seems to be able to repair bone and cartilage. (Here's a list of all CIRM awards targeting bone, muscle or cartilage.) What's exciting about a lot of the basic stem science going on today is that it could lead to new ways of treating a wide range of different injuries, either by injecting a person's own stem cells or by helping the native stem cells heal more effectively.

As a runner who is inevitably aging, I think it's good news that research into chronic, debilitating conditions such as osteoarthritis could also provide some benefit down the road to my own damaged joints.

A.A.

Disease in a dish model provides insight on aging

Normal aging takes many decades to create major changes in our cells, so it is very difficult to study. As a result, very little is known about this fundamental inevitability of life. But that may change with the help of an unfortunate child, who by the bad luck of a single point mutation developed a rare disease that results in aging at eight to 10 times the normal pace.

A Salk Institute research team lead by Juan-Carlos Izpisua Belmonte has reprogrammed skin cells from the child, who has Hutchinson-Gifford progeria, into induced pluripotent (iPS) stem cells and then forced them to mature into smooth muscle cells in a dish that displayed all the characteristics of aging cells, a model for aging in a dish.

In a Salk press release Belmonte said:

Having a human model of accelerated aging may give us new insights into how we age. It may also help prevent or treat heart disease in the general aging population.

In a paper in Nature, the Salk team noted that this progeria is caused by a single point mutation in the gene encoding lamin A, and that there is evidence that defective lamin A also accumulates in the normal aging process via sporadic gene splicing.

The beauty of this model is the researchers were able to provide evidence for the impact of the defective protein. When the reprogrammed cells were in the embryonic-like state the lamin A was silenced, but when those cells were differentiated into smooth muscle the signs of premature aging appeared.

CIRM funding: Guang-Hui Liu  (TG2-01158)
Nature, February 23, 2011

D.G.

Longevity gene regulates neural stem cells in mice

Researchers at the Stanford University School of Medicine have found that a gene long-known to regulate the lifespan of tiny roundworms also plays a role in regulating neural stem cells in mice.

Variations of the gene family, called FoxO, help roundworms live to an unusually ripe old age in the lab, and mutations in the FoxO3 gene have also recently been associated with long life in Japanese, German, American and Italian populations. Laboratory mice lacking FoxO3 live to about half their usual age of 30 months before dying of cancer.

The group found that in addition to dying young, adult mice lacking FoxO3 had fewer neural stem cells than normal mice of the same age. These neural stem cells normally generate new brain cells as needed, and also replenish their own population to maintain a lifetime pool of cells.

According to a press release by the Stanford University School of Medicine:

The researchers also discovered that the few stem cells found in the adult mice without FoxO3 more rapidly churned out neural cell precursors — those cells destined to become new neurons — than did the mice with normal FoxO3 levels. In fact, the brains of the mice that lacked FoxO3 were heavier than the control group, perhaps because they were burning through their pool of neural stem cells by making too many new nerve cells.

A better understanding of how neural stem cells maintain the brain as it ages could help those researchers who are developing therapies for disorders such as Alzheimer’s and Parkinson’s disease or stroke.

Cell Stem Cell: November 6, 2009
CIRM funding: Anne Brunet (RN1-00527-1)

Related Information: Stanford University School of Medicine, Brunet bio

A.A.

Old muscle stem cells experimentally returned to youth

Researchers at the University of California, Berkeley have found molecular pathways that human muscle stem cells rely on to repair damaged muscle. These pathways are active in younger people but less active in older people, explaining why muscles repair more slowly with age. The group found that younger volunteers had double the number of regenerative muscle stem cells in their thigh muscles compared to older volunteers. After two weeks in a leg cast, both groups began exercise routines to rebuild muscle. During this phase, the older volunteers had four times fewer muscle stem cells and rebuilt muscle more slowly. The researchers said that the poor response wasn’t the fault of the older stem cells. Instead, signals in the aging muscle and blood locked the stem cells in an inactive state. From their work in mice, the researchers knew that proteins present in the muscle surrounding the stem cells helped these cells respond to distress signals from the injured tissue. In the human cells, they found a protein called MAPK that interprets these distress signals and triggers the muscle stem cells to begin the repair process. Young people have high levels of MAPK and older people have low levels of MAPK, providing one explanation for the older volunteers’ poor response to exercise. In a lab dish, the group found that by artificially blocking MAPK in young muscle stem cells they could make young cells respond like older cells in a matter of days. The reverse was also true. Amplifying MAPK in older muscle stem cells in a lab dish rejuvenated the older cells. This work is an important step in verifying results from mouse stem cell aging studies in humans. The researchers hope their work could lead to therapies for muscle diseases and help older people to remain active, build stronger muscles and recover from injury.

EMBO Molecular Medicine: September 30, 2009
CIRM funding: Irina Conboy (RN1-00532-1), Morgan Carlson (T1-00007)

Related Information: Press Release, University of California, Berkeley

A.A.

Aging Muscles Inhibit Stem Cells, Prevent Repair

Researchers at UC, Berkeley identified a signaling molecule that interferes with the ability of older skeletal muscle to regenerate. After injury, adult skeletal muscle regenerates by activating muscle stem cells that fuse with the existing muscle cells to repair the damage. This ability to regenerate diminishes with age, not because of a decline in the number of resident stem cells, but because stem cells in the older muscle don’t respond when damage occurs. It turns out that older muscles release molecules that actively inhibit the resident stem cells. In this study, the team identified one of those molecules and showed that interfering with that molecule’s function restores the ability of muscle in older mice to regenerate after injury. This research illustrates the potential for recruiting adult resident stem cells in tissue repair.

Nature: June 15, 2008.
CIRM funding: Morgan Carlson (T1-00007)

Related Information: Press release, Berkeley Stem Cell Center