Long-term hoarding of cellular ‘garbage’ could trigger old age

Fred Hutch scientists find long-lived molecules influence aging
Yeast "mother" cells
Yeast “mother” cells budding and giving birth to newborn “daughter” cells. Fred Hutch researchers have found a link between a long-lived protein (in red) and how mother cells age. Image courtesy of Dr. Kiersten Henderson / Gottschling Lab

As we age, many parts of our bodies break down, never to be repaired. It turns out that the same is true of our cells. New research findings from Fred Hutchinson Cancer Research Center scientists point to microscopic systems that degenerate over time, triggering cellular aging that may in turn spur human aging and age-related diseases.

Their findings also help explain the link between fasting and longer life. It’s long been known that calorie restriction increases lifespan in several different animals, including humans, but the reasons why are unclear.

The molecular and cellular building blocks of most body parts undergo rapid turnover. Skin renews itself roughly once a month, gut cells in just a few days. But there are exceptions; some bodily structures – such as parts of the eye, joints and brain – are present from childhood to death.

For example, the eye lens, a flexible structure on the front of the eye that helps focus light to the retina, is made up of special, very long-lived proteins.

“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,” said Fred Hutch basic scientist Dr. Daniel Gottschling, who studies the mechanisms of aging.

The breakdown of that special protein over time leads to cataracts, a clouding of the eye lens our bodies can’t repair because they are unable to regenerate the lens tissue. But scientists haven’t been sure whether these irreparable body parts are exceptions to the rule or whether similar long-lived proteins might underlie aging in other cells throughout the body.

In two recently published studies, Gottschling and his team reported that certain proteins stick around for the entire lifespan of cells, which could be the cause of cellular old age. Using baker’s yeast, a single-celled fungus that shares certain characteristics with human stem cells, the scientists identified several ways these proteins could cause cellular aging, from changing the acidity of cells to creating stockpiles of molecular “garbage” that build up over time.

Mother cells as ‘trash keepers’

Long-lasting proteins in the eyes, brain, and joints are unique because they exist outside of cells or inside cells that don’t divide. Stem cells grow and divide over our lifetimes but eventually give out; one theory of human aging suggests that a dwindling pool of stem cells may drive old age as fewer cells are available to repair or regenerate failing body parts.

Both stem cells and yeast divide asymmetrically, with aging “mother” cells giving birth to newborn “daughter” cells. Yeast mothers can generate 30 to 35 daughter cells before dying; their normal lifespan when dividing lasts less than two days. Gottschling’s discoveries point to the reason mother cells age and die and how their daughter cells are able to start their life anew after budding.

To look for long-lived proteins in yeast, the scientists used a special protein-labeling technique to track molecules from a mother cell’s birth to her death. They found a collection of 135 proteins present only in mother cells that don’t turn over during the cell’s lifespan. To the scientists’ surprise, all but 21 of these proteins were non-functional fragments.

A new glimpse into old cells

“No one’s ever seen proteins like this before [in aging],” said Nathaniel Thayer, a graduate student in Gottschling’s lab and one of the lead authors of the long-lived protein study, which was published Sept. 16 in the journal Proceedings of the National Academy of Sciences. “We still don’t completely understand what an old cell looks like, but this gives us a little insight.”

Although the scientists don’t yet understand what the individual protein fragments do in the cell or how they might initiate aging, these fragments are not good news. Because of the specific pieces present and their sheer number, they are likely to interfere with normal proteins and cellular functions.

“With the number of different fragments, we think they’re going to cause trouble in the cell,” Gottschling said.

As the daughter yeast cells grow and split off, somehow mom retains all these protein bits, even though the contents of the cells mix before division. 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, Gottschling said.

“We have no idea how she’s doing this or why,” he said.

The base of aging

One of the few unbroken long-lived proteins in mother cells caught the scientists’ attention. This protein, Pma1, keeps cells from becoming too acidic or basic (acids, such as vinegar and lemon, have a pH value below 7 and bases, such as hand soap, have a pH value above 7). Gottschling’s team made a seminal finding in 2012 that acidity within certain cellular structures, called vacuoles, is critical to maintaining mitochondria, the energy source of cells. Cells lose that acidity over time; Gottschling and colleagues showed that as vacuoles become more basic, the cells’ energy sources break down.

Dr. Kiersten Henderson, a postdoctoral fellow in Gottschling’s lab, found that yeast mother cells grow more basic with each cell division, and that decreasing acidity is dependent on Pma1. As with the unequal distribution of protein fragments, new daughter cells are born with no Pma1 and are much more acidic than their mothers.

In a paper published Sept. 4 in the journal eLife, Henderson, the lead author, explained that if she dialed down levels of Pma1, mother cells lived longer. When she boosted the protein, daughter cells were born with Pma1 and became more basic, like their mothers.

Pma1 plays a key role in cellular feeding, Gottschling said. The protein sits on the surface of cells and helps them take in nutrients from their environment. Unlike mothers’ trash keeping of protein fragments, Gottschling thinks their retention of Pma1 may be easily explained by their need to keep eating.

“She’s in a good state because there’s plenty of food, and she is gorging herself to make more progeny,” he said. “But there’s a consequence, it turns out, because she does it very efficiently.”

That consequence, mother cells’ changing acidity, could also explain why aging happens more in rich environments and why caloric restriction can increase lifespan. If cells take in less food, their acidity doesn’t nosedive as quickly. Of course, if they get fewer calories, they produce fewer daughters.

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

Dr. Daniel Gottschling
Dr. Daniel Gottschling, a member of the Basic Sciences Division at Fred Hutch, became interested in aging about 15 years ago after hearing a colleague talk about the link between aging and cancer. Bo Jungmayer / Fred Hutch News Service

The birth of old age

Gottschling, 59, became interested in aging about 15 years ago after hearing a colleague talk about the link between aging and cancer – after age 40, the risk of many cancers increases exponentially. In the years since, he has been using yeast to get at the heart of the question: When and how does aging start?

His team’s recent findings of long-lived proteins and changing acidity suggest that for yeast, aging begins at birth. Now, Gottschling is planning to test cellular acidity in other laboratory models such as fruit flies or worms to see whether these discoveries hold up in other creatures. Researchers don’t yet know whether cellular acidity could influence human aging, but there are proteins similar to Pma1 that build up in “mother” human stem cells as the cells divide, which leads Gottschling to believe there may be similar processes happening in our aging cells.

But Gottschling’s not banking on a simple answer or a single drug that could reverse aging. The biology of age is still so convoluted and poorly understood that he doesn’t yet want to conjecture about possible anti-aging therapies based on his work.

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

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Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.

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