Our immune system can turn on us with age

We spend most of our lives thinking of our immune system as our personal security guard. It fights off viruses, bacteria, and anything else that doesn’t belong. But as it turns out, the very thing that protects us might also be helping us break down as we age.

A recent study sheds light on how our immune system pulls this off – and it starts with a surprising source of power: proteins that can snap together in a split second to launch an attack.

The immune system and age mechanisms

When a virus sneaks into your body, the immune system doesn’t waste time. Cells pick up the warning signs and switch into defense mode, triggering a chain reaction: inflammation, cell death, and a full-on alert to the rest of your body.

Behind this fast response are proteins lying in wait inside cells. They sit in huge numbers – more than the cell even needs – storing energy until a tiny signal sets them off. Once triggered, they fold into complicated 3D structures that lock tightly together.

“Like the striking of a match to produce a flame, our immune cells, which are found throughout our body, must undergo a large and irreversible response when encountering a tiny stimulus like a single molecule of viral DNA,” said Randal Halfmann of the Stowers Institute for Medical Research, whose lab led the study.

“Specific proteins within these cells that can quickly assemble are the death decision makers, and the process of their assembly is the decision for the cell to die. We are beginning to think that this may be one of the fundamental mechanisms of why we age.”

Proteins acting like batteries

The research team studied more than 100 human proteins with what’s called a “death fold domain” – a feature that allows them to snap together when needed – and tested their behavior using yeast cells.

“There are always more than enough of these proteins available to assemble in our cells, which allows the cell to rapidly respond to a threat,” said Alex Rodríguez Gama, who led the study.

“This protein overpacking or ‘supersaturation’ is biology’s equivalent of a battery, storing energy until it is needed to boost a signal that warns the body of an invasion, activating an immune response and inflammation.”

Rodríguez Gama explained that a microscopic signal can tap into the battery’s energy storage to suddenly form a very stable protein assembly and fight infection.

The immune system tradeoff with age

This speed comes with a price. With so many proteins ready to assemble, the chance of one snapping together by accident increases over time. The longer a cell lives, the more likely this random activation becomes.

“As we age, it’s inevitable that a death fold domain protein in a cell – if that cell lives long enough – will eventually change shape even in the absence of an invader, triggering protein assembly, cell death, and inflammation,” Halfmann said.

“It is a ‘Catch 22.’ Essentially, we are trading longevity for an immune system, or the greater certainty of life right now at the expense of potential longer life.”

According to Rodríguez Gama, the findings provide insight into the mechanism of how inflammation can first start and what happens as we age, which can help to identify new ways to address inflammation associated with infection and aging.

Reducing the risk of disease

Researchers are now exploring whether it’s possible to stop the body’s defenses from turning against us.

“Inflammation is one of the major features of many of the diseases that are presently incurable – Alzheimer’s, Parkinson’s, most of the diseases associated with aging, and some cancers – but it starts within individual cells,” said Halfmann.

“If we could reduce the probability of inflammation by perhaps removing some of those puzzle pieces or reshaping them so they can’t assemble, then we might be able to block the inevitability of inflammation, and with time, develop ways to decelerate some of these diseases.”

Halfmann noted that while slowing or stopping the puzzle assembly could possibly increase susceptibility to pathogens, perhaps some patients would be willing to accept that risk.

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