AMPK Activation: Flip your metabolic “master switch”

Every cell in our body requires a steady supply of energy to function. Cells obtain energy in the form of ATP (aka the energy currency of the cells). Every time you eat, food is broken down and converted into ATP. The body breaks down food into energy sources, such as glucose and fatty acids, which enter metabolic pathways like glycolysis,the citric acid cycle, and oxidative phosphorylation to produce cellular energy. The more ATP, the more energy supply the cell has. When ATP is broken down and used for energy, the end product is adenosine monophosphate (AMP). The citric acid cycle (also known as the Krebs cycle) generates citric acid and other intermediates that are crucial for ATP synthesis and the biosynthesis of amino acids, which are essential for protein synthesis and metabolic processes. AMPK, a critical cellular energy sensor, helps maintain energy homeostasis by regulating the balance between ATP production and consumption.

As cells use up their ATP, AMP levels increase. When AMP increases, this signals to AMPK that cells are in a low-energy state and need more ATP. The cellular energy response triggered by AMPK activation involves turning on pathways that generate more ATP and turning off pathways that require ATP. AMPK activation also suppresses energy consuming processes when cellular energy is low, prioritizing ATP production.

AMPK activation kickstarts fat-burning and enhances glucose utilization, which helps maintain glucose homeostasis and supports metabolic health by lowering blood sugar levels and improving energy balance [1].

It increases fatty acid oxidation, a key energy-producing process that can supply up to 80% of the body’s energy needs during fasting [2].

Clinical trials revealed that chamomile-containing apigenin may contribute to easier wake ups. A study reported that chamomile extract induced a trend towards an improvement in daytime functioning in those with chronic primary insomnia (difficulty falling asleep or staying asleep) [5].

Additionally, research on apigenin suggests that it does not significantly affect body weight, even though it may improve other metabolic markers.

AMPK phosphorylation boosts autophagy, initiating cellular recycling processes that remove damaged components and help keep cells functional and healthy [3]. AMPK mediated phosphorylation reduces protein synthesis by targeting translation initiation factors, which contributes to longevity pathways associated with dietary restriction and mTOR (mechanistic target of rapamycin) inhibition. Additionally, AMPK phosphorylates downstream targets to regulate autophagy and inhibit mTOR signaling, thereby influencing cell growth and metabolism.

It protects cells against senescence caused by oxidative stress, helping preserve cellular function and delay age-related decline [4].

AMPK activation enhances glucose uptake by promoting the transport of glucose into cells, ensuring efficient energy utilization and improved insulin sensitivity.

AMPK inhibits the nuclear factor kappa-b signaling pathway, a major driver of chronic inflammation, thereby promoting a healthier inflammatory balance [5].

It promotes mitochondrial biogenesis, leading to the creation of new mitochondria and enhancing the body’s capacity for energy production [6].

AMPK helps regulate circadian rhythm (our sleep-wake cycle), ensuring that metabolic processes are aligned with the body’s internal clock for optimal function [7].

Influencing cell death mechanisms and apoptosis, particularly under energy stress and DNA damage, AMPK activation helps mitigate cellular damage and promotes metabolic homeostasis.

AMPK activation has been dubbed “geroprotective” because it significantly suppresses several types of age-related damage along with many processes of biological aging by inhibiting mTOR, a regulator of lifespan in animal models [8, 9]. AMPK also helps control cell growth by inhibiting mTOR signaling, which is particularly relevant in the context of cancer cells and tumor suppression. Growth factor signaling interacts with both AMPK and mTOR pathways to regulate cellular proliferation and metabolism. AMPK also activates FOXO proteins, key regulators of evolutionarily conserved longevity pathways, as well as SIRT-1, a sirtuin protein that regulates DNA repair and the epigenome [10].

AMPK has been shown to have pro-longevity effects in several model organisms [10]. Activation of AMPK increased autophagy in the brain and gastrointestinal tract of fruit flies, resulting in a significant increase in lifespan [11]. In rats, AMPK activation also protects against cellular senescence (a process that generates senescent, pro-inflammatory “zombie cells”) by increasing autophagy and reducing oxidative damage [12]. Small molecules, such as metformin and resveratrol, have been shown to activate AMPK and influence pathways relevant to aging in mammalian cells.

Unfortunately, AMPK activation declines with age, impairing metabolic regulation, increasing oxidative stress and inflammation, and decreasing autophagy and resistance to cellular stress [13]. This cascade of dysfunction can also lead to low-grade chronic inflammation (AKA inflammaging) and metabolic disorders [13]. The good news is that lifestyle and supplementation may restore a loss of AMPK activation.

Molecular cellular biology studies have elucidated the structural and functional aspects of AMPK signaling, providing insight into its molecular mechanisms. AMPK substrates are involved in pathways related to aging and lifespan extension, suggesting that further exploration of AMPK’s role in biological processes like mitochondrial function and epigenetics is needed.

AMPK activation supports metabolic homeostasis by enhancing energy balance and insulin sensitivity. AMPK regulation is crucial for maintaining energy balance, as it is influenced by factors such as adenine nucleotides, cellular energy status, and upstream kinases like LKB1. Calmodulin dependent protein kinase (CaMK) is another important upstream kinase that activates AMPK in response to changes in cellular calcium levels.

AMPK is activated when levels of AMP rise as a result of physiological stressors [14]; fortunately, there are some simple everyday habits that can activate AMPK: