Unlocking the 4 Longevity Pathways

In a nutshell

The four molecular pathways of mTOR, IIS, sirtuins, and AMPK play integral roles in our bodies’ aging processes. These pathways are often referred to as longevity pathways because they have been shown to affect the lifespan.
mTOR and IIS, pathways that promote cellular growth, are more active when nutrients are abundant. Conversely, sirtuins and AMPK, which play crucial roles in cellular repair and energy production, thrive during times of energy and nutrient scarcity. As such, inhibiting mTOR and IIS and boosting sirtuins and AMPK may hold the key to enhanced longevity judging from the experiments on animal models.
In this article, we explain the science behind each of these pathways and suggest lifestyle and pharmacological interventions that are known to affect these molecular cascades. By understanding these pathways, you can apply the knowledge to your everyday life to positively influence your aging process.

Is aging inevitable, or can we slow it down… or even reverse it? Experts believe that we can regulate the pace at which we age. It can be done by switching on longevity pathways in our bodies. So far, there are four of them well-known and described.¹ These pathways are, in essence, channels through which our cells in the body communicate with each other; they are called nutrient-sensing pathways.

These pathways regulate cellular metabolism by coordinating how cells utilize nutrients and energy to support various cellular functions, including growth, repair, and maintenance. They are sensitive to levels of energy and nutrients coming from food, such as amino acids, glucose, and fatty acids.

With aging, these longevity-regulating pathways get impaired and deregulated, leading to the development of chronic health conditions. In fact, nutrient-sensing dysregulation is one of the hallmarks of aging. Let’s have a closer look at each of these pathways.

1. mTOR pathway

The mTOR (mechanistic target of rapamycin) pathway is a cellular signaling pathway that plays a critical role in regulating protein synthesis, cell growth, metabolism, and autophagy (a process in which the cell breaks down and recycles its own components).

This pathway is responsible for muscle growth, forming new blood vessels (including those in cancer), and boosting overall cell metabolism. The pathway is activated by various signals, including growth factors, nutrients (such as amino acids and glucose),² ³ and energy levels (ATP). ⁴

Activation of the mTOR pathway has been associated with accelerated aging and developing various hallmarks of aging, including nutrient sensing deregulation, mitochondrial dysfunction, and stem cell function decline.⁵ In contrast, inhibiting mTOR has been demonstrated to extend lifespan and improve healthspan. However, it is important to mention that these conclusions are drawn from the experiments on animal models. So, in the longevity community, there is a camp of researchers thinking that the same rules can be applied to human subjects, given that mTOR is a very conservative protein present across all the species of the animal kingdom.

On the other hand, mTOR plays an important role in muscle maintenance and growth. And it is also critical to maintain adequate muscle mass for healthy aging and longevity. Studies have shown that muscle mass is inversely related to the risk of falling in older age and the risk of dying from fall-related consequences. Therefore, probably the best approach so far is to maintain a balanced level of mTOR activity to support muscle growth while preventing excessive activation that may contribute to aging.

Conclusion on mTOR

You don’t want to overstimulate the mTOR pathway for longevity purposes, but you want to keep it in balance.

What activates mTOR?

1. Amino acids (especially L-leucine and serine) from food sources, mostly meat protein⁶ ⁷2. Insulin and glucose⁸

What inhibits mTOR?

1. Calorie restriction and fasting⁹
2. Food high in polyphenols ¹⁰
3. Supplements such as resveratrol, curcumin, and quercetin ¹¹ ¹² ¹³

How to keep mTOR in balance?

Alternate periods of scarcity when you practice intermittent fasting or calorie restriction with periods of abundance when you take enough protein and exercise to build muscles. A longevity expert, Dr.David Sinclair, in this clip, explains his strategy. He keeps mTOR downregulated during most of the week by fasting, having a diet full of polyphenols, taking metformin, and alternating this period with a few days a week of exercising and protein consumption.

2. IIS pathway

The IIS (insulin/insulin-like growth factor) longevity-regulating pathway is another important cellular growth and metabolism regulator. It is activated by insulin and insulin-like growth factors (IGF), mainly IGF-1 in response to nutrient availability, promoting cell growth and division.

IGF-1 stimulates the growth of all cell types and is mainly sensitive to the levels of proteins in the blood. ¹⁴ Circulating IGF-1 signals cells that nutrients are abundant for cells to undergo hypertrophy and cell division. This is one of the reasons why increased levels of IGF-1 are associated with cancer and cancer growth.¹⁵

Inhibition of the IIS pathway in mammals has been shown to extend lifespan.¹⁶ Also, it has been noticed that centenarians have significantly lower levels of circulating IGF-1.¹⁷

Conclusion on IIS

For longevity purposes, you don’t want to have high levels of circulating IGF-1.

What activates the IIS pathway?

1. Protein¹⁸2. Dairy food¹⁹

What inhibits the IIS pathway?

1. Low-protein diet²⁰2. Caloric restriction and fasting²¹ ²²
3. Low-intensity aerobic exercise²³4. Dietary folate.²⁴

3. Sirtuins pathway

A family of proteins called sirtuins regulates the sirtuins pathway. These proteins play an important role in aging²⁵ and can effectively counteract some hallmarks of aging.²⁶

Sirtuins control many processes, including DNA repair, genome stability, inflammatory response, apoptosis, cell cycle, and mitochondrial functions.

Conclusion on Sirtuins

Given the vital role of sirtuins in genomic stability and DNA repair, you would like this pathway to be active in your body.

What activates sirtuins?

1. Increased NAD+, which can be achieved either through any type of exercise (aerobic, HIIT, vigorous training),²⁷ or NMN or NR supplements²⁸
2. Nutrient scarcity and fasting, like caloric restriction and intermittent fasting²⁹
3. Supplements, including resveratrol, curcumin, fisetin, and quercetin³⁰

What inhibits sirtuins?

1. Nutrient abundance
2. Low levels of NAD+

4. AMPK pathway

AMPK (adenosine monophosphate-activated protein kinase) is an enzyme in our cells that plays a critical role in energy homeostasis. It activates the glucose uptake by tissues from the bloodstream and the oxidation of fatty acids.

The evidence is growing that boosting AMPK activity can prevent and even reverse some age-related changes in the body, as shown in humans. ³¹ ³² In animal models, activation of the AMPK pathway extended the lifespan.³³ ³⁴

Conclusion on AMPK

Due to its effect on glucose metabolism, it is important to keep AMPK levels high to prevent insulin resistance and, as a consequence, type 2 diabetes in the long run.

What activates AMPK?

1. Low ATP levels (cells’ energy currency) that can be achieved through regular moderate exercise³⁵
2. Calorie restriction or fasting³⁶ are great ways to keep the level of AMPK activity high. Cold/heat exposures also can activate this pathway.³⁷
3. A prescribed drug for diabetes, metformin³⁸
4. A non-prescribed alternative to metformin, called berberine ³⁹

What inhibits AMPK?

1. Insulin resistance during obesity⁴⁰

So, keeping a healthy BMI, eating a healthy balanced diet, and keeping your glucose post-meal peaks under control to avoid the development of insulin resistance is important. Some tricks on how to keep glucose levels under control without major changes in diet can be found in Fast Hacks for Managing Blood Glucose Levels.

Interaction between longevity pathways

Scientists have found that four different pathways – mTOR, sirtuins, AMPK, and IIS – can all impact on how long we live. But what’s really interesting is that these pathways all work together and affect each other in different ways.⁴¹

An example of this is how all four pathways are influenced by nutrient availability. Additionally, they have the ability to potentiate or suppress each other. For instance, during starvation, AMPK is activated and it changes intracellular metabolism in a way that leads to increased NAD+ levels in cells. This results in a rise in sirtuins activity. Situins, in their turn, will downregulate the IIS pathway.⁴².

Moreover, activation of AMPK causes some suppression in mTOR activity.⁴³ So, this is amazing how with one simple lifestyle intervention like fasting, one can simultaneously activate many longevity switches in the body.

Recap and final thoughts

In conclusion, we’ve delved into the intricate science behind the longevity pathways—mTOR, IIS, sirtuins, and AMPK—and how our lifestyle choices and potential pharmacological interventions influence them. This knowledge is not just for understanding but for transforming our approach to aging, with the promise of nurturing our healthspan alongside our lifespan.

However, it’s crucial to remember that these pathways are part of an intricate biological ballet, with each element playing a vital role. Notably, the mTOR pathway, while its inhibition might appear to extend life based on animal studies, is also essential for muscle maintenance—an aspect crucial to healthy aging. It’s a delicate balance and a subject of ongoing scientific debate.

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