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. 2015 Dec 31;3(4):e53. doi: 10.15190/d.2015.45

AMPK activation can delay aging

Andreea L Stancu 1,*
PMCID: PMC6941559  PMID: 32309575

Abstract

AMPK controls the regulation of cellular homeostasis, metabolism, resistance to stress, cell survival and growth, cell death, autophagy, which are some of the most critical determinants of aging and lifespan. Specific AMPK activation was recently shown to delay aging and prolong lifespan in Drosophila melanogaster. Indirect AMPK activators, such as resveratrol, metformin and exercise, are currently in clinical trials for studying their impact on human aging-related characteristics, tissue homeostasis and metabolic dysfunctions. In this minireview, I am briefly discussing the recent advances on AMP involvement in aging and lifespan elongation.

Keywords: AMP-activated protein kinase, lifespan, energetic metabolism

Introduction

As a sensor of cellular energy status, AMP-activated protein kinase (AMPK) is expressed in almost all eukaryotic cells1. Activation of AMPK is able to restore the energy balance when the energy state of a cell is decreased. This is performed by stimulating catabolic processes that generate ATP and by inhibiting anabolic processes that consume ATP2. AMPK controls the regulation of cellular homeostasis, metabolism, resistance to stress, cell survival and growth, cell death, autophagywhich are some of the most critical determinants of aging and lifespan3. AMPK can integrate critical cellular signals and controls many signaling pathways that regulate these processes. Recent studies show that the AMPK activation and AMPK responsiveness decrease with age, which may explain the altered metabolic regulation, resulting in reduced autophagic clearance of unnecessary products and an increase in oxidative stress3.

Caloric restriction was shown to protect against senescence by increasing autophagic activity and reducing oxidative damage4. These mechanisms are at least in part mediated by caloric restriction-induced activation of AMPK and its downstream signaling pathways5. Dietary restriction can at least in part mediate longevity by activating the AMPK-FOXO axis6-8.

At least five clinical trials (Table 1) with AMPK activators, such as resveratrol9-11, metformin12 and exercise13,14, investigate their impact on human aging related characteristics, tissue homeostasis and metabolic dysfunctions15.

Table 1. Clinical trials investigating the impact of AMPK activators (such as resveratrol, metformin and exercise) on human aging-related characteristics, tissue homeostasis and metabolic dysfunctions.

Study name Status (Dec. 2015) Conditions Purpose Ref.
Beneficial Effects of Exercise and Healthy Diets on Muscle and Adipose Tissue Recruiting Metabolic Syndrome Intends to verify if physical exercise and/or Mediterranean diet, in middle aged individuals with metabolic syndrome, preserve adequate adipose tissue functionality and delay skeletal muscle aging; AMPK is one of the studied markers 16
Effect of Age on Glucose and Lipid Metabolism Active, not recruiting Metabolism Disorders Tests the hypotheses that the decrease in muscle fat oxidation from elderly human individual is secondary to an age-mediated reduction in AMPK signaling, in vivo, and exercise-induced increase in the AMPK signaling will result in/correlate with improved insulin action, increased fat oxidation & reduced intramyocellular lipids 17
Metformin and Longevity Genes in Prediabetes Completed Aging, Insulin Resistance, Prediabetes, Inflammation Investigates the effects of the AMPK pathway activation on longevity genes and inflammation in the setting of pre-diabetes in vivo and in vitro 18
Metformin in Longevity Study (MILES) Ongoing Aging Examine the effects of metformin treatment on the potential of changing the gene expression profile of older adults with impaired glucose tolerance, to that of young healthy subjects 19
Resveratrol to Enhance Vitality and Vigor in Elders (REVIVE) Not yet recruiting Physical and Mitochondrial function Investigates if resveratrol improves the mitochondrial function within the skeletal muscles of elders; AMPK is one of the studied markers 20
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AMPK activation protects against aging and elongates lifespan in several species

Recent reports demonstrated that AMPK can exert pro-longevity effects in several species21. AMPK activation in gastrointestinal tract increases Drosophila melanogaster’s lifespan by 30%, from six weeks to eight weeks21. Caloric restriction-induced AMPK activation protects against senescence by increasing autophagic activity and reducing oxidative damage in rats4. This process is at least in part executed by the AMPK-FOXO signaling pathway, as shown in C. elegans6. Moreover, metformin was shown to prevent sedentariness-related damages in mice, a process which may be related to AMPK activation. In mice, metformin activated signaling mediated by AMPK and CAMKII, while inactivating ERK, thus modulating hepatic stress. In mouse skeletal muscle, metformin induced phosphorylation of Akt and its activation, process important for skeletal muscle mass maintenance22.

AMPK signaling and aging

AMPK is shown to be a central regulator and integrator for several intracellular signaling pathways controlling cellular homeostasis, metabolism, response to stress, oxidative damage proliferation, cell growth, cell death, autophagy, cellular polarity and cellular senescence. Some of these pathways were shown to promote longevity in lower organisms. It is now well known that DAF-16/FoxO transcription factor can be regulated by AMPK23 and acts as a pro-longevity axis in C. elegans3. FoxO family of transcription factors are well known for the regulation a broad range of biological critical processes, such as apoptosis, cell cycle progression, resistance to oxidative stress, metabolism, differentiation and senescence23-25. Moreover, muscle aging can be delayed by modulating the muscle-specific dFOXO/4E-BP/activin signaling, which can induce autophagy. These events are related to extended organismal lifespan26,27.

Other groups have reported the involvement of p53 tumor suppressor, NF-kB signaling pathway and Sirtuins in cellular senescence and aging of mammalian organisms. SIRT1 is well known for inducing signaling changes that mediate caloric restriction-induced lifespan elongation2,28. Several other AMPK downstream signaling pathways with potential involvement in aging were previously described3.

Targeting AMPK activation to increase lifespan

Discovery of AMPK’s critical cellular functions has led to the identification of a huge number of products that can (most of them indirectly) activate AMPK. To date, over 100 natural products (many used in Asian medicine) are uncovered. Very few of them directly modulate AMPK, however, even those are expected to have AMPK-independent effects1. For example, salicylate is shown to directly bind AMPK, although it also binds and modulates the activity of other cellular enzymes. Some of these compounds, indirectly activate AMPK by inhibiting mitochondrial respiratory chain: berberine, galegine etc. Moreover, at least two of these compounds, salicylate and metformine, are some of the most used drugs worldwide for the treatment of common pathologies. Although these drugs can activate AMPK, involvement of AMPK in their therapeutic effects is not yet well characterized1. Metotrexate was also recently shown to activate AMPK, promoting glucose uptake and lipid oxidation in skeletal muscle27.

In 2015, the US Food and Drug Administration (FDA) has given the green light for human clinical trials evaluating the potential metformin-induced elongation of human lifespan19. In addition to its well characterized effects of regulating the glucose metabolism, being used in the treatment of type 2 diabetes for many years, metformin can influence a wide rage of cellular processes critical in aging process and the development of age-related conditions, such as apoptosis, autophagy, cellular senescence, oxidative damage and inflammation28-31. Interestingly, metformin mimics some of the benefits of calorie restriction without a decrease in caloric intake. It improves physical performance, reduces cholesterol and low-density lipoprotein levels and increases sensitivity to insulin32. Both metformin and rapamycin can prolong lifespan in mice32,33. AMPK was previously shown to mediate the anti-aging effects of metformin32, while autophagy was proposed to be involved in inducing the anti-aging effects of rapamycin34,35.

Conclusions

AMPK is a sensor of cellular energy status and a critical regulator of cellular homeostasis, metabolism response to stress, oxidative damage and many other processes involved in aging. We now know, that localized activation of AMPK in key tissues such as the brain, can slow aging in a non-cell autonomous manner21. AMPK activation in the Drosophila’s nervous system induces autophagy both in the brain and the intestinal epithelium, which is related to the anti-aging effects and extended lifespan21. Autophagy, which is a bulk protein degradation process35,36, was previously proposed to be involved in inducing the anti-aging effects of rapamycin34,35. Thus, AMPK-induced autophagic clearance and increased resistance to stress are major players involved in lifespan elongation in lower organisms. Recent reports3,21,37 established that AMPK activation and AMPK responsiveness decrease with age, which may explain the altered metabolic regulation, resulting in reduced autophagic clearance of unnecessary products (via mTOR), an increase in oxidative stress and decrease resistance to cellular stress (potentially due to DAF-16/FoxO and/or p53 signaling pathways downregulation). Thus, finding efficient strategies of increasing AMPK responsiveness and activation may be of important use as anti-aging treatments and for lifespan elongation. Metformin, resveratrol and exercise are the leading examples currently tested in human clinical trials.

  • AMPK activation/responsiveness decreases with age, resulting in:

    • reduced autophagic clearance of unnecessary products

    • an increase in oxidative stress

    • a decrease resistance to cellular stress

  • AMPK-mediated autophagic clearance and increased resistance to stress are major players involved in lifespan extension in lower organisms.

Footnotes

Conflict of interests: The author declares that there are no conflicts of interest.

Abbreviations

AMP-activated protein kinase (AMPK); US Food and Drug Administration (FDA); Forkhead box protein O (FOXO); Silent mating type information regulation 2 homolog 1 (SIRT1)

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