A time to kill, a time to heal: cells linked to aging also help heal wounds

Senescent cells, so called because of the role they play in the aging process, have acquired a bit of a bad reputation.

Yet new research from the Buck Institute suggests that these cells may not be so bad after all.

Buck Institute faculty Judith Campisi and Postdoc Marco Demaria. [Credit: The Buck Institute]

Buck Institute Professor Judith Campisi and Postdoc Marco Demaria. [Credit: The Buck Institute]

Reporting in today’s issue of Developmental Cell, Buck Institute scientists have found that, while senescent cells do indeed contribute to cellular aging and age-related diseases, they also play an important role in healing wounds. Furthermore, the team has identified the specific molecule in senescent cells that does the healing—pointing to a new therapy that could harness the good aspects of senescent cells, while flushing out the bad.

As we age, so do our cells. During cellular senescence, cells begin to lose their ability to grow and divide. The number of so-called senescent cells accumulates over time, releasing molecules thought to contribute to aging and age-related diseases such as arthritis and some forms of cancer.

But experiments led by Buck Institute Professor Judith Campisi and postdoctoral fellow Marco Demaria revealed that following a skin wound, cells that produce collagen and that line the blood vessels become senescent, and lose the ability to divide. Instead, they accelerate wound healing by secreting a growth factor called PDGF-AA. And once the wound was healed, the cells lost their senescence and shifted back into their normal state.

Because cellular senescence has long been linked to aging and age-related diseases, some research has been focused on finding ways to flush out senescent cells entirely. But the findings by the Buck Institute team throw a wrench in that idea, by revealing that these cells do in fact serve an important purpose.

According to Campisi, there is still a lot to learn:

“It is essential that we understand the full impact of senescence. The possibility of eliminating senescent cells holds great promise and is one of the most exciting avenues currently being explored in efforts to extend healthspan. This study shows that we can likely harness the positive aspects of senescence to ensure that future treatments truly do no harm.”

Cells’ Knack for Hoarding Proteins Inadvertently Kickstarts the Aging Process

Even cells need to take out the trash in order to maintain a healthy clean environment. And scientists are now uncovering the harmful effects when cells instead begin to hoard their garbage.

Cells' penchant for hoarding proteins may spur the cellular aging process, according to new research.

Cells’ penchant for hoarding proteins may spur the cellular aging process, according to new research. [Labyrinth (1986)]

Aging, on the cellular level is—at its core—the increasing inability for cells to repair themselves over time. As cells begin to break down faster than they can be repaired, the risk of age-related diseases escalates. Cancer, heart disease and neurological conditions such as Alzheimer’s disease are some of aging’s most deadly effects.

As a result, scientists have long searched for ways to give our cells a little help and improve our quality of life as we age. For example, recent research has pointed to a connection between fasting (restricting calories) and a longer lifespan, though the molecular mechanisms behind this connection remain somewhat cryptic.

But now Dr. Daniel Gottschling, a scientist at the Fred Hutchinson Cancer Research Center and an aging expert, has made extraordinary progress toward solving some of the mysteries of aging.

In two studies published this month in the Proceedings of the National Academy of Sciences and eLife, Gottschling and colleagues discover that a particular long-lasting protein builds up over time in certain cell types, causing the buildup of a protein hoard that damages the cell beyond repair.

Clearing out the Cobwebs

Some cells, such as those that make up the skin or that reside in the gut, are continually replenished by a stockpile of adult stem cells. But other cells, such as those found in the eye and brain, last for years, decades and—in some cases—our entire lifetimes.

Within and surrounding these long-lived cells are similarly long-lived proteins which help the cell perform essential functions. For example, the lens of the human eye, which helps focus light, is made up of these proteins that arise during embryonic development and last for a lifetime.

Dr. Daniel Gottschling is looking to unlock the mysteries behind cellular aging.

Dr. Daniel Gottschling is looking to unlock the mysteries behind cellular aging. [Image courtesy of the Fred Hutchinson Cancer Research Center]

“Shortly after you’re born, that’s it, you get no more of that protein and it lives with you the rest of your life,” explained Gottschling.

As a result, if those proteins degrade and die, new ones don’t replace them—the result is the age-related disease called cataracts.

But scientists weren’t exactly sure of the relationship between these dying proteins and the onset of conditions such as cataracts, and other disease related to aging. Did these conditions occur because the proteins were dying? Or rather because the proteins were building up to toxic levels?

So Gottschling and his team set up a series of experiments to find out.

Stashing Trash

They developed a laboratory model by using yeast cells. Interestingly, yeast cells share several key properties with human stem cells, and are often the focus of early-stage research into basic, fundamental concepts of biology.

Like stem cells, yeast cells grow and divide asymmetrically. In other words, a ‘mother’ cell will produce many ‘daughter’ cells, but will itself remain intact. In general, yeast mother cells produce up to 35 daughter cells before dying—which usually takes just a few days.

 Yeast “mother” cells budding and giving birth to newborn “daughter” cells.  [Image courtesy of Dr. Kiersten Henderson / Gottschling Lab]

Yeast “mother” cells budding and giving birth to newborn “daughter” cells.
[Image courtesy of Dr. Kiersten Henderson / Gottschling Lab]

Here, the research team used a special labeling technique that marked individual proteins that exist within and surrounding these mother cells. These microscopic tracking devices then told researchers how these proteins behaved over the entire lifespan of the mother cell as it aged.

The team found a total of 135 long-lived proteins within the mother cell. But what really surprised them was what they found upon closer examination: all but 21 of these 135 proteins appeared to have no function. They appeared to be trash.

“No one’s ever seen proteins like this before [in aging],” said Nathanial Thayer, a graduate student in the Gottschling Lab and lead author of one of the studies.

Added Gottschling, “With the number of different fragments [in the mother cell], we think they’re going to cause trouble. As the daughter yeast cells grow and split off, somehow mom retains all these protein bits.”

This startling discovery opened up an entirely new set of questions, explained Gottschling.

“It’s not clear whether the mother’s trash keeper function is a selfless act designed to give her daughters the best start possible, or if she’s hanging on to them for another reason.”

Hungry, Hoarding Mother Cells

So Gottschling and his team took a closer look at one of these proteins, known as Pma1.

Recent work by the Gottschling Lab found that cells lose their acidity over time, which itself leads to the deterioration of the cells’ primary energy source. The team hypothesized that Pma1 was somehow intricately tied to corresponding levels of pH (high pH levels indicate an acidic environment, while lower pH levels signify a more basic environment).

In the second study published in eLife, led by Postdoctoral Fellow Dr. Kiersten Henderson, the team made several intriguing discoveries about the role of Pma1.

First, they uncovered a key difference between mother and daughter cells: daughter cells are born with no Pma1. As a result, they are far more acidic than their mothers. But when they ramped up Pma1 in the mother cells, the acidity levels in subsequent generations of daughter cells changed accordingly.

“When we boosted levels of the protein, daughter cells were born with Pma1 and became more basic (they had a lower pH), just like their mothers.”

Further examination uncovered the true relationship between Pma1 and these cells. At its most fundamental, Pma1 helps the mother cells eat.

“Pma1 plays a key role in cellular feeding,” said Gottschling. “The protein sits on the surface of cells and helps them take in nutrients from their environment.”

Pma1 gives the mother cell the ability to gorge herself. The more access to food she has, the easier it is for her to produce more daughter cells. By hoarding Pma1, the mother cell can churn out more offspring. Unfortunately, she is also signing her own death certificate—she’s creating a more basic environment that, in the end, proves toxic and contributes to her death.

The hoarding, it turns out, may not all be due to the mother cells’ failure to ‘take out the trash.’ Instead, she wants to keep eating and producing daughters—and hoarding Pma1 allows her to do just that.

“There’s this whole trade off of being able to divide quickly and the negative side is that the individual, the mother, does not get to live as long.”

Together, the results from these two studies provide a huge boost for researchers like Gottschling who are trying to unravel the molecular mysteries of aging. But the process is incredibly intricate, and there will likely be no one simple solution to improving quality of life as we get older.

“The whole issue of aging is so complex that we’re still laying the groundwork of possibilities of how things can go awry,” said Gottschling. “And so we’re still learning what is going on. We’re defining the aging process.”

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.

shutterstock_160378703

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