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Knowledge Base:  Anti-Aging Compounds

Knowledge Base: Anti-Aging Compounds

Most “anti-aging” supplements that many popular websites and books recommend do not slow aging.

These are substances like vitamin A, vitamin E, coenzyme Q10, lipoic acid, B-vitamins, calcium, omega-3 fatty acids, zinc, multivitamins, curcumin, EGCG, nicotinamide riboside (NR), mushroom extracts and many more.

All these substances have failed in well-conducted studies to extend lifespan in organisms (we explain here why this is the case).

Also, many touted “anti-aging” supplements are antioxidants, like vitamin A, vitamin E, coenzyme Q10, lipoic acid and so on. However, most antioxidants don’t slow down aging. Some antioxidants can even accelerate aging, like lipoic acid or vitamin A and vitamin E.

Luckily, there are far better, more science-based anti-aging supplements. We compiled a list below.

1. Fisetin

Fisetin

Fisetin is a natural ingredient found in vegetables and fruits, especially in strawberries. Fisetin is mostly known for its senolytic activity, meaning it can clear away senescent cells, and increase lifespan in various organisms (R,R,R,R).

Senescent cells accumulate everywhere in our body during aging. Senescent cells were previously normal cells that turned into “zombie cells”: senescent cells are cells that cannot divide anymore, but refuse to die, and secrete all kinds of substances that damage healthy surrounding cells.

Senescent cells in the skin contribute to wrinkles, senescent cells in the blood vessels make them more stiff, and senescent cells in the liver impair its proper functioning.

There are various natural substances that can have senolytic activity. One of them is quercetin. In fact, quercetin and fisetin look very similar. However, fisetin seems to be the most potent natural senolytic (R):

Fisetin is far better in destroying senescent cells (red bar) than other substances, such as quercetin or curcumin or EGCG.
Source image: Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine, 2018

Researchers concluded that “fisetin had the most potent senotherapeutic effects in several cell types in vitro and showed strong anti-geronic effects in vivo.”

Besides clearing senescent cells, fisetin reduces inflammation (R,R), inhibits mTOR (an important aging switch) (R), reduces glycation (which also contributes to aging) (R), increases the production of cell protective substances, and has many more beneficial effects.

Various studies show the lifespan extending effects of fisetin (R,R,R). For example, one study found that fisetin extends median and maximum lifespan in mice, even when taken late in a mouse’s life (equivalent to 50 or 60 years old for a human) (R):

Fisetin extends  lifespan (red graph) versus control group (black graph) in mice.
Source image: Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine, 2018

Learn more about the anti-aging effects of fisetin here.

2. Alpha-ketoglutarate (the calcium form)

alpha_ketoglutarate

Alpha-ketoglutarate (AKG) is a substance that naturally occurs in our bodies. When we get older, the levels of AKG decline.

Various studies show that AKG extends lifespan (R,R,R,R,R). In one study, mice that received AKG lived on average 14 percent longer (R).

But even more interestingly, the mice stayed healthy for much longer: The mice that received AKG had less aging-related diseases and symptoms, including a fur that became grey at a slower rate.

This probably has to do with alpha-ketoglutarate improving the stem cell function of the stem cells surrounding the hair shaft.

How can alpha-ketoglutarate extend healthspan and lifespan?

AKG has many functions in the body. For example, it is involved in mitochondrial health. Mitochondria are the power plants of our cells, which create energy so cells can go about their daily business. When we get older, our mitochondria function less and less well. Alpha-ketoglutarate provides energy for the mitochondria, among many other functions (R).

AKG also helps to maintain the epigenome (R). The epigenome determines which genes are active or not. The older we get, the more the epigenome gets dysregulated. Substances like AKG can slow down this decline. Alpha-ketoglutarate is also involved in stem cell maintenance (R). Interestingly, AKG also improves synthesis of collagen (R), which could improve skin appearance (R).

It’s important that the right form of alpha-ketoglutarate is used, namely calcium alpha-ketoglutarate. Most supplements contain alpha-ketoglutarate, not the calcium form.

Alpha-ketoglutarate needs vitamin C to function properly, especially for its epigenetic functioning (R). So ideally, a good anti-aging supplement would contain both AKG and vitamin C to enable synergistic effects. Interestingly, vitamin C also has epigenetic effects (R).

Learn more about the anti-aging effects of alpha-ketoglutarate here.

3. Microdosed lithium

Lithium is a mineral found in nature. It seeps from rocks into water, including drinking water.

Various studies showed links between the amount of lithium in the drinking water and mortality rates (R,R), while other studies showed that people living in regions with more lithium in the drinking water had less neurodegenerative diseases like Alzheimer’s (R) and have lower suicide rates.

Of course, correlation is not causation. However, many studies in animals show that lithium can reduce the risk of Alzheimer’s disease and various other neurodegenerative diseases (R,R,R).

A systematic review and meta-analysis demonstrated that lithium may have beneficial effects on cognitive performance in people with mild cognitive impairment (often the precursor to Alzheimer’s disease) and Alzheimer’s disease (R).

Also, many studies show that lithium can extend lifespan in organisms (R,R,R).

Lithium also has been used for many decades as a medicine to treat psychiatric diseases, especially to stabilize mood disorders, such as bipolar disorder.

However, the amounts of lithium given to psychiatric patients are hundreds to thousands of times higher compared to the amounts of lithium in drinking water, dosages given in trials to reduce dementia, and amounts in longevity supplements like NOVOS. We see that very low or micro doses of lithium (in the range of 0.3 milligram to a few milligrams) can have lifespan effects and protect the brain against neurodegenerative diseases like Alzheimer’s (R,R,R).

There are many ways by which lithium can impact the aging process. Lithium has been shown to increase autophagy (the digestion of proteins that would otherwise accumulate in the cells, a process that contributes to aging) (R,R), enhance the generation of pluripotent stem cells demonstrating its epigenetic effects (R), and improve neurogenesis (R), the formation of new neurons.

Learn more about the anti-aging effects of microdosed lithium here.

4. Glycine

Glycine is an amino acid that occurs naturally in our body. When we age, glycine levels decline.

Low glycine levels also have been associated with various aging-related diseases like cardiovascular disease and with type 2 diabetes.

Glycine extends lifespan in different species (R,R,R,R).

Glycine has many functions in the body. It improves the epigenome (the machinery that determines which genes are switched on or off, a process that goes increasingly awry when we get older). Glycine especially improves the epigenome of mitochondria, the power plants of our cells (R).

Glycine also functions as a chaperone. Chaperones are small molecules that gently stick to and protect the proteins. That is important, because one of the reasons why we age is due to proteins accumulating everywhere inside and outside our cells, eventually hampering the proper functioning of our cells.

Glycine also reduces inflammation (R) and has many other beneficial effects, especially for the cardiovascular system. People with higher glycine levels in the blood had less risk of a heart attack (R), and glycine can protect the blood vessels (R).

Learn more about the anti-aging effects of glycine here.

5. Pterostilbene

Pterostilbene is the better brother of the famous anti-aging substance resveratrol.

Resveratrol has long been hyped as a longevity substance. However, it unfortunately did not live up to that hype. Studies showed disappointing results when it came to resveratrol extending lifespan.

One reason for this is that resveratrol has a very short half-life: most of it is broken down in less than an hour. Also, resveratrol, when taken orally, is not very well absorbed.

Pterostilbene, on the other hand, has a far longer half-life and better absorption, so that higher levels reach the blood and stay around for longer in the body.

We see in studies that pterostilbene performs better than resveratrol (R).

Pterostilbene has been associated with longer lifespans (R,R), and could reduce various aging symptoms and mitigate aging-related diseases, including Alzheimer’s disease (R,R,R).

Learn more about the anti-aging effects of pterostilbene here.

 

6. Malate or malic acid

Malic acid (copper & gold) with a magnesium atom (silver) (image: NOVOS)

Malate, also called malic acid, is found in apples, and in our own bodies.

Malate is an important substance in the mitochondria. In fact, malate is a component of the Krebs cycle, which consists of various substances that are chemically modified to provide the energy that keeps all cells going.

Studies show that malate can extend lifespan in simple organisms (R).

In humans, malate can confirm various health benefits. For example, malate is given to provide energy, increase stamina and cognition, especially in combination with magnesium (R).

That’s why the best form of magnesium for anti-aging purposes is magnesium malate (and not magnesium oxide, magnesium citrate and other forms of magnesium).

Learn more about the anti-aging effects of malate here.

7. Magnesium

Malic acid (copper & gold) with a magnesium atom (silver) (image: NOVOS)

Magnesium is an indispensable mineral for the body to function properly.

Magnesium helps innumerable enzymes in our body to function properly. Cells shuttle magnesium in and out to propagate nerve signals and to generate muscle impulses, including the beatings of our heart.

Magnesium also sticks to our DNA, stabilizing our DNA, protecting it against damage (R). Increasing DNA damage is one of the reasons why we get older.

Low intakes of magnesium are associated with increased inflammation, increased blood pressure, increased risk of heart disease, neurodegenerative diseases, insulin resistance, osteoporosis and even development of cancers (R).

Magnesium also provides energy, and can help people to deal with stress. Magnesium especially teams up well with malate, another substance that can provide energy.

Learn more about the anti-aging effects of magnesium here.

8. Glucosamine (the sulfate form)

Most people know glucosamine as a substance to reduce wear and tear of cartilage and to improve joint health.

Few people know that glucosamine can also extend lifespan in different organisms, including mice (R,R).

Interestingly, studies show that glucosamine is one of the few supplements associated with reduced mortality in humans (R,R), and also reduced risk of cardiovascular disease in humans (R). There are also associations between people taking glucosamine and reduced inflammation (R).

Various animal studies showed that glucosamine reduces atherosclerosis (R,R) and inhibits platelet aggregation (R), making the blood less clotty.

This should not be surprising, given the many effects glucosamine has on the body. It does much more than protect cartilage.

Glucosamine can improve mitochondrial health, thus enabling the mitochondria (the power plants of our cells) to function better. One way of doing this is by increasing “mitochondrial biogenesis”, which means that glucosamine induces the formation (genesis) of extra mitochondria.

Glucosamine also reduces inflammation (R,R,R), which is a good thing given inflammation increases during aging. This low-grade inflammation is called “inflammaging”.

The best form of glucosamine is glucosamine sulfate. Many supplements contain only glucosamine, not the sulfate form.

Learn more about the anti-aging effects of glucosamine here.

9. Hyaluronic acid

Hyaluronic acid is an important component of the skin. But hyaluronic acid (HA) surrounds and embeds many other cells in the body than just the skin cells.

The older we get, the less hyaluronic acid there is in the body. A 70-year-old has only about 19 percent of the amount of hyaluronic acid of a young person.

Studies show that hyaluronic acid, taken orally, can improve skin appearance by reducing wrinkles, improving moisturization of the skin and increasing skin radiance (R,R). It can also improve osteoarthritis (R,R,R), which makes sense given joints and cartilage contain a lot of hyaluronic acid.

Interestingly, hyaluronic acid is made up of acetyl-glucosamine (do not confuse with glucosamine).

Acetyl-glucosamine has been shown to extend lifespan in mice (R).

Acetyl-glucosamine could do this by inducing the “unfolded protein response”, which is a defense mechanism that kicks into action when the cell senses that there are too many improperly folded proteins accumulating in the cell (R).

Protein accumulation is one of the reasons why we age. When you consume hyaluronic acid, parts of the molecule are broken down in the gut into acetyl-glucosamine, which can be absorbed by the gut cells and end up in the bloodstream.

Learn more about the anti-aging effects of hyaluronic acid and its component acetylglucosamine here.

10. Ginger

Gingerol, an important bioactive ingredient in ginger (image: NOVOS)

Ginger is a well-known spice. But it’s not just any spice.

Many scientific studies demonstrated multiple beneficial health effects of ginger, like reducing inflammation (R) and protecting cells against damage (R).

Ginger has been found to extend lifespan in simple organisms, like fruit flies (R).

Ginger can improve type 2 diabetes (R,R) and inflammation in humans (R,R).

Studies show that ginger can protect mice against lethal doses of radiation, which is quite impressive (R). The mice that received ginger before they got exposed to a high dose of radiation lived considerably longer. High-energy radiation is very damaging to cells, as the radiation oxidizes (damages) many components of the cells, rips molecules, including DNA apart, and induces strong inflammation.

However, ginger seems to be able to mitigate this molecular onslaught.

Learn more about the anti-aging effects of ginger here.

11. Rhodiola rosea

Salidroside, a component of Rhodiola rosea (image: NOVOS)

Rhodiola rosea is a very interesting plant that grows in the northern regions of Europa and Asia.

Rhodiola rosea has been used for centuries as an adaptogen, a substance that can improve resilience against both physiological stress and mental stress.

Rhodiola rosea extends lifespan in various organisms, for reasons that scientists have not completely understood yet (R,R,R,R).

Interestingly, Rhodiola can also improve nerve regeneration; specific substances in Rhodiola, like salidroside could be responsible for this very interesting effect (R,R). This could be one of the several reasons demonstrating neuroprotective effects of Rhodiola rosea (R,R,R).

Studies in humans show that Rhodiola rosea can improve memory, concentration and can reduce fatigue (R). Students and people with demanding jobs take Rhodiola rosea to improve their productivity and energy levels (R,R,R).

Learn more about the anti-aging effects of Rhodiola rosea here.

12. L-theanine

Theanine is a substance found in green tea, and is one of the reasons why green tea is healthy.

Theanine has been shown to extend lifespan in simple organisms (R,R,R).

Theanine has been associated with healthier blood vessels, and could reduce blood pressure and even obesity (R).

Theanine has shown to reduce neurodegeneration and protect neurons (R,R,R). It could also perhaps improve neuronal stem cell health and neurogenesis (the creation of new neurons in the brain) (R,R,R).

In humans, theanine can improve concentration, while also improving relaxation.

Learn more about the anti-aging effects of theanine here.

13. Nicotinamide mononucleotide (NMN)

Nicotinamide mononucleotide (NMN) is needed to make NAD+.

NAD+ is a very important substance in the cells. It provides energy for cells and is also a cofactor for proteins that repair and maintain our epigenome and our DNA.

The epigenome is the intricate machinery that surrounds the DNA and that determines which genes are active. During aging, the epigenome becomes more and more dysregulated.

NMN also improves the functioning of our mitochondria, the power plants of our cells.

NMN improves metabolism and reduces inflammation.

The older we get, the less NAD+ is present in our cells. Taking in NMN can increase NAD+ levels.

Various studies show that NMN has beneficial effects on aging diseases and symptoms (R,R,R,R).

For example, long term administration of NMN mitigated age-associated decline in mice: NMN reduced the typical age-associated increase in body weight, improved energy metabolism, improved lipids in the blood and insulin sensitivity and ameliorated eye function (R).

NMN can also improve aging-related decline in fertility (R), improve bone health (R) and vascular health (R,R,R).

For more information on NMN and aging, click here. For a comparison between NMN and NR (nicotinamide riboside), click here.

 

The importance of synergy in anti-aging supplements

cellular repair

In conclusion, many anti-aging supplements are based on outdated insights and don’t have any or just very little science backing up their claims.

Also, they do not contain substances that have been shown to act on aging mechanisms (the “hallmarks of aging”).

A good anti-aging supplement is one that contains substances that are based on science and that acts on aging mechanisms. This also enables these supplements to have an additional important benefit: synergy.

After all, aging is a complex process caused by various different mechanisms, such as epigenetic dysregulationmitochondrial dysfunction, and accumulation of proteins.

If you have an anti-aging supplement that only focuses on “improving mitochondrial health”, you are not addressing other important aging mechanisms, like epigenetic dysregulation or accumulation of proteins.

Therefore, this supplement, even if it could improve mitochondrial health, will have little impact on extending lifespan given it only tackles one facet of the aging process.

As such, it’s very important for a good anti-aging supplement to contain substances that act on different aging mechanisms and this in a synergistic way.

For example, alpha-ketoglutarate (AKG) can maintain the epigenome and improve mitochondrial health. AKG can work together with other substances that improve mitochondrial health, like fisetin and malate, or that improve the epigenome, like NMN and glycine.

But addressing the aging epigenome and mitochondria is not enough. You also need to tackle many other aging mechanisms, like protein accumulation and DNA damage.

For this, other anti-aging substances need to be added, like lithium (which can reduce the accumulation of proteins by stimulating autophagy – the digestion of proteins) or acetyl-glucosamine which can also reduce protein accumulation, or magnesium that can help stabilize the DNA.

So the ideal anti-aging supplement contains not just one or two substances that focus on one aging mechanism (like mitochondrial health or the NAD+ metabolism), but contains many substances that act on many aging pathways, and this in a synergistic way.

Source: Novos Lab

What You Should Know about Your Dietary Supplements

What You Should Know about Your Dietary Supplements

Many adults and children in the United States take one or more vitamins or other dietary supplements. In addition to vitamins, dietary supplements can contain mineralsherbs or other botanicalsamino acidsenzymes, and many other ingredients. Dietary supplements come in a variety of forms, including tablets, capsules, gummies, and powders, as well as drinks and energy bars. Popular supplements include vitamins D and B12; minerals like calcium and iron; herbs such as echinacea and garlic; and products like glucosamine, probiotics, and fish oils.

The Dietary Supplement Label

Products sold as dietary supplements come with a Supplement Facts label that lists the active ingredients, the amount per serving (dose), as well as other ingredients, such as fillersbinders, and flavorings. The manufacturer suggests the serving size, but your health care provider might decide a different amount is more appropriate for you.

Effectiveness

Some dietary supplements can help you get adequate amounts of essential nutrients if you don’t eat a nutritious variety of foods. However, supplements can’t take the place of the variety of foods that are important to a healthy eating routine. To learn more about what makes a healthy eating routine, the Dietary Guidelines for Americansexternal link disclaimer and MyPlateexternal link disclaimer are good sources of information.

Some dietary supplements can improve overall health and help manage some health conditions. For example:

Many other supplements need more study to determine if they have value. The U.S. Food and Drug Administration (FDA) does not determine whether dietary supplements are effective before they are marketed.

Safety and Risk

Many supplements contain active ingredients that can have strong effects in the body. Always be alert to the possibility of a bad reaction, especially when taking a new product.

You are most likely to have side effects from dietary supplements if you take them at high doses or instead of prescribed medicines, or if you take many different supplements. Some supplements can increase the risk of bleeding or, if taken before surgery, can change your response to anesthesia. Supplements can also interact with some medicines in ways that might cause problems. Here are a few examples:

  • Vitamin K can reduce the ability of the blood thinner warfarin to prevent blood from clotting.
  • St. John’s wort can speed the breakdown of many medicines and reduce their effectiveness (including some antidepressants, birth control pills, heart medications, anti-HIV medications, and transplant drugs).
  • Antioxidant supplements, such as vitamins C and E, might reduce the effectiveness of some types of cancer chemotherapy.

Manufacturers may add vitamins, minerals, and other supplement ingredients to foods you eat, especially breakfast cereals and beverages. As a result, you may get more of these ingredients than you think, and more might not be better. Taking more than you need costs more and might also raise your risk of side effects. For example, too much vitamin A can cause headaches and liver damage, reduce bone strength, and cause birth defects. Excess iron causes nausea and vomiting and may damage the liver and other organs.

Be cautious about taking dietary supplements, beyond a standard prenatal supplement, if you are pregnant or nursing. Also, be careful about giving supplements to a child, unless recommended by their health care provider. Many supplements have not been well tested for safety in children and in those who are pregnant or nursing.

If you think that you have had a bad reaction to a dietary supplement, let your health care provider know. They may report your experience to the FDA. You may also submit a report directly to the FDA by calling 800-FDA-1088 or completing an online formexternal link disclaimer. You should also report your reaction to the manufacturer by using the contact information on the product label.

 

Quality

The FDA has established good manufacturing practices (GMPs) that companies must follow to help ensure the identity, purity, strength, and composition of their dietary supplements. These GMPs can prevent adding the wrong ingredient (or too much or too little of the correct ingredient) and reduce the chance of contamination or improper packaging and labeling of a product. The FDA periodically inspects facilities that manufacture supplements.

Several independent organizations offer quality testing and allow products that pass these tests to display a seal of quality assurance that indicates the product was properly manufactured, contains the ingredients listed on the label, and does not contain harmful levels of contaminants. These seals do not guarantee that a product is safe or effective. Organizations that offer quality testing include:*

  • ConsumerLab.com
  • NSF International
  • U.S. Pharmacopeia

      * Any mention of a specific company, organization, or service does not represent an endorsement by ODS.

Talk with Your Health Care Providers

Tell your health care providers (including doctors, dentists, pharmacists, and dietitians) about any dietary supplements you’re taking. They can help you determine which supplements, if any, might be valuable for you.

Keep a complete record of any dietary supplements and medicines you take. The Office of Dietary Supplements website has a useful form, ”My Dietary Supplement and Medicine Record,” that you can print and fill out at home. For each product, note the name, the dose you take, how often you take it, and the reason for use. You can share this record with your health care providers to discuss what’s best for your overall health.

Keep in Mind

  • Consult your health care provider before taking dietary supplements to treat a health condition.
  • Get your health care provider’s approval before taking dietary supplements in place of, or in combination with, prescribed medicines.
  • If you are scheduled to have any type of surgical procedure, talk with your health care provider about any supplements you take.
  • Keep in mind the term “natural” doesn’t always mean safe. Some all-natural botanical products, for example, like comfrey and kava, can harm the liver. A dietary supplement’s safety depends on many things, such as its chemical makeup, how it works in the body, how it is prepared, and the amount you take.
  • Before taking any dietary supplement, use the information sources listed in this brochure and talk to your health care providers to answer these questions:
    • What are its potential benefits for me?
    • Does it have any safety risks?
    • What is the proper dose to take?
    • How, when, and for how long should I take it?

Federal Regulation of Dietary Supplements

Dietary supplements are products intended to supplement the diet. They are not medicines and are not intended to treat, diagnosemitigate, prevent, or cure diseases. The FDA is the federal agency that oversees both supplements and medicines, but the FDA regulations for dietary supplements are different from those for prescription or over-the-counter medicines.

Medicines must be approved by the FDA before they can be sold or marketed. Supplements do not require this approval. Supplement companies are responsible for having evidence that their products are safe, and the label claims are truthful and not misleading. However, as long as the product does not contain a “new dietary ingredient” (one introduced since October 15, 1994), the company does not have to provide this safety evidence to the FDA before the product is marketed.

Dietary supplement labels may include certain types of health-related claims. Manufacturers are permitted to say, for example, that a supplement promotes health or supports a body part or function (like heart health or the immune system). These claims must be followed by the words, “This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.”

Manufacturers must follow good manufacturing practices (GMPs) to ensure the identity, purity, strength, and composition of their products. If the FDA finds a dietary supplement to be unsafe, it may remove the product from the marketplace or ask the manufacturer to voluntarily recall the product.

The FDA monitors the marketplace for potential illegal products that may be unsafe or make false or misleading claims. The Federal Trade Commission, which monitors product advertising, also requires information about a supplement product to be truthful and not misleading.

The federal government can take legal action against companies and websites that sell dietary supplements when the companies make false or deceptive statements about their products, if they promote them as treatments or cures for diseases, or if their products are unsafe.

Federal Government Information Sources on Dietary Supplements

NATIONAL INSTITUTES OF HEALTH (NIH)

NIH supports research and provides educational materials on dietary supplements.

U.S. FOOD AND DRUG ADMINISTRATION (FDA)

FDAexternal link disclaimer issues rules and regulations and oversees dietary supplement labeling, marketing, and safety. Recall notices are also posted on the FDA webpage or you can subscribe to receive FDA notices of recalls, market withdrawals, and safety alertsexternal link disclaimer.

FEDERAL TRADE COMMISSION (FTC)

FTCexternal link disclaimer regulates health and safety claims made in advertising for dietary supplements.

U.S. DEPARTMENT OF AGRICULTURE (USDA)

USDAexternal link disclaimer provides information on a variety of food and nutrition topicsexternal link disclaimer.

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES (HHS)

HHS provides wellness information, personal health tools, and health newsexternal link disclaimer.

Disclaimer

This fact sheet by the National Institutes of Health (NIH) Office of Dietary Supplements (ODS) provides information that should not take the place of medical advice. We encourage you to talk to your health care providers (doctor, registered dietitian, pharmacist, etc.) about your interest in, questions about, or use of dietary supplements and what may be best for your overall health. Any mention in this publication of a specific product or service, or recommendation from an organization or professional society, does not represent an endorsement by ODS of that product, service, or expert advice.