Fight Aging!

Today I'll point out a review article that laments the present state of progress towards the control of inflammation in the human body. While acknowledging that great strides have been made in ways to interfere in inflammatory signaling, benefiting many patients, present tools are crude in comparison to the technologies that will most likely be needed in order to truly control unresolved, chronic inflammation and eliminate its contribution to age-related disease. True control of inflammation would imply the ability to (a) trigger resolution mechanisms with specificity, avoiding impairment of the operation of inflammation where it is needed, or at least (b) remove the lion's share of the causes of chronic inflammation. Both seem tall orders, but one or both must be achieved.

The reasons why old tissues generate inflammation are manifold. One of the better understood mechanisms is the presence of growing numbers of senescent cells, actively secreting pro-inflammatory cytokines. Further, the microenvironment of aged tissue contains damage-associated molecular patterns of various sorts, produced by stressed or dying cells, and which are a trigger for innate immune system overactivation. Visceral fat tissue is particularly at fault when it comes to ways in which cells can provoke the immune system via signals that are close enough to those produced during infection to rouse an inflammatory response. There are many distinct paths to inflammation, which makes controlling even a majority of them a daunting process. Hence the hope for some smaller set of points of intervention, perhaps to be found in the master regulators of inflammatory behavior that react to these diverse signals.

Nonresolving inflammation redux

A review in 2010 entitled "Nonresolving Inflammation" began, "Perhaps no single phenomenon contributes more to the medical burden in industrialized societies than nonresolving inflammation." That view has not changed. In 2021, a leading thinker in the field wrote that "inflammation is associated with almost every major human disease". That same year, 13,905 review articles flagged "inflammation" as a key word and 1,284 of them included "inflammation" in their titles. This not only reflects that the topic is important but underscores that we are struggling to get a grip on it.

Since 2010, the toll of inflammation on human health has not subsided, despite major advances in understanding of the underlying biology, the tireless efforts of drug developers, and the clinical success of several interventions, such as biologics that block signaling by interleukin-1β (IL-1β) or tumor necrosis factor-α (TNF-α) have driven the death toll from nonresolving inflammation to the highest level in the lifetime of anyone reading these words. Meanwhile, the striking but partial success of immuno-oncology has focused attention on the ability of intra-tumoral inflammation to either frustrate or assist the immunological control of cancer. Accordingly, efforts to resolve inflammation as a treatment for autoinflammatory and autoimmune diseases have been joined by efforts to modulate inflammation in the treatment of malignancies.

Despite an extensive preclinical and clinical anti-inflammatory pharmacopoeia, as yet there is no drug that abolishes nonresolving inflammation in the majority of people treated, in the sense that patients remain free of inflammation when they stop taking the drug. There is no single drug that benefits a substantial proportion of those treated for nonresolving inflammation no matter which inflammatory disease they have. Few drugs that afford substantial benefit by strongly mitigating nonresolving inflammation are free of the risk of major toxicities. There is no way short of clinical trials to establish which of the diseases that nonresolving inflammation underpins will be most responsive to a given anti-inflammatory agent. We do not have a non-empirical basis for rationally designing combination anti-inflammatory therapies.

Despite these challenges, there is reason for optimism. Earlier clinical advances have been stunning, among them the impact of antagonists of IL-1β and TNF-α on autoinflammatory diseases, rheumatoid arthritis, and inflammatory bowel disease. The marked increase in basic research into inflammation gives hope for a knowledge roadmap that will identify practically actionable, highly effective, and safely addressable pathogenic pathways for patients suffering from atherosclerosis, obesity-related metabolic syndrome, asthma, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, scleroderma, non-alcoholic steatohepatitis, Alzheimer's disease, multiple sclerosis, and other diseases in which nonresolving inflammation plays a major role.