Advanced Glycation End Products

I have occasionally complained about my mother in law’s bland cooking methods.  Boiled this, steamed that.  How about a sauté?  How about frying something?  And yet, she is aging gracefully and the scientific evidence has begun to justify her insipid cooking.

A growing body of research shows that advanced glycation end products (AGEs) sit at the crossroads of metabolic dysfunction, chronic inflammation, and accelerated aging. They form when sugars bind to proteins or lipids through non‑enzymatic reactions, creating irreversible compounds that accumulate in tissues over time. High‑temperature cooking, processed foods, hyperglycemia, and oxidative stress all accelerate their formation.

How AGEs Form and Why They Accumulate

AGEs arise from the Maillard reaction—initially a browning reaction in foods, but also a slow, ongoing process inside the body. They come from two sources:

  • Exogenous AGEs
    from foods cooked at high temperatures (grilling, frying, roasting) and ultra‑processed products.
  • Endogenous AGEs
    generated in vivo, especially when glucose levels run high or oxidative stress is elevated. Oxford Academic

In humans, endogenous AGE’s predominate.  Exogenous AGEs from food matter too, but their impact is smaller and more modifiable.

Why AGEs Matter for Metabolic Health

AGEs are not passive byproducts; they actively disrupt metabolic homeostasis through several mechanisms:

  1. Chronic Inflammation via RAGE Activation

AGEs bind to the receptor for advanced glycation end products (RAGE), triggering inflammatory signaling cascades. This amplifies oxidative stress and promotes a persistent low‑grade inflammatory state—one of the hallmarks of metabolic syndrome.

  1. Impaired Insulin Sensitivity

By damaging insulin receptors and altering intracellular signaling, AGEs contribute to insulin resistance. High AGE levels are strongly linked to diabetes and its complications.

  1. Structural Damage to Metabolic Tissues

AGEs crosslink collagen and other structural proteins, stiffening blood vessels, impairing microcirculation, and disrupting extracellular matrix integrity. This affects adipose tissue remodeling, pancreatic β‑cell function, and vascular health.

  1. Mitochondrial Stress and Reduced Metabolic Flexibility

Oxidative stress induced by AGEs impairs mitochondrial function, reducing the body’s ability to switch efficiently between fuel sources—an early feature of metabolic decline.

  1. Acceleration of Age‑Related Metabolic Diseases

AGE accumulation is associated with diabetes, cardiovascular disease, kidney dysfunction, and neurodegeneration—conditions that share overlapping metabolic pathways.

The Dietary Connection: How Food Choices Influence AGE Load

Cooking methods dramatically influence AGE content:

  • High‑AGE methods:
    frying, broiling, grilling, roasting
  • Low‑AGE methods:
    steaming, boiling, poaching, slow‑cooking

Processed foods rich in sugars and fats are particularly dense in AGEs. Reducing dietary AGE intake has been shown to improve markers of inflammation and metabolic health.

Strategies to Reduce AGE Burden

Research highlights several interventions that meaningfully lower AGE accumulation:

  • Lower‑temperature cooking
    and moisture‑rich methods
  • Higher intake of antioxidants
    (fruits, vegetables, herbs) to counter oxidative stress
  • Increased dietary fiber
    , which improves glycemic control and reduces endogenous AGE formation
  • Regular physical activity
    , which improves glucose handling and reduces oxidative load
  • Limiting ultra‑processed foods
    and added sugars

Emerging therapies aim to inhibit AGE formation or block RAGE signaling, but lifestyle strategies remain the most accessible and evidence‑supported tools.

Glylo is one evidence based option to reduce the burden of AGE’s that’s commercially available.

The AgeProof Takeaway

AGEs are not just biochemical curiosities—they are active drivers of metabolic dysfunction and accelerators of biological aging. They damage tissues, amplify inflammation, impair insulin signaling, and undermine mitochondrial resilience. The good news: AGE burden is modifiable. Small shifts in cooking methods, food choices, and metabolic health behaviors can meaningfully reduce exposure and slow the metabolic wear‑and‑tear that AGEs impose.

What is the effect size of AGE’s?

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Transposons and Aging

Aging is often described as the slow accumulation of damage—oxidative stress, mitochondrial decline, epigenetic drift. But one of the most intriguing and increasingly central players in this process isn’t a metabolic byproduct or a failing repair system. It’s a piece of DNA that behaves like it still remembers being a virus.

These sequences are called transposable elements, or transposons. They make up nearly half of the human genome and are probably related to ancient retroviruses that have been fossilized into our DNA. For most of our lives, they sit quietly, locked down by epigenetic machinery. But with age, that lockdown weakens. And when transposons wake up, they cause trouble.  They trigger the manufacture of alien products and induce inflammation.

Understanding how and why this happens is opening a new frontier in longevity science.

What Exactly Are Transposons?

Transposons are DNA sequences that can copy and paste themselves into new locations in the genome.  They are present in all DNA based life forms and were originally described as “jumping genes” in corn plants, where transposons can make up the majority of genetic information.

As sequences of DNA, they hijack the cell’s own protein machinery, directing it to insert new copies of the transposon into fresh genomic territory. Sometimes these insertions land harmlessly. Other times they disrupt essential genes or regulatory regions.

Where did these sequences come from?

As mentioned above, the leading theory is that they are the fossilized remains of ancient viral infections.  Another theory is that they predate viruses and represent some genetic information that evolved because jumping genes confer a survival advantage–in addition to causing havoc, transposons have also been powerful engines of evolution, reshaping gene networks and creating new regulatory elements.  Indeed some organisms with an abundance of transposable elements do not experience reduced lifespans, so the narrative that they are necessarily harmful may be an oversimplification.

How the Body Keeps Transposons Contained

In early life, transposons are tightly suppressed. The genome is packaged so that transposon‑rich regions are buried in heterochromatin, a dense, inaccessible form of DNA. Epigenetic marks—methylation, histone modifications—reinforce this lockdown.  The result is a genome that is orderly, quiet, and stable. But epigenetic regulation declines with age and loss of tissue identity. As chromatin structure loosens and methylation patterns erode, the once‑silent transposons begin to stir.

Aging and the Awakening 

With advancing age, several things happen simultaneously:

  • Heterochromatin becomes patchy and disorganized
  • DNA methylation patterns erode
  • Histone modifications shift toward a more open chromatin state
  • Transposon‑silencing proteins decline in abundance and fidelity

This combination creates the perfect storm.  Transposons that were once locked away become transcriptionally active. They begin producing RNA and, in some cases, proteins capable of reinserting themselves into new genomic locations.

The Damage Isn’t Just Mutational—It’s Immunological

Transposon activity carries the risk of mutating important genes, and that does happen. But the more immediate and systemic threat is inflammation.

When transposons activate, they generate RNA and DNA fragments that look suspiciously like viral material. The cell’s innate immune system recognizes these molecules as foreign and launches an antiviral response.

This leads to:

  • Chronic interferon signaling
  • Activation of cytosolic DNA sensors
  • Inflammatory cascades that spread beyond the cell of origin (inflammaging)

In other words, the body reacts to its own genome as if it were under viral attack.

This contributes to the persistent, low‑grade, sterile inflammation—inflammaging—that disrupts tissue function across the body.

Some researchers now argue that this inflammatory signaling, not the mutational damage, is the primary way transposons accelerate aging.

The Epigenetic–Transposon Feedback Loop

One of the most striking features of transposon biology is how tightly it is intertwined with epigenetic aging.

  • Epigenetic drift → transposon activation
  • Transposon activation → inflammatory signaling
  • Inflammation → further epigenetic disruption

This creates a self‑reinforcing loop that pushes cells toward dysfunction, senescence, and immune activation. It’s a genomic version of a feedback amplifier: once the system destabilizes, the noise grows louder.

This loop may help explain why interventions that restore youthful chromatin structure—such as partial reprogramming—also suppress transposon activity.

Transposons sit at the intersection of several hallmarks of aging:

  • Genomic instability
  • Epigenetic alterations
  • Loss of proteostasis
  • Deregulated nutrient sensing
  • Chronic inflammation

They are active participants in the aging process and this makes them an appealing target for intervention. Strategies under investigation include:

  • Reinforcing heterochromatin structure (reprogramming)
  • Enhancing transposon‑silencing pathways
  • Dampening transposon‑triggered inflammatory signaling
  • Blocking reverse transcriptase activity

Reverse transcriptase inhibition is a plausible geroscience target.  Experiments on fruit flies have shown positive effects of treatment with the RT inhibitor lamivudine–increase in longevity and stress tolerance. But no randomized human trials have tested RT inhibitors as longevity or healthspan interventions.  RT inhibitors have well‑characterized toxicities (mitochondrial, metabolic, hepatic, bone), which are non‑trivial for long‑term use in otherwise healthy people.  That hasn’t stopped people from trying: in one phase 2 trial, patients with Alzheimer’s who were given RT inhibitors showed some improvement. 

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Why do we have to die?

If we are to understand aging, the primary question is why should there be aging and death in the first place?  Why is it almost universal in living organisms and what evolutionary purpose, if any, might aging and death serve?  First let’s clarify that I don’t have any formal education in evolutionary biology, I think it’s a fascinating field and I’m frustrated by my status as a dilettante.  Yet I proceed in the spirit of an amateur and offer my hypothesis.

Mainstream View

Established evolutionary theory holds that genes that lead to the death of an organism would not be adaptive, and so aging and death are not part of some program.  The current hegemonic aging theory is animated by the spirit that aging is a product of evolutionary neglect, not intent.

This is the theory of “accumulated mutations,” which holds that the organism accrues wear and tear from the processes of life, primarily genetic mutations that compromise function and lead to aging and death.  We know that this is true, that over time organisms show an increased burden of DNA damage.  This can happen because of errors in replication, it can happen from retrotransposons, or from free radicals, from radiation, toxins and all manner of other things.   DNA damage is posited to be one of the hallmarks of aging.

The cell can repair DNA mutations, and it has enzymes to do so, but this process is costly and to some extent the cell needs to balance repair-energy with growth-energy.  If an organism devoted all its energy to repair, it would not win the evolutionary battle against the organism who went all in on growth and early reproduction.  The growth-organism would die earlier but it would outgrow and outcompete the long-lived organism into extinction–it would probably physically eat it.  This state of affairs is referred to as “antagonistic pleiotropy,” meaning that survival to reproduction is prioritized by evolution and the very genes that improve survival to reproductive age will result in aging and death with the passage of time.  Or put differently, genes that code to preserve the organism do not improve evolutionary fitness.

Similarly, Medawar’s mutation accumulation theory holds that harmful genetic mutations that affect us late in life are weakly selected against, because most organisms in the wild die from predation, disease, or accidents before those mutations matter. Over generations, these late-acting mutations have accumulated, leading to functional decline in contemporary humans who no longer get eaten the wild with any regularity.

These theories suggests that death is a byproduct of evolutionary forces. It is not some program.  And yet I’m so tempted to think there is a program.   Take development:  we see that an organism develops according to a certain path.  Consider the well-worn path from embryogenesis through childhood and puberty.  Even our deterioration after the young adult phenotype is patterned–consider male pattern baldness.  These changes appear to occur as a non-random program.   There are few bald adolescents, after all.   I believe that aging is an extension of the same program as development (consider the Pacific salmon who swims upstream and suddenly dies) and this program has evolved for a specific reason:  a non-immortal population benefits because there are increased iterations of natural selection and therefore increased chance of developing evolutionary fitness to a particular habitat.

Finite lifespans can accelerate adaptation

And so that is my hypothesis: finite lifespans can accelerate adaptation. A population where individuals eventually die allows for more “generational turnover,” increasing the number of natural selection cycles and the speed at which the population adapts to its environment.  And this is “why” there is a program.

Consider two two heritable strategies in a sexually reproducing population, one with finite lifespan (Lf) in which individuals experience age related decline, and one with an immortal lifespan (Li) where individuals have negligible senescence and can reproduce for many more seasons.

In environments where change is rapid, such as the Cambrian explosion and the post-permian recovery, the early Cenozoic period and most recently, the Pleistocene epoch, there is accelerated evolutionary change.  This is shown in the fossil record.  Rapid evolution is advantageous during these periods of instability because organisms with accelerated evolutionary change will be better able to specialize to new niches and outcompete and displace those who evolve slowly.  My hypothesis is that Lf will outcompete Li during these key epochs.  The entire history of life is replete with countless epochs of violent change and it’s likely that as a result, organisms with Li have been largely eliminated.  This is why in nature, negligible senescence (hydra, some jellyfish) is exceedingly rare.

The program is part of development.  And the mechanism for the program is likely epigenetic.

Well, the question is what about the cheaters?  What I mean is, what about the mutation that codes for long life?  The thinking is that if there were some programmatic death, eventually some organism would develop the mutation to the program such that it lives much longer and thereby gains evolutionary fitness.  But what I’m saying is that this would need to be balanced against the evolutionary fitness accrued by shorter lifespans. In other words, whatever evolutionary benefit of more offspring accrued from longer life would be balanced by better evolutionary fitness from more cycles of natural selection due to shorter life.  So the cheater genotype ultimately loses out to the short lived genotype.

This is the end of my brief career as an evolutionary biologist.

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Why Nature Wants Us to be Fat by Richard Johnson

The two popular theories that purport to explain the obesity pandemic are the carbohydrate insulin model and the standard model of energy balance.  In Why Nature Wants Us to be Fat, nephrologist Richard Johnson bravely proposes another theory:  the survival switch.

In his formulation, nature has evolved a survival mechanism allowing organisms to rapidly gain weight in response to stress or in preparation for periods of scarcity.  It is meant to be turned on occasionally in response to adversity, but our food environment has interacted with our evolutionary biology to turn the switch on continuously, leading to widespread obesity.  The survival switch is mediated by the molecule fructose, and Johnson pins much of the blame on pervasive consumption of high fructose containing foods and beverages which were introduced in the 1970’s.  Fructose metabolism triggers an intracellular starvation type response in the liver that ultimately leads to leptin resistance and diminished satiety, which then causes persistently disordered appetite.  Fructose causes obesity not because of its caloric or nutritive value, but rather by hijacking appetite.  Sucrose too is implicated, as it is broken down to equal parts fructose and glucose.

The book impressively draws from biochemistry and clinical science as well as comparative biology, evolutionary science, bio-anthropology and paleontology to synthesize a coherent theory to explain our current global metabolic perdicament.  According to Johnson, a classic example of the survival switch is mammalian hibernation.  To take that example, in preparation for winter the bear markedly ramps up its consumption of fructose-containing blueberries in order to build fat stores, which become a source of both calories and water during its hibernation.  Similarly, birds often switch from insect diets to fruit and nectar-filled diets as winter approaches in order to gain fat.  In this way animal and fruit-bearing plant life are in seasonal harmony.

The fundamental issue is that fructose metabolism simulates an intracellular energy deficit in a dose dependent fashion by rapidly diminishing intracellular ATP by 20-60%.  As a result, appetite and fat deposition are stimulated.  Fructose is known to cause central leptin resistance by hypothalamic inflammation, which would naturally increase appetite.  Additionally, in the presence of fructose, saturated fats are particularly obesogenic.  Finally, mitochondria suffer oxidative stress because of fructose.

In the absence of fructose, other stimuli such as high salt, dehydration and umami (glutamate) can also trigger the survival switch by pushing conversion of glucose to sorbitol and then to fructose through the polyol pathway. High glycemic carbs will  increase fructose production as well, and this is probably the number one way in which people are exposed to fructose today outside of supplemented HFCS.

According to Johnson, animals are drawn to salt-licks because the salt triggers the conversion of glucose to fructose, which in turn helps them put on weight. To the extent that ultra-processed foods are formulated with high concentrations of salt and sugar, they are continually triggering this metabolic switch on a global scale.

Johnson suggests inhibitors of fructose metabolism would prevent the adverse consequences of the western diet and would by themselves prevent NAFLD.  There happens to be a number of Pharma groups working on fructokinase inhibitors.  Luteolin is a naturally occurring flavone that blocks fructose metabolism and has been associated with renal protection.

This is a fascinating book by a researcher who has stature and standing in the field, but his identification of the survival switch as the cause of the majority of  maladies afflicting mankind gives pause.    Yet the theory is cohesive, supported by empirical evidence and powerfully explains much of our current predicament.  I am swayed.

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Muscle, Protein and Aging

Muscle is a metabolically active tissue that plays a central role in health and longevity.  Beyond functional roles such as helping one get up from a chair, going up stairs and avoiding falls as we age, muscle accounts for 75% of glucose disposal and makes the greatest contribution to resting energy expenditure of any tissue in the body.  For these reasons, we need to be mindful of preserving our muscle mass if we are to age well.  Unfortunately, it becomes harder to maintain (let alone build) muscle as we get older.  There is evidence of anabolic resistance in the elderly, a barrier to building muscle, and it is not uncommon for the elderly become sarcopenic.  Sarcopenia (from the Greek “loss of flesh”) can be a tremendous burden on geriatric populations and is the leading cause of frailty and deterioration.  What follows is a discussion of muscle metabolism that owes a debt of gratitude to the food industry scientist Don Layman and also to a review article by Tezze et. al.

Protein
The main drivers of muscle synthesis and retention are resistance exercise and to a lesser extent, protein intake.   But what kind of exercise?  And what kind of protein?  And how much?  And when?

Not all protein is equal.  

  • Protein is made of amino acids, some of which are categorized as essential because they cannot be manufactured by our body and must be consumed.
  • The essential amino acids are: histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine.
    • Leucine in particular is thought to be a notable driver of muscle protein synthesis
    • Leucine is also a primary driver of the enzyme mtorc1, which is thought to advance the ticking of the clock (aging).
  • Proteins differ in their amino acid composition and degree of binding / accessibility.
  • All essential amino acids are derived from bacteria.
    • Plants will absorb them as part of their root system to incorporate into plant protein.
    • Ruminative animals like cows have nitrogen fixing bacteria in their stomachs that very efficiently convert plant protein in grass / grain to essential amino acids, accounting for the high protein of herbivores who themselves consume very little protein.
  • Typically, meats and fish have a complete assortment of essential amino acids that are easily accessible for use in the body.
  • Plants are often deficient in various essential amino acids and plant protein is more likely to present difficulties with extraction. They have a lower protein digestibility corrected amino acid score.
      • DIAAS is the digestible indispensable amino acid score.
      • To take an example, whey protein, a byproduct of cheesemaking, is 20% better than a soy protein isolate on the basis of its essential amino acids
  • This doesn’t mean that plant protein is not good for you.  Scientists like Walter Longo suggest that low protein / plant based diets throughout life may limit inflammation and slow the ticking of the clock.
  • The case of frailty / sarcopenia is a separate issue considered below.

Muscle Homeostasis

  • Muscle tissue is in a constant state of turnover characterized by rates of muscle protein breakdown and muscle protein synthesis.
  • The relationship of building muscle tissue to fostering longevity is seemingly paradoxical.  On the one hand, having muscle mass is good for aging and associated with less frailty.  On the other hand, it requires the anabolic activation of mtorc1, which is a driver of aging and frailty.  How do we reconcile these realities?
    • Muscle protein breakdown is inhibited by insulin, which is the body’s main anabolic hormone.
    • Beyond that, muscle protein synthesis is more heavily regulated and amenable to modification, typically stimulated by agents that increase the activity of mtor, which is believed to accelerate aging. We know that branched chain amino acids such as leucine drive mTORC1 and drive muscle growth.
    • Yet ITP studies in mice suggest L-leucine enriched diets reduce lifespan (ITP 2017) and chronic activation of mTORC1 stimulates progressive muscle damage and loss. Moreover, inhibition of mTORC1 with rapamycin prevents age-related muscle loss (1).
  • The resolution of this paradox is lies in the complexity of muscle homeostasis and the mTORC1 enzyme and there are various explanations.  Some authors (1) have suggested that Akt dependent activation of mTORC1 prevents muscle atrophy whereas Akt independent pathways will induce muscle atrophy, largely mediated by mitochondrial oxidative stress.  Others (2) have suggested that mTORC1 inhibition rejuvenates muscle stem cells by preventing senescence.

Another way of looking at this issue is to consider the essential amino acid leucine, which is a relatively muscle-specific activator of mtor.  Insulin on the other hand activates mtor in a range of tissues.  What this means functionally is that people who eat a lot of small carbohydrate meals, each of which leads to the secretion of insulin, continuously activate mTOR and drive anabolic pathways / aging across tissues.  This is probably the worst-case scenario and a real justification not to snack.   On the other hand, infrequent / periodic high protein meals with large leucine loads will stimulate muscle growth while reducing broader mtor activation associated with snacking.  Does this mean there is no role for carbs in the diet?  Of course, not, but that is a matter for another time.

Timing of protein consumption—is it better to spread your intake across the day or consume the bulk of your protein in one or two meal?

  • To build muscle you need large individual servings of protein.  Muscle anabolism is not stimulated until you have a significant ingestion. Muscle tissue senses the concentration of amino acids in the blood that serve as a signal that a meal has adequate quality for muscle to trigger the very expensive process of protein synthesis.
  • Protein should be front loaded in the day, ~30g for breakfast to interrupt overnight catabolism and then at dinner to forestall overnight catabolism. Ideally, we pair this with some resistance activity.
  • For the rest of your physiological needs (cardiac, liver, etc.), you don’t need large individual servings.
  • This is not true for kids—their muscle growth is more insulin oriented. They can use protein regardless of the absorption schedule.

Exercise and muscle

  • Resistance exercise is a necessary co-factor for muscle growth along with protein.
    • Resistance exercise stresses the muscle, disrupting homeostasis and leading to protein turnover. With protein turnover, there is protein misfolding, leading to endoplasmic reticulum stress.
    • ER stress leads to the activation of the “integrated stress response” a signaling pathway whose goal is to restore muscle homeostasis.
    • How? via upregulation of ATF4, which controls LARS, a leucine sensor.  Clearly more complicated than this, but here’s your broad outline.
  • Exercise induces both hyperplasia and hypertrophy of muscle fibers. In other words, it increases both the number of fibers and their size.
  • Exercise enhances the ability of the muscle to take-up more amino acids from the bloodstream, and this effect lasts multiple days.

Protein as a diet food

  • Protein is also the most satiating food.
  • It also has a higher thermogenic effect (burns more calories) than either carbs or fat. So eating protein it increases energy consumption.
  • Hi protein percentages during dieting preserves muscle mass.

Protein use / reversing catabolism with age

  • As we get older, our ability to use protein is diminished, referred to as “anabolic inflexibility.”
  • This is partly due to diminished physical activity with age, but also because of features intrinsic to the muscle tissue.
  • This anabolic resistance can be largely overcome by increasing protein intake.  Yet you also need resistance–it doesn’t matter how much protein you consume if you don’t also engage in some degree of muscle exercise. You need both.
  • Older adults need more protein.  There are varying recommendations between, 1-1.5 mg/kg/day (3), keeping in mind that not all protein is created equal.
  • Plant or animal protein?  In one recent prospective cohort study from Hong Kong, older patients who ate plant protein were less likely to develop sarcopenia than those who ate animal protein whereas those who ate predominantly animal protein were more effectively rescued from sarcopenia.
  • Beyond driving muscle synthesis, certain branched chain amino acids found in animal sources such as isoleucine and isoleucine may actually drive mtor and accelerate aging.  In which case, in the setting of tonically activated mtor (middle/old age), a diet high in protein from vegetable sources makes most sense.
  1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738401/?fbclid=IwAR3vAqW1MLIF-kY1utROauhs2i8xHFSlqjeL95SRN02Cdgoif-FW1PWXw0c
  2. https://www.mikhailblagosklonny.com/blog/how-rapamycin-prevents-muscle-loss-and-sarcopenia-first-draft/
  3. https://pubmed.ncbi.nlm.nih.gov/24039411/
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