The Multipathway Approach to Slowing and Reversing the Aging Process


Throughout history and in folklore, numerous people have sought the Fountain of Youth. This isn’t surprising as some bodily functions deteriorate as we age. On the flipside, we have acquired knowledge and skills—having built our lives—and we want to enjoy old age, not suffer from aches and pains, or look permanently tired.

As a result, people at times go to extreme lengths to stay or look young, ranging from surgery to blood transfusions. Some of these interventions might help, others are experimental and come with extreme risks. Some even lack scientific backup that they actually work!

Thankfully, a lot of scientific research has been done into aging…and how to prevent or even reverse some of the biological mechanisms involved in the aging process.

And this is an important thing to understand before we even begin to look at how to reverse aging—it’s not one biological process that causes aging, but a plethora of different ones.

All the different processes in our body are interlinked, so if you support one, you support the rest. However, to achieve potent results, you need to support more than one process. Think of it like an ecosystem—all the different parts need to function optimally to create a well-working system.

Even what we consider as “one” process in the body, usually happens through different pathways. For example, for metabolism to take place a number of different biological processes occur in the body. And if you want to speed up or slow down the metabolic rate, you can sometimes do so by speeding up or slowing down one single process, or you can look at affecting several processes.

This is what we refer to as the multi-pathway approach to improving health and vitality. Others might use terms like a “holistic” approach, but we want to really zero in on the different biological processes that directly affect one thing or another, so we think this is a more apt description.

Below we dive into what makes us age and the things we can do to slow down or even reverse the process in some instances, showing why the multi-pathway approach is so important. We’ve referenced over 60 different medical papers in this review, so if you want to dive into the science, there’s plenty to read…but if you just want the conclusions we found, have a look at the infographics below.

 

What Happens to Our Body As We Age?

To understand what to do to slow the aging process, we first need to understand what happens in our bodies as we age. Of course, there are a myriad of things going on, but below are some of the main contributing factors to the negative aspects of aging.

Cell Damage

As we get older, our cells accumulate damage from things like stress, toxins, and genetic changes. This damage can make our cells work less well, which affects our overall health. (1)

Decline in Collagen

Production Collagen is like the glue that holds our body together, giving our skin its firmness, our bones their strength, and our joints their flexibility. As we age, we make less collagen, which can lead to saggy skin, stiff joints, and weaker bones. (2)

Decreased Hormone Production of Certain (Not All) Hormones

Hormones are like messengers in our body, controlling things like growth, metabolism, and reproduction. But as we get older, we make fewer hormones, which can cause issues like weaker muscles, slower metabolism, and changes in our ability to have children. (3) (4)

Neurotransmitter Imbalance

Neurotransmitters are chemicals in our brain that help nerve cells communicate. As we age, the levels of these chemicals can change, affecting things like memory, mood, and behavior. (5)

Sirtuin Dysfunction

Sirtuins are proteins that help our cells do important tasks like repair DNA and control inflammation. When sirtuins don’t work properly, it can contribute to problems like diabetes, Alzheimer’s, and cancer. (6) (7)

Mitochondrial Dysfunction

Mitochondria are like tiny power plants in our cells, making energy for everything we do. But as we age, these power plants can get damaged, leading to less energy and more stress in our cells. (8)

Telomere Shortening

Telomeres are like protective caps on the ends of our chromosomes, which hold our DNA. Each time our cells divide, these caps get shorter, eventually leading to aging and changes in how our tissues work. (9) (10)

Inflammation

Inflammation is our body’s way of fighting off infections and injuries, but as we get older, we can have more inflammation even when there’s no threat (usually a low grade chronic inflammation). This can lead to problems like heart disease, arthritis, and memory loss. (11)

Epigenetic Changes

Our genes can be turned on or off by chemical changes in our DNA, called epigenetic changes. As we age, these changes can affect how our cells function and contribute to health problems. (12) Protein Misfolding and Aggregation Sometimes proteins in our body don’t fold properly and can clump together, especially as we get older. This can cause problems like Alzheimer’s and Parkinson’s disease. (13)

Stem Cell

Exhaustion Stem cells are like repair crews in our body, helping to fix damaged tissues. But as we age, we have fewer of these repair crews, which can make it harder for our body to heal itself. (14)

Glycation

Sugars in our blood can stick to proteins in our body and form harmful compounds called advanced glycation end products (AGEs). As we age, these AGEs can build up and contribute to problems like tissue damage and inflammation. (15) As you can see, there are a lot of processes that affect aging. Thankfully, science has started to figure out both what accelerates these processes and what slows them down. We will look at both below.

What Happens to Our Body As We Age?




Things That Can Speed up the Aging Process

While aging is a natural process that occurs over time, certain lifestyle factors and environmental influences can accelerate the aging process, leading to premature aging and increased risk of age-related diseases. Understanding these factors is crucial for promoting healthy aging and longevity.

Below are the things that contribute to speeding up the aging process:

1. Lack of Sleep or Irregular Sleep Patterns:

Poor sleep quality or insufficient sleep disrupts the body’s natural circadian rhythm and impairs various physiological processes involved in repair, regeneration, and immune function. Chronic sleep deprivation has been associated with accelerated aging, cognitive decline, inflammation, and increased risk of chronic diseases. (16)

2. Unhealthy Diet:

A diet high in processed foods, refined sugars, unhealthy fats, and low in essential nutrients accelerates aging by promoting inflammation, oxidative stress, and metabolic dysfunction. Poor dietary choices contribute to the development of obesity, diabetes, cardiovascular disease, and other age-related conditions. Consuming too much food lowers the oxygen levels in our cells, a decline that reduces the amount of NAD+* in the human body, in turn possibly spending up the aging process. An excessive rise in blood sugar levels or reduction in insulin levels also affects the NADH-NAD+ ratio and lowers the NAD+ levels while increasing the risk for diabetes. (17)

3. Sedentary Lifestyle:

Lack of physical activity and prolonged periods of sedentary behavior accelerate aging by impairing cardiovascular health, muscle mass, bone density, and metabolic function. Regular exercise helps maintain physical fitness, mobility, and overall vitality, reducing the risk of age-related decline. (18)

4. Chronic Inflammation:

Persistent low-grade inflammation, often triggered by factors such as poor diet, obesity, a sedentary lifestyle, smoking, and chronic stress, accelerates aging by promoting tissue damage, DNA damage, and cellular senescence. Chronic inflammation contributes to the development of age-related diseases, including cardiovascular disease, arthritis, and neurodegenerative disorders. (19)

5. Chronic Stress:

Prolonged exposure to psychological or physiological stress accelerates aging by dysregulating stress hormone levels, impairing immune function, and promoting oxidative stress and inflammation. Chronic stress has been linked to accelerated telomere shortening, cellular aging, and increased risk of age-related diseases. (20)

6. Excessive Sun Exposure:

You need sunlight exposure to stay healthy, but too much can be damaging. Ultraviolet (UV) radiation from the sun accelerates skin aging by promoting the formation of free radicals, DNA damage, and collagen degradation. Chronic sun exposure leads to the development of wrinkles, age spots, and an increased risk of skin cancer. (21)

7. Environmental Toxins:

Exposure to environmental pollutants, heavy metals, pesticides, and other toxins accelerates aging by promoting oxidative stress, inflammation, and cellular damage. Environmental toxins contribute to the development of age-related diseases and impair overall health and longevity. (22)

8. Smoking and Excessive Alcohol Consumption:

Tobacco smoking and excessive alcohol consumption accelerate aging by promoting oxidative stress, DNA damage, inflammation, and cellular dysfunction. Smoking and heavy alcohol use increase the risk of premature aging, cardiovascular disease, cancer, and other age-related conditions. Oxidation of alcohol by antidiuretic hormone also reduces the oxidized NAD+. (23) (24)
In summary, several lifestyle factors and environmental influences can accelerate the aging process and increase the risk of age-related diseases.

That said, even if you have led an unhealthy lifestyle for some time, by changing your habits now, you can prevent further damage and potentially even reverse some of the damage done.

*NAD+ stands for nicotinamide adenine dinucleotide, and is something needed for various cellular processes.

 

Combating Aging—Scientifically Proven Methods

Above we looked at various things that cause the body to age which, in turn, can lead to impairment of bodily and cognitive functions as well as increased risk for various diseases. So what can we do to prevent this from happening?

Unfortunately, there’s no magic bullet. You will age. Your body will change. But there are ways of slowing down the process. In fact, some research suggest that some things can make you younger than what is considered your biological age. Below you will find what research has discovered so far.

Cellular Damage:

  • Antioxidants: Studies consistently support the potential of various antioxidants (naturally found in fruits, veg, etc.), like Vitamin C, Vitamin E, and polyphenols, in combating free radical damage linked to aging. However, definitive conclusions about their impact on lifespan are yet to be drawn. (25)
  • Increasing  NAD+: Research suggests that strategies to increase NAD+ levels, like supplementing with the NAD+ precursors nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), as well as improving the pathways to turn the precursors into NAD+, and minimizing the pathways that would use up NAD+ (which when combined is a multi-pathway approach) might activate sirtuins. Sirtuins have been shown to promote DNA repair and cellular stress resistance, potentially mitigating cellular damage. However, long-term human trials are needed to confirm their efficacy and safety. (26)



Collagen Decline:

  • Vitamin C: Plays a crucial role in collagen synthesis. While topical application may improve skin appearance, evidence for oral supplementation impacting overall collagen levels is inconclusive. (27)
  • Hydrolyzed collagen supplements: Some studies suggest modest improvements in skin elasticity with supplementation. However, more research is required to draw definitive conclusions. (28)
  • Retinoids (vitamin A): Prescription and over-the-counter retinoid products have been shown to stimulate collagen production and improve skin appearance. (29) (30)
  • NAD+: NAD+ acts as a cofactor for enzymes involved in collagen synthesis, potentially supporting tissue integrity and skin health. (31)

Hormone Decline:

  • Hormone Replacement Therapy (HRT): This requires strict medical supervision due to potential risks, but it
  • can help manage symptoms and improve quality of life for some individuals. (32)
  • Lifestyle changes: Maintaining a healthy diet, engaging in regular exercise, and managing stress can positively influence hormone levels and overall health. (33)
  • NAD+: NAD+ may regulate the activity of enzymes responsible for hormone synthesis and metabolism, potentially mitigating age-related hormonal changes. (34)

Neurotransmitter Imbalance:

  • Balanced diet rich in Omega-3 fatty acids: Studies suggest these fatty acids found in fish, nuts, and seeds support brain function. (35)
  • Exercise: Promotes neurotransmitter balance and mood regulation. (36)
  • Mindfulness and stress reduction: Practices like yoga and meditation can help manage stress, which can influence neurotransmitter function. (37)
  • NAD+: Is essential for maintaining neurotransmitter balance and cognitive function. (38)
  • Medications: Antidepressants and anti-anxiety medications, as well as specific herbs, such as St. John’s Wort (Hypericum perforatum), can be helpful in specific cases if used under medical supervision. Please note that even herbal extracts that might alter serotonin levels, such as St. John’s Wort, can have severe side effects and often can’t be taken with other medications especially NOT antidepressants (it can even be fatal) and you should always seek medical care before trying either herbs or medications for depression. (40, 41, 42)

Sirtuin Dysfunction:

  • NAD+ boosting strategies: As mentioned above, research on NR and NMN supplementation is ongoing to explore their potential role in activating sirtuins. Sirtuins play a role in various cellular processes, including metabolism, DNA repair, and inflammation. (43)
  • Calorie restriction: Studies in animals show calorie restriction activates sirtuins. However, long-term effects and feasibility in humans are unclear. (44)
  • Resveratrol: This polyphenol shows promise in sirtuin activation in studies, but human evidence needs further research. Resveratrol is found in blackberries, grapes, dark chocolate, mulberries, peanuts, pistachios, grape juice, and red wine, among other things. (45) (46) (47)
  • Exercise: SIRT1 and SIRT3 appear to be activated by exercise. (48)
  • Sirtuin activating compounds (STACs): Researchers are investigating compounds and molecules beyond resveratrol that might directly enhance sirtuin activity. (49) > reference

Mitochondrial Dysfunction:

  • Exercise: Regular physical activity promotes mitochondrial health and function. (48)
  • Coenzyme Q10 (CoQ10): This antioxidant plays a role in mitochondrial energy production. Studies on its impact on aging are ongoing. (50)
  • Alpha-lipoic acid: Another antioxidant with potential benefits for mitochondrial health, but further research is needed. (51)
  • NAD+: Supports mitochondrial function by acting as a cofactor for energy production enzymes, potentially promoting mitochondrial health and energy production. (52)
  • Sirtuins: Research suggests that sirtuins might regulate cellular metabolism, influencing mitochondrial function. However, further investigation is needed to clarify this link. (53)

 Telomere Shortening:

  • Telomerase activators: Research is ongoing, but these are not yet recommended for general use due to safety concerns. (54)
  • Healthy lifestyle: Factors like stress management and a nutrient-rich diet might have a small protective effect, but research is ongoing. (55)
  • NAD+: Might play a role in telomere maintenance and genomic stability, potentially slowing down cellular aging. (56)

 Inflammation:

  • Anti-inflammatory diet: Emphasize fruits, vegetables, whole grains, omega-3 fatty acids, and limit processed foods. (57) You can read more here and here if you are looking for a diet plan.
  • Regular exercise: Reduces chronic inflammation. (58)
  • Stress management: Techniques like mindfulness and meditation can dampen the inflammatory response. (59)
  • NAD+: Adequate NAD+ levels may help modulate inflammation, potentially mitigating the effects of chronic inflammation on health and longevity. (60)
  • Curcumin: Curcumin, the active compound in turmeric, has been extensively studied for its anti-inflammatory effects and its ability to modulate inflammatory pathways. (61)
  • Probiotics: Probiotic supplements containing beneficial bacteria can help promote a healthy balance of gut microbiota, which in turn may reduce systemic inflammation (there also appears to be a link to better brain health, including mood). (62)

Epigenetic Changes:

Research is ongoing to investigate the potential of different interventions to modulate epigenetic changes, but there are currently no definitive recommendations for the general population. (63) (64)


Protein Misfolding and Aggregation:

Sirtuins may play a role in protein quality control and preventing protein misfolding. However, this area requires further research, and there are currently no definitive recommendations. (65) (66) (67)

Interestingly, almost all of the above is related to the sirtuins and the coenzyme NAD+ which is needed for sirtuins to “work.”

In addition, a lot depends on getting rid of or preventing inflammation. A poor lifestyle and aging can both cause inflammation, which in turn causes some of the age related symptoms, including a decrease in NAD+.

Your body is an ecosystem, which is why the multi-pathway approach is so crucial, both when it comes to lifestyle and supplements. 

The Different Pillars for Slowing the Aging Process

It can be overwhelming looking at all the science behind aging and what’s scientifically been proven to show promines when it comes to slowing or reversing the aging process. However, the steps you can take are actually pretty simple!

Below is a summary of what you can do that might reverse or slow the aging process:

Lifestyle Choices

  • Eat well (an anti-inflammatory diet)
  • Sleep well (go to bed at the same time every night and get enough sleep)
  • Spend time in nature (improves the immune system and reduces stress)
  • Exercise (including some cardio)
  • Meditate d do breathing exercises (reduces stress)

Supplements

  • A multivitamin—take it a couple of time per week, or as prescribed by a healthcare professional (it helps checking if you suffer any deficiencies, and also note that eating too much vitamins is not healthy)
  • Alpha-lipoic acid
  • Co-enzyme Q10
  • Omega-3
  • Resveratol and resveratrol containing compounds
  • NAD+ precursors and supplements that support the making of and levels of NAD+ in the body
  • Sirtuin precursor and supplements that support the making of and levels of NAD+ in the body
  • Antioxidants (also found in fruits, veg, herbs, tea, coffee, etc.)
  • Anti-inflammatory herbs and spices, incl.: curcumin (as a supplement that increases its bioavailability), ginger, cloves, rosemary, and cayenne pepper
  • Probiotics

Seeing it like this hopefully helps make it easier to grasp, but what also, hopefully, becomes clear is that beyond a holistic approach to your lifestyle, you also need a holistic, or multi-pathway approach where supplements are concerned.

Put this way: you need to support several bodily functions at the same time whether you want to fight inflammation, or increase NAD+ and sirtuin levels.

Seeing it like this hopefully helps make it easier to grasp, but what also, hopefully, becomes clear is that beyond a holistic approach to your lifestyle, you also need a holistic, or multi-pathway approach  where supplements are concerned.

“Put this way: you need to support several bodily functions at the same time whether you want to fight inflammation, or increase NAD+ and sirtuin levels”.

The Multi-pathway Approach—What Good Supplements Do

The issue with many supplements, as explained, is that they provide one thing or another, but not the entire chain of things the body needs to, for example increase the amount of NAD+ available in the body.

For instance, you can take a vitamin A supplement, but if your body cannot convert vitamin A into what it needs (synthesize it), or is using up all the vitamin A because something’s out of balance, then the supplement doesn’t work as intended.

Likewise, if you lead an unhealthy lifestyle, your body is constantly struggling to perform its functions. Supplements can help it perform those functions better, but they can’t entirely fix the problem.

However, even when leading the best of lifestyles, as we age, our body naturally deteriorates. Certain things start to malfunction due to wear and tear. To help boost your cells and bodily functions, you have to look at correcting all the imbalances, not just one. That way, your body starts repairing itself again. 

If you look at a great NAD+ supplement, it shouldn’t just contain nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), as well as tryptophan, but also support the various pathways for converting them into NAD+ and keeping those NAD+ levels stable. 

Here’s a breakdown for what you should expect from a good NAD+ supplement:

  • Boost NAD+ precursors
  • Promote NAD+ synthesis (i.e. for the body to create NAD+ from the precursors—there are many ways of doing this, including increasing NAMPT, activate SIRT1, and increase the de Novo pathway)
  • Reduce NAD+ consumption by lowering excessive PARP activation (PARP repairs damaged DNA and plays a crucial role in health, but with age it can become over activated, using up too much NAD+)
  • Prevent oxidative stress (i.e. the supplement should contain antioxidants as oxidative stress depletes NAD+ due to PARP activation)
  • Decrease chronic inflammation (which activates CD38, which in turn depletes NAD+)

Various botanical ingredients have been proven, at least tentatively, to tackle all of the above.

Interestingly, working with the above pathways also helps to boost sirtuin levels. So with sirtuin supplements it’s therefore necessary that they don’t just boost NAD+ (which is needed for them to function), but also deal with the above.

If you’re curious about what sirtuins actually do, here’s a breakdown for you (and it’s pretty incredible when you see everything they’re involved with!):

  • Sirtuins 1,3, and 7 work together for DNA repair and regulation, stem cell activity, fights inflammation, etc.
  • Sirtuins 1,3, and 7 oversee DNA repair and regulation.
  • Sirtuins 1, 3,4 and 5 work together to control cell respiration, i.e., energy production, mitochondria formation and activity.
  • Sirtuins 2 and 5 regulate immune response.
  • Sirtuins 1 and 6 coordinate endocrine hormone functions and insulin, IGF-1 activities.
  • Sirtuins 2, 3, 6, and 7 control aspects of the rate of the aging process.
  • Sirtuins 1, 4, 5, 6, and 7 regulate metabolism of fats, cholesterol, glucose, and protein synthesis.
  • Sirtuins 3, 4, and 5 are important for certain vital organs including the heart, brain, liver, and kidneys.
  • Sirtuins 2, 5 and 6 regulate stem cell activity.
  • Sirtuins 1, 2 and 5 regulate autophagy and apoptosis, processes involved in removing damaged cells and recycling older or damaged cell parts, respectively.
  • Sirtuins 2, 3, and 6 helps with adapting to cell and organism stress.
  • Sirtuins 2 and 6 regulate oxidative stress response and antioxidant activity.

Just remember: it’s not just about boosting NAD+ and sirtuins, but also about fighting inflammation and leading a healthy lifestyle. Those are probably the three most important pillars when it comes to slowing down the aging process.

 

The Conclusion—What Slows and Reverses Aging

To slow the aging process it’s incredibly important to lead a healthy lifestyle. As we become more prone to inflammation as we age, it’s also important to fight inflammation, both through lifestyle and supplements. In addition, as NAD+ and sirtuins are involved in almost everything to do with the aging process, taking supplements that boost and activate them is important. NAD+ naturally declines with age, so that’s why a healthy lifestyle alone is not enough.

When considering what supplements to choose it’s important to note that sometimes providing a certain compound or precursor isn’t enough—you also need to reinforce the pathways that help the body make use of it. For example, B vitamins are needed for NAD+, but if the pathways to transform them into NAD+ aren’t working properly, the B vitamins alone aren’t enough. Likewise, inflammation causes depletion of NAD+ so you need to fight inflammation for NAD+ levels to rise, or else all the NAD+ will be used for that.


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