Fight Aging!

Raised levels of chronic inflammation play an important role in degenerative aging, as well as in many medical conditions. Much of this inflammation in aging is driven by systemic changes, as it is very similar in every individual: it is partly a consequence of the evolved limits of the immune system when operating over a long period of time and faced with the presence of persistent pathogens like cytomegalovirus that cannot be permanently cleared from tissues. There are of course numerous other mechanisms at work, and the big picture is still being filled in by ongoing research - a lot of the immune system remains poorly understood. One way of looking at the evolution of biological systems is that they tend to be optimized for survival during youth at the expense survival at later ages. Reproductive success is the primary measure of selection, and this seems to product outcomes such as an adaptive immune system that is highly effective at birth, yet runs off the rails after being exposed to too many diverse threats, or even a single persistent viral threat it cannot deal with, such as herpesviruses, HIV, or similar.

In recent years the characteristic age-related malfunctioning of the immune system has come to be called inflammaging as researchers explore its details. The immune system even considered portion by portion is immensely complex, and so is the character of the inflammatory response, especially when it becomes harmful. Inflammatory contributions to various medical conditions, aging included, can be spurred by many different mechanisms. Immune activity is regulated and influenced by numerous genes and proteins, and so naturally many research groups are attempting to catalog this space in order to find the basis for potential treatments to suppress inflammation, or better, ways to exert more sophisticated control over inflammation.

One gene of particular interest of late is NLRP3, a part of the inflammasome of the innate immune system. Here are a couple of recently published research results relating to this narrow slice of the broader field, one of which identifies a mechanism triggered by activities that reduce inflammation while the other is news of a possible new drug aimed at roughly the same area.

Anti-inflammatory mechanism of dieting and fasting revealed

The compound β-hydroxybutyrate (BHB) directly inhibits NLRP3, which is part of a complex set of proteins called the inflammasome. The inflammasome drives the inflammatory response in several disorders including autoimmune diseases, type 2 diabetes, Alzheimer's disease, atherosclerosis, and autoinflammatory disorders. "These findings are important because endogenous metabolites like BHB that block the NLRP3 inflammasome could be relevant against many inflammatory diseases, including those where there are mutations in the NLRP3 genes."

BHB is a metabolite produced by the body in response to fasting, high-intensity exercise, caloric restriction, or consumption of the low-carbohydrate ketogenic diet. It is well known that fasting and calorie restriction reduces inflammation in the body, but it was unclear how immune cells adapt to reduced availability of glucose and if they can respond to metabolites produced from fat oxidation. Working with mice and human immune cells, researchers focused on how macrophages -- specialized immune cells that produce inflammation -- respond when exposed to ketone bodies and whether that impacts the inflammasone complex. The team introduced BHB to mouse models of inflammatory diseases caused by NLP3. They found that this reduced inflammation, and that inflammation was also reduced when the mice were given a ketogenic diet, which elevates the levels of BHB in the bloodstream.

Scientists uncover marvel molecule that could lead to treatments for inflammatory diseases

Researchers showed how the molecule MCC950 can suppress the 'NLRP3 inflammasome', which is an activator of the key process in inflammatory diseases. Inflammasomes have been identified as promising therapeutic targets by researchers over the last decade. And now the discovery of MCC950's abilities represents a hugely significant development in the effort to find treatments for inflammatory diseases, for which current therapies are either highly ineffective or have major limitations. "MCC950 is blocking what was suspected to be a key process in inflammation. There is huge interest in NLRP3 both among medical researchers and pharmaceutical companies and we feel our work makes a significant contribution to the efforts to find new medicines to limit it."

So far, the results have shown great promise for blocking multiple sclerosis in a model of that disease, as well as in sepsis, where in response to bacteria, potentially fatal blood poisoning occurs. However, the target for MCC950 is strongly implicated in diseases such as Alzheimer's disease, atherosclerosis, gout, Parkinson's disease and rheumatoid arthritis, which means it has the potential to treat all of these conditions.

Reading between the hype there, it sounds like the next generation of anti-inflammatory treatments for various conditions will probably be an incremental improvement over the present state of the art, which is much as one would expect. At some point the methods of tinkering with the controlling signals may become useful enough to apply to the common processes of inflammaging that occur in every older individual, though this is a very top-down, messing-with-metabolism approach. If not addressing the underlying causes for increased chronic inflammation, even sophisticated means of suppression are just papering over the real issue. Lowering the rate at which some tertiary damage occurs by suppressing some secondary damage doesn't tackle the primary damage, which remains to grow as the root causes of all degeneration and dysfunction - so benefits from this approach to therapy will by necessity be limited.

This unfortunately describes the majority of modern medicine when it comes to age-related disease, and is why it is very important for the research and development community to unite behind the new approach of treating the mechanisms of aging as the cause of age-related disease. No more patching, and much more going after root causes should be the name of the game. Ultimately medicine for aging should consist of forms of repair for the damage that lies at the base of the pyramid of consequences: that is the place where the lion's share of the effort should be directed if we want to see real progress.