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.

The Role of Advanced Glycation End Products in Aging and Metabolic Diseases: Bridging Association and Causality

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.

Comments

Aubrey de Grey has been teasing Revel's launch for what seems like 2 years now.

If glucosepane does even half of what is suspected, I hope I can buy some enzymes to cut it one day soon, and I hope it makes my skin (and everyone else's) look more youthful.

Posted by: Jim at September 14th, 2018 6:52 PM

So as far as I can tell the only substances proven to break AGE's dont break the main AGE which is glucosepane

Rosemarinic acid for instance will break multiple AGEs but not glucosepane. So currenly we know of no substance to consume that will break glucosepane. If this is incorrect please let me know.

Also, does the Maillard reaction always produce AGEs when cooking meat? Its the Maillard reaction that gives burgers that nice crispy skin. Or is it the sugar in the BBQ sauce that creates the AGEs in BBQ meats?

And why is olive oil so high in AGEs?

Posted by: Phoebus at September 14th, 2018 8:20 PM

@Jim
A nicer skin is superficial, just skin deep ;) . While having better blood vessels, reversed presbyopia, and better kidney/liver/muscle function will literally save lives.

Posted by: Cuberat at September 14th, 2018 8:47 PM

I would rather be healthy inside but look not so good on the outside than the alternative although having both would be best (ah youth, I should have embraced it when I was young). That is one reason I will not touch steroids.

Posted by: Robert at September 14th, 2018 9:59 PM

Hi there, just a 2 cents,

Some AGEs inhibitors:
- carnosine
- benfothiamine
- thiamine
- b6, all b vit.
- pepper/piperlongumine/capsaicin and pretty much any other herb/plant/spice (oregano, parsley, ginger, cinnamon, ginkgo, ginseng, thyme, mint, clove, green tea camelia etc)
- rosmarinic acid/carnosic acid from rosemary is a potent lipid peroxidation inhibitor, and AGEs also, it compares to carnosine or Trolox Vit. E alpha-tocopherol, it's better than BHT (butylhydrotoluene) food preservative, a poison added to keep food from spoiling (it's found in over 50% of all foods plastic wrappings in groceries), when fed to mice it causes DNA damage in their cells.
- carnitine/raspberry ketones/ketonic diet
- berry fruit polyphenols, from cyanins (blue food), carotenoids (red food), chlorophylls (green food), xanthines/limonenes (yellow/orange), and other flavonoids.
- cinnamon is the best insulin sensitizer, cinnamaldehydes and hydroxycinnamates/cinnamic acids behave like insulin and potently sensitize pancreatic beta-cells to secrete insulin; in turn reducing blood glucose and thus, blood glycation, glycoxidation and AGEs formation, specifically HbA1c (glycated hemoglobin in the blood).
- Of all the herbs I took, I feel, along cinnamon; ginkgo biloba deserves top place. It is filled with terpenes, bilobalides and other components. Resveratrol, trans stilbenes, or quercetin don't take its place, we have to remember that ginkgo biloba trees are ancient, and have negligeable senescence - they live 700 years or more. Not so surprisingly, ginkgo and great basin bristle cone pines (lives 5000 years) share the same pathway allowing their extreme lifespan : they produce continuous telomerase in the trunk and roots, while storing tons of resistant starch to grow new branches and keep growing/age. Telomerase is not enough for humans, still studies demonstrated telomerase activation by herbs, like ginkgo, ginseng, astragalus. Plus, studies showed that ginkgo improves brain function the best, it boots neurogenesis via BDNF, slows Alzheimer's onset by blocking protein aggregation clumping and amyloid formation. Bilobalides increase the replicative lifespan of human fibroblasts.

None of them stop glucosepane crosslinks formation, and MMPs (matrix metalloproteinases) enzymes can't degrade it.

But the more important question is how much or how bad is it, I believe glucosepane is low 'cumulative' product of AGEs processes but is Not the be all end all, it's contribution is more cosmetic (pun intended), inflammation wise, it would contribute to ECM degeneration and break down, which does speed up aging - ECM maintenance is very important for longevity. It ties with cartilaginous, filamentous, fibrous, interstitial tissues, fleshy layers and vasculature. Evolution optimized two specific mechanism in long-lived critters, namely ECM construction and mitochondrial membrane lipid reordering. These two 'updates' allowed animals to live for centuries long. It's certainly not antioxidants it updated nor DNA repair (DNA repair is on average pretty much equal all over the board, the Large differences are maintenance/preservation without more repair and susceptibility to mitochondrial ROS)..

Also, it's not AGEs we should be most concerned with, but ALEs instead. ALEs (Advanced Lipoxidation Products) are orders of magnitude more concerning, and damaging, because they are the culprit that Evolution optimized via mitochondrial lipid reordering. Mitochondrial lipoperoxidation and lipoxidation, cause massive destruction on macromolecular level. Analogy : a fire, you want the flames to be bigger, you throw a TNT dynamite stick in it... the flames burst into a huge fiiery bombastic mushroom. ALEs and mitochondrial peroxidation-prone lipids' fatty acids are that analogical figurative TNT dynamite. Everyday, every hour, every second, the cells are bombarded by fig. 'TNT'..

@Phoebus

Hi Phoebus! Just a 2 cents. Pretty much yes, some foods resis this though, mostly because they produce flavonoids 'in compensation' for the rising oxidative stress caused by heat stress/thermal cooking, it is the same thing as skin melanogenesis to protect against excess UV rays (skin pigmentation 'barrier'/pigment shield to block UV rays from entering skin ECM layers). There is a tipping point, where the food's flesh starts 'browning', Maillard Reaction, formation of AGEs create this. The difference is that 'tanning/bronzing' is different than the 'browning', tanning is a natural response by pigmentation melanogenesis to void UV rays. While, browning is AGEs formation that gives this 'sweet golden' bake taste, taste sweet but is poison, AGEs are poison for you. What is conderning with BBQ 'browning' 'baking' 'charring' 'crispy' look is Acrylamides, they are volatile products created by this charring of food when BBQing. They are toxic, (you guessed it). Try avoiding burgers and meat consumption (I have not eaten Any meat in years.. it is not needed, but eat what you wish, centenarians ate tons of crispy fried BBQ meat and made it to a 100 (albeit, they are a very small minority, the 99% percent of Other people die from these diets and it shortens lifespan for them, not everyone has centenarian lucky family genetics that protect them). Olive oil may turn rancid, MDA and AGEs will form in it over time and in its shelf life, regular olive oil is not extra virgin olive oil, the cold pressed method of olive oil extraction from olives. It may be subject to industrial 'expeller' type extraction that is not best, not only that, regular olive oil has lost most of its polyphenolic content during industrial extraction or it was purposely removed, kind of like 'bleaching' or 'pasterizing'. All these polyphenols gone from the oil means that the oil will turn rancid quicker; because, by having lost its natural polyphenolic content, the oil has no more antioxidative power to counter oxidation and rancidity over time. Polyphenols in Extra Virgin olive oil are what protect it and gives you its benefits, over regular generic olive oil.

Just a 2 cents.

Posted by: CANanonymity at September 15th, 2018 1:12 AM

I will not be surprised at all if dietary AGEs are eventually shown to have little direct connection with levels of intracellular AGEs, in mammals. I recall the assertion -- which turned out not to be so clear -- that dietary cholesterol directly increased serum cholesterol levels.

Posted by: cacarr at September 15th, 2018 9:29 AM

Having all this discussions shows that the glucosepane is a very plausible source of problems. So, before we start trying gettint rid of it, we should have good ways to measure the concentration of glucosepane that is not in the cross-links yet, and the cross-links that are due to Glucosepane and the ones that have further due to different reasons. Then we could do studies to measure the correlation between the glucosepane concentration and the level of cross-links versus various cardiovascular diseases and conditions. Than we can measure the effects of various interventions like diet change, supplements and anti-glucosepane enzyme s.

Posted by: Cuberat at September 15th, 2018 9:52 PM

@CANanonymity

You have listed interesting and plausible. Do you happen to have a blog or wiki where you systemize it?

Posted by: Cuberat at September 15th, 2018 9:55 PM

Hi Cuberat! Thanks for that, (no I don't. It's all 'in the head' from memory and making compilatory comparison, conjecture and résumés).

@CD

Hi CD! Just a 2 cents. That's mostly true, skin is a large organ, and is 'in general' close surrogate of age in other internal organs.
Certain organs, or specific 'locations' in an organ can show accelerated or deccelerated aging compared to surrounding organs/tissue, and as shown in DNA methylation epigenetic clock studies can be Older or Younger than the surrounding ones;
generally, there was a 0 to 15 year difference in very rapidly organs vs regular speed (meaning that, for example, your stomach could be biologically/epigenetically older than your liver - you could be someone who is 44 years old (chronologically in real time/real life) but your stomach is 57 years old biologically by DNA epigenetic clock; while your liver is 39 years old biologically)). In general, in healthy people, the in between organ age gap is small, so is aging speed rate between organs, pretty much equal and constant; while in chronically unhealthy (over long term) people, they show more variance and larger in between organ age gaps, and aging speed gaps. Inflammation targets specific organs and (sub) sub-specific locational compartments. Thus, it is not 100% balance and equal all over, but in healthy people, it's pretty close to being so, and why, one day much older, one 'specific epigenetically older/damaged dysfunctional ' organ 'will let go' before the others (if a vital one, killing you unless replaced with functional unrejected real or synthetized mechanical artificial organ clone transplant).

If your skin is young looking, a good sign of 'overall' health but is not 100% accurate of 'total' combined average biological age from all organs tallied up and averaged for a 'whole' 'sum age',
Loss of collagen in type I n agingskin is major skin aging event, and roughly correlates to total biological age of individual.
Loss of skin elasticity, plumpness (plump 'baby skin') equals collagenous scaffold depth that includes hyaluronan, deccan, and other skin ECM (extra cellular matrix) elements that 'hold' the scaffold together. Skin biological age can be measured by SSS (subsurface scattering) gradient illumination caused by light rays penetrating skin depth layers and 'scattering ' in them; causing the radiant glow/glowing soft plump baby skin (due to collagen type I amount and qualitative state). If you have a 'baby face' with young tight skin (not sagging, but form fitting to skull bones elastic rebounding), then you have a good chance of being internally biologically younger than your chronological real age.

Just a 2 cents.

Posted by: CANanonymity at September 16th, 2018 11:12 AM

re: supplements - taurine is another one, apparently quite beneficial to diabetics
~
Will age-breakers restore the extracellular matrix to its youthful state after gravity has done its work to stretch out elastin? The elasticity of arterial walls should be restored after treatment, but if they are still stretched out, there may still be issues with gene expression, as cellular deformation causes gene expression changes.

Posted by: CD at September 16th, 2018 11:15 AM

@CANanonymity
Oh, I agree - you can look young without necessarily having all your other tissues in a particularly youthful state (but it is unusual to be an a diseased state and still look good). As I mentioned in another post Liz Parrish may look radiant because of her gene therapy treatments, or she may owe her youthful appearance to some really good topicals.

OTOH, I think it would be hard to imagine an effective rejuvenation treatment that didn't have a beneficial effect on skin aging / outward appearance. I can image, though, a rejuvenation therapy or set of therapies that would work on most aspects of aging while not fully addressing brain aging - and that would be a problem.

As an aside, I'd like to point out the importance of the skin as an organ; it is our first line of protection from the rest of the world. I've noticed my wound healing slowing over the years and it is more than an annoyance. Diabetics of course have awful problems with ulcers and slow wound healing; the advanced elderly often have problems with pressure ulcers which are reportedly quite painful.

Posted by: CD at September 16th, 2018 11:42 AM

"nice looking" (e.g. sexually attractive) is defined by smooth, unblemished skin, good muscle tone, and being height-weight proportional. The last and to a large degree, the second, is 100% under individual control as we speak. Naturally, anti-aging treatments that restore youthful molecular biology and physiology ought to restore skin elasticity and smoothness.

Posted by: Abelard Lindsey at September 16th, 2018 9:32 PM

I think there is a lot of guilt shaming and talking down to middle aged and older people who express sorrow at the loss of sexual attractiveness which comes with aging. Its similar to the argument that we shouldn't rejuvenate old people because "they have already had their share".

But this kind of economic attitude assumes that their some some kind of pie for each good like wealth, health, youth, income, and that this pie can't be grown at all.

Sure if you said to me - you've got to choose between being healthy enough on the inside to reach LEV, or healthy and youthful looking on the outside but with aged innards, I'd choose the later. But is that option even realistically on the table?

Also I think a sea change in public attitude towards rejuvenation biotechnology will only happen when they are shocked that someone they meet or see on TV is much much older than they assumed.

Leafscience wrote a good article on this:

https://www.leafscience.org/is-the-preservation-of-beauty-as-we-age-just-vanity/

Posted by: Jim at September 17th, 2018 1:58 AM

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.