Creaky Cell Machinery Affects the Aging Immune System, CIRM-Funded Study Finds

Why do our immune systems weaken over time? Why are people over the age of 60 more susceptible to life-threatening infections and many forms of cancer? There’s no one answer to these questions—but scientists at the University of California, San Francisco (UCSF), have uncovered an important mechanism behind this phenomenon.

Reporting in the latest issue of the journal Nature, UCSF’s Dr. Emmanuelle Passegué and her team describe how blood and immune cells must be continually replenished over the lifetime of an organism. As that organism ages the complex cellular machinery that churns out new cells begins to falter. And when that happens, the body can become more susceptible to deadly infections, such as pneumonia.

As Passegué so definitively put it in a UCSF news release:

“We have found the cellular mechanism responsible for the inability of blood-forming cells to maintain blood production over time in an old organism, and have identified molecular defects that could be restored for rejuvenation therapies.”

The research team, which examined this mechanism in old mice, focused their efforts on hematopoetic stem cells—a type of stem cell that is responsible for producing new blood and immune cells. These stem cells are present throughout an organism’s lifetime, regularly dividing to preserve their own numbers.

Molecular tags of DNA damage are highlighted in green in blood-forming stem cells. [Credit: UCSF]

Molecular tags of DNA damage are highlighted in green in blood-forming stem cells. [Credit: UCSF]

But in an aging organism, these cells’ ability to generate new copies is not as good as it used to be. When the research team dug deeper they found a key bit of cellular machinery, called the mini-chromosome maintenance helicase, breaks down. When that happens, the DNA inside the cell can’t replicate itself properly—and the newly generated cell is not running on all cylinders.

One of the first things that these old stem cells lose as a result is their ability to make B cells. B cells, a key component of the immune system, normally make antibodies that fight infection. As B cell numbers dwindle in an aging organism, so too does their ability to fight infection. As a result the organism’s risk for contracting dangerous illnesses skyrockets.

This research, which was funded in part by CIRM, not only informs what goes wrong in an aging organism at the molecular level, but also points to new targets that could keep these stem cells functioning at full capacity, helping promote so-called ‘healthy aging.’ As Passegué added:

“Everybody talks about healthier aging. The decline of stem-cell function is a big part of age-related problems. Achieving longer lives relies in part on achieving a better understanding of why stem cells are not able to maintain optimal functioning.”

ISSCR 2014: If we learn how to help our stem cells keep their balance we might reduce the effects of aging

The effects of aging come from a decline in our stem cells’ ability to do their job. Four speakers on the second day of the International Society for Stem Cell Research (ISSCR) conference laid out how this happens and showed the results of some early attempts to make our aging stem cells perform like young whippersnappers.

Part of the discussion centered on finding balance in our systems, kind of like Goldilocks looking for the bed that was not too hard and not too soft. Scientists refer to this balance in a living organism as homeostasis. We need our stem cells active enough to conduct routine repair and replacement but not so active they cause cancer.

Heinrich Jasper of the Buck Institute for Research on Aging talked about using a fruit fly model to track how stem cell homeostasis gets thrown off in the intestine as the flies age. This is a great model because a five day-old fly can be considered a geezer, which speeds up the research.

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He found that the issue is not a drop off in the number of stem cells, but rather an over production to such an extent that they cannot integrate with the surrounding tissue. The team’s sleuthing uncovered a complex set of interactions including oxidative stress—the over-exposure to oxygen containing chemical compounds like the ones you try to moderate with anti-oxidant foods and supplements. The bacteria that naturally live in the gut also changed, becoming more abundant and less diverse, which seemed to be a response to a down regulation of the immune response. He said, the map of these interactions and some of the genetic triggers provides targets for potential intervention in the effects of aging on the stem cells.

Amy Wagers from Harvard gave some more detail on work we have described before doing “parabiosis” experiments. That is when you connect the blood circulation of two different animals. This lets you expose the stem cells of old animals to the blood from young ones. The rational for the work comes from the fact that many of our systems start to show signs of aging around the same time. So, she thought that might mean there is a global regulator of the process, and a good place for a master switch to come in contact with tissue all over the body is the blood stream.

She used new systems for screening large numbers of chemical compounds to find proteins that were abundant in young blood but not old blood. She honed in on one called GDF-11. When she injected the substance into old mice daily for a couple weeks she saw the same effects as hooking their blood stream up to younger mice. Their muscle was better able to repair damage and they had better grip strength. (Having not shaken the hand of a mouse, I am not sure how she measured that, but I trust her.) She found improved repair function in the heart and brain as well.

Shyh-Chang Ng talked about work he began in George Daly’s lab at Harvard and has continued in his first faculty post at the Genome Institute of Singapore. They worked on the nematode, a small worm. Some years ago they had found that the protein Lin 28 regulates the ability of stem cells to replicate and that it declines with age. In recent research he found out part of why the decline results in aging. When it is present it improves the metabolism of our mitochondria, the tiny organs within all our cells that provide energy for the cell to function.

Next, Gabrielle Kardon from the University of Utah talked about the loss of muscle mass we all begin to experience around the age of 45 (around 17 months old for mice). The loss of muscle mass makes us more vulnerable to injury and to the insulin resistance that is the hallmark of type 2 diabetes. The muscle stem cells that are supposed to help keep our muscle in shape are called satellite cells, but exactly what they do is not well understood. So Kardon used genetic tricks to label them and monitor their activity. She found that they were important for repair as well as for maintaining homeostasis, but their activity varied between types of muscle, like the muscle in the diaphragm versus in our legs.

All this work provides clues to intervening to allow healthier aging. The technical term for muscle mass loss with aging is Sarcopenia. From now on when someone tells me I look tired, I will just tell them, “nah it is just my sarcopenia acting up, but we are working on that.”
Don Gibbons