Ancient Viruses Could Help Explain Why Some People Live To Exceptional Ages

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Life expectancy in most developed nations hovers around 80 years, yet a rare group of people live significantly longer, into their 100s or 110s – a 25%+ increase over the population average. This exceptional longevity doesn’t seem to be entirely down to luck (though luck may play a role). There’s something special about this group, and many hope that studying them could unravel secrets about how we age and how human health and lifespan could be extended.

When looking for clues, the immune system isn’t a bad place to start. The immune system is thought to play an important role in the ageing process. With age, the immune system becomes increasingly dysfunctional, impairing its ability to clear both foreign pathogens and dysfunctional human cells like cancer cells. Immune dysfunction also results in chronic inflammation that damages tissues throughout the body and contributes to all manner of age related diseases, from dementia to atherosclerosis. Interestingly, people who have lived past the age of 100 often have less chronic inflammation than people many decades younger than them.

Now, in this recent study, researchers provide some fascinating insight into what might be different about long-lived individuals’ immune systems, and it involves ancient viral DNA embedded within our genomes.

HLA, A Universal Threat Detector

In the study, researchers looked at a protein group called human leukocyte antigen (HLA). HLA is expressed on the surface of most cells and is absolutely essential for the immune system to function. HLA proteins have three main functions:

• Allows immune cells to recognise which cells belong to the body and which do not. This is why organ transplants can be rejected – everyone’s HLA is slightly different, so immune cells are able to recognise that the donor organ is not ‘supposed’ to be there.
• HLA is able to bind to a wide range of pathogen-derived molecules called antigens. When a cell is infected by a pathogen, HLA molecules display its antigens to the immune system to indicate that they are infected and should be destroyed.
• Cells called antigen-presenting cells that detect the presence of pathogens use HLA to present their antigens to T and B cells, which initiates a specialised immune response that is tailor-made to target that antigen.

Now back to the study. Since everyone’s HLA is slightly different, a given individual’s HLA might bind more or less strongly to a given antigen than someone else’s. The researchers wanted to investigate whether the HLA of exceptionally long-lived people had some kind of advantage in this regard. To do this, they recruited nearly 1000 people from a wide age bracket (24 to 90+) and studied the genetic elements that encoded their HLA. They then used computer modelling to predict the binding affinity of these HLA molecules for various viral antigens.

The Discovery

The researchers found only one statistically significant relationship between age and antigen binding affinity, and that was for a virus called human endogenous retrovirus K (HERVK). They also identified 13 alleles (gene variants) that were significantly more common in those aged 90 and above, all of which predicted higher binding affinity for HERVK.

Why is this so interesting? HERVK is no ordinary virus, but rather the remnants of a family of ancient viruses that infected our evolutionary ancestors. Retroviruses are able to insert their own genetic material into the host’s DNA, meaning that each time that cell divides, both daughter cells also contain the viral DNA. But retroviruses sometimes infect germline cells (sperm and egg), causing portions of retroviral DNA to be passed on to an organism’s offspring. If that happens, then retroviral DNA can become a permanent feature of the species’ genetic code.

What does this have to do with ageing? Previous research has shown that in youth, this viral genetic material is locked away within compact DNA structures, preventing it from being read and used to make proteins. However, with age, HERVK sequences can become unlocked, resulting in the production of viral proteins. While these proteins can’t cause an actual viral infection, there is evidence that they can trigger inflammation, disrupt gene regulation and potentially contribute to some age-related diseases like cancer. There’s also some evidence from animal models that suppressing these proteins reduces the burden of senescent cells – non-dividing cells thought to play a role in the ageing process.

What Are The Implications?

The increased presence of these alleles among the oldest individuals suggests that endogenous retroviruses might be a limiting factor when it comes to exceptional longevity. Having HLA with a high affinity for HERVK antigens may allow the immune system to efficiently clear cells in which HERVK elements have become active, thereby reducing its damage.

That said, by no means does this fully explain why some people are able to live to 100 – it’s part of a much larger and very complex picture involving both genetics and environment. There’s not yet any evidence to suggest that suppressing HERVK in humans would improve lifespan at all. It does however raise the possibility of other important interactions between genetics, the immune system and the environment that we might be missing.