Fight Aging!

Today's open access paper presents an interesting discussion of the apparent lack of age-related autoimmunity in centenarians. The immune system becomes ever more dysfunctional with age, and some of that dysfunction can take the form of maladaptive changes that either (a) allow the immune system to direct attack tissues or (b) disrupt important relationships between immune cells and the rest of a tissue. Far from all of these issues are well understood or even well identified as discrete problems distinct from the rest of degenerative aging. A potential type 4 diabetes was only comparatively recently discovered, for example.

The oldest of old people tend to be robust in comparison to age-matched peers who die at younger ages. In one sense this is self-evident, as they would have to be robust in order to avoid a higher risk of mortality that would lead to an earlier death. In another sense, it is interesting to examine the physiological and biochemical details of this robustness. That said, centenarians are rare survivors from a very large birth cohort, and it doesn't take much of a change in the odds of survival over decades of later life to tilt the characteristics of centenarians in one direction or another. Thus it isn't clear that discoveries made in long-lived people actually have much practical application to medicine; they may largely represent only small gains.

Still, as asked by the authors of today's paper, why is it the case that age-related autoimmunity seems absent from the oldest segment of the population? Is this actually an absence, or a case of too little examination of the fine medical details in these usually frail individuals? If it is an absence, what does that say about the function of the immune system in late life, and the details of the role of immune system alterations, damage, and adapative and maladaptive changes in age-related mortality?

Autoimmunity in centenarians. A paradox

Autoimmune diseases (ADs) constitute one of the most prevalent chronic conditions. During the aging process and through continuous exposure to various stressors, pathogens, and other environmental factors throughout life (i.e., exposome), accompanied by the aging of the immune system (i.e., immunosenescence) and the onset of age-related chronic diseases, a persistent proinflammatory systemic environment theoretically increases the probability of developing an AD. This is because the immune system's responsiveness would be lower and irregular when exposed to a greater number of stressors and causes of cellular dysregulation. For this reason, age has been considered to be an important risk factor for autoimmunity.

Aging implies a complex array of changes and remodeling in homeostatic mechanisms that control the immune system, both in terms of numbers and functions of the different cellular subsets. Rather than being a mere process of immunosenescence, age-related transformations redesign the immune architecture and the balance between proinflammatory and anti-inflammatory protective factors. Cellular senescence occurs in response to endogenous and exogenous stresses, including telomere dysfunction, oncogene activation, and persistent DNA damage. Immunosenescence includes three events: a reduction in immune response, an increase in the inflammatory and oxidation background (inflammaging and oxiinflammaging), and a production of autoantibodies.

However, there is a group of humans, increasingly observed, that contradicts this paradigmatic view, and whose health phenotype raises numerous questions for which there are currently no answers. Centenarians represent the most successful model of biological aging in humans. These individuals, who have a chronological age equal to or greater than 100 years, have special health characteristics, mostly partially known, that contradict the previously described theoretical concept of autoimmunity in the elderly.

Unfortunately, there is a lack of robust evidence describing or discussing autoimmunity in centenarians. Even studies describing the health phenotypes of centenarians worldwide report that the prevalence of ADs in this population is practically nil, except for some series mentioning imprecise data and methodology. Therefore, this field represents a niche of original, novel, and relevant knowledge for the in-depth understanding of new pathophysiological mechanisms, protective and risk factors for autoimmunity, based on the identification of new markers, signaling pathways, and targets related to aging, adaptation, or remodeling of the immune system. Herein we discuss current questions and gaps regarding the understanding of autoimmunity in centenarians, proposing possible hypotheses that would explain this scenario.