Chronic inflammation is a very important downstream consequence of molecular damage in the progression of aging, arising from numerous causes. The past decade of work on the presence of lingering senescent cells in old tissues indicates that their signaling is significant cause. In animal studies, removing senescent cells can reverse the course of many age-related and other conditions that are primarily inflammatory in nature. Visceral fat tissue in excess amounts can accelerate the production of senescent cells, but it also generates inflammation through other mechanisms, such as debris from dead cells, signaling by non-senescent fat cells that resembles the signaling of infected cells, and so forth.
There are also numerous other contributing factors relating to the growing dysfunction of the immune system, or some of the metabolic issues that accompany excess fat tissue. The one examined in today's open access paper is the interaction of advanced glycation end-products (AGEs) with the receptor for AGEs (RAGE). There are a couple of different issues in aging, type 2 diabetes, and obesity relating to AGEs. The more interesting one for the SENS rejuvenation research community is the accumulation of persistent cross-links in the extracellular matrix formed from glucosepane; these cross-links degrade tissue elasticity, which in turn contributes to hypertension via arterial stiffening, among many other issues. However, there are many other short-lived AGEs that arise from the diet and from cellular metabolism, and which are particularly prevalent in the distorted metabolism of obese and diabetic patients.
These short-lived AGEs produce inflammation by overactivating RAGE; this mechanism has been fairly well studied in past years, particularly in diabetic patients. As the authors of this paper note, however, even well studied parts of human biochemistry have plenty of unanswered questions left for researchers to work on. As for a number of processes that may operate to a significant degree in both diabetes and aging, it is an open question as to the degree to which RAGE is important in purely age-related dysfunction, versus other mechanisms such as the accumulation of senescent cells. Older people tend to have more fat tissue, which obscures the matter.
In its full-length form the receptor for advanced glycation end products, RAGE, is a multi-ligand, transmembrane receptor promoting activation of key pro-inflammatory and pro-oxidative pathways. The deleterious effects of its activation via the binding of AGEs (the advanced glycation end products after which it is named) are widely reported, especially in diabetes mellitus. Indeed, our current understanding of RAGE relies heavily upon research on this metabolic disorder, but it is simplistic to apprehend this receptor solely within a diabetic context or through its interactions with AGEs. RAGE is more broadly implicated in both immunity and inflammation: more than 28 RAGE ligands are known, many of which are damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs).
RAGE can thus be more accurately considered a pattern recognition receptor (PRR), and has been labelled a "noncanonical Toll-like receptor (TLR)" by some authors. This wider involvement of RAGE signalling nevertheless remains poorly-studied relative to research involving diabetes and AGEs, but evidence is accumulating of its role in what has come to be known as "inflammaging". RAGE deletion has been shown to be protective against both cardiovascular disease and Alzheimer's disease in RAGE-/- mice, and while the impact of anti-RAGE therapeutics remains to be demonstrated in humans, laboratory results highlight the potential of targeting this receptor to address multiple public health issues.
RAGE has obvious similarities with other PRRs and there are acknowledged pro-aging mechanisms such as oxidative stress, mitochondrial dysfunction or inflammasome activation resulting from its interaction with several of its ligands. The concomitant, age-related increase of circulating DAMPs, and the expression of RAGE on many cell membranes, even in the absence of a pathological event, could favour low-grade, persistent, pro-inflammatory processes which in turn could drive increased production of DAMPs and expression of RAGE. This pro-aging vicious circle of events places RAGE firmly in the spotlight as a key-actor in inﬂammaging, not least because senescent cells also produce RAGE ligands like HMGB1 and S100s.
This hypothesis is attractive and opens up significant possibilities in the development of anti-RAGE therapeutics, but many questions remain. To what extent do the different RAGE ligands compete for binding, and how does this competition modulate its activation? Are the activated signalling pathways ligand-specific, or perhaps specific to the configuration of RAGE in its various forms? Are there negative effects to RAGE inhibition?