Zinc Pyrithione Reduces Shedding and Moderately Promotes Hair Growth

Zinc Pyrithione Reduces Shedding and Moderately Promotes Hair Growth
Zinc pyrithione is found in some anti-dandruff shampoos (Photo by Andy Houghton)

I've written a couple of posts on the hair growth promoting effects of Nizoral, but ketoconazole isn't the only proven anti-dandruff ingredient in shampoos that is claimed to grow hair. In this post, we'll review the evidence behind something that's been available for a long time but deserves a closer look: zinc pyrithione.

The most famous product containing zinc pyrithione is probably Head & Shoulders, but there are numerous different shampoos out there with the same active ingredient. A bit of Googling comes up with readily available products such as John Masters Organic Zinc and Sage shampoo, and prescription-only products like Dan-gard A-D. As long as the product contains 1% zinc pyrithione (the amount used in the studies), it probably doesn't matter much which one you choose.

Zinc pyrithione and dandruff

The epidermal layer of the scalp renews itself constantly by pushing old cells outward where they eventually die and flake off. Normally this process takes about a month. In people with dandruff, however, these cells are shed in a matter of days, resulting in visible white flakes.

In the old days, it was thought that dandruff is caused by the fungus Pityrosporum ovale (now known as Malassezia furfur), which occurs naturally in the skin. However, it was later discovered that the cause of dandruff was in fact Malassezia globosa, a fungus found only in scalp skin.

Although the real cause of dandruff was not known at the time, a few decades ago zinc pyrithione was found to effectively reduce dandruff after just three uses (link). Several studies have since shown similar results.

Zinc pyrithione vs. ketoconazole vs. piroctone olamine

These days, getting rid of dandruff is the easy part. In fact, there are several good choices for the job, and zinc pyrithione isn't even the best one. In most studies ketoconazole and piroctone olamine seem to do somewhat better. Even natural products like tea tree oil or other essential oils with anti-inflammatory and antibacterial properties seem to help many people.

But what about fighting hair loss? Whereas the evidence behind tea tree oil is shaky at best, ketoconazole has actually been shown to improve male-pattern baldness. The trouble with Nizoral is that it can dry the scalp if used very often, so accompanying products can be useful.

Zinc pyrithione to the rescue: to my knowledge there are two papers that looked at whether it also has hair growth promoting activity. In the first study, zinc pyrithione was compared against ketoconazole and piroctone olamine. 150 men with androgenic alopecia and dandruff were given one of the three shampoos (each containing 1% of the active ingredient) and told to use the product 2-3 times a week for six months (link).

All treatments reduced dandruff significantly. Hair density was unchanged after 6 months, but hair shedding decreased (ketoconazole: -17.3%, piroctone olamine: -16.5%, zinc pyrithione: -10.1%) and the percentage of hairs in anagen phase increased (ketoconazole: 4.9%, piroctone olamine: 7.9%, zinc pyrithione: 6.8%).

The effect on mean hair diameter was less uniform: ketoconazole and piroctone olamine showed increases of 5.4 and 7.7%, respectively, while zinc pyrithione actually decreased hair diameter by 2.2%.

Zinc pyrithione vs. minoxidil

The second paper compared the effect of zinc pyrithione and minoxidil on hair density (link). The duration of this study was the same as before, but this time 200 participants with male pattern baldness were enrolled. A quote from the full paper:

The mean age of the patients in this study was 40 years. Patients were predominantly (97%) caucasian. The majority of patients presented with type III vertex baldness at the baseline visit. The remainder had type IV. About half reported losing hair for less than 10 years. For almost half balding began in their late 20s or earlier.

The subjects used either a 1% zinc pyrithione shampoo (Head & Shoulders) once daily, 5% minoxidil (extra strength Rogaine) twice daily, a combination of both, or a placebo. The results were measured at weeks 9, 17 and 26.

Minoxidil alone increased hair density at all three measurements. At week 9, there was an increase of ~14% in hair counts per cm^2 compared to the placebo; after week 26, the difference was ~12%. Thus, the subjects using Rogaine saw an increase in hair counts rather quickly and maintained it for at least six months.

The group using zinc pyrithione saw an increase of ~5% after 9 weeks and ~6% after 26 weeks in hair density compared to placebo. In other words, the number of hairs was increased and maintained with Head & Shoulders also, albeit only about half as effectively as with Rogaine.

Oddly enough, the combination of minoxidil and zinc pyrithione gave a good result at the first measurement but a worse one at the end of the study. After 6 weeks, the increase in hair density was ~12% compared to placebo, but after 24 weeks the difference was only ~6%. Although the subjects using the combination still had more hairs than the placebo group, the trend is a bit worrying.

Mean hair widths generally decreased in all groups, with zinc pyrithione being no more or less effective than the placebo. In the minoxidil groups, hair width decreased but slightly less than in other groups. In other words, hairs get thinner in androgenic alopecia with time, and minoxidil can slightly slow down the progress while zinc pyrithione apparently can't.

Conclusion

In addition to its anti-dandruff action, zinc pyrithione has been shown to modestly increase hair growth. In the first study, hair shedding decreased by ~10% and the percentage of hairs in anagen phase increased by ~7%. Hair density was unchanged and hair thickness decreased by ~2%. In the second study, hair density increased by ~6% and hair thickness was not different between the zinc pyrithione and placebo groups.

So what might explain the differences between the two studies? First, although the duration of the experiments was the same, in the second study the shampoo was applied daily, whereas in the first one it was used 2-3 a week. This could explain why hair density was not increased in the first study; perhaps daily use is needed.

Furthermore, in the second study hair thickness was slightly reduced but only when compared to baseline. Compared to the placebo group, there was no difference. In the first study, no placebo group existed, so the reasonable conclusion is not that zinc pyrithione reduces hair thickness but rather that it does not counteract the effect of alopecia on thinning.

In general, zinc pyrithione seems to be somewhat effective in promoting hair growth. Still, ketoconazole and minoxidil came out on top when the three were compared. Ketoconazole is also more effective in reducing dandruff than zinc pyrithione (link). Since daily use of ketoconazole is too harsh for most people, combining or rotating the two may be the best option (link).

For more information on hair growth, see these posts:

Hair Growth with Ayurveda – The Nutrich Oil Experiment
Eclipta Alba Extract Grows Hair Quicker than Minoxidil
2% Nizoral Shampoo Increases Hair Growth in Men with Male Pattern Baldness
Emu Oil and Hair Growth: A Critical Look at the Evidence

Dietary Supplement Increases Lifespan by 11% in Healthy Mice

When will they start serving anti-aging cocktails in bars?
When will they start serving anti-aging cocktails in bars? (Photo by fanfan2145)

Declining physical activity with aging is seen in almost all species – just think of how much more active kids are than elderly people. This decline contributes to things like metabolic syndrome and frailty in old age. More importantly, life is less enjoyable in general when you're physically unable to do the things you could when you were younger.

To some degree, this process can be slowed down by physical activity itself. People who exercise tend to be more physically fit than people who don't. Nevertheless, no matter how active you are, the decline can only be postponed, not completely prevented. To retain our youthful vigor indefinitely, scientific breakthroughs in regenerative medicine are needed.

And yet, anything that is postponing the inevitable at this point might just prove to have been postponing what is evitable in the future. Stay healthy and stick around long enough and you might just see those breakthroughs happen in your lifetime. That's why anything that gives us even a few extra years of healthspan should be warmly welcomed.

Many people who are proponents of exercise are skeptical of using dietary supplements to increase healthspan, and rightly so: there is little if any evidence to show that popping a generic multivitamin will do any good. But what about a supplement that has a more scientific basis to it? A new study shows that a dietary supplement containing readily available ingredients ameliorates locomotor, neurotransmitter and mitochondrial aging in mice (link). It also modestly extends their lifespan.

Study design

The dietary supplement was developed with five factors related to aging in mind: oxidative stress, inflammation, mitochondrial function, insulin resistance and membrane integrity. A slurry of the supplement was soaked onto pieces of bagel and then given to normal mice and transgenic growth hormone mice (which show accelerated aging compared to normal mice). Here's the ingredient list:











































IngredientMg
Bioflavonoids7.93
Vitamin A (beta-carotene) 0.22
Vitamin B1 0.31
Vitamin B3 0.31
Vitamin B6 0.61
Vitamin B9 0.006
Vitamin B12 0.02
Vitamin C 3.51
Vitamin D .0002
Vitamin E 3.27
Rutin 3.05












Chromium picolinate 0.003
Magnesium 0.46
Manganese 0.19
Potassium 0.18
Selenium 0.0005












Acetyl L-carnitine 1.47
Alpha-lipoic acid 1.83
Aspirin 1.32
Coenzyme Q10 0.61
Cod liver oil 12.20
Flax seed oil 12.20
Garlic 0.04
Ginger root extract 6.00
Ginkgo biloba 0.18
Ginseng 6.31
Green tea extract 4.88
L-Glutathione 0.31
Melatonin 0.007
N-acetyl cysteine 3.05


The amounts of ingredients in the original data are given in "mg/day/100 mice"; presumably all the treated mice were allowed to eat from the same food lot, which would mean that the amount of ingredients eaten varied between mice. I've divided the numbers by a 100 here to show the average amount for each mouse. You can get the original data from the link to the study if you need it.

Effect on activity levels

According to the authors, when the untreated normal mice reached 24 months of age, their physical activity levels had dropped by more than half. The untreated normal mice are represented by the second line from the top (and I may be missing something here, but it doesn't seem like the decrease is over 50% in the graph
still, a significant drop). Normal mice given the supplement, on the other hand, were almost as active in old age as in young ages.

dietary supplement and effect on physical activity
As you can see, the transgenic mice (represented by the two bottom lines) showed much lower activity in general than the normal mice, which is to be expected. In the untreated transgenic mouse group (the first line from the bottom), activity was pretty uniformly low with not much further decline from aging. In younger transgenic mice (the second line from the bottom), the supplement clearly increased activity, but by the time they reached 13 months, they were as inactive as the untreated group.

According to the authors, exercise duration generally declined with age, but remained higher in supplemented normal mice across all ages. Bouts of intense activity decreased with age even in these mice, but this was offset by increases in moderate activity.

Effect on protein carbonyls

Protein carbonyls, a marker of oxidative damage, correlate negatively with cognitive skills and activity levels. Protein carbonyl levels were lower in the brains of supplemented mice than in untreated mice. Although this kind of damage tends to correlate well with aging (link), the number of protein carbonyls in the brain did not increase with age in either group of normal mice. In transgenic mice, supplementation resulted in a non-significant trend for reduced carbonylation.

Mitochondrial protein carbonyls increased with aging in normal mice. Young normal mice had only 34% of the mitochondrial carbonyls seen in old normal mice, and supplemented normal mice had only 64% of the carbonyls seen in untreated normal mice. In untreated transgenic mice, protein carbonyl levels were the highest, while in supplemented transgenic mice they were the lowest of all four groups. For some reason there appears to be U-curve in the level of protein carbonyls in transgenic mice, with young and old mice showing higher levels than middle-aged mice.

The fact that the dietary supplement reduced protein carbonyls in the brain and mitochondria means that it was able to cross the blood-brain barrier and mitochondria. These are considered key goals of aging interventions. Indeed, supplemented normal mice had an 11% increase in lifespan. The authors think of this as a modest increase and suggest that the increases in physical and mitochondrial activity are the reason the mice didn't live even longer. I'm not sure the "higher metabolic rate = pro-aging" theory they hint at is correct, but nevermind: the fact that normal, healthy mice showed increased maximum lifespan is what's important.

Conclusion

A dietary supplement containing non-prescription ingredients ameliorated the age-related decline in physical activity in both normal and senescence-accelerated mice. The supplemented mice retained their physical activity more than non-supplemented mice and had lower levels of protein carbonyls, an age-related marker of oxidative damage. Importantly, an lifespan increase of 11% was seen in normal mice, showing that an "anti-aging cocktail" based on dietary supplements is feasible at least in mice.

For more information on aging and lifespan extension, see these posts:

Aubrey de Grey in Helsinki, Finland
Giving Heat Shocks to Roundworms Extends Lifespan by Almost 40%
How to Live Forever: My 5 Steps to Immortality
Drinking 10 Cups of Green Tea Daily and Not Smoking Could Add 12 Years to Your Life

Ashwagandha as a Nootropic – Experiment Begins

Ashwagandha, the 'Indian ginseng', shares some of the properties of Korean ginseng.
Ashwagandha, the 'Indian ginseng', shares some of the properties of Korean ginseng. (Photo by bartpogoda)

Ashwagandha is one of the plants used in Ayurvedic medicine. Also known as Indian ginseng, the scientific name of this nightshade family member is Withania somnifera. The latter part of the name means "sleep-inducing" in Latin, suggesting that the plant is used for its relaxing properties.

Ashwagandha is also said to be an adaptogen – a herb that increases the body's resistance to stress, anxiety and fatique by "normalizing" its functions. Before you dismiss the whole thing as new age garbage, let me point out that unlike some other Ayurvedic herbs, this one has been studied quite extensively. A pubmed search on 'ashwagandha' gives about 360 results.

Having browsed through the entire list, it appears that ashwagandha has a variety of effects on health. In this post, however, I will concentrate on the nootropic aspect of the herb. Bear in mind that I'm using the term in a very broad sense here: any paper examining the effect of the herb on cognition, mood, stress-relief, or motivation will be included. We'll save the studies on topics such as immune function for later.

The effect of ashwagandha on mood and libido

GABA, which is short for gamma-Aminobutyric acid, is the chief inhibitory neurotransmitter in mammals. GABA agonists – drugs that stimulate or increase the action at the GABA receptor – usually have a relaxing and stress-relieving effect. Alcohol is one such agonist. At least one paper has shown that ashwagandha contains an ingredient that activates the GABA receptor in a dose-dependent manner (link). Thus, the GABAergic activity may explain why many people report feeling more relaxed after taking ashwagandha.

GABA agonists are sometimes also used to treat psychostimulant addiction. Indeed, in animal models of drug addiction, ashwagandha apparently reduces alcohol intake and morphine tolerance (link). Ashwagandha itself appears to be well-tolerated: a review concluded that it has little or no risk of toxicity (link).

In a study that examined the role of stress in male infertility, 5 grams of ashwagandha root powder was given daily for 3 months to infertile men suffering from psychological stress (link). The treatment resulted in a decrease in stress levels and an increase in the level of antioxidants. At the same time, semen quality improved, which led to pregnancy in 14% of the subjects' partners.

Another study showed similar results, with reduced oxidative stress and improved sperm count and motility in infertile men (link). Testosterone levels increased significantly, while prolactin decreased. This is interesting, because prolactin counteracts the effect of dopamine. Dopamine is responsible for sexual arousal and motivation, while prolactin is thought to cause the sexual refractory period after an orgasm. High levels of prolactin cause impotence and loss of libido. The increase in testosterone and decrease in prolactin may therefore explain some of the claimed positive effects of ashwagandha on motivation and libido.

Some of the evidence on ashwagandha and libido is contradictory, however. When male rats were given 3,000 mg/kg of the root extract for 7 days, a marked impairment in libido, sexual performance, sexual vigour and penile function was seen (link). The authors state that since no change in testosterone levels was seen, the negative effects may be due to an increase in prolactin levels or the activity of GABA and serotonin. The increase in prolactin is interesting because it's opposite to what was seen in the study on humans. Note, however, that the dose used here was much higher than in the other rodent studies – perhaps the dose-response curve is U-shaped and more is not necessarily better.

Ashwagandha, stress and memory function

In mice, ashwagandha improves retention of a passive avoidance task (link). In this task, the mouse learns to refrain from stepping through a door to an apparently safer but previously punished compartment, which allows their memory to be assessed. The dosages used were 50, 100 and 200 mg/kg orally. The treatment also reversed the negative effects of scopolamine and electroconvulsive shocks on memory. Furthermore, mice and rats seem to do better on a forced swimming test when treated with ashwagandha (link, link).

Korean red ginseng, also known as Panax ginseng, is also called an adaptogen and shown to be helpful in treating stress. In a study comparing the two, both Panax ginseng and ashwagandha alleviated stress-related conditions such as sexual dysfunction, cognitive deficits and depression in mice subjected to footshocks (link). Ashwagandha was given orally in a dose of 25 or 50 mg/kg and was apparently more effective than Panax ginseng.

Acetylcholinesterase (AChE) is an enzyme that degrades the neurotransmitter acetylcholine, which is a facilitator of memory formation. AChE inhibitors increase the availability of acetylcholine, presumably leading to an improvement in memory. They can be extremely harmful in high doses: AChE inhibitors occur in natural venoms and poisons and are also used in nerve gases. However, AChE inhibitors are also used for medicinal purposes, for example to treat Alzheimer's disease. Huperzine A and galantamine, which are used for memory support and as nootropics, inhibit acetylcholinesterase. Ashwagandha appears to be an AChE inhibitor as well, with methanol extracts being more potent than water extracts (link).

In memory-deficient mice with neuronal atrophy and synaptic loss in the brain, withanolide A – an extract of ashwagandha – induced significant regeneration of nerve fibers and dendrites, as well as a reconstruction of pre- and postsynapses in the neurons (link). Treatment with the extract resulted in a reversal of the memory deficit. Two other extracts, withanoside IV and withanoside VI, appear to have similar effects (link). Ashwagandha or its extracts could thus be used to reconstruct neuronal networks.

Methanol extracts and withanolides are not the only useful part of ashwagandha, however. One study showed that even a withanolide-free water extract of ashwagandha roots had significant antistress activity (link).

Conclusion & my self-experiment

The evidence supports the claims that ashwagandha is an adaptogen and a nootropic. While there are no studies showing that ashwagandha improves mood per se, it does have a range of benefits.

The relaxing and anti-stress effect can be at least partly attributed to the fact that ashwagandha acts as a GABA agonist. It also improves stress-related memory problems by acting as a AChE inhibitor, and has the ability to prevent cognitive degeneration and even reconstruct neuronal networks.

Ashwagandha also seems to correct hormonal imbalances and reduced libido in men by increasing testosterone and decreasing prolactin. Very high doses may have the opposite effect, however.

For the purposes of my own human experiment, I have a bottle of NOW Foods' Ashwagandha extract. The bottle contains 90 capsules with 450 mg of root extract standardized to a minimum of 4.5% total withanolides. Once again, the measuring stick will be my own subjective evaluation of my mood, stress level and libido. Stay tuned for a conclusion of the experiment once I've finished the bottle.

Meanwhile, if you've tried ashwagandha, feel free to drop a comment about your experience. For more information on cognition, stress, mood and libido, see these posts:

Nootropic Battle Conclusion: Acetyl-L-Carnitine vs. Ginkgo Biloba vs. Taurine
Green Tea Protects from the Psychological Effects of Stress in Rats
The Effect of Maca Root on Energy and Libido – Experiment Conclusion
Caloric Restriction Improves Memory in the Elderly

Carotenoids and Lipid Peroxidation: Can Vegetables & Fruit Reduce ALEs?

Can we reduce ALEs by eating carotenoid-rich foods?
Can we reduce ALEs by eating foods rich in carotenoids? (Photo by tibchris)

When you cook foods until they have that delicious brown color, what you're really seeing is advanced glycation end-products, or AGEs. In cooking, they're formed by heating sugars with fats or proteins, but they can also be formed inside the body through normal metabolism. The problem with AGEs is that with time, they accumulate in the body and cause harm.

Similar products are formed when polyunsaturated fats are oxidized, as a result of heating or contact with oxygen. These are known as advanced lipid peroxidation end-products, or ALEs. Lipid peroxidation is even more problematic than glycation, because it leads to ALEs much more rapidly than glycation leads to AGEs.

So what can we do to reduce the accumulation of ALEs? As we've seen, one obvious way is to avoid cooking with fats that contain lots of polyunsaturated fatty acids. Still, as in the case of AGEs, ALEs are formed not only on the frying pan but also inside the body as a result of metabolism. Since completely avoiding polyunsaturated fats is probably not feasible (and they may even have certain benefits), looking for ways to inhibit metabolic lipid peroxidation seems very useful.

In addition to fatty acids, other components of the diet play a role in the accumulation of AGEs and ALEs. One particular group of micronutrients that may be beneficial is carotenoids, the compounds which give vegetables and fruit their bright color. In this post, we'll take a look at what the studies say on carotenoids and lipid peroxidation.

Various carotenoids and lipid peroxidation

One study found that carotenoids inhibited lipid peroxidation in mouse embryo cells (link). The carotenoids tested were alpha-carotene, beta-carotene, canthaxanthin, lutein, lycopene, and bixin. Bixin, which is extracted from annatto seeds, was the most effective out of the six.

In another study, the effect of various carotenoids on lipid peroxidation were measured in membranes enriched with polyunsaturated fatty acids (link). Surprisingly, only astaxanthin reduced peroxide formation, while beta-carotene and lycopene increased it significantly. Zeaxanthin and lutein also increased peroxide formation slightly.

The authors of the second paper note that this may be because conventional antioxidant assays use high concentrations of free radicals over a period of a few hours, whereas this study observed the effects over a longer period (48 hours). The relevance to biological systems is not entirely clear, but these results might help explain some of the controversial effects of carotenoids (for example, beta-carotene increasing lung cancer risk in smokers).

Zooming in on lutein

While the above studies suggest that other carotenoids such as astaxanthin may be useful, many of the studies on lipid peroxidation focus mainly on lutein. One paper I've posted earlier about as part of my self-experiment claimed an improvement in skin elasticity, hydration and photoprotection from a supplement containing lutein. Interestingly, a reduction in lipid peroxidation was also seen.

In another study, when spinach or perilla preparations containing 5 mg lutein were given to healthy volunteers for 10 days, their plasma concentrations of lutein increased significantly (link). The increase was more pronounced after consumption of perilla, even though the amount of lutein in both preparations was the same. In other words, other micronutrients in the food in question have an effect on lutein absorption.

Glutathione peroxidase was unchanged, but superoxide dismutase increased slightly. Both of these enzymes protect the body from oxidative damage. As for lipid peroxidation, the concentration of malondialdehyde (MDA) in plasma tended to decrease and the time span until a rapid increase in oxidation (known as lag time) tended to increase after spinach and perilla. MDA is a product of lipid peroxidation which eventually forms ALEs.

It's interesting to note that while lutein is absorbed rather well from vegetable foods, it is also absorbed from carotenoid supplements. In fact, the bioavailability of lutein from vegetables is only 67% compared to a preparation of pure carotenoids (link). In contrast to some of the findings in other studies, in this study healthy volunteers fed a high-vegetable diet or given 9 mg lutein and 6 mg beta-carotene daily for 4 weeks did not show an increased resistance to LDL oxidation ex vivo. The authors suggest that one possible explanation is that while lutein and beta-carotene concentrations increased, plasma lycopene concentrations decreased on both diets.

In one human study on healthy men, subjects were first put on a low carotenoid diet and then given either 330 mL tomato juice, 330 mL carrot juice or 10 g spinach powder for 2 weeks to see how the diets affected LDL oxidation. This time it was tomato juice that reduced the lag time of lipoprotein oxidizability, while carrot juice and spinach powder had no effect (link). Glutathione peroxidase was again unchanged. Given that tomatoes contain both lutein and lycopene, perhaps this hints at some kind of a synergy between the two?

Finally, let's take a brief look at two studies suggesting that lutein might be useful in treating diseases related to lipid peroxidation.

Lipid hydroperoxides are non-radical intermediates of lipid peroxidation that are involved in many diseases. For example in dementia, the number of phospholipid hydroperoxides (PLOOH) in red blood cells is greatly increased. When six healthy subjects took 9.67 mg lutein daily for 4 weeks, PLOOH levels decreased in red blood cells (link). An antioxidant effect was confirmed in red blood cells but not in plasma.

Genetically modified mice (ApoE-/-) that have high cholesterol and develop atherosclerosis as a result. They also have increased levels of systemic and retinal lipid peroxidation compared to wild mice. Supplementing them with 0.09 mg/kg lutein per day protects their retinas from this oxidative damage (link), suggesting that lutein might be helpful for patients with hypercholesterolemia.

Conclusion

Carotenoids may be effective in reducing lipid peroxidation and thus the accumulation of ALEs. Lutein in particular seems useful: at doses of 5-10 mg per day, it has been shown to increase plasma levels of lutein and reduce some of the markers of lipid peroxidation. Other carotenoids, such as astaxanthin and bixin, may be beneficial as well.

It should be noted that some of the evidence is contradictory. Some studies have found no benefit, and one study even found a slight increase in lipid peroxidation from various carotenoids. A certain balance of carotenoids may be necessary for inhibiting the formation ALEs; lycopene in particular may be important.

For more information on AGEs, ALEs and aging, see these posts:

Sugar and AGEs: Fructose Is 10 Times Worse than Glucose
Eating Meat or Going Vegan? Comparing AGE Levels in Vegetarians and Omnivores
AGE Content of Foods
Green Tea Reduces the Formation of AGEs