If there is one health-related topic that we can agree on, it is that we all want to live longer. Anti-aging research has progressed to a respectable point where we can draw on science to employ lifestyle, diet and supplement interventions that promote longevity.  While it may be unknown how much longer we can extend our lives with these tactics, we can be reassured that taking many of these steps will, at a minimum, enhance our quality of life.  Notwithstanding, there are still more unanswered questions in this field of research than answered ones.

There are many theories of aging and possibly nine (9) or more causes that collectively contribute to aging.  Nevertheless, there are four (4) major associated pathways that we know from research that we can target with the hope of adding a decade or two to our lifespan (1).  These include:

  • mammalian target of rapamycin (mTOR);
  • adenosine monophosphate-activated protein kinase (AMPK);
  • silent information regulators (SIR) or sirtuins;
  • nuclear factor-kappa B (NF-kB).

The focus of this article is to demystify these pathways, and demonstrate lifestyle and diet choices that most effectively target these pathways in a synergistic manner, so you can save time and money.  Product/supplement recommendations will follow in Part 2 of this article series and will be geared to whole food options and full spectrum extracts.  As you will find out below, exercise, fasting, a polyphenol/ phytochemical-rich diet, cold and hot stress, are our best bets for living longer and healthier until more and better research comes in.

mTOR

mTOR is a cellular pathway that acts as a signaling controller for cell growth and lifespan, metabolism, and propagation (2). The mTOR pathway regulates processes that convert or utilize energy and nutrients. Essentially, mTOR reacts to nutrients and calories in determining if times are plentiful or stressful; mTOR ramps up if energy and nutrients are in abundance and ramps down in times of stress, such as in caloric restriction (3).  Dysfunctional mTOR controlling prompts several detrimental cellular actions, such as those correlated with multiple types of cancers (4).  Overactivation of mTOR is linked to many aging-related diseases and conditions, therefore approaches to lower or normalize its activity are a prudent way to proactively promote cellular longevity (5).  Exercise activates mTOR the desired way, by increasing activity primarily in the muscles and brain (6).  Generally speaking, increasing AMPK will inhibit mTOR.

The primary way to inhibit the mTOR pathway is through caloric restriction (CR).  Supplements and food compounds that target this pathway in a similar manner to CR are considered caloric restriction mimetics.  Food sources should be pursued at this time since there has been lack of human studies affirming the anti-aging potential of many of these compounds.

Best mTOR inhibitors:

  • Calorie restriction (7)
  • Plant phytochemicals including polyphenols, terpenes and glucosinolates / isothiocyanates (e.g. resveratrol, pterostilbene, quercetin, curcumin, anthocyanins, sulforaphane, thymoquinone and catechins like epigallocatechin gallate) (8) (9)

AMPK

AMPK is a cellular energy controller that adjusts how and by which our body utilizes and converts energy.  AMPK levels decrease as we age.  Higher levels of AMPK guard our bodies against diabetes, obesity, and accelerated aging (10).

Studies show that increased AMPK activity is linked to an increased lifespan by up to 20%.  Increased AMPK has been found to reduce multiple markers of aging including body-fat, blood sugar, blood lipid levels, and inflammation (10) (11) (12).   Activating AMPK also protects against dementia, memory impartment and hypertension (13) (14) (15).

Best AMPK activators:

  • Calorie restriction(16)
  • Exercise(17) (18)
  • Reducing inflammation(19)
  • Cold and heat stress(20) (21) (22)
  • Plant phytochemicals including polyphenols, terpenes and glucosinolates / isothiocyanates (e.g. resveratrol, pterostilbene, quercetin, curcumin, anthocyanins, sulforaphane, thymoquinone and catechins like epigallocatechin gallate)(23) (24)
  • Trace minerals including lithium, boron; minerals such as zinc and selenium; and Vitamin C (25)(26)

SIRT

Sirtuins work amongst many cellular pathways that control apoptosis (programmed cell death), turn anti-aging genes on and off, help repair DNA and regulate metabolism. SIRT also plays an important role in blood sugar control and insulin sensitivity (27) (28) (29).  SIRT genes require nicotinamide adenine dinucleotide (NAD+) for their activation.  NAD+ is found in all cells and is required for the proper functioning of mitochondria (the “working engine” of the cell) since it facilitates the transfer of energy from the foods we eat into forms utilized by the cell.  NAD+ is also required for “turning off” genes that are associated with accelerated aging.  Like AMPK, NAD+ levels decrease with age (30).  Sirtuins also play a role in mitigating the shortening of telomeres (like “caps” on the end of DNA strands, serving to protect the chromosomes within).  The shortening of telomeres is associated with a shortening of lifespan (31).

Caloric restriction is the most powerful way to activate SIRT enzymes.  This happens through increasing NAD+ levels which, in turn, activate anti-aging SIRT genes (32) (33) (34) (35).  SIRT activation inhibits mTOR and insulin growth factor 1 (IGF-1) (36) (37).  An increase in NAD+ results in increased activity of AMPK.

Best SIRT activators (38) (39):

  • Calorie restriction or fasting (40)
  • Cold and heat stress (22)(41)(42)
  • Plant phytochemicals including polyphenols, terpenes and glucosinolates / isothiocyanates (e.g. resveratrol, pterostilbene, quercetin, curcumin, anthocyanins, sulforaphane, thymoquinone and catechins like epigallocatechin gallate) (23)(24)(43)
  • Sun (nitric oxide, vitamin D, and proper circadian rhythm) (44)(45)
  • Exercise (46)(47)
  • Fish oil (primarily DHA) (48)
  • Magnesium (49)

NF-kB

NF-kB is the central mediator of the immune response, in other words, the master switch for inflammation.  It is a like a super sensor detecting threats like free radicals, bad bacteria infiltration, and infections.  With age, NF-kB expression increases resulting in chronic inflammation and in the body overreacting to “threats”.  This is extremely important because chronic inflammation is related to numerous age related diseases and conditions; in fact, it is associated with 98% of the age related degenerative conditions including cancer, heart disease, diabetes, neurodegeneration (50).  Obviously, NF-kB activity is something we want to control if we are aiming to increase our life and health span. Inflammatory responses related to exercise are beneficial and necessary.  Inhibiting the inflammatory response post-exercise may negate the benefits of exercise.

It also important that your PON1 gene is functioning optimally.  PON1 is one of the most studied genes and plays a critical role in cardiovascular risk, oxidative stress and inflammation.  Its enzymes are also responsible for breaking down chemicals that are detrimental to human health.  Recent systems biology perspectives on longevity have identified that PON1 and NF-kB are linked, shedding light on the importance of both in inflammation (51) (52).  Undertaking a Nutrition Genome analysis will identify polymorphisms in your PON1 and recommend ways for improving gene function.  Lucky for us, PON1 gene function increases by many of the same inhibitors of NF-kB, which you can read more about here.

Best NF-kB inhibitors:

  • Sleep (proper circadian rhythm and melatonin levels)(53) (54) (55)
  • Yoga, meditation and reducing phycological stress(56) (57) (58)
  • Calorie restriction or fasting(59)
  • Fish oil (EPA and DHA)(60)
  • Anti-inflammatory foods and plant phytochemicals including polyphenols, terpenes and glucosinolates / isothiocyanates (e.g. resveratrol, pterostilbene, quercetin, curcumin, anthocyanins, sulforaphane, thymoquinone and catechins like epigallocatechin gallate)(61) (62)
  • Magnesium (63)
  • Vitamin D (64)
  • Heat stress (65)

What do all these pathways have in common?

Here is the good news:  these four pathways interact with each other and in most cases inducing the beneficial effect on one pathway typically does so on other linked pathways.  This allows us to target multiple pathways with one lifestyle or diet intervention; killing multiple birds with one stone if you will.

Looking at these pathways holistically, what do they all have in common?  What do they tell us about longevity? The answers to these questions can be distilled into the following:

  • We need to keep inflammation low;
  • We must ensure essential hormones, vitamins and minerals are present in the body at adequate levels to not inhibit cellular and enzyme activity;
  • It is important that we maintain insulin sensitivity and glucose tolerance (and are metabolically flexible);
  • Implementing lifestyle and diet changes (at the right dose) that stress the body in a positive manner (i.e. hormesis), invoke a stress response that targets nearly all these pathways in a beneficial way; truly embodying the expression “what doesn’t kill us makes us stronger”.

Furthermore, with a review of all the noted strategies to inhibit or activate these pathways, we can safely conclude that the cheapest ways are still the best ways to target the mTOR, AMPK, NFkB and SIRT pathways (66).  To reiterate, these lifestyle and diet strategies are:

  • Eating a diverse healthy diet with many plant phytochemicals;
  • Heat stress;
  • Cold stress;
  • Caloric restriction / fasting;
  • Exercise;
  • Meditation / psychological stress reduction.

Below is a visual depiction of how these four pathways interact.  Note the relationship between the pathways and inflammation, energy/calories and insulin.  A few select food compounds are included to demonstrate how they target these pathways through activation or inhibition.

Figure 1 – Interactions of longevity pathways with select supplements (arrow represents activate; arrowless represents inhibit)

Source:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2504011/figure/F1/

While some phytochemical compounds  (polyphenols in most cases) have been touted as anti-aging such as those listed in this article and Figure 1, this does not imply other phytochemicals are ineffective; it more accurately means that science has yet to catch up with the plethora of beneficial plant phytochemicals that we ingest through foods, herbs, and teas.  Since there are thousands of these compounds present in plants and foods, it will take time before scientists can test each for their effects on longevity pathways. Our judgement is that many of these “yet to be studied” compounds will produce similar results as to those already studied more extensively, especially if they are in the same phytochemical family (e.g. resveratrol is a stilbene, so it should not be a surprise that pterostilbene is also effective since it is in the same chemical family).

As you may have presumed by now, here at The Health Beat we are not fond of extracts of isolated compounds, since whole foods, (and potentially full spectrum extracts) include co-factors, synergistic compounds and “checks and balances” that isolated compounds do not.   We have evolved alongside these plant chemicals that provide a positive stress response when consumed in food form, so it is logical to hypothesize that the natural doses present in food (with co-factors) affect our cells the most beneficially, especially over the long term.  The Health Beat takes a food first approach; therefore, pharmaceuticals and high dose isolated extracts will not be recommended for daily use.  A herbal or food alternative will instead be identified for consideration in your anti-aging regime, not a laundry list of pills to pop which would only be speculative, may be unsafe (especially with chronic use) and can be very expensive.

There is no exception to the above principle in the analysis of these longevity pathways.  Isolated compounds identified as promising have mostly only been studied extensively in vitro and in vivo animal studies and lack human studies to affirm their efficacy as anti-aging supplementation (66).  Furthermore, it is important to not neglect critical vitamins and minerals related to nearly all processes in the body including, but not limited to, Magnesium, Vitamin D,  B vitamins, Vitamin C, trace minerals (e.g. Boron, Lithium), Selenium, and Zinc.  Remember:  22% of all enzymes require a micronutrient to function (67).  Only when we have supplied our bodies with adequate macro and micronutrients can we then look to improve upon our genetic baseline.  Nutrition Genome is a tool that may be used to maximize the potential of our genes since some of us, with our gene mutations, may need more or less of these critical vitamins and minerals.  For a more detailed article on the necessity of nutrients in the body, read this article.

Some Major Questions Regarding Longevity Still Remain

Lastly, longevity research still has more unanswered questions than answered ones. Having said that, there are some important facts that we currently do know:

  • we do not know how multiple anti-aging strategies interact(68);
  • most chemical compounds and supplements have yet to be extensively tested in humans(68);
  • doses in studies are usually unpractically high and we do not know the effects of long-term use at those levels;
  • high doses of isolated phytochemical/polyphenols may be detrimental (69)(70);
  • small chronic doses of studied compounds (and in a food matrix) seem to be more effective, and are more in line with what humans would have evolved consuming (71)(70);
  • Diminishing returns result as we compound these lifestyle and diet habits; the same goes for supplements, antioxidants, and phytochemical ingestion; CR mimetics and fasting seem to have reduced impact the better the diet, and the healthier and fitter one is (72)(70); we suspect the same applies to the “stacking” of hormetic strategies (i.e. more is not necessarily better; we need to find the right “dose” and attempt to get the maximum benefit for the least effort).

Until research tells us otherwise, the recommendations herein and in Part 2 of this article series take a conservative pragmatic approach. The recommendations focus on nutritional synergies and count on the checks and balances of phytochemical, micronutrient, mineral, macronutrient complexes that are natural to whole foods.

 

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