Life Extension Magazine®

Man riding bike taking AMPK for youthful properties

Turn on Your Body’s “Youth Switch”

AMPK promotes regenerative pathways throughout the body. Human studies show that two plant extracts activate AMPK, reduce blood glucose, and promote weight loss.

Scientifically reviewed by: Dr. Carol Campi, RN, DC, in August 2023. Written by: James Robbins.


An enzyme called AMPK is one of the body’s most powerful anti-aging tools.

AMPK promotes regenerative pathways and acts in every cell to restore youthful function.1

Over time, AMPK activity declines. The result is accelerated aging.

AMPK activation in animal models contributes to longer, healthier lifespans.1-3

Two low-cost nutrients have demonstrated potent AMPK-activating effects.

By taking steps to activate AMPK, it becomes possible to enhance youthful functionality throughout our body.

AMPK: A “Youth Switch”

Image with Caption
Note: AMPK is the
acronym for: adenosine
protein kinase

AMPK is a master metabolic regulator in cells.2,4,5 It helps the body run more efficiently.

When activated, AMPK helps combat degenerative changes by several pathways including:1,5,6

  • Enhancing energy metabolism, meaning AMPK tells cells to burn fuel for energy rather than storing it as fat.

  • Promoting cellular “housekeeping” functions (autophagy) that help clean up “junk” proteins that otherwise accumulate in aging cells.

  • Reducing chronic inflammation.

These functions usually operate at peak efficiency when we’re young.

But like so many other systems in our bodies, AMPK signaling declines with aging. This results in impaired metabolic function, increased inflammation and reduced cellular housekeeping functions—all of which accelerate aging.1,2,6

Activating AMPK boosts health and can help prevent many of the most common causes of premature death.4,7 Increasing AMPK helps restore cells’ youthful function, and its effects can be seen throughout the body.

From the Journal of the American Medical Association

JAMA Network™
Scientific Discovery and the Future of Medicine

“The largest overall longevity increase has been found using a combination of rapamycin and metformin …studies suggest that interventions as late as the mouse-equivalent of older than 70 years of age could significantly extend (human) life by more than 20 years and increase health span even more substantially.”

(On September 17th 2018, the Journal of the American Medical Association published an article about the longevity-enhancing potential of drugs that boost AMPK and suppress excess mTOR. When the cellular enzyme AMPK is activated, there is indirect suppression of mTOR.)

“Aging as a Biological Target for Prevention and Therapy” Nir Barzilai, MD, Anan Maria Cuervo, MD, PhD, Steve Austad, PhD JAMA. Published online September 17, 2018.

Benefits of AMPK Activation

The anti-diabetes drug metformin is perhaps the best-known AMPK activator. Activating AMPK with metformin has been shown to overcome many of the negative effects of AMPK decline.7

For example, studies show that activating AMPK may:4,8-10

  • Reduce the risk of atherosclerosis, heart attack, and stroke.

  • Prevent overgrowth of heart chambers (ventricular hypertrophy) and congestive heart failure.

  • Ameliorate metabolic syndrome, reduce the risk of type II diabetes, and help diabetics control blood sugar.

  • Reduce the risk of weight gain.

  • Decrease the risk of several common cancers while improving outcomes in cancer therapy.

  • Reduce the risk of dementia and other neurodegenerative disorders.

  • Support healthy bone and cartilage structure.

  • Help prevent and control autoimmune disorders.

In short, activating AMPK is analogous to flipping on a “youth switch” that has the potential to decelerate—and potentially reverse—some of the harmful effects of degenerative aging.

Those without diabetes may be unable to obtain a prescription for metformin, leaving them searching for an alternative.

Scientists at Life Extension have identified two compounds proven to activate AMPK: hesperidin, a citrus flavonoid, and Gynostemma pentaphyllum leaf extract.

By activating cellular AMPK, we can help combat age-accelerators—and one of the primary ones is abdominal fat.

What You Need to Know

Anti-Aging Benefits of Activating AMPK

  • Aging slows our cellular processes and makes them less efficient than they were in our youth.
  • AMPK functions as the body’s “youth switch.”
  • Activated AMPK programs cells to recover several aspects of youthful function.
  • Research shows that activating AMPK drives down blood sugar, resolves lipid disturbances, prevents cancer, and protects brain cells and blood vessels.
  • Studies show that both hesperidin and G. pentaphyllum extracts boost AMPK activation, reduce blood glucose and lipids, enhance vascular health, and promote weight loss.
  • AMPK activation is an essential part of any anti-aging, healthspan-enhancing regimen.

The Obesity/Aging Connection

More than 70% of Americans are overweight or obese.11

This presents a major health problem because abdominal fat churns out massive amounts of inflammation, which damages blood vessels, heart muscle, brain cells, and other tissues throughout the body.12

One of AMPK’s functions is to help reduce abdominal fat and the inflammation it produces. As AMPK activity decreases with age, weight gain and chronic inflammation often follow because the body is more likely to store fat rather than burn it for energy.5,13,14

Both hesperidin and G. pentaphyllum help get to the root of these aging processes by combatting abdominal obesity and the inflammation it generates.

AMPK Activator 1:
Gynostemma pentaphyllum

Gynostemma pentaphyllum is a Chinese medicinal herb with a long history of use in preventing metabolic disorders such as obesity, elevated lipid levels, and fatty liver.15-17

More recently, lab and animal studies have shown that G. pentaphyllum is an AMPK activator.16,18,19

This makes Gynostemma extracts appealing in the quest to reduce abdominal obesity (and its consequences) by shutting down fat production and accelerating fat burning.

Lab studies show that G. pentaphyllum extracts stimulate fat burning and cellular uptake of glucose in muscle cells. An animal study shows it can decrease body weight gain, liver weight, and blood cholesterol levels by activating AMPK.15,16

Human Studies

Based on these promising findings, researchers set out to determine if G. pentaphyllum extract could help reduce abdominal obesity in humans.

In a randomized, placebo-controlled trial, 80 people who were overweight or obese were randomly assigned to receive 450 mg/day of G. pentaphyllum extract or a placebo.19

After 12 weeks, the supplemented subjects experienced decreases in total abdominal fat area, body weight, body fat mass, percent body fat, and BMI.19 Specifically,

  • Total fat area fell by 6.3% in supplemented subjects (but by less than 1% in placebo recipients).

  • Visceral fat (fat that accumulates around internal organs in the belly) fell 11% (compared to 3% in placebo group).

This study shows how G. pentaphyllum extracts contribute to fat-reduction, and further highlights how AMPK activation favorably affects human metabolic parameters.

Aging as a Biological Target

A recent article published in JAMA proposes that aging is a process that can be biologically targeted and modified.36 As scientific understanding of the mechanisms of aging become better understood, targets such as AMPK and others can be used to prevent age-related functional decline and extend lifespan.

Remarkably, from animal studies, it appears possible that interventions starting as late as the equivalent “of older than 70 years of age could significantly extend life by more than 20 years and increase health span even more substantially,” according to the authors.

The studies to date which have achieved the greatest longevity have utilized a combination therapy of metformin and rapamycin. Metformin, prescribed primarily for metabolic diseases such as diabetes, activates AMPK, the same mechanism by which hesperidin and G. pentaphyllum act.

Rapamycin is a drug used following organ transplant and for other conditions. It acts primarily by blocking biological pathways related to the protein mTOR. An efficient non-drug method to inhibit excess mTOR is by activating cellular AMPK.37

Reduced Markers of Liver Damage

Non-alcoholic fatty liver disease (NAFLD) is a condition in which excess fat is stored in the liver. It is a troublesome consequence of insulin resistance and is increasingly recognized as a liver manifestation of metabolic syndrome.20,21

In a clinical trial, 56 adults with NAFLD were assigned to a treatment or placebo group. All participants followed a standard weight loss diet for two months prior to receiving supplementation. In the second month of the study, individuals started taking G. pentaphyllum or a placebo for four months.22

Both groups lost weight and saw a range of improvements in liver function and insulin resistance measures, indicating that weight loss is helpful in NAFLD.

However, in the G. pentaphyllum group, these changes were greater, indicating that G. pentaphyllum extract is capable of “supercharging” the beneficial effects of weight loss in those with NAFLD.22

Reduced Blood Sugar Levels

Reduced Blood Sugar Levels  

Activating AMPK helps reduce blood sugar levels.

In one study, a group of type II diabetics who had never been treated with medication was randomly assigned to receive either a tea made with G. pentaphyllum or a placebo tea.23

After 12 weeks of treatment, fasting blood glucose levels in the supplemented group dropped an average of 54 mg/dL. Placebo recipients saw an average drop of just 11 mg/dL.

Levels of hemoglobin A1C (a measure of long-term blood glucose levels) fell by 2 percentage units in supplemented subjects—a 10-fold greater drop than seen in placebo patients.

Supplemented subjects became significantly less insulin resistant, while those in the placebo group saw their insulin resistance increase significantly.

Anything that safely reduces blood sugar and improves insulin sensitivity is of tremendous interest to anyone with type II diabetes or prediabetes. But since even modest blood sugar elevations and insulin resistance play a role in risk of cardiovascular disease and neurodegeneration, this finding is of interest to all, and especially to those who want to take pro-active measures against aging.

AMPK Activator 2:
Hesperidin from Orange Extract

Hesperidin is a flavonoid that is highly concentrated in citrus peel. Like G. pentaphyllum, hesperidin has been shown to inhibit obesity, reduce high blood sugar and lipids, and reduce insulin resistance.24,25

These benefits are likely due to hesperidin’s ability to activate AMPK.

An animal study showed that hesperidin increases measures of activated AMPK, which helps regulate genes that in turn regulate blood sugar, cholesterol, and other fats.26

Human studies show that hesperidin reduces abdominal fat. In one clinical trial, obese subjects taking 500 mg of hesperidin daily showed modest reductions in abdominal fat comparable to those seen in a separate study of the drug, metformin, a potent AMPK activator.27,28

Improving Arterial Function

Improving Arterial Function  

Hesperidin has vascular benefits that can improve arterial function.

In a two-part study, scientists from the National Center for Complementary and Alternative Medicine at the National Institutes of Health (NIH) treated endothelial cells in culture with hesperetin (the form of hesperidin that is absorbed into the bloodstream after ingestion).29,30

They found that this treatment promoted AMPK activation in direct correlation with the dose, while simultaneously boosting eNOS, the enzyme that produces vessel-relaxing nitric oxide.

eNOS (endothelial nitric oxide synthase) is a common target for interventions aimed at improving blood vessel health.

The second part of their study confirmed hesperidin’s vascular benefits in humans.

For this randomized, placebo-controlled, double-blind, cross-over study, a group of people with metabolic syndrome took either a placebo or 500 mg of hesperidin once daily.30

After three weeks, the hesperidin group experienced a significant 33% reduction in blood levels of C-reactive protein (a measure of overall inflammation) compared to baseline.

Supplemented subjects also demonstrated an approximate 29% associated treatment effect (improvement) in flow-mediated dilation (a measure of how well a blood vessel relaxes) in comparison to placebo.30

Finally, the study showed that the hesperidin group had a significant improvement in ApoB, a cholesterol carrier associated with increased risk of heart disease.30-32

In another study, when obese or overweight individuals with early signs of endothelial dysfunction took 450 mg of hesperidin daily, it protected against the vascular changes induced by a high-fat meal.33

Those changes included significant reductions in adhesion molecules implicated in atherosclerosis (such as sVCAM-1 and sICAM-1). The production of these atherogenic molecules is inhibited by AMPK activation.34


Scientists are only beginning to scratch the surface of AMPK modulation as a powerful anti-aging tool.  

Scientists are only beginning to scratch the surface of AMPK modulation as a powerful anti-aging tool.

Activated AMPK re-establishes a youthful intracellular environment.

In addition to protecting against conditions such as type II diabetes and cardiovascular disease, activating AMPK has been shown to extend healthspan and lifespan in animal models4,7 and to improve markers of longevity in humans.35

Many critical factors that contribute to aging are regulated in part by AMPK. Its activation is one of the promising anti-aging interventions being investigated by scientists worldwide.

Two proven AMPK activators, hesperidin and an extract of Gynostemma pentaphyllum, have been shown to help combat aging factors such as obesity, inflammation, elevated blood sugar and cholesterol, and arterial dysfunction.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.


  1. Salminen A, Kaarniranta K. AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev.2012 Apr;11(2):230-41.
  2. Salminen A, Kaarniranta K, Kauppinen A. Age-related changes in AMPK activation: Role for AMPK phosphatases and inhibitory phosphorylation by upstream signaling pathways. Ageing Res Rev. 2016 Jul;28:15-26.
  3. Stenesen D, Suh JM, Seo J, et al. Adenosine nucleotide biosynthesis and AMPK regulate adult life span and mediate the longevity benefit of caloric restriction in flies. Cell Metab. 2013 Jan 8;17(1):101-12.
  4. McCarty MF. AMPK activation--protean potential for boosting healthspan. Age (Dordr). 2014 Apr;36(2):641-63.
  5. Liu WY, Jiang RS. Advances in the research of AMPK and its subunit genes. Pak J Biol Sci. 2013 Nov 15;16(22):1459-68.
  6. Salminen A, Hyttinen JM, Kaarniranta K. AMP-activated protein kinase inhibits NF-kappaB signaling and inflammation: impact on healthspan and lifespan. J Mol Med (Berl). 2011 Jul;89(7):667-76.
  7. Martin-Montalvo A, Mercken EM, Mitchell SJ, et al. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;4:2192.
  8. Vazquez-Manrique RP, Farina F, Cambon K, et al. AMPK activation protects from neuronal dysfunction and vulnerability across nematode, cellular and mouse models of Huntington’s disease. Hum Mol Genet. 2016 Mar 15;25(6):1043-58.
  9. Luo T, Nocon A, Fry J, et al. AMPK Activation by Metformin Suppresses Abnormal Extracellular Matrix Remodeling in Adipose Tissue and Ameliorates Insulin Resistance in Obesity. Diabetes. 2016 Aug;65(8):2295-310.
  10. Li C, Reif MM, Craige SM, et al. Endothelial AMPK activation induces mitochondrial biogenesis and stress adaptation via eNOS-dependent mTORC1 signaling. Nitric Oxide. 2016 May 1;55-56:45-53.
  11. Available at: Accessed September 5, 2018.
  12. Virdis A, Santini F, Colucci R, et al. Vascular generation of tumor necrosis factor-alpha reduces nitric oxide availability in small arteries from visceral fat of obese patients. J Am Coll Cardiol. 2011 Jul 12;58(3):238-47.
  13. Liu F, Benashski SE, Persky R, et al. Age-related changes in AMP-activated protein kinase after stroke. Age (Dordr). 2012 Feb;34(1):157-68.
  14. Rojas J, Arraiz N, Aguirre M, et al. AMPK as Target for Intervention in Childhood and Adolescent Obesity. J Obes. 2011;2011:252817.
  15. Wang M, Wang F, Wang Y, et al. Metabonomics study of the therapeutic mechanism of Gynostemma pentaphyllum and atorvastatin for hyperlipidemia in rats. PLoS One. 2013;8(11):e78731.
  16. Gauhar R, Hwang SL, Jeong SS, et al. Heat-processed Gynostemma pentaphyllum extract improves obesity in ob/ob mice by activating AMP-activated protein kinase. Biotechnol Lett. 2012 Sep;34(9):1607-16.
  17. Tan Y, Kamal MA, Wang ZZ, et al. Chinese herbal extracts (SK0506) as a potential candidate for the therapy of the metabolic syndrome. Clin Sci (Lond). 2011 Apr;120(7):297-305.
  18. Nguyen PH, Gauhar R, Hwang SL, et al. New dammarane-type glucosides as potential activators of AMP-activated protein kinase (AMPK) from Gynostemma pentaphyllum. Bioorg Med Chem. 2011 Nov 1;19(21):6254-60.
  19. Park SH, Huh TL, Kim SY, et al. Antiobesity effect of Gynostemma pentaphyllum extract (actiponin): a randomized, double-blind, placebo-controlled trial. Obesity (Silver Spring). 2014 Jan;22(1):63-71.
  20. Williams T. Metabolic Syndrome: Nonalcoholic Fatty Liver Disease. FP Essent. 2015 Aug;435:24-9.
  21. Paschos P, Paletas K. Non alcoholic fatty liver disease and metabolic syndrome. Hippokratia. 2009 Jan;13(1):9-19.
  22. Chou SC, Chen KW, Hwang JS, et al. The add-on effects of Gynostemma pentaphyllum on nonalcoholic fatty liver disease. Altern Ther Health Med. 2006 May-Jun;12(3):34-9.
  23. Huyen VT, Phan DV, Thang P, et al. Antidiabetic effect of Gynostemma pentaphyllum tea in randomly assigned type 2 diabetic patients. Horm Metab Res. 2010 May;42(5):353-7.
  24. Parhiz H, Roohbakhsh A, Soltani F, et al. Antioxidant and anti-inflammatory properties of the citrus flavonoids hesperidin and hesperetin: an updated review of their molecular mechanisms and experimental models. Phytother Res. 2015 Mar;29(3):323-31.
  25. Suzuki H, Asakawa A, Kawamura N, et al. Hesperidin potentiates ghrelin signaling. Recent Pat Food Nutr Agric. 2014;6(1): 60-3.
  26. Pu P. [Protection mechanisms of hesperidin on mouse with insulin resistance]. Zhongguo Zhong Yao Za Zhi. 2016 Sep;41(17):3290-5.
  27. Ohara T, Muroyama K, Yamamoto Y, et al. Oral intake of a combination of glucosyl hesperidin and caffeine elicits an anti-obesity effect in healthy, moderately obese subjects: a randomized double-blind placebo-controlled trial. Nutr J. 2016 Jan 19;15:6.
  28. Wang H, Ni Y, Yang S, et al. The effects of gliclazide, metformin, and acarbose on body composition in patients with newly diagnosed type 2 diabetes mellitus. Curr Ther Res Clin Exp. 2013 Dec;75:88-92.
  29. Yamamoto M, Jokura H, Hashizume K, et al. Hesperidin metabolite hesperetin-7-O-glucuronide, but not hesperetin-3’-O-glucuronide, exerts hypotensive, vasodilatory, and anti-inflammatory activities. Food Funct. 2013 Sep;4(9):1346-51.
  30. Rizza S, Muniyappa R, Iantorno M, et al. Citrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing inflammatory markers in patients with metabolic syndrome. J Clin Endocrinol Metab. 2011 May;96(5):E782-92.
  31. Sacks FM, Alaupovic P, Moye LA, et al. VLDL, apolipoproteins B, CIII, and E, and risk of recurrent coronary events in the Cholesterol and Recurrent Events (CARE) trial. Circulation. 2000 Oct 17;102(16):1886-92.
  32. Jacobson TA. Opening a new lipid “apo-thecary”: incorporating apolipoproteins as potential risk factors and treatment targets to reduce cardiovascular risk. Mayo Clin Proc. 2011 Aug;86(8):762-80.
  33. Salden BN, Troost FJ, de Groot E, et al. Randomized clinical trial on the efficacy of hesperidin 2S on validated cardiovascular biomarkers in healthy overweight individuals. Am J Clin Nutr. 2016 Dec;104(6):1523-33.
  34. Bai HB, Wang Y, Zhang YH, et al. [AMP-activated protein kinase activation regulates adhesion of monocytes to vascular endothelial cells and the underlying mechanism]. Sheng Li Xue Bao. 2016 Feb 25;68(1):41-9.
  35. de Kreutzenberg SV, Ceolotto G, Cattelan A, et al. Metformin improves putative longevity effectors in peripheral mononuclear cells from subjects with prediabetes. A randomized controlled trial. Nutr Metab Cardiovasc Dis. 2015 Jul;25(7):686-93.
  36. Barzilai N, Cuervo AM, Austad S. Aging as a Biological Target for Prevention and Therapy. JAMA. 2018 Sep 17.
  37. Huang S. Inhibition of PI3K/Akt/mTOR signaling by natural products. Anticancer Agents Med Chem. 2013 Sep;13(7):967-70.