Slow Aging with AMPK
Since then, the term “antioxidant” has become ubiquitous, as commercial companies widely use it to advertise products.
In this article, we describe a method to counteract a deadly aging factor that is today as obscure as antioxidants were 35 years ago. Slow aging with AMPK.
This novel approach is not new to most Life Extension members. We have long recommended the drug metformin to protect against aging.1 The challenge in obtaining a doctor’s prescription has prevented many of Life Extension members from using metformin.
In a major advance, a pair of botanical extracts has been shown to work perhaps better than metformin to increase a critical enzyme (called AMPK) that enables cells to function with youthful vitality.
This article discusses the anti-aging effects that occur in response to higher AMPK activity. What should fascinate the public is a recent finding showing that ingestion of just one of these botanical extracts resulted in significant reductions of abdominal fat.2
Longevity enthusiasts will be thrilled to learn about the many degenerative processes that can be reversed when AMPK activity is enhanced.
The biological effects of increasing AMPK activity include inhibition of fat storage, reduced cholesterol-triglyceride synthesis, and increased glucose uptake into muscle.3-11 The diverse properties of AMPK may soon make this the most sought-after method to slow and reverse degenerative aging processes.
To understand the significance of AMPK, it is important to review some causes of aging that are not adequately addressed by the nutrients and hormones we currently take.
As we mature, our cells lose the ability to purge themselves of accumulated debris, often referred to as “cellular junk.”12-14 As junk-laden cells accumulate, they emit signals that generate low levels of inflammation.15 These senile cells lose their ability to degrade cellular junk through a process called autophagy. The accumulation of these defective “zombie” cells creates a catalyst for virtually all degenerative diseases.
The problems described in the previous paragraph can be traced to an AMPK deficit.15 Low AMPK activity cripples aging cells to the point where they no longer maintain their internal stability. This disturbance caused by insufficient AMPK signaling provokes disease and jeopardizes healthy aging.15
The term “energy” is a highly misused commercial term. Lay people associate it with caffeinated drinks that induce a temporary surge of adrenalin.
When we talk about enhancing energy metabolism through activation of AMPK, we are referring to turning back “on” youthful control of cellular functions that are critical to healthy longevity.
AMPK stimulates energy metabolism by signaling cells to burn glucose and fatty acids.8,10,16-18 This is just one way that AMPK lowers blood glucose and reduces storage of body fat.
AMPK Declines With Aging
AMPK stands for adenosine monophosphate-activated protein kinase. It is an enzyme that plays a critical role in cellular homeostasis.19,20 AMPK acts as a master switch to regulate cell functions such as uptake of glucose, burning of fats, and formation of new mitochondria.15,21-25
When observing what happens to aging humans, such as steadily rising blood glucose levels and excess body fat accumulation, the impact of AMPK deficit can clearly be seen.
Nutritional overload impairs AMPK activity.26,27 It thus should not be surprising that one method of maintaining higher AMPK activity is calorie restriction.28,29 To better understand how this works, in a low-calorie environment, cells turn “on” survival signals (such as AMPK) to optimize their energy balance.30,31 Chronic overeating deactivates AMPK and shortens life spans.
Primate studies validate age-delaying effects when calorie restriction is properly executed.32-37 Humans find it challenging to consistently under-eat. Fortunately, there are methods to mimic the AMPK-enhancing effects of low-calorie diets.
Just imagine that you had a sawmill factory where debris was routinely removed as part of the manufacturing protocol. At some point, however, your workers decided to stop taking out the debris and wood chips start accumulating. This might not be an immediate problem, but as wood chip rubble piled up, your factory’s efficiency would decline, and at some point become dysfunctional.
Cells continuously produce metabolic waste products that are efficiently removed by AMPK signaling.15 As AMPK activity declines, waste products (cellular junk) accumulate and eventually render our cells dysfunctional.15
The dysfunction is so severe that senile cells cannot even commit suicide (apoptosis) because they lack sufficient energy instructions to perform even simple housekeeping tasks. Yet these senile cells emit chronic external signals that create a systemic state of low-level inflammation throughout the aging body.38-40
AMPK augments cellular housekeeping. Reduced AMPK signaling, on the other hand, can exacerbate common problems related to cellular dysfunction like heart failure.41 When you hear that an elderly person’s heart “wore out,” what often is being stated is that their cardiac muscle became dysfunctional due to reduced AMPK signaling.
Likewise, when type II diabetes manifests, it is often caused by a loss of cellular insulin sensitivity.42 AMPK improves insulin sensitivity,9,15 which is one mechanism by which the drug metformin lowers blood sugar levels.
AMPK Promotes Removal Of Senile Cells
Aging results in the accumulation of cells that can barely function yet create a host of problems such as chronic inflammation.
As AMPK activity declines with aging, defective cells linger and create metabolic havoc throughout the body.15,39,43,45 To purge the body of these senile cells, strong AMPK signaling is needed to facilitate the beneficial self-removal process.
Combatting Cellular Stress
Cellular stress occurs in response to extremes in temperature,46,47 exposure to toxins,48 mechanical damage,49 inflammation,50 and free radicals.51 A healthy stress response enables cells to survive these damaging/destructive events.
AMPK triggers signaling pathways that improve cell stress response.52
The ability of AMPK to react to cellular stress declines with age and this impairs the maintenance of cellular energy balance. In particular, a deficiency in AMPK signaling can make aging humans more vulnerable to the lethal impact of immune senescence and chronic inflammation.15
Boosting Sirtuin 1
The sirtuins are a family of genes involved in the regulation of cellular energy metabolism.
SIRT1 is one of the most studied of these genes because of its multifaceted role in cell survival, inflammation, and beneficial apoptosis (programmed cell death).15,53,54 SIR stands for “silent information regulator.”55
AMPK promotes the functional activity of SIRT1, which favorably influences beneficial longevity factors.56,57 Several studies indicate that SIRT1 signaling is associated with the extension of life span.58-60 SIRT1 increases during calorie restriction and can enhance cellular stress resistance, which is a well-known defense against the aging process.61-65
Resveratrol supplements have become popular because of their ability to enhance SIRT1.66-68 Resveratrol may do this by boosting AMPK.69 It is unlikely that resveratrol alone will optimally restore cellular AMPK activity to youthful ranges.
Controlling The Cell-Signaling Network
Researchers have identified several “signaling” pathways involved in the regulation of aging processes. These “signaling pathways” promote longevity in lower organisms.
One of these “signals,” named p53, controls cell proliferation.70 P53 is known as a tumor-suppressor gene and loss of p53 predisposes cells to malignancy.71-73 P53 is also involved in regulating cell metabolism and self-destruction (apoptosis) of senescent cells.74-76
Nuclear factor-kappa beta (NF-kB) is an internal cell signal that induces chronic inflammation.77,78 We take nutrients like curcumin to suppress NF-kB activation.79,80
By maintaining higher AMPK activity, our functional p53 is protected, while pro-inflammatory NF-kB is suppressed.
Summary Of AMPK
AMPK is a critical regulator of energy metabolism. The initial benefits of AMPK activation are lower glucose and triglyceride blood levels, along with reductions in abdominal fat mass.3-9,15,80-86
AMPK enables the desirable elimination of dysfunctional cell components (autophagy), which helps reduce chronic low-grade inflammation.87
Cellular stress resistance improves in response to greater AMPK activation.15
Increased AMPK activity can extend life span in lower organisms.15,88,89 The efficient clearance of “zombie” cells and improved cellular stress response are characteristics by which AMPK can enhance one’s ability to enjoy healthy longevity.
To state this simply, AMPK controls an integrated signaling network that has a major role in the regulation of the aging process.
How To Boost AMPK
Exercise activates AMPK, though this effect diminishes as one matures into their elder years.90,91 The ability of metformin to boost AMPK activity has caused some people to call metformin “exercise in a bottle.”92-95
In response to reduced calorie intake, cells activate AMPK as a survival mechanism.28,29 This beneficial AMPK activation vanishes when normal food consumption resumes.26,27
Nutrients like resveratrol and quercetin have some effect on activating AMPK, but are probably not as impactful as metformin.18,97 Those taking metformin are probably achieving optimal AMPK activation.
For those not aggressively exercising or taking at least 1,000 mg a day of metformin, a combination of two botanical extracts has emerged as perhaps the most effective way to activate cellular AMPK.98
The Animal Data
A 2011 published study on diabetic mice compared the effect of one of these botanical extracts to metformin. After 15 days, there was up to a 23% reduction in glucose in the metformin-administered mice. The group receiving the botanical extract saw an up to 30% reduction in glucose.99
A 2012 published mouse study showed the following results when one of these botanical extracts were administered orally:100
10.3% reduction in sub-cutaneous belly fat (compared to control group), and
15.5% reduction in deep visceral fat (compared to control group).
The fat that builds up around the internal abdominal organs (called visceral fat) is the most dangerous form of body fat. Visceral fat generates chronic pro-inflammatory signals and distorts hormone balance.102-104 Most humans need to reduce their abdominal fat mass to avoid age-related disease.
The Human Data
In 2014, a randomized, double-blind, placebo-controlled study was published that evaluated the effects of one of these AMPK-enhancing agents on body composition. Eighty human subjects were evaluated. One group received one of the new AMPK-augmenting botanical extracts and the second group received placebo.
The average body mass index (BMI) of the study subjects was 27.53, meaning they were clinically overweight but not obese. After 12 weeks, the group receiving the botanical extract showed reduction of 3.24 square inches in abdominal fat area (not waist circumference), whereas the placebo arm lost only 0.44 square inches.2 The botanical extract group lost more than an inch in abdominal circumference and nearly one-half inch in hip circumference, both of which are risk factors for the fat-driven inflammation that produces cardiovascular and metabolic diseases.
Reductions in belly fat have been reported in some people who take metformin, so it is not surprising that this novel botanical extract that activates cellular AMPK would reduce abdominal fat.
Fat accumulation in the abdomen 105,106 and liver 107-109 is often accompanied by the reduction in AMPK activity similar to what occurs during aging.15,110 For those who have been unable to shed meaningful weight in their bellies, these botanical extracts could provide the energy needed for abdominal cells to burn their surplus stored lipids (fat).
Decades Of Research
The first mention of AMPK on the National Library of Medicine’s database occurred in 1971.
It was not until 2001 that published research linked decline in AMPK activity with pathological aging and shortened life spans.112
Life Extension® and others have spent enormous amounts of time and money investigating compounds that restore youthful AMPK activity. We long ago urged widespread use of metformin, but our members were challenged to find doctors to write prescriptions for this drug that the FDA approves only to treat type II diabetes.
With the discovery that two botanical extracts that have been safely used for centuries also promote AMPK activity, aging humans have a potent new weapon in their arsenal of age-delaying and potentially age-reversing compounds.
The two botanical extracts mentioned are Gynostemma Pentaphyllum and Trans-tilitoside to increase signaling AMPK activity.
In 2014, Life Extension® funded over $8.4 million in bio-medical research aimed at finding cures for today’s common ailments and eradicating premature death. This research would not be possible if it were not for the loyalty members show every time they choose a Life Extension supplement.
References see lef.org