AMPK and longevity

The AMPK signaling pathway is one that is increasingly being viewed as playing a central role in metabolism and growth(ref). And that pathway appears to have a lot to do with longevity.  In fact, it is possible that some degree of life extension in humans might be realized through activation of AMPK. I review selected facts and publications about AMPK here and its relationship to other longevity topics previously discussed in this blog.  I discuss the possible role of AMPK activation as a diabetes treatment and how exercise activates AMPK.  Finally, I discuss the anti-aging effects of metformin, a widely-used diabetes drug that activates AMPK, and how exercise and several supplements in my dietary regimen also activate AMPK and may therefore have anti-aging effects.

About AMPK

AMP-activated protein kinase (AMPK) acts like a thermostat in the body’s metabolic handling of energy.  AMP stands for Adenosine 5-monophosphate.  AMPK “is viewed as a fuel sensor for glucose and lipid metabolism. — In mammals, the control of glucose homoeostasis is governed by the balance between glucose absorption from the intestine, endogenous production by the liver and uptake and metabolism by peripheral tissues. This requires continuous adaptation of metabolic pathways to maintain glycaemia in the physiological range. The AMP-activated protein kinase (AMPK) has been proposed to act as a ‘metabolic master switch’ capable of mediating the cellular adaptation to nutritional environmental variations. AMPK is a ubiquitous serine/threonine protein kinase activated in response to environmental or nutritional stress factors which deplete intracellular ATP levels, including heat shock, hypoxia, hypoglycaemia and prolonged exercise. Regardless, the result of AMPK activation is the inhibition of energy-consuming biosynthetic pathways, such as fatty acid and sterol synthesis, and activation of ATP-producing catabolic pathways, such as fatty acid oxidation(ref).”  One of the catalytic subunits of AMPK, AMPKα2, also appears to have additional functions: it controls whole-body insulin sensitivity and has a role in coordinating autonomous nervous system activity(ref).

The 2005 paper AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism offers another view.  “The AMP-activated protein kinase (AMPK) is an evolutionarily conserved sensor of cellular energy status, and recent data demonstrate that it also plays a critical role in systemic energy balance. AMPK integrates nutritional and hormonal signals in peripheral tissues and the hypothalamus. It mediates effects of adipokines (leptin, adiponectin, and possibly resistin) in regulating food intake, body weight, and glucose and lipid homeostasis. AMPK is regulated by upstream kinases of which the tumor suppressor, LKB1, is the first to be identified. Complex signaling networks suggest that AMPK may prevent insulin resistance, in part by inhibiting pathways that antagonize insulin signaling. Through signaling, metabolic, and gene expression effects, AMPK enhances insulin sensitivity and fosters a metabolic milieu that may reduce the risk for obesity and type 2 diabetes.”

The 2007 paper AMPK and SNF1: Snuffing Out Stress offers yet-another take.  “In mammals, metabolic stresses that inhibit ATP synthesis (e.g., hypoglycemia) or accelerate ATP consumption (e.g., muscle contraction) cause increases in the cellular AMP:ATP ratio that activate the AMP-activated protein kinase (AMPK) system. AMPK protects cells against such stresses by activating alternate catabolic pathways and inhibiting cell growth and division. This cellular energy-sensing role is most likely the function for which the AMPK system originally evolved. However, in multicellular organisms it also plays a key role in the regulation of whole-body energy balance, being involved in the control of food intake and energy expenditure by mediating effects of hormones like leptin and adiponectin (Kahn et al., 2005).”

The AMPK 1 catalytic subunit of AMPK plays a role in muscle health as described in the 2005 publication AMP-activated protein kinase signaling stimulates VEGF expression and angiogenesis in skeletal muscle.  “Here, we investigated whether AMPK signaling in muscle has a role in regulating VEGF-mediated angiogenic processes. — These data indicate that AMPK-p38 MAPK signaling cascade can increase VEGF production in muscle and promote angiogenesis in response to ischemic injury.”  Additional non-metabolic functions of AMPK are discussed in the 2007 publication The AMP-activated protein kinase: more than an energy sensor.

AMPK and Type 2 Diabetes

The 2009 publication AMPK: An Emerging Drug Target for Diabetes and the Metabolic Syndrome is one of many highlighting the possible use of the AMPK channel for the control of diabetes and metabolic syndrome. “According to National Diabetes Statistics, the number of people with diagnosed and undiagnosed diabetes in the United States reached 23.6 million, which is 7.8% of the general population, in 2007. The total number of people worldwide with diabetes is projected to rise to 366 million in 2030. A number of therapeutic agents exist for the treatment of type 2 diabetes mellitus (T2DM), including metformin, sulfonylureas, DPP-4 inhibitors, PPARγ agonists, α-glucosidase inhibitors, insulin, and GLP-1 analogs. However, in addition to inadequate efficacy and durability, some of these agents suffer from liabilities, including hypoglycemia, weight gain, edema, fractures, lactic acidosis, and gastrointestinal intolerance (Nathan et al, 2009).   In aggregate, there is a pressing need to develop novel modalities for the treatment of diabetes to stem the spread of this global epidemic. AMP-activated protein kinase (AMPK) is a potential target for novel agents that may meet this challenge.”  Metformin in particular is an already widely-used AMPK activator.

Agents that can increase expression of AMPK

A number of known substances have a capacity to directly or indirectly activate AMPK including metformin, thiazolidinediones, adiponectin, leptin, ciliary neurotrophic factor, interleukin-6, alpha-lipoic acid, resveratrol, epigallocatechin-3-gallate (a main catechin of green tea), cannabinoids, ghrelin(ref) and certain plant polyphenols(ref).  The therapeutic usefulness of these substances as AMPK activators except for metformin is mostly still to be explored.

AMPK and exercise

Even brief bouts of exercise activate AMPK.  The 2009 publication Brief intense interval exercise activates AMPK and p38 MAPK signaling and increases the expression of PGC-1alpha in human skeletal muscle reports “We tested the hypothesis that an acute session of intense intermittent cycle exercise would activate signaling cascades linked to mitochondrial biogenesis in human skeletal muscle — We conclude that signaling through AMPK and p38 MAPK to PGC-1alpha may explain in part the metabolic remodeling induced by low-volume intense interval exercise, including mitochondrial biogenesis and an increased capacity for glucose and fatty acid oxidation.”  Among other publications relating to the same theme is the 2009 report Molecular responses to high-intensity interval exercise.

AMPK and aging

AMPK activity is key for mitochondrial biogenesis and declines with age.  The 2010 publication Regulation of mitochondrial biogenesis points this out.  “Mitochondrial dysfunction is an important component of different diseases associated with aging, such as Type 2 diabetes and Alzheimer’s disease. PGC-1alpha (peroxisome-proliferator-activated receptor gamma co-activator-1alpha) is a co-transcriptional regulation factor that induces mitochondrial biogenesis by activating different transcription factors — The latter drives transcription and replication of mitochondrial DNA. PGC-1alpha itself is regulated by several different key factors involved in mitochondrial biogenesis, which will be reviewed in this chapter. Of those, AMPK (AMP-activated protein kinase) is of major importance. AMPK acts as an energy sensor of the cell and works as a key regulator of mitochondrial biogenesis. AMPK activity has been shown to decrease with age, which may contribute to decreased mitochondrial biogenesis and function with aging.

The 2008 publication Mitochondrial biogenesis and healthy aging identifies yet-another theory of aging: that aging is due to decline in biogenesis of cell mitochondria.  The publication discusses how not only AMPK but how also some other old friends like calorie restriction  and even resveratrol might be implicated. “Aging is associated with an overall loss of function at the level of the whole organism that has origins in cellular deterioration. Most cellular components, including mitochondria, require continuous recycling and regeneration throughout the lifespan. Mitochondria are particularly susceptive to damage over time as they are the major bioenergetic machinery and source of oxidative stress in cells. Effective control of mitochondrial biogenesis and turnover, therefore, becomes critical for the maintenance of energy production, the prevention of endogenous oxidative stress and the promotion of healthy aging. Multiple endogenous and exogenous factors regulate mitochondrial biogenesis through the peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha). Activators of PGC-1alpha include nitric oxide, CREB and AMPK. Calorie restriction (CR) and resveratrol, a proposed CR mimetic, also increase mitochondrial biogenesis through activation of PGC-1alpha. Moderate exercise also mimics CR by inducing mitochondrial biogenesis. Negative regulators of PGC-1alpha such as RIP140 and 160MBP suppress mitochondrial biogenesis. Another mechanism involved in mitochondrial maintenance is mitochondrial fission/fusion and this process also involves an increasing number of regulatory proteins. Dysfunction of either biogenesis or fission/fusion of mitochondria is associated with diseases of the neuromuscular system and aging, and a greater understanding of the regulation of these processes should help us to ultimately control the aging process.”

Activation of the AMPK pathway results in inhibition of the mTOR pathway conferring possible longevity benefits(ref)(see this diagram).  It is known that inhibition of mTOR expression can result in life extension for flies, worms and mice.  See the blog entries More mTOR links to aging theories, Viva mTOR! Caveat mTOR!  and Longevity genes, mTOR and lifespan.

Anti-aging interventions

Metformin is a drug which is widely used for treating Type 2 diabetes.  Metformin is an AMPK activator(ref) and suppressor of mTOR and has been considered as a candidate health-extending and possibly life-extending substance.  Several publications have appeared relating metformin to aging such as studies that indicate that metformin slows down aging in certain strains of transgenic mice. “Here we show the chronic treatment of female outbred SHR mice with metformin (100 mg/kg in drinking water) slightly modified the food consumption but decreased the body weight after the age of 20 months, slowed down the age-related switch-off of estrous function, increased mean life span by 37.8%, mean life span of last 10% survivors by 20.8%, and maximum life span by 2.8 months (+10.3%) in comparison with control mice(ref).” “The chronic treatment of female transgenic HER-2/neu mice with metformin (100 mg/kg in drinking water) slightly decreased the food consumption but failed in reducing the body weight or temperature, slowed down the age-related rise in blood glucose and triglycerides level, as well as the age-related switch-off of estrous function, prolonged the mean life span by 8% (p < 0.05), the mean life span of last 10% survivors by 13.1%, and the maximum life span by 1 month in comparison with control mice. The demographic aging rate represented by the estimate of respective Gompertz’s parameter was decreased 2.26 times. The metformin-treatment significantly decreased the incidence and size of mammary adenocarcinomas in mice and increased the mean latency of the tumors(ref).”

The 2010 publication Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans Healthspan via AMPK, LKB1, and SKN-1 reviews the case for metformin as a life-extending substance.  The publication reports “Metformin, a biguanide drug commonly used to treat type-2 diabetes, has been noted to extend healthspan of nondiabetic mice, but this outcome, and the molecular mechanisms that underlie it, have received relatively little experimental attention. To develop a genetic model for study of biguanide effects on healthspan, we investigated metformin impact on aging Caenorhabditis elegans. We found that metformin increases nematode healthspan, slowing lipofuscin accumulation, extending median lifespan, and prolonging youthful locomotory ability in a dose-dependent manner. — Energy sensor AMPK and AMPK-activating kinase LKB1, which are activated in mammals by metformin treatment, are essential for health benefits in C. elegans, suggesting that metformin engages a metabolic loop conserved across phyla. — skn-1, which functions in nematode sensory neurons to promote DR longevity benefits and in intestines for oxidative stress resistance lifespan benefits, must be expressed in both neurons and intestines for metformin-promoted healthspan extension, supporting that metformin improves healthy middle-life aging by activating both DR and antioxidant defense longevity pathways. In addition to defining molecular players operative in metformin healthspan benefits, our data suggest that metformin may be a plausible pharmacological intervention to promote healthy human aging.”

Some blog writers have gone so far as to suggest that metformin could be used as an anti-aging drug although I stop short of advocating that here.  As more is learned about the AMPK pathway and its relationship to mTOR, and as more longevity experiments are done on animals using metformin, I might review that choice.  My suggested combined anti-aging firewalls Supplement Regimen already includes other probable activators of AMPK as mentioned above including alpha-lipoic acid, resveratrol, green tea supplements and a number of other plant polyphenols.  I also regularly exercise which activates AMPK.  I don’t know how good a job these do towards suppression of mTOR and life extension.  It could well be that many of the positive actions of those supplements result from activating AMPK.