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Want to Age with Grace? Here are Two Critical Biochemical Pathways You Need to Know About

Longevity is currently a hot topic of discussion in the health community. The science of longevity is fascinating and quite technical, and discussions on this topic can cause us to quickly lose sight of why we want to optimize our longevity in the first place! Before diving into a discussion on two of the most important biological pathways involved in aging, AMPK, and Nrf2, I want you to envision what you’d like your life to look like 20, 30, or 40 years from now. As you grow older, do you envision a life filled with vibrant health, physical activity, independence, and fulfillment? Or do you imagine yourself as a less-capable human, destined to suffer the “inevitable” health declines we typically associate with aging, such as a loss of cognitive acuity, stiff joints, brittle bones, and low energy?

While most people don’t actively want to suffer poor health as they age, many have resigned themselves to this fate, waving it off as an eventuality. But, what if these age-associated changes weren’t inevitable? What could our lives look like 10, 20, or more years from now if we could slow down, halt, or even reverse the progression of age-related health declines?

Rather than feeling fatigued and unwell, we could be vibrant, active, and healthy in body, mind, and spirit. If you’re in the latter camp, empowered to optimize your health as you age, then you’ll want to focus on optimizing two powerful longevity pathways – AMPK and Nrf2.

Enter AMPK and Nrf2 – A Dynamic Duo for Healthy Aging  

Adenosine monophosphate-activated protein kinase, or AMPK for short, is a master regulator of longevity. It modulates cellular metabolism in diverse life forms, ranging from worms to mice to humans. It acts as an intracellular sensor, detecting when cellular energy levels, in the form of ATP, are low. Upon detecting low ATP levels, AMPK upregulates cellular processes that make energy, including the breakdown of sugars and stored fats. What does this mean to you? It means better blood sugar regulation, a cleaner burning metabolism with the flexibility to utilize both carbs and fats for fuel, and more energy! And if that’s not enough, AMPK also helps the body maintain a healthy inflammatory balance. What inactivates AMPK?  Things like excessive calorie intake, lack of exercise and overall decreased physical activity, and the aging process itself, leaving most adults in the Western world, where food is plentiful and exercise sparse, with a steadily declining level of this vital protein. (1)

A growing body of research indicates that AMPK activation is essential for healthy aging, regulating multiple age-related factors, including

  • Balanced blood sugar levels (2)
  • A sharp, flexible mind (3)
  • A healthy heart (4)
  • Healthy kidney function (5)
  • The generation of new mitochondria, the energy “powerhouses” of your cells: A reduction in the number of mitochondria is associated with aging, so the more healthy mitochondria our bodies can make, the better the aging process may be. (6)
  • Activation of autophagy, the body’s “cellular quality control” system (7)

Strategically targeting AMPK with botanical, nutritional, and lifestyle strategies can help you age with grace and vitality. 

Nuclear factor erythroid 2-related factor, or Nrf2 for short, is a transcription factor – a protein that helps turn genes “on” or “off” by binding to sections of DNA. In particular, it regulates the expression of antioxidant proteins, protecting the body against oxidative stress. Oxidative stress is defined as an imbalance between levels of damaging reactive oxygen species or free radicals and the body’s ability to detoxify them or repair the resulting damage created by them. This damage occurs at a cellular and DNA level with far-reaching effects to the body. Oxidative stress can be caused by environmental toxins, such as mercury and BPA, and by natural processes such as UV light exposure and the aging process itself. As a result, excessive DNA damage, without sufficient repair mechanisms, and depletion of intracellular glutathione, our body’s master protective antioxidant, has shown to be an age-accelerator. (8, 9

As we get older, Nrf2 activity inside our bodies declines, rendering us more susceptible to the harmful effects of oxidative stress. (10) Because of this, it’s clear that supporting Nrf2 activity plays a pivotal role in longevity and healthy aging. 

Interestingly, AMPK and Nrf2 appear to engage in cross-talk during the aging process. In fact, the activation of Nrf2 by several plant compounds, including berberine and quercetin, appears to be AMPK-dependent. (11, 12) Furthermore, the beneficial health effects of AMPK-supporting phytochemicals are blunted when Nrf2 is inactivated.

How to Support AMPK and Nrf2 Activity for Healthy Aging

Supplementing with Plant Compounds

A variety of compounds from the plant kingdom, known as “phytochemicals,” have been found to support the healthy expression of AMPK and Nrf2. AMPK-supporting plant compounds include:

  • Resveratrol: Resveratrol is a phytochemical found in red grapes, red wine, peanuts, and blueberries. It modulates AMPK, supporting healthy metabolic function and energy production in the brain and muscles. These changes in AMPK activity may, in turn, support healthy cognitive function and exercise performance. (13
  • Berberine: Berberine is a bitter compound found in plants from the Berberis genus, including Oregon Grape and Barberry. By supporting AMPK activity, berberine supports balanced blood glucose levels and insulin activity. (14, 15
  • Quercetin: Quercetin is a phytochemical found in onions, capers, apples, and berries. It modulates AMPK, encouraging a balanced inflammatory response. (16, 17
  • Milk thistle: Milk thistle is a time-honored herb long used in traditional herbalism. Silymarin, a group of phytochemicals found in milk thistle, activates AMPK to support the liver, a hub for metabolic health. (18)

A handful of botanical compounds have also been found to support Nrf2 signaling, including:

  • Milk thistle: Once again, milk thistle emerges as a powerful ally for longevity due to its beneficial effects on Nrf2 expression. Silymarin maintains robust antioxidant defenses by supporting glutathione levels. (19
  • Curcumin: Curcumin is a component of the bright golden turmeric root, a staple of Indian Ayurvedic medicine and cuisine. Curcumin upregulates Nrf2 expression and activity and has been suggested as a long-term botanical intervention for healthy aging. (20)
  • DIM: Diindolylmethane is a sulfur-containing compound found in cruciferous vegetables such as broccoli, cauliflower, cabbage, and kale. It supports detoxification, a balanced inflammation response, a healthy spectrum of estrogen metabolites, and Nrf2 antioxidant activity. (21)
  • CoQ10: Coenzyme Q10 (abbreviated CoQ10) is a fat-soluble antioxidant that is particularly important for the health of lipid-based cellular and mitochondrial membranes. It also upregulates Nrf2 activity. Supplemental CoQ10 modulates oxidative stress, supporting muscle strength, heart health, and brain function with age. (22

Coffee for AMPK and Nrf2 Activation 

Great news! Research indicates that coffee activates Nrf2, meaning your morning cup of Joe could ultimately be supporting your longevity. (23) Phenolic compounds in coffee beans upregulate Nrf2, turning up the body’s cellular antioxidant and detoxification activities. Coffee constituents, such as caffeine and chlorogenic acid, may also upregulate AMPK. (24)

Coffee constitutes the primary source of dietary antioxidants for the vast majority of our global population, making coffee one of the most commonly utilized AMPK activators.

Eat the Rainbow

Don’t forget about the importance of your diet for healthy aging! Time and time again, the diet has been found to play a decisive role in longevity. (25) Part of the longevity-enhancing effects of a healthy diet may be mediated by high intakes of vegetables and fruits rich in phytochemicals that activate Nrf2 activity. (26) Every day, try to eat vegetables and fruits from the following color categories, as each color of vegetable contains different phytochemicals to support Nrf2:

  • Red: Red fruits and veggies contain lycopene, a phytonutrient that scavenges free radicals. Lycopene metabolites have also been found to activate Nrf2. (27
  • Orange and Yellow: Orange and yellow fruits and vegetables, such as yellow bell pepper and winter squash, contain cryptoxanthin, an antioxidant molecule that activates the Nrf2 pathway. (28)
  • Green: Green vegetables, such as broccoli and kale, are rich in phytochemicals, such as sulforaphane, an Nrf2 activator that supports healthy aging. (29)
  • Purple and Blue: Blue and purple vegetables and fruits, such as purple cabbage and blackberries, contain phytochemicals called anthocyanins, promoting DNA integrity. (30

Be sure to choose organic produce as much as possible, particularly for the 12 vegetables and fruits that tend to be most commonly contaminated with pesticides, herbicides, and fungicides, according to the Environmental Working Group (EWG). Pesticides and other agricultural chemicals strain the body’s antioxidant system and add to its toxin burden, two effects that may accelerate aging. (31) Below are the foods recommended by EWG to prioritize when buying organic:

EWG’s Dirty Dozen

  1. Strawberries
  2. Spinach
  3. Kale, collard greens, and mustard greens
  4. Nectarines
  5. Apples
  6. Grapes
  7. Cherries
  8. Peaches
  9. Pears
  10. Bell peppers and hot peppers
  11. Celery
  12. Tomatoes

Exercise & Intermittent Fasting for AMPK Activation and Nrf2 

While most of us think of exercise as a way to lose or manage our weight, it is so much more than a weight loss tool! Exercise is a multipurpose tool for health promotion across the lifespan, with significant implications for the aging process. Exercise helps with blood sugar regulation by activating AMPK signaling in skeletal muscle, promoting the efficient glucose uptake by skeletal muscle in aged individuals, preventing blood glucose from spiking too high, and promoting a healthy metabolism. (32

Exercise also stimulates Nrf2 activity by acutely exposing the body to oxidative stress, which, in turn, elicits Nrf2 activation to repair exercise-induced damage. (33) The process by which intermittent exposure to a stressor, such as exercise, stimulates favorable and beneficial adaptive responses in the body is referred to as “hormetic stress.” In other words, by intermittently stressing your body with regular exercise sessions, you can turn on your internal antioxidant “switch” and DNA repair processes, promoting healthier aging. (34)  

Intermittent fasting, or voluntarily abstaining from food for a set period each day, boosts AMPK activity since the fasting state necessitates that ATP or energy production is produced by existing body fat stores. (35

If you’re someone who envisions living a life that is not just long but full of health and vitality, then you’ll want to prioritize upregulating your body’s AMPK and Nrf2 activity. By strategically weaving potent botanicals, a healthy diet, exercise, and fasting into your routine, you can aid AMPK and Nrf2 and set a trajectory for healthy aging. 

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