Pudgy middle age: Does a little fat have an upside?

Fat gets a bad rap. Too much is linked to an increased risk of Type 2 diabetes and cancer, but the fat-rehabilitation movement has already started. Research is starting to accentuate its positives, and work by scientists at Fred Hutchinson Cancer Research Center suggests another possible upside: protection against stress.

Published June 3 in Nature Communications, the work used single-celled yeast (which, like humans, go through a midlife slump and plump) to study aging at the cellular level. Dr. Anthony Beas, a postdoctoral fellow in the lab of Dr. Susan Parkhurst, found that middle-aged yeast cells with a little extra pudge withstood cold better than skinny middle-aged yeast cells.

The findings suggest that “in normal aging, fat may not impact longevity,” said Beas, who initially joined the team of Hutch aging expert Dr. Dan Gottschling before Gottschling left to head research at Calico, a biotech company dedicated to studying aging.

Beas also found that fat doesn’t indicate poorer aging. By genetically manipulating the genes involved in aging and fat accumulation, he was able to create pudgy yeast that lived longer than average, while some skinny yeast died younger. By manipulating metabolic pathways in the yeast, he was also able to show that longevity and lipid accumulation in the yeast did not rely on the NAD+ pathway, which has been linked to the length of good health during one’s life span in other studies.

Yeast as a model of cellular aging

A middle-aged metabolic slowdown is a familiar concept to many. But signs of creeping age at the organismal level, such as greying hair or deepening crow's feet, don’t give much insight into the changes occurring at the cellular level. Beas joined Gottschling’s lab to study cellular aging, and yeast make a great model, he said.

They age too, and in similar ways to higher organisms like humans and mice.

Gottschling’s team had already shown that in aging yeast, the DNA grows unstable and the mitochondria, which power the cell, decline in function — just like in mammalian cells. It’s easy to see cellular age-related changes in yeast using a microscope, and it’s quick. The species of yeast that Beas studies reproduces by budding. Each mother cell buds a median of 24 times (about half will bud a few more times and half will bud a few less) and hits middle age around its 16th bud.

Having begun to experience his own metabolic changes associated with midlife, Beas was interested in using yeast to study fat accumulation associated with aging. In particular, he hoped to understand whether it has a detrimental effect on health and life span. Most of the studies that have linked fat to negative outcomes have used high-fat diets or looked at scenarios where it’s present in extreme excess, closer to obesity than a little extra pudge, Beas noted.

One of the first things he discovered was that yeast store the same type of fat as human cells, and they start stockpiling it in large droplets beginning around their 12th budding event.

“There’s a widely held belief that fat is detrimental to aging,” Beas said. “I thought that this fat accumulation was potentially going to harm or decrease the life span of yeast.”

Life span and fat accumulation are independent in yeast

Beas’ goal was to untangle the metabolic pathways that lead to fat accumulation as yeast age. He genetically manipulated a wide array of genes to see which affected the yeast cells’ tendency to begin increasing their lipid content in middle age.

Through this, he first identified a gene, BNA2, that regulates the creation of NAD+, a cofactor involved in many metabolic reactions inside cells, from yeast to humans. It was a tantalizing hit: research by others has shown that NAD levels decline with age and suggested that increasing NAD+ levels could increase health span, the length of time an individual remains free of age-related diseases.

But the potential link between NAD, fat accumulation and life span quickly unraveled.

He created yeast that amped up their levels of BNA2. These yeast lived longer and didn’t accumulate much fat — but their NAD levels didn’t change.

“I was shocked,” Beas recalled. It didn’t make sense that the yeast lived longer without increasing their NAD levels.

Next, Beas began combining mutations of genes upstream and downstream of BNA2 to untangle the metabolic pathways that regulate lipid stockpiling and life span. He was able to find genes that affected lipid accumulation and life span independently — another surprise.

“I could find examples of cells where I can have [the yeast cells] accumulate fat but have extended lives,” Beas said. “I can also have cells with very little fat die sooner.”

Beas’ further work examining key metabolites suggests that the conundrum arises from the way yeast cells use glucose, or simple sugar. Glucose can fuel many a yeast cells’ metabolic processes.

“You have to use it to make energy for the cell, to make new cells, to replicate your DNA — all of that has to be powered by the sugar that comes in, or by the fat [stores],” Beas explained.

The sugar can be thought of as akin to a cadre of cars being carried on a ferry — once the ferry docks, the cars may travel the same road for a distance but quickly start turning off onto side roads with different destinations. In a cell, each of these side roads is a different metabolic process. This can explain why upregulating BNA2 increases life span while decreasing fat accumulation: sugar that generally would have gone down the road to become fat gets shunted into metabolic pathways that lead instead to increased longevity.

And NAD+ levels remain normal in cells with high BNA2, Beas believes, because this same sugar is getting rerouted to life span-enhancing pathways that branch off before the sugar gets turned into NAD. The extra sugar never arrives at this destination, and NAD+ levels remain unchanged.

“The ferry keeps coming in and delivering sugar. What do you do with it? [One road leads to] fat and the other one to NAD+. And something else [goes to] longevity. And that's what we're trying to figure out,” Beas said.

Fat protects against stress

After separating fat buildup and life span, Beas was left with a nagging question: Do the extra midlife lipids serve a purpose?

It turns out they do, at least for yeast. Beas exposed his genetically manipulated yeast to cold conditions — and received surprise No. 3. Fat protected them against stress: plump yeast survived, skinny yeast died.

Getting specific

There are many unanswered questions, Beas said. For one thing, he didn’t discover the sequence of metabolic reactions that lead to fat accumulation; he just knows that the metabolic pathway branches prior to NAD formation.

He’d also like to understand why, if the fat is so helpful, it only starts accruing in midlife. Why don’t young yeast need a buffer against stress? Or, if they have one, what prompts them to switch to fat later in life?

Beas would also like to get into the nitty-gritty of the interconnected metabolic pathways that regulate life span and health in yeast. If NAD isn’t affecting their life span, is there a specific metabolite that does?

All of these questions underlie Beas' overarching one: Is age-related fat always harmful? His yeast suggest it isn’t, it may not make much difference when yeast are living an easy life, but it appears that it provides a metabolic cushion when their lives take a nasty turn.

“So why does fat accumulate? Maybe it's to help you during stressful times when you're older,” Beas said, though he cautioned against extrapolating too far from yeast to humans.