Major Advance In Slowing Aging

By William Faloon
When we �rst described antioxidants in 1980, the concept was virtually unknown outside the scienti�c
community.

Since then, the term “antioxidant” has become ubiquitous, as commercial companies widely use it to
advertise products.

In this issue, we describe a method to counteract a deadly aging factor that is today as obscure as
antioxidants were 35 years ago.

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 precluded many
of our 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 �nding showing that ingestion of just one of these botanical extracts
resulted in signi�cant 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 signi�cance 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
in�ammation.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 de�cit.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 de�cit 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
�nd it challenging to consistently undereat. Fortunately, there are methods to mimic the AMPK-enhancing
effects of low-calorie diets.

Cellular Housekeeping
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 in�ammation 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 in�ammation.

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 signaling44 is needed to facilitate the
bene�cial self-removal process.

Combatting Cellular Stress

Cellular stress occurs in response to extremes in temperature,46,47 exposure to toxins,48 mechanical
damage,49 in�ammation,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 de�ciency in AMPK signaling can make aging humans more vulnerable to
the lethal impact of immune senescence and chronic in�ammation.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,
in�ammation, and bene�cial apoptosis (programmed cell death).15,53,54 SIR stands for “silent information
regulator.”55

AMPK promotes the functional activity of SIRT1, which favorably in�uences bene�cial 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 identi�ed 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 in�ammation.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-in�ammatory NF-kB is
suppressed.

Summary Of AMPK
AMPK is a critical regulator of energy metabolism. The initial bene�ts 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 in�ammation.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 AMPK96 as a survival mechanism.28,29 This bene�cial
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-in�ammatory signals101 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 in�ammation 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 abdomen105,106 and liver107-109 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 �rst mention of AMPK on the National Library
of Medicine’s database occurred in 1971.111

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 �nd 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.

William Faloon

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