Inflammation is Still Poorly Understood in Comparison to its Importance in Aging

Many researchers investigate inflammation, but like everything involving the immune system it is a very complex collection of processes, yet to be fully understood, and especially in the role it plays in degenerative aging. The greater the capabilities of modern biotechnology, the more details of molecular biology become visible for scientists to catalog and puzzle over: the deeper they look, the more there is to find. Here I pick one paper out of many - a look at the JAK-STAT signaling pathway in the context of inflammation in nervous system tissues - to illustrate this point.

Numerous age-related diseases count chronic inflammation as a factor contributing to pathology: think of it as a source of cell and tissue damage, even where the link isn't as direct and well understood as is the case for atherosclerosis, to pick an example. Even if you manage to evade all of the common ways to inflict significant additional unnecessary inflammation upon yourself - smoking, chronic injury, a sedentary lifestyle, and perhaps most significantly excess visceral fat tissue - your immune system still steadily malfunctions with advancing age. You're better off for being a fit, thin, non-smoker, but only better off, not immune. Your immune system falls into a state in which it is both ineffective and chronically overactive, and this and its consequences are given the name inflammaging.

If you read around the subject you'll see that enough is known to paint defensible summaries regarding inflammation and the activity of the immune system, but you don't have to wander far beyond the outline to find yourself off the maps and into unknown or hotly debated territory. This is one of the reasons why I favor work on comparatively simple engineering approaches to near-future treatments for immune aging, such as targeted destruction of memory T cells, or complete destruction and recreation of the immune cell population, or regeneration of the thymus. These strategies avoid the need to gain a far greater knowledge of immune system organization before producing new therapies. Gaining that knowledge is proving to be costly and slow, and while it will be needed for meaningful progress in the treatment of some autoimmune conditions such rheumatoid arthritis, the the more direct approaches noted above offer an alternative path with a shorter time to clinical application.

It is interesting that this team has focused on the JAK-STAT pathway in the context of nerve tissue and inflammation, as their research must have overlapped that of another comparatively recent discovery related to this pathway. In that other work, scientists showed that interfering in the JAK-STAT pathways can restore stem cell activity in aged muscle tissue, and via processes that don't immediately seem to be much related to inflammation.

Control of Inflammatory Responses: a New Paradigm for the Treatment of Chronic Neuronal Diseases

The term 'inflammation' was first introduced by Celsus almost 2000 years ago. Biological and medical researchers have shown increasing interest in inflammation over the past few decades, in part due to the emerging burden of chronic and degenerative diseases resulting from the increased longevity that has arisen thanks to modern medicine. Inflammation is believed to play critical roles in the pathogenesis of degenerative brain diseases, including Alzheimer's disease and Parkinson's disease. Accordingly, researchers have sought to combat such diseases by controlling inflammatory responses.

We identified Janus kinase-signal transducer and activators of transcription (JAK-STAT) as a new inflammatory signal in the brain and showed that its inflammatory signals can be activated by LPS, IFN-γ, gangliosides and thrombin. The receptor activated by these ligands or cytokines phosphorylates JAKs, leading to the phosphorylation (i.e. activation) of STAT molecules. Activated STATs form dimers and translocate to the nucleus, where they act as transcription factors; they induce the expression of inflammatory genes that have STAT-binding sites in their promoter regions, thereby activating subsequent inflammatory responses. Because the JAK-STAT pathways mediate the actions of numerous growth factors and cytokines, their negative feedback pathways are well developed and tightly regulated. The endogenous negative feedback molecules include phosphatases and inhibitory proteins, such as the suppressor of cytokine signaling (SOCS) proteins. Because the individual SOCS family proteins regulate different molecules of the JAK-STAT signaling pathways, we could possibly use them to specifically or synergistically control different JAK-STAT pathways. Indeed, the anti-inflammatory properties of many clinically available drugs, including aspirin, are mediated via SOCS proteins. Thus, it is particularly interesting to consider the development of additional SOCS-targeting drugs.

Despite years of research, inflammatory responses and the mechanisms underlying the actions of anti-inflammatory drugs remain to be clarified. Current studies in the field of immunology are expected to provide new insights into inflammation responses, inflammation-regulating drugs, and the relevant control mechanisms. Some antibodies and drugs used in clinical practice are capable of directly targeting specific signaling molecules/receptors. In the case of anti-inflammatory drugs, however, most such specific targeting therapeutics have been used only casually or experimentally.

Detailed information is now being obtained regarding the pharmacological actions of typical non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and steroids. If we hope to effectively regulate inflammation for the treatment of diseases, the mechanisms responsible for controlling the inflammatory response need to be firmly established. We should also seek to better understand the cause-and-effect relationships between inflammatory responses and the progression of related human diseases. Given that inflammatory/immune responses are physiological phenomena that can provide protection or cause damage, their therapeutic modulation must be precisely controlled in quantitative, qualitative and temporal terms. Improper control could compound the disease processes or cause a new disease. Thus, additional research is warranted to improve our understanding of the inflammatory response.

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