A Discussion of the Role of Inflammaging in Age-Related Frailty

Immune system dysfunction is an important component of age-related frailty, not just because of an increased vulnerability to infection and cancer, but also because the immune system falls into a state of chronic inflammation. It is overactive and ineffective at the same time, and this inflammation produces widespread dysfunction in tissues and processes throughout the body. This state has been given the name inflammaging. Here, researchers discuss inflammaging in the context of frailty in older individuals. It should go without saying that new therapeutic approaches that are able to restore correct immune function in the elderly will go a long way towards improving health and extending healthy life span. Developing such therapies, such as regrowth of the thymus, restoration of hematopoietic stem cells, regeneration of lymph nodes, and clearance of damaged immune cells, should be a higher priority than is presently the case.

Increasing attention has been paid to frailty as a potential explanation of the health diversity found in the elderly. Although a clear definition is still lacking, frailty is commonly understood as a geriatric state associated with increased vulnerability to internal and external stressors resulting from a significant loss of physiological reserve. Described as a disorder of multiple inter-related physiological systems, frailty is characterized by sedentariness, fatigue, weight loss, and poor muscle strength, and it increases the risk of adverse outcomes. However, frailty is a dynamic process that may be delayed or even reversed.

Several pathophysiological factors, including dysregulation of inflammatory processes, oxidative stress, mitochondrial dysfunction, and cellular senescence, underlie the frailty syndrome, and it is also influenced by many other factors, such as sociodemographic characteristics, psychological conditions, nutritional status, lack of physical activity, and comorbidities. However, is not clear what drives frailty and little is known about the risk factors that contribute to the development of the syndrome. Genetic differences together with environmental factors can contribute to the dysfunction of physiological mechanisms associated with frailty, leading, in turn, to the dysregulation of multiple systems, including the immune system. Furthermore, diet has been proposed to be a key element in the development frailty. Low intake of certain micronutrients and protein is associated with a higher risk of developing frailty.

Aging of the immune system leads to a low grade, chronic systemic inflammatory state, dubbed InflammAging, and it has been suggested that there exists a relationship between changes in inflammatory molecule levels and diseases and syndromes typical of old age. The InflammAging inflammatory phenotype is characterized by elevated inflammatory molecule levels, and associated with increased morbidity and mortality in older adults. It is suggested that InflammAging is a systemic physiological process that may involve one or several organs, leading to an increased risk of age-related chronic diseases and frailty. More recently it has been speculated that InflammAging is a dynamic auto-inflammatory process that can be amplified and propagated to neighbouring and distant cells and organs, thus accelerating and expanding aging processes both locally and systemically.

Furthermore, the concept of anti-inflammation, understood as an active phenomenon, has also been introduced. The rising levels of pro-inflammatory molecules in aging stimulate an increase in levels of anti-inflammatory mediators, serving to neutralize the dangerous inflammatory processes. The balance between inflammation and anti-inflammation has been suggested to determine the rate of aging, the onset and severity of age-associated disorders, and the individual's ability to achieve extreme longevity.

In conclusion, with study of the frailty syndrome still in its infancy, frailty analysis remains a major challenge. It is a challenge that needs to be overcome in order to shed light on the multiple mechanisms involved in the pathogenesis of this syndrome. Although several mechanisms contribute to frailty, immune system alteration seems to play a central role: this syndrome is characterized by increased levels of pro-inflammatory markers and the resulting pro-inflammatory status can have negative effects on various organs. Future studies should aim to better clarify the immune system alteration in frailty, and seek to establish exactly when the inflammation appears.

Link: https://doi.org/10.1016/j.arr.2019.100935

Comments

Approximately 42% of the human genome consists of repeats of retrotransposons that are maintained in an inactive state by DNA methylation. With aging, these repeats are hypomethylated, which has been known since the 1980s. (Романов, Г. А., & Ванюшин, Б. Ф. (1980). Внутригеномная специфичность метилирования ДНК у животных. Тканевая разнокачественность и изменение метилирования повторяющихся последовательностей при старении, канцерогенезе и гормональной индукции. Молекулярная биология, 14(1-3), 357-362).
This causes transposons (and in particular LINE-1 (long interspersed nuclear element-1)) to be activated. LINE-1 in turn drives Interferons in senescent cells and promotes age-associated inflammation. https://doi.org/10.1038/s41586-018-0784-9
Reverse transcriptase inhibitors specific for mammalian LINE-1 retrotransposons, such as lamivudine and GBS-149, prevent LINE-1 from multiplying and thus reduce inflammation. However, this is not enough - InflammAging still develops due to the activation of the remaining hypomethylated transposons. Obviously, in order to prevent the development of InflammAging, it is necessary additionally to restore the young methylation level of LINE-1 DNA globally. CRISPR/dCas9 DNA methylase can do this. And it should be checked in the near future.

Posted by: Dmitry Dzhagarov at July 31st, 2019 9:41 AM

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