AMPK: The Secret to Slowing Aging
AMPK: The Secret to Slowing Aging
As we age, the activity of AMPK (AMP-activated protein kinase) tends to decline, which can lead to reduced cellular energy metabolism efficiency and impact the aging process.
While aging is inevitable, scientists have discovered that AMPK, a key enzyme in regulating energy metabolism, cellular health, and aging, plays a crucial role in maintaining vitality and slowing down the aging process. Understanding how AMPK helps maintain cellular function could also open new doors for drug development.
What is AMPK? The Key Enzyme for Cellular Energy Regulation
AMPK is an enzyme that is vital in cellular energy metabolism. When a cell’s energy reserves (ATP) are depleted, AMPK is activated to trigger energy-saving mechanisms and boost energy production, which is critical for cell survival under stress.
AMPK activation enhances mitochondrial function. As the “powerhouses” of the cell, mitochondria generate most of the energy a cell needs. Once AMPK is activated, mitochondrial activity is boosted, helping to improve energy generation and maintain overall metabolic balance.
Many methods that activate AMPK—such as exercise, calorie restriction (fasting), resveratrol, and metformin (a prescription drug for type 2 diabetes)—can promote autophagy, a process that clears aging mitochondria and helps slow down aging. As we age, autophagy decreases, leading to the accumulation of damaged mitochondria, which further accelerates aging.
The Connection Between AMPK Deficiency and Aging
- With aging, AMPK activity may decline, reducing energy metabolism efficiency and accelerating the aging process. When AMPK activity is low, cells struggle to cope with metabolic stress, which causes mitochondrial dysfunction and speeds up aging.
- As we age, DNA damage (such as double-strand breaks) increases, which activates an enzyme called DNA-PK, inhibiting AMPK activity. AMPK activation is linked to the key mechanism of autophagy. Reduced autophagy as we age is considered one of the factors that shorten lifespan.
- AMPK helps promote mitochondrial autophagy, clearing out damaged mitochondria that accumulate with age, which would otherwise reduce energy production and accelerate aging. Animal studies have shown that mice lacking AMPK exhibit defects in mitochondrial autophagy in skeletal muscle, leading to muscle dysfunction and sarcopenia (muscle loss). Additionally, AMPK regulates skin aging by controlling important cell factors, such as interleukin-15.
- When AMPK is inhibited, the cell’s repair mechanisms, such as autophagy, may be compromised, allowing damaged organelles to accumulate and exacerbate aging-related problems.
- AMPK activation can also reduce inflammation, which is commonly associated with aging. Research has shown that metformin can increase AMPK activity, improve mitochondrial function, and reduce oxidative damage and chronic inflammation, thus extending lifespan.
AMPK’s Role in Aging Regulation
AMPK integrates key cellular signals and regulates multiple pathways, making it essential for maintaining cellular homeostasis and metabolic balance. However, as we age, AMPK activity and responsiveness decline, potentially leading to metabolic imbalances, reduced autophagy, and increased oxidative stress. Therefore, AMPK is seen as a critical factor in influencing aging and lifespan, playing a role in:
- Maintaining cellular homeostasis
- Regulating metabolism
- Enhancing stress resistance
- Promoting cell survival and regeneration
- Regulating cell death and autophagy
With clinical trials exploring anti-aging treatments such as metformin and resveratrol, we may soon see promising results validated in humans, bringing us closer to the dream of extending human lifespan.
Approved AMPK-Related Drugs
Although some studies indicate the potential of AMPK activators in the field of anti-aging, no drugs specifically targeting anti-aging through AMPK activation have been approved. It is important to note that the following drugs, while potentially activating AMPK, are not intended for anti-aging treatment. Always follow your doctor’s instructions when using these medications.
Metformin
Metformin directly impacts glucose and lipid metabolism in the liver by activating AMPK. It enhances glucose uptake and breakdown through AMPK activation of hexokinase and pyruvate kinase. Additionally, metformin improves insulin signaling, aiding in blood sugar control. It also inhibits lipid synthesis via AMPK, particularly acetyl-CoA carboxylase (ACC), reducing lipid production and promoting fatty acid oxidation.
In muscle tissue, metformin increases insulin sensitivity, improves glucose uptake and utilization, and slows intestinal glucose absorption.
Common side effects include nausea, vomiting, diarrhea, and abdominal discomfort.
Canagliflozin
Canagliflozin, approved for treating type 2 diabetes, inhibits glucose reabsorption by blocking the sodium/glucose cotransporter (SGLT2) in the kidneys. This helps lower blood glucose levels without affecting SGLT1-mediated glucose absorption in the intestines.
Canagliflozin can activate AMPK in the liver, but not in muscle, fat, or spleen. Since AMPK phosphorylation of ACC reduces liver lipid content, canagliflozin may offer additional benefits compared to other SGLT2 inhibitors. Side effects include asymptomatic hypoglycemia, increased urination, elevated blood ketones, and constipation.
AMPK-Related Drugs in Development
While AMPK’s potential in anti-aging research is promising, no anti-aging-specific AMPK drugs have been officially developed or approved. However, many pharmaceutical companies and research institutions are actively exploring AMPK’s role in treating metabolic, neurodegenerative, and rare diseases. These conditions often involve energy metabolism imbalances, and as AMPK is a key “energy sensor” in cells, it may help restore balance and improve these diseases. We look forward to innovative breakthroughs in this field, which could ultimately lead to longer, healthier lives.
PXL770
- Developed by Poxel SA, PXL770 is an AMPK activator used to treat X-linked adrenoleukodystrophy (ALD).
- In 2022, the FDA granted PXL770 Fast Track and Orphan Drug designations for treating X-ALD.
- PXL770 has completed Phase 2 trials for non-alcoholic fatty liver disease (NAFLD), showing good treatment tolerance but not meeting primary liver fat improvement outcomes compared to a placebo.
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ATX-304 (formerly O304)
- Originally developed by Betagenon AB, ATX-304 is a PAN-AMPK activator now under Amplifier Therapeutics. It targets metabolic and cardiovascular diseases.
- In clinical trials, ATX-304 combined with metformin lowered fasting blood glucose (FPG) and insulin resistance (HOMA-IR) in type 2 diabetes patients, showing significant FPG reduction between days 21 and 28, suggesting extended treatment may further lower FPG.
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EF-API-001 >>more information
- EF-API-001 is a key small molecule developed by Everfront Biotech, with multiple therapeutic mechanisms. It has potential applications in treating various diseases, including cancer (such as brain cancer, pancreatic cancer, and solid tumors), neurodegenerative diseases (ALS, cerebellar atrophy), fibrosis (idiopathic pulmonary fibrosis, liver fibrosis), and obesity.
- In studies involving high-fat diet-induced obesity (DIO) in mice, EF-API-001 was shown to improve metabolic conditions by:
- Inhibiting weight gain in obese mice
- Improving biochemical markers in blood
- Increasing energy expenditure
- Promoting the browning of white fat
- Reversing fatty liver in obese mice
Brown fat contains numerous mitochondria, which can dissipate excess energy as heat through uncoupled respiration, making brown fat highly metabolically active compared to energy-storing white fat.
Mechanism of Action:
- Changes in lipid droplet morphology: EF-API-001 promotes the formation of multilocular lipid droplets in fat cells, a key feature of fat browning.
- β-Adrenergic receptor and AMPK signaling: EF-API-001 regulates β-adrenergic receptors and activates downstream cAMP/PKA/AMPK signaling pathways.
- Phosphorylation of AMPK: EF-API-001 enhances AMPK phosphorylation and increases the protein expression of downstream molecules such as ACC and SIRT1.
- Increased oxygen consumption: Functional analysis showed that EF-API-001 increases oxygen consumption in fat cells, indicating enhanced energy expenditure.
- AMPK and PGC-1α interaction: EF-API-001 promotes the interaction between AMPK and PGC-1α, a critical mechanism in energy metabolism and fat cell browning.
ENERGI Platform
The ENERGI platform, developed by Hua An Biomedicine, focuses on activating AMPK to boost cellular energy and promote self-healing.
It has been applied to various fields, including wound care, metabolic diseases, inflammatory diseases, and neurodegenerative conditions.
Leading development projects include:
A topical gel for treating diabetic foot ulcers (Phase II in Taiwan completed; Phase III ongoing in the U.S.)
A topical solution to prevent hair loss (Phase II completed in Taiwan and the U.S.)
A topical gel for lower limb venous ulcers (Phase II ongoing in Taiwan)
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Additional AMPK Activator Drugs in Development
1. Nimbus Therapeutics & Eli Lilly Collaboration
Nimbus and Eli Lilly are collaborating to develop small molecule AMPK activators, specifically targeting AMPK-β2, for the treatment of metabolic diseases. This collaboration is focused on leveraging AMPK’s potential to regulate energy balance and improve metabolic health.
2. Kallyope’s Oral AMPK Activator
Kallyope is developing an oral small molecule designed to target the gut. By activating AMPK, this drug aims to restore intestinal epithelial cell homeostasis and inhibit the activation of immune cells and gastrointestinal mucosal inflammation. This innovative approach could address gut-related metabolic and immune disorders.
3. OMEICOS’s OMT-28
OMEICOS is developing OMT-28, a drug that activates the AMPK/SIRT-1/PGC1-α pathway, reducing mitochondrial dysfunction and oxidative stress. OMT-28 has completed Phase II clinical trials for patients with muscle diseases and/or cardiomyopathy associated with inflammation (PMD). This drug shows promise in treating conditions related to mitochondrial and muscle health. (EudraCT No. 2022-003307-16)
These early-stage drug development projects highlight the expanding interest in utilizing AMPK activation for addressing a wide range of health challenges, from metabolic diseases to inflammation and mitochondrial dysfunction.
Natural AMPK Activators
The following natural compounds have shown AMPK-activating potential in animal studies. While these findings are promising, clinical trials in humans are still needed. When considering these natural sources, maintain a balanced diet and avoid excessive consumption of single foods.
Exercise
Endurance exercise is a natural and effective way to activate AMPK in multiple tissues and organs, promoting metabolic health and energy balance. This process improves fat burning, enhances mitochondrial function, and boosts long-term metabolic health.
Resveratrol
Found in grape skins and red wine, resveratrol is linked to AMPK activation. It helps improve energy efficiency, promote fat breakdown, and enhance mitochondrial function, potentially delaying aging and improving metabolic health.
Gynostemma (Jiaogulan)
Gynostemma contains active compounds called gypenosides, which have shown glucose-lowering effects in animal studies by activating AMPK. This helps regulate energy metabolism, improve insulin resistance, and enhance liver glucose metabolism.
Curcumin
Curcumin, the active compound in turmeric, has been shown to increase AMPK activity. It may help regulate metabolism, reduce fat accumulation, and improve overall health, particularly for those with metabolic imbalances like obesity.
Reference
- https://doi.org/10.1016/j.bbalip.2021.159033
- https://www.nature.com/articles/s41573-019-0019-2
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8919726/
- https://www.sciencedirect.com/science/article/pii/S2213453022000672
- http://www.tsim.org.tw/journal/jour24-6/06.pdf
- https://pubmed.ncbi.nlm.nih.gov/27381369/
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941559/
