Calorie Restriction and AMPK for Longevity

There is a growing interest in how to stimulate healthy aging, no longer simply for the mere desire to extend life, but to do so with quality and good health. In this article we will explore the relationship between calorie restriction and AMPK, two of the most currently under study and promising a great future, highlighting the potential of AMPK modulation as a therapeutic strategy to promote healthy aging and longevity. If you are ready, we will start right now.

Let’s Talk About Aging by Eating Less

Aging is a complex biological process characterized by the progressive decline of physiological function and an increase in the risk of age-related diseases. Despite being an inevitable aspect of life, significant efforts have been made to understand and potentially modulate this process. One of the most studied and promising dietary interventions for promoting longevity is calorie restriction.

This dietary intervention is a valuable strategy for promoting healthy aging. As we said before, one of the most famous is caloric restriction without malnutrition, which significantly increases longevity and delays the onset of diseases and pathologies associated with age in most model organisms and mammals. DOI: 10.1016/j.mad.2005.03.012

The efficacy of this intervention in a clinical setting is limited because it is difficult to maintain for prolonged periods of time. As a result, alternative eating regimens have become increasingly popular, including intermittent fasting and repeated cycles of fasting-mimicking dieting, topics we’ve already covered on our blog.

Defined as a reduction in caloric intake without malnutrition, caloric restriction has been shown to extend lifespan and delay the onset of age-associated disorders in multiple species, including yeasts, worms, flies, rodents, and non-human primates. The mechanisms underlying these effects are not fully understood, but recent research points to the role of cellular energy sensors, particularly AMP-activated protein kinase (AMPK).

AMPK: Cellular Energy Sensor

One aspect of cellular metabolism and energy homeostasis is the maintenance of adenosine derivatives: AMP, ADP and ATP at relatively constant levels.

AMPK is a highly conserved serine/threonine kinase that plays a crucial role in maintaining cellular energy homeostasis. It acts as an energy sensor that activates under conditions of energy stress, such as low glucose levels, hypoxia, or intense exercise. When the intracellular AMP/ATP ratio increases, AMPK is activated, leading to the stimulation of ATP-generating catabolic processes and the inhibition of ATP-consuming anabolic processes.

Through this mechanism, AMPK ensures that the cell adapts to energy shortages.

• It makes energy production pathways, such as glucose uptake and fatty acid oxidation, more efficient.
• It reduces pathways such as protein synthesis and lipid biosynthesis.

Thanks to the regulation of energy balance, AMPK has gained popularity in the context of aging and age-related diseases. As AMPK is a heterotrimeric protein kinase composed of a catalytic subunit (α) and two regulatory subunits (β and γ), they detect low levels of cellular energy (changes in the AMP/ATP ratio). Binding of AMP to the γ subunit induces a change that allows the catalytic subunit α to be phosphorylated and activated by the AMPK-activating protein kinases LKB1 and CAMKKβ. AMP also contributes to AMPK activation by reducing the dephosphorylation of the catalytic subunit α. AMPK coordinates the adaptation of cellular metabolism and growth at reduced energy levels. One of the two α catalytic subunits of AMPK (AMPKα2 or AAK-2) has recently been found to increase longevity. DOI: 10.1016/j.cub.2007.08.047

Calorie restriction and AMPK activation

Among the regulators of caloric restriction, AMPK regulates energy homeostasis by increasing production and reducing energy waste under low-energy conditions. In single-celled eukaryotes, such as yeasts, it directly detects intracellular energy status and modulates fitness in response to nutritional conditions. However, in multicellular eukaryotes, AMPK is ubiquitously expressed and has evolved to perform specific and overlapping functions depending on tissues, such as neuronal and peripheral tissues. In mice, hypothalamic AMPK integrates signals from peripheral tissues through hormones, including leptin and ghrelin, which in turn modulate feeding and metabolism.

In peripheral tissues, such as the liver and muscles, this protein autonomously regulates fatty acid oxidation, lipogenesis, glucose uptake, gluconeogenesis, and protein synthesis through phosphorylation of several targets, including mTOR. These indicate the divergent evolution of AMPK into being a sensor and effector to control the energy homeostasis of the whole organism. However, it remains poorly understood whether AMPK promotes longevity in peripheral tissues or through endocrine signaling initiated in neurons. https://doi.org/10.1038/s41467-023-35952-z

Mechanisms of AMPK-induced longevity

AMPK’s potential to promote longevity can be attributed to several key mechanisms. First, AMPK activation enhances mitochondrial biogenesis, which is essential for maintaining cellular energy production and reducing the generation of reactive oxygen species (ROS). Studies have shown that mitochondrial dysfunction is a hallmark of aging, and by improving mitochondrial function, AMPK helps maintain cellular health.

In addition, AMPK promotes autophagy, a process crucial for the degradation and recycling of damaged proteins and organelles. Enhanced autophagy has been associated with longer lifespan in multiple model organisms, suggesting that AMPK-mediated autophagy could be a vital mechanism for promoting longevity.

Finally, AMPK activation inhibits the mammalian target of rapamycin (mTOR) pathway, a central regulator of cell growth and proliferation. By suppressing mTOR activity, AMPK promotes a state of reduced cell growth and increased resistance to stress, both of which are conducive to longevity.

How to induce AMPK activation

The discovery of the critical cellular functions of AMPK has led to the identification of a large number of products that can activate it. To date, more than 100 natural products have been discovered, many used in Eastern medicine for centuries.

Very few modulate directly to the protein but are expected to have effects independent of the primordial AMPK. For example, salicylate has been shown to bind directly to AMPK, although it also binds to and modulates the activity of other cellular enzymes. Some of these compounds indirectly activate AMPK by inhibiting the mitochondrial respiratory chain, such as berberine. DOI: 10.15190/d.2015.45

Although lifestyle interventions such as calorie restriction and exercise are the most natural ways to activate AMPK, pharmacological agents offer an attractive alternative for people who may not be able to adhere to these practices. In particular, metformin has gained attention not only for its hypoglycemic effects but also for its potential role in promoting longevity. It has been proposed that AMPK activation by metformin leads to improved insulin sensitivity, improved mitochondrial function, and reduced inflammation, all of which are beneficial for healthy aging. Resveratrol, a polyphenol found in grapes and red wine, has also been shown to activate AMPK, mimicking some of the metabolic effects of calorie restriction.

Berberine as an AMPK activator

Evidence has indicated that insulin resistance and cognitive impairment share the same pathogenesis, and berberine could reverse glucose metabolism abnormalities and muscle mitochondrial dysfunction induced by a high-fat diet. Berberine would improve through activation of the AMPK/SIRT1/PGC-1pathway α, age-related reductions in cognitive ability and muscle function in aged rats.

To test this, a study was conducted to investigate whether berberine could be used as an anti-aging drug to prevent cognitive deficits and muscle dysfunction in natural aging. The results showed that administration of this supplement for 6 months significantly improved cognitive deficits and insulin resistance in naturally aged rats.

In addition, berberine treatment helped normalize the disordered alignment and decreased number of muscle fibers in the skeletal muscle of 24-month-old rats. Berberine also decreased ROS levels in both serum and skeletal muscle of 24-month-old rats and increased protein expression of p-AMPK, SIRT1 and PGC-1α, which resulted in an increase in ATP production in the skeletal muscle of those rats. https://doi.org/10.1007/s12603-018-1015-7

Getting to know more about Berberine

Berberine could inhibit mitochondrial respiration by targeting complex I, leading to electron leakage that causes a higher rate of reactive oxygen species (ROS) production in the mitochondria. ROS could transduce signals to the nucleus triggering the oxidation of various Cys reactive residues in a redox-dependent manner.

Redox modification of proteins could translocate and accumulate in the nucleus to induce host antioxidant defense genes, such as mammalian Kelch-like ECH-associated protein 1 (KEAP1), factor 2-related nuclear factor erythroid 2 (NRF2). Berberine was also proposed as a possible anti-aging agent and exhibited a neuroprotective effect through the ROS-mediated pathway.

In this way, a transient increase in ROS levels induced by a low dose of berberine can protect cells through a possible feedback mechanism involved in antioxidant defense or stress defense pathways, such as the Nrf2 signaling pathway, to resist further damage induced by subsequent stress. https://doi.org/10.1186/s10020-020-0136-8

Active Berberina

Salengei’s Active Berberina contains dry extract of barberry (Berberis aristata DC.), as well as white mulberry extract (Reducose®), vitamin E and chromium. It is recommended to administer 2 capsules 10 minutes before one of the main meals. This dosage allows constant maintenance of plasma levels, which favors the sustained activation of AMPK, simulating the beneficial effects of caloric restriction and improving cellular energy efficiency.

The use of berberine-based food supplements, such as Salengei’s, could be a useful tool for those looking to boost AMPK activation through means in addition to dietary and lifestyle changes. However, it is always recommended to consult with a healthcare professional before initiating any supplementation regimen, especially in the context of chronic diseases or the use of other medications.

Conclusion

We have already proven the connection between calorie restriction, AMPK activation, and longevity, which has opened up new avenues for the development of anti-aging therapies. However, translating these findings into clinical practice remains a challenge. Although calorie restriction has been shown to extend lifespan in animal models, in the long term in humans it can be difficult to maintain and not feasible for everyone.

As a result, there is a growing interest in identifying compounds that can mimic the effects of calorie restriction by activating AMPK. Metformin is currently being studied in clinical trials to evaluate its potential as an anti-aging drug, and research on other AMPK activators continues to expand.

At the moment, calorie restriction represents one of the most robust and studied interventions to promote longevity, and its effects are thought to be due, at least in part, to AMPK activation. As the master regulator of energy homeostasis, AMPK improves metabolic efficiency, improves stress resistance, and promotes processes that are essential for cell maintenance and survival.