In The Top Pathways to Achieve Longevity Part I, we explored the longevity pathways mTOR, AMPK, SIRT1, and NF-kB. Now that you have a base understanding of these pathways, you will learn how to epigenetically target them for extending life. If you are really serious about longevity, consider genetic testing through Nutrition Genome to discover your genetic strengths and weaknesses, and see which pathways need the most attention.

Top 7 compounds for targeting longevity pathways

1. Resveratrol

Defined:  Resveratrol is a plant chemical known as a polyphenol stilbene.

Research:  protects against heart disease; showed to extend life in worms, fish, and flies; extends life in obese mice; improved health of all mice (73).


Food sources: red wine, peanuts, pistachios, berries (blueberries, bilberries, cranberries), cacao, muscadine grape

2. Pterostilbene

Defined:  Pterostilbene is a plant chemical know as a polyphenol stilbene.

Research:  reduces oxidative damage; acts as an anti-inflammatory; a powerful control of gene expression and enzyme activity modulator; similar benefits as resveratrol but more bioavailable (potential for better absorption) (74)


Food sources: blueberries, red wine, almonds, peanuts, cacao

3. Curcumin

Defined:  Curcumin is a plant rhizome chemical known as a polyphenol curcuminoid.

Research:  shows antioxidant activity similar to Vitamin C and E; acts as an anti-inflammatory; liver protective; reduces cholesterol and triglyceride levels; cancer and Alzheimer’s Disease protection, glucose lowering activity (75) (76)


Food sources: turmeric

4. Magnesium

Defined:  Magnesium is a critical mineral essential to human life.

Research:  45% of the USA are deficient in magnesium; required by all the enzymes that use and produce ATP (the energy form used by cells); it is involved in ion transport; cell signaling; and has structural functions

Pathways:  ACTIVATE SIRT1 (77); a critical co-factor to proper functioning pathways; over 300 enzymes within the body require magnesium (78)

Food sources: spinach, swiss chard, beet greens, pumpkin seeds, summer squash, turnip greens

5. Melatonin

Defined:  Melatonin is the main hormone of the pituitary gland, which is primarily responsible for maintaining normal circadian rhythm (sleep-wake cycle)

Research:  shown to extend lifespan in mice; linked to reduce cancer; associated with neuroprotection; improve immune system function; powerful antioxidant (79)

Pathways:  ACTIVATES AMPK; INHIBITS NF-kB, ACTIVATES SIRT1 (80) (81) (36) Melatonin appears to be unique in that it seems to target the AMPK and SIRT pathways differently depending on normal cells or a cancerous cell.  In the case of cancerous cells, AMPK and SIRT are downregulated and inhibited by melatonin.

Food sources: Montmorency (tart) cherry, goji berries, walnuts, almonds, raspberries, tomatoes, other berry varieties, other cherry varieties, Barolo and Barbaresco red wines

6. Vitamin D

Defined:  Vitamin D is a synthesized in the skin when it is exposed to sunlight and then metabolized by the liver and the kidney to a hormone variant.  In supplement form, Vitamin D is known as Vitamin D3 (cholecalciferol).

Research:  Vitamin D regulates the expression of hundreds of genes; blood levels of Vitamin D are associated with reduced dementia, cancer, and heart disease risk; it ensures bone health and strength; Vitamin D inhibits autoimmune disease; lowers likelihood of cold and flu; inadequate blood levels of vitamin D are associated with asthma, stroke, neurodegenerative disease and multiple sclerosis (82)

Pathways:  ACTIVATES AMPK; INHIBITS mTOR; INHIBITS NF-kB, ACTIVATES SIRT1 (83) (84) (85) (86) (87) (64) (88) (89) (90)

Food sources: Cold liver oil, whole salmon oil, salmon, sardines, cow’s milk, egg yolks

7. EPA & DHA

Defined:  Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are essential omega-3 fatty acids found primarily in marine products like fish.

Research:  Fish oil has shown to protect against cognitive decline; slows the aging process in general; associated with slower telomere shortening; reduces oxidation in blood cells; reduces inflammation (91)


Food sources: fish and other seafood, marine oil supplements

NOTE:  AMPK increases SIRT1 by increasing NAD+ levels within cells. SIRT1 activation also indirectly activates AMPK. Moreover, what increases AMPK activity typically inhibits mTOR.

Resveratrol Pterostilbene Curcumin Magnesium Melatonin Vitamin D DHA/EPA
Top Food Source: Red wine Wild blueberries Turmeric Spinach Montmorency cherries Cod Liver Oil Fish and seafood, Fish Oil
Inhibits mTOR X X X * ** X X
Activates AMPK X X X * X X X
Activates SIRT X X X X X X X
Inhibits NF-kB X X X * X X X

* magnesium is a necessary co-factor in all pathways and many people are deficient in this mineral ** Satisfactory references could not be found so this was left blank, although mTOR tends to be inhibited if AMPK is activated

Top 6-diet and lifestyle choices for synergistically targeting mTOR, AMPK, NF-kB and SIRT

Try to attempt the below as best you can without stressing (the bad kind) about achieving perfection.  Following the 80/20 rule is a good way to approach these recommendations.  For most, 20% of the effort applied to the recommendations will most likely present 80% of the benefit.  Another way to look at it, is if you are following this protocol 80% of the time, do not fret over the other 20%.  Our bodies are amazing and resilient so keep a positive mind, do not over do it; and take lots of time for recovery, rest and relaxation.  Remember, too much of a good thing is a still a bad thing.

1. Skip a meal once and a while or eat within a 9-12 hour window each day

Most of us will not realistically be able to stick to a caloric restricted diet indefinitely.  But we can rejoice and reap some of the benefits of CR by intermittently fasting or by condensing our eating window to 9-12 hours each day, with the latter being the easiest to implement and stick to.  Try to eat or drink your last stint of calories no later than 8pm each night and hold off on anything that requires metabolizing (that includes coffee with caffeine) until 8am the next day.  This will give you 12 hours of fasting for your body to repair and regenerate.

2. Take a cold shower or (if you are up to it) a cold bath, and hit the sauna

Some studies have shown with mice that as few as 2 exposures to cold each week (we are talking about ~50F bath for 15-20mins) promote health benefits that persist in the body for multiple weeks after the cold exposure discontinues.  Heat exposure in saunas causes the body to release heat shock proteins (HSP), which offer many benefits.  After one exposure, HSP remains elevated in the body for around 48 hours.

With that, we suspect 2-3 times a week may be a sufficient dose and an approach that is easy to maintain. Remember, pay attention to your body and do not overdo it.  We do not recommend “stacking” these stressors, although a cool shower after a sauna may be necessary to cool the body down more quickly so we can return to daily life without sweating profusely.

At The Health Beat, our favorite way to cool down after a sauna session is to drink a cold 750ml Gerolsteiner mineral water while rinsing off in the shower.  This also helps replenish the minerals lots through sweating.  Try to stay away from cold therapy right after weight training, since it may blunt the beneficial muscle-building inflammatory response. Our recommendation is to focus on heat in the warm months and cold in the winter months.  This more closely mimics the environmental thermal stressors we would have experienced naturally in the past, and also improves our acclimation to those seasons, making outdoor activities more enjoyable (less sweating and overheating in summer and less shivering and chills in the winter!).

3. Exercise: mix it up between aerobic activities and high-intensity training

We pretty much always hear good things about exercise.  The advice here is to mix it up and rotate between endurance (aerobic) type activities like jogging and muscle building high-intensity interval training.  They have both shown enormous health benefits but target different pathways and mechanisms in the body. Again, do not forget to rest.  Going for a walk or hike in nature counts too.

4. Take up Yoga and Meditation

In addition to reducing inflammation by inhibiting the NF-kB pathway, yoga and meditation also reduce phycological stress in studies.  Meditation even enhances grey matter in the brain. A good strategy would be to slip in these de-stressing activates between other stressors like exercise or do them on alternating days. Yoga, deep breathing techniques, Qi Gong, and mindfulness are examples that would fit this category.

5. Eat a more diverse diet and keep inflammation low

Before we dive into all things phytochemicals, we need to first remind you again of the importance of vitamins and minerals.  Cells, genes, and enzymes need these macro and micro nutrients, trace minerals and essential minerals to undertake their complex and essential activities in the body.  We all need to ensure we are getting adequate intake of hard-to-get minerals and vitamins such as Magnesium, Vitamin D,  B-vitamins, Vitamin C, choline, trace minerals (e.g. Boron, Lithium), Selenium, and Zinc.

Recall:  22% of all enzymes require a micronutrient to function (67). Eating a diet rich in phytochemicals is a must, and with conflicting research around supplementing with anti-aging compounds in isolation, a food first strategy is our recommendation.  Aim to increase your intake of a diverse variety of vegetables, fruits, herbs, and spices.  Many foods that are rich in polyphenols tend to have anti-inflammatory effects and also contain many of the compounds identified above.  Some polyphenol-rich foods are:

Cloves Peppermint Star anise Raw cacao
Mexican oregano Celery Fennel Flaxseed meal
Black elderberry Chestnut seeds Dried sage Rosemary
Spearmint Thyme Blueberries Blackcurrant
Capers Olive oil Hazel nuts Pecans
Coffee Tea Black cumin seed Cardamom


If you do a quick search on the internet for these foods, you will notice that Black cumin (nigella sativa) seed oil is touted as a miracle health food.  This may be a stretch from the truth but it does offer some impressive health benefits.  In vivo treatment with black cumin seed oil exerts an insulin-sensitizing action and has also been shown to activate AMPK. Black cumin seed oil contains a phytochemical called thymoquinone, which protects the liver from injury, boosts our bodies master antioxidants glutathione and superoxide dismutase, and inhibits NF-kB activity (94)

Polyphenols can also affect other pathways such as COMT in a negative way.  Catechins are especially troubling for slow COMT, which you will find a ton of in teas (especially green tea), coffee and chocolate; and concentrated berry/grape products such as red wine.  In addition, if you are a slow metabolizer of caffeine, tea and coffee may cause more harm than good.  Fortunately, there are some high quality decaffeinated varieties available if you still choose to consume these products for their polyphenols.

For tea, look for products that are organic and remove the caffeine with supercritical CO2.  For coffee, organic products that use the Swiss Water Method for caffeine removal are a good choice.  A Nutrition Genome Report will identify if you COMT gene needs some extra attention and if caffeine is your friend or foe. Polyphenols get most of the attention when it comes to health-promoting plant phytochemicals, but terpenes are also very important to consume.  They are especially good at inhibiting the NF-kB pathway and keeping chronic inflammation low (95).  Here are some Terpenoid rich foods (96):

  • Monoterpenes: Lemons, oranges, grapefruit, caraway, bergamot, peppermint, spearmint, dill, tomatoes
  • Diterpenes: Carrots, spinach, pumpkin, broccoli, mango, papaya, cherries, tomatoes, oranges, cabbage, watermelon, lettuce
  • Triterpenoids: Olives, mangos, strawberries, grapes, figs
  • Terpenoid chromanols: Almonds, walnuts
  • Carotenoids: Tomatoes, oranges, carrots, peas, sprouts, greens


Research suggests that for reducing inflammation and for inhibiting the NF-kB pathway, Triterpenoids may be the most beneficial.  Many herbs and mushrooms are high in these compounds including: reishi mushroom, ashwagandha, ginseng and boswelia (97).  Reishi mushroom is especially rich in triterpenes; containing more than 100 different types, with 50 of these being new and unique to this mushroom (98).

Another notable mushroom with anti-aging properties is Cordyceps.  Cordyceps enhances the activity of AMPK while also assisting with hypothalamic–pituitary–adrenal axis (HPA axis) balance and anti-cancer activity. Its ability to activate AMPK is believed to be one of its anti-aging components in the body, along with its anti-diabetic effects. Cordyceps also inhibit intracellular lipid accumulation and the militaris variety induces fatigue recovery.  These results are primarily attributed to activating AMPK, targeting mTOR pathways and regulating serum hormone level (99). Some additional foods that are colloquially known as “anti-inflammatory” are:

Green leafy vegetables Bok Choy Celery Beets
Broccoli Blueberries Pineapple Salmon / Fish oil
Fermented Vegetables Bone Broth Coconut Oil Walnuts
Chia Seeds Flaxseeds Turmeric Ginger
Buckwheat Tea Garlic Shiitake Mushrooms


An honorable mention goes to the Isothiocyanate phytochemical class and the specific potential of sulforaphane.  Sulforaphane offers a lot of promise since it helps the liver with detoxification, acts as an antioxidant, offer broad spectrum antimicrobial activity and is a power anti-inflammatory.  Sulforaphane seems to hold promise in the prevention and treatment of nearly all age-related diseases including, but not limited to, cancer, cardiovascular disease, inflammation, dermatitis, cognitive decline and blood vessel health (100).  Studies show that sulforaphane significantly reduces the activity of NF-kB, so eat your broccoli sprouts (101)! Depending on your gut health, you may also want to consider a probiotic supplement since consuming them activates SIRT and inhibits NF-kB.  Probiotics and a proper gut lining and microbiome play an important role in managing inflammation (102) (103).

6. Sleep, Circadian rhythm, and sun

We all know intuitively sleep is important.  It is great that science has verified this intuition, and demonstrated that it effectively and beneficially targets anti-aging pathways.  We recommend that you keep a routine with sleep (bedtime and wake time) and try not to deviate from it by more than 2 hours on the weekend.

It is also important to expose yourself to bright blue (short wavelength) light during the day to ensure melatonin and cortisol are following the proper circadian rhythm dance. It may also be important to aid your body in boosting melatonin levels at night.  This can be done with the consumption of foods that contain melatonin such as wine, cherries, and berries.  Please note that alcohol affects sleep (especially deep sleep), so if you chose to consume it do so with quantities that boost PON1 activity, with your dinner meal and ideally 3-4 hours prior to bedtime.

That same blue light that we want exposure to during the day is detrimental to our circadian rhythm if we are exposed to it after sunset.  Try to limit “screen time” since most devices emit blue light.  If you are on devices or watching TV in the evening, it has been shown that wearing short-wavelength blocking glasses increases nighttime melatonin levels by 58% compared to carrying out the same digital routine in the evening without the glasses (104).

We recommend staying away from melatonin supplements since they can cause dependency and reduce the bodies natural production of this important hormone. Getting adequate sunshine not only enhances our mood but creates Vitamin D and boosts nitric oxide production which activates AMPK.  As a rule of thumb, if your shadow is longer than you are tall, you are not producing Vitamin D from the sun.  Blood Vitamin D levels should be measured to ensure they are in the optimal range and Vitamin D supplementation may be necessary.  As with other recommendations in this article, do not overdo it with the sun since overexposure to the sun can accelerate skin aging, cause sunburns, increase inflammation and increase skin cancer risk.

Top whole-food supplements for targeting mTOR, AMPK, NF-kB and SIRT

In addition to eating a diet rich in the above-mentioned foods, and employing the lifestyle changes recommended herein, some may wish to supplement to take their anti-aging regime to the next level.  Below is a list of the top whole spectrum extracts or whole food supplements that may possibly improve your longevity game.  The supplements listed below have also been chosen because they offer many other health benefits, in addition to targeting anti-aging pathways.

1. Turmeric by Synergy Read more about how turmeric works as an anti-depressant here.

2. Black Cumin Seed Oil

3. Cordyceps – AMPK, NAD+, NfkB

4. Reishi, Turkey Tail or Maitake – NFkB

5. Berrimax Includes quercetin, ellagic acid, caffeic acid, benzoic acid, resveratrol, pterostilbene, cyanidin-3-glucoside and cyanidin-3-rutinoside.

6. Herbal Zzz or Montmorency Cherry concentrate for melatonin (can ferment out the sugars if desired) Tart cherry concentrate contains around 17,000 mcg/100g.  To put this into perspective, according to the Society for Light Treatment and Biological Rhythms, approximately 5-25 mcg of melatonin circulate in the bloodstream of healthy young and middle-aged men at night time

7. Magnesium Malate Glycinate Read more about magnesium here.

8. Fish Oil Read an in-depth review of all fish oil products in the link above. 9. Vitamin D


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*Alex is no longer able to answer comments due to very limited time outside of Nutrition Genome. If you are interested in nutrigenomic testing, please check out