A View of Advanced Glycation End-Products that is Primarily Inflammatory
In the materials noted here, a Buck Institute researcher puts forward a view of just one side of the science of advanced glycation end-products (AGEs) and their role in degenerative aging. AGEs are sugary metabolic byproducts of many different varieties, both present in the diet and generated in the body. In the view of AGEs and aging expounded here, near all of the many types of AGE are important, most are transient and levels will vary in response to day to day circumstances, dietary intake of AGEs probably has a significant negative influence on long-term health, and AGEs present in tissues disrupt metabolism by hammering on a set of receptors that trigger chronic inflammatory signaling and a range of other inappropriate cellular behavior.
This leads to proposals for interventions that run along the lines of eating a better diet, finding ways to block the interaction between AGEs and receptors such as RAGE and RANKL, and so forth. If successful, these approaches could be expected to slightly slow the pace of aging, largely via reduced levels of chronic inflammation. It isn't an unreasonable viewpoint: the evidence for AGEs to cause inflammation is fairly robust; the involvement of RAGE is well demonstrated; inflammation does indeed accelerate the progression of all of the common age-related diseases. The question of whether or not dietary intake of AGEs is important in comparison to the creation of AGEs in the body can be debated. It is hard to separate this one potentially negative contribution to health from the many others associated with the sort of sugary, fatty diet that is high in AGEs.
All of this, however, is just the one side of considerations of AGEs and aging. In the materials here there is no mention of the other side, which is that in humans, the overwhelming majority of persistent cross-links formed by AGEs involve glucosepane rather than any of the other varieties of AGE. So when it comes to damage to the material properties of the extracellular matrix, leading to structural change in skin and blood vessels due to loss of elasticity, or structural change in bone and cartilage due to loss of tensile strength, only one type of AGE really counts. In this view of AGEs and aging, the vast majority of short-lived AGEs ebb and flow, while age-related degeneration is driven by the glucosepane AGEs that persist to shackle molecules of the extracellular matrix to one another, weakening and stiffening tissues.
A key challenge in this area of research is that the important classes of persistent AGEs and cross-links are completely different between mammalian species, and hence (a) past attempts to remove cross-links failed to translate from mice to humans, while (b) the ability to work with glucosepane at all was only developed comparatively recently, as this compound isn't a focus for groups working primarily in mice, and (c) ongoing work on AGEs in short-lived species is of little relevance to cross-links and aging in humans. That said, give it another five to ten years or so and I'd imagine we'll have solid evidence to back a declaration regarding which of these views of AGEs is the more important in aging. Glucosepane cross-link breaker development at the Spiegel Lab and elsewhere has been nearing the leap from laboratory to startup company for a few years now. If the Buck Institute is signaling interest in the other side of the AGE field, then approaches on that side of the house may also start to emerge in the near future.
Advanced Glycation End Products As Drivers of Age-Related Disease
An inevitable by-product of metabolism, advanced glycation end products (AGEs) are toxic molecules formed when proteins, DNA, and fats become bound after exposure to sugar. They are also in some of the foods we eat. Some Buck Institute researchers think the research community has neglected the importance of AGEs because they are challenging to study. Now they are on a mission to get scientists to focus on them as a driver of many age-related diseases. AGEs affect nearly every cell type and our bodies have inherent defense mechanisms that can clear them. But the production of AGEs really ramps up when blood sugar is high, and eating a typical high-carbohydrate, highly processed Western diet can overwhelm those natural defenses. Further, some of us are likely to be genetically prone to develop more of them, no matter what we eat.
AGEs make our cells old before their time, and over time the molecules accumulate in our tissues. The AGEs cause chronic inflammation, make proteins lose their shape, and send our metabolism into a sugar burning state, making it hard to lose weight. To make matters worse, the molecular damage from AGEs is irreversible. AGEs contribute to obesity and metabolic syndrome. They've long been implicated in insulin-resistant type 2 diabetes and are linked to its complications. In addition, AGEs are now seen as potential players in neurodegeneration. Recent findings associate AGEs with familial, early-onset and sporadic forms of Parkinson's disease, and with proteins linked to Alzheimer's disease. In one study, plaques extracted (post-mortem) from brains of patients with Alzheimer's show a 3-fold increase in AGEs content compared to age-matched individuals who died from other causes. AGEs are even found in cataracts.
The chemistry behind the formation of AGES was discovered in 1912 and an AGEs-based theory of aging was proposed more than three decades ago. Interest in the then red-hot field flagged when a drug designed to clear AGEs in diabetic kidney disease failed in clinical trials in 1998. But it's nearly impossible to study the biological development of AGEs and their implications in humans because they take decades to accumulate and there are obvious ethical concerns in encouraging the development of the toxic molecules in test subjects. So how to get researchers excited about understanding and exploiting the biology of AGEs?
The Buck Impact Circle, a donor group that pools its resources to support collaborative early-stage research at the Institute, has chosen to fund many projects involving AGEs. In addition to supporting research on the complications of diabetes and the link between AGEs and Parkinson's disease, the group has also funded projects aimed at determining if a ketogenic diet can protect against the complications of diabetes. This year they put their money toward research that tests compounds that show promise in lowering AGES associated with Alzheimer's disease pathology.
Accumulation of advanced glycation end products (AGEs) on nucleotides, lipids, and peptides/proteins are an inevitable component of the aging process in all eukaryotic organisms, including humans. To date, a substantial body of evidence shows that AGEs and their functionally compromised adducts are linked to and perhaps responsible for changes seen during aging and for the development of many age-related morbidities. However, much remains to be learned about the biology of AGE formation, causal nature of these associations, and whether new interventions might be developed that will prevent or reduce the negative impact of AGEs-related damage. To facilitate achieving these latter ends, we show how invertebrate models, notably Drosophila melanogaster and Caenorhabditis elegans, can be used to explore AGE-related pathways in depth and to identify and assess drugs that will mitigate against the detrimental effects of AGE-adduct development.