Longevity Briefs: Why Don’t The Oldest Old Get Autoimmune Diseases?

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Some people are able to live 25-50% beyond average human life expectancy. In the UK, your chances of living to the age of 100, making you centenarian, are about 1 in 100 if you’re a man and 3 in 100 if you’re a woman. The odds are low, but research suggests that more than luck is involved. Many organ systems in centenarians appear to be biologically younger than we might expect, and centenarians somehow manage to dodge age-related chronic conditions that most people develop decades earlier. One such condition is autoimmune disease. While not all autoimmune diseases are caused by ageing, we do know that changes in the immune system during ageing make autoimmune disease (as well as many other diseases) more likely. Despite this, reports of autoimmune disease among centenarians are very rare. Why? This article discusses the evidence and theories surrounding this question.

The discovery:

The authors cover 5 hypotheses that could explain why centenarians don’t appear to get autoimmune diseases:

• Less inflammation: As we age, we suffer from increasing levels of chronic inflammation that has been termed inflammageing. This low level of inflammation inflicts damage on our tissues and increases the risk that our immune system will falsely recognise our own native molecular patterns as a hostile threat, resulting in an autoimmune response. Studies suggest that compared to other older adults, centenarians have lower levels of certain inflammatory molecules. The ratio between inflammation-promoting T cells and inflammation-suppressing T cells (known as regulatory T cells) also appears to be smaller in centenarians. 
• Less immunosenescence: Immunosenescence refers to the general decline of the immune system during ageing, which includes a reduced production of T and B cells (the ‘precision weapons’ of the immune system, able to recognise and attack specific pathogens without much harm to human tissues). At the same time, levels of inflammation increase. This makes older people more vulnerable to infections and to autoimmune diseases. Centenarians still suffer from immunosenescence, but their immunosenescence may have specific characteristics that allows them to maintain more appropriate immune function than their peers. 
• Avoiding or resisting hyperstimulation: One theory is that centenarians have managed to limit their exposure to environmental factors that overstimulate the immune system. Frequent infections or exposure to pollutants, for example, may repeatedly activate the immune system. The more often the immune system is activated, the more likely it is that a native molecule will be falsely identified as part of a pathogen. Alternatively, it’s possible that genetic factors protect centenarians from hyperstimulation.
• Better proteostasis: Proteostasis can be summarised as the accurate production of proteins and their subsequent maintenance, as well as the destruction of damaged and misfolded proteins. Proteostasis deteriorates with age, resulting in the accumulation of ‘molecular junk’ like the amyloid protein hypothesised to be involved in neurodegenerative disease. This junk leads to chronic inflammation as cells try and fail to break it down, while the immune system attacks cells that have become overwhelmed with damaged proteins. Centenarians may be gifted with more faithful translation of the genetic code into proteins. According to the previous theory, they may also be exposed to fewer environmental factors that might cause protein damage. 
• Protective gene variants: Research has shown exceptional longevity to be associated with certain gene variants, mostly those linked to cell division and those affecting inflammation (like APOE, of which the e4 variant greatly increases the risk of Alzheimer’s disease).

The implications:

Many are hopeful that studying centenarians can teach us why these people are able to evade age-related diseases for so long, and perhaps allow others to do the same. Others are more sceptical, suggesting that centenarians are rare outliers whose path to longevity is not accessible to the rest of us. We do know that being a centenarian has a large hereditary component, so lifestyle factors alone will not allow the average person to replicate the successful ageing of the oldest old. We still don’t understand exactly how autoimmune diseases are triggered, let alone how centenarians are able to avoid them. Based on what we do know, we might make a guess that limiting unnecessary stimulation of the immune system in adulthood (such as from repeated exposure to pathogens or pollutants) and limiting sources of inflammation and oxidative stress would reduce the risk of autoimmunity in old age.