Combat an Underlying Cause of Degenerative Aging

To remain alive, your cells generate a continuous flow of energy.

When energy is produced by burning hydrocarbons such as coal or oil, the result is residual waste pollutants that damage living beings.

A similar event occurs during cellular energy metabolism. Left behind in the energy cycle is toxic debris.

The primary way cells “clean house” is via autophagy.¹

Autophagy defines a natural process whereby cells clear damaged proteins and other metabolic waste products.^1,2

An emerging body of evidence points to imbalanced autophagy as a driver of premature aging.^3,4

Recent discoveries show that almost every intervention proven to extend healthy lifespan involves activation of autophagy (removing toxic cellular waste).^3,4

Restoring balanced autophagy is a critical factor in reversing biological aging.⁴

How to Restore Autophagy

Rapamycin is a drug that regulates autophagy. Preliminary evidence points to its potential to delay aging.^5,6

Although rapamycin has consistently demonstrated lifespan extension in animal models, mainly by delaying cancer onset,⁵ such a powerful drug needs more human studies to ensure against potential risks.

There are natural methods to improve autophagy that include supplementation with lithium and NAD⁺ precursors like nicotinamide riboside.^7-9

One of the safest and most effective methods to optimize autophagy is by activating an enzyme in our cells called AMPK.^10-12

When AMPK is activated, it signals cells to remove internal pollutants via the process of autophagy.^13,14

This enables cells to function in a more youthful manner, as evidenced by reduced abdominal fat stores in many people using AMPK-activating compounds.¹⁵

 

AMPK Signals Cells to Devour Internal Fat

AMPK was first identified in 1973 for its cell-regenerative effects.¹⁶

When people practice calorie restriction, AMPK activity increases in cells.^17,18

Increasing AMPK activity helps protect against degenerative aging.^3,19,20

AMPK turns down cell proliferation to conserve energy in the face of restricted food intake.^17,18,20,21

AMPK signals cells to devour stored fat in response to perceived energy (food) shortages.^20-22

This is how our ancestors survived famines. When confronted with food scarcity, cells react by slowing their replication and utilizing stored fat reserves for essential energy production.

Powerful Anti-Aging Mechanism Optimize AMPK to Balance mTOR signaling

Modern populations consume an abundance of calories throughout the day. The pathologic impact: AMPK is chronically suppressed while mTOR stays elevated. Excess calorie consumption in adults causes pathological mTOR activity that can result in malignant transformation, accelerated aging, and excess fat storage. Those consuming typical modern diets need to enhance AMPK activity, which has the side benefit of normalizing hyperactivated mTOR.

New Longevity Factor: mTOR

AMPK performs its fat-removing process, in part, by regulating a protein called mTOR, which stands for “mechanistic target of rapamycin.”^14,23-25

The drug called rapamycin is a powerful autophagy-inducer. It is demonstrating significant age-delaying effects in older animals.²⁶ Differing doses of rapamycin are being studied in humans to assess if a once-per-week dosing can provide benefits without the immunosuppression that occurs when rapamycin is taken daily.²⁷

To clean out metabolic waste from aging cells today, the best way of regulating mTOR is to boost AMPK functionality.

Balance mTOR to Burn Fat

When cell mTOR is properly balanced, the initial effect is breakdown of fat stores that are used to fuel cellular energy.^14,23-25,28

If mTOR is not balanced, aging individuals often accumulate unwanted fat stores, even when they don’t excessively ingest calories.^14,23-25,28

When nutrient signaling pathways are saturated, the result is storage of excess energy in adipose tissue, which manifests outwardly as body fat. This happens because of increased size of adipocytes (fat cells).

Excessive nutrition (calorie intake) causes up-regulation of mTOR, which sets the stage for increased risk of malignancy and atherosclerosis.

In our youth, energy-sensing AMPK delicately balances cellular energy and fat storage.^29,30 Young bodies do a wonderful job of adapting to nutrient availability and energy demands.

Many factors contribute to the age-related loss in flexibility of our signaling pathways. Cell culture and animal data suggest that sensitivity of key energy regulators is lost with age. This causes some pathways to become hyperactive, whereas others are underactive.^19,31

AMPK is a key energy regulator that seems an ideal target of longevity-enhancing therapeutics that can also help reduce unwanted belly fat.

Optimizing AMPK activity facilitates removal of cellular debris (via autophagy) and suppresses excess cell propagation.^10,11,32 When mTOR is inhibited by AMPK activators there are reductions in cancer risks.^20,33

As it relates to combatting aging, achieving optimal mTOR activation status is a critical factor.

What you need to know

The Benefits of AMPK

• Autophagy is a process in which cells “clean house” by removing damaged proteins and other metabolic waste products. Almost every intervention proven to extend healthy lifespan involves the promotion of autophagy.
• Activation of an enzyme in our cells called AMPK is a particularly safe and effective method to optimize autophagy.
• AMPK signals cells to remove internal pollutants via autophagy. This enables cells to function in a more youthful manner, as evidenced by reduced abdominal fat in many who use AMPK-activating compounds.
• Abdominal fat isn’t just unsightly. It can also generate the systemic inflammation and glucose/lipid imbalances at the root of metabolic syndrome and type II diabetes.
• AMPK performs its fat-removing process, in part, by regulating a protein called mTOR. Currently, the best way to sweep out metabolic waste from aging cells is through regulating mTOR by boosting AMPK functionality.
• Laboratory results show that the citrus flavonoid hesperidin markedly activates AMPK.
• As well, an extract from the Gynostemma pentaphyllum plant has demonstrated strong AMPK-activating properties.
• Gynostemma pentaphyllum extract and hesperidin provide a dual boost to cell AMPK activity, which in turn helps reduce fat by burning it for energy and helps mitigate some of the deleterious mechanisms of aging.
• AMPK can be activated with prescription drugs like metformin or by using a new once-daily combination of standardized extracts of Gynostemma pentaphyllum and hesperidin.

New Way to Activate AMPK

One of the most stubborn aspects of normal aging is accumulation of deep visceral (abdominal) fat.³⁴

Not only can this be unsightly, but it generates systemic inflammation and glucose/lipid imbalances that are root causes of metabolic syndrome and type II diabetes.^34-36

Seeking a natural approach to boosting AMPK, researchers studied a citrus flavonoid called hesperidin. Laboratory results show that hesperidin markedly activates AMPK.³⁷

Hesperidin Studied in High-Risk Patients

Metabolic syndrome describes a cluster of factors that markedly increase heart attack and stroke risk.

Patients with metabolic syndrome typically have:³⁸

• High blood pressure
• Elevated blood sugar
• Lipid imbalance (high triglycerides/low HDL)
• Excess fat around the waist
• Low-level systemic inflammation

Metabolic syndrome patients are at increased risk to progress to type II diabetes.

Based on this festering heart attack epidemic, researchers tested standardized hesperidin on a group of metabolic-syndrome patients.³⁷

In this randomized double-blind crossover clinical trial, half the metabolic-syndrome subjects took 500mg/day of hesperidin or placebo over a three-week period. They were all “crossed over” so that each patient received either hesperidin or placebo at some point during the study period.

Participants were explicitly counseled before initiation of the study to maintain their usual physical activity and dietary habits. Baseline and follow-up tests included blood markers of cardiac risk and an ultrasound measure of arterial function.

C-reactive protein is a marker of inflammation that increases risk of heart attack and stroke. Those with excess belly fat often have elevated C-reactive protein blood levels.³⁹

In this study, metabolic syndrome patients taking the hesperidin supplement had a striking 33% reduction in C-reactive protein levels compared to baseline.³⁷

Flow-mediated dilation is a non-invasive test that utilizes ultrasound to assess endothelial function in humans.⁴⁰

When these metabolic syndrome study subjects were given hesperidin, there was a 25% improvement in this (ultrasound) assessment of arterial health.³⁷

When the same metabolic syndrome patients were crossed-over and given placebo, endothelial function slightly worsened. (Metabolic syndrome is characterized by declining arterial health along with increased inflammation.)

Metabolic Syndrome Risk Factors

Apolipoprotein B is a protein portion of LDL cholesterol. Those with high apolipoprotein B levels are at significantly greater risk for coronary artery disease.^41,42

In this study of metabolic syndrome patients, apolipoprotein B decreased 2.2% in the hesperidin arm but increased 3.3% when the recipients were given placebo.³⁷

Those afflicted with metabolic syndrome have a cluster of conditions that include excess belly fat, high blood pressure, high blood sugar, inflammatory indicators and abnormal lipids.
These factors are an underlying cause of many heart attacks and strokes.³⁸

This three-week study demonstrated reductions in measures of cardiovascular risk in metabolic syndrome patients given a standardized hesperidin supplement. We attribute many of these benefits to the increase in AMPK activity that hesperidin was recently found to induce at the cellular level.

Activating AMPK to Reduce Belly Fat

AMPK activation helps remove excess stored fat by telling your cells that energy is needed so they will stop storing fat and begin using it for energy production.

Based on the known fat-reducing effects of AMPK activation, a study evaluated people with moderately high body mass index 24-30 kg/m².⁴⁶

Study participants were provided with a daily dose of nearly 400 mg of hesperidin that was administered over a 12-week period.

All participants in this study were advised to maintain their regular activity levels and meal size for the duration of the study. Baseline and follow-up tests included CT-scan imaging of abdominal fat.

At the study conclusion, abdominal fat in the placebo group increased over 5%, whereas the group receiving hesperidin had about a 1.5% abdominal-fat reduction.

This is comparable to average belly fat-loss effects of metformin recorded in a separate open-label study of type II diabetics who were given exercise and diet plans.^46,47

Hesperidin demonstrated marked AMPK activation in the laboratory. This discovery has now been corroborated by findings of abdominal fat loss and improved vascular function in humans who supplemented with standardized hesperidin.

Comparing AMPK-Boosting Nutrients to Metformin

Metformin is an antidiabetic drug that Life Extension® recommended to combat degenerative aging processes starting in February 1995.

The most studied mechanism of metformin action is its ability to boost AMPK activity.

Research indicates that hesperidin yields significant AMPK-activating properties.

Extracts from the Gynostemma pentaphyllum plant have also demonstrated AMPK-activating effects.^48,49

Combining Gynostemma pentaphyllum with hesperidin may promote a greater increase in AMPK activity. This has been suggested by human studies that show reduction in abdominal adiposity in response to supplementation with these nutrients individually.

Impressive Results with Gynostemma Pentaphyllum

An extract from the Gynostemma pentaphyllum plant has previously demonstrated potent AMPK-activating properties.^48,49

In a randomized study of 80 obese-but-otherwise healthy people, supplementation with 450 mg a day of Gynostemma—standardized extract resulted in a 6.29% total decline in belly fat compared to a 0.86% drop in the placebo group.¹⁵

More impressively, obese individuals receiving the standardized Gynostemma extract had nearly an 11% drop in dangerous visceral fat compared to 2.96% in the placebo arm.¹⁵

Visceral fat accumulates around internal organs in the belly. It is the most dangerous kind of fat as it emits inflammatory cytokines that inflict systemic damage.^50,51

Reducing visceral fat is a difficult but crucial objective for prevention of cardiovascular disorders, dementia and malignancies.^52,53

Gynostemma pentaphyllum extract and hesperidin provide a dual boost to cell AMPK activity, which in turn helps mobilize fat stores by utilizing them as energy sources.

Combat Aging While Reducing Belly Fat

The age-related decline in AMPK activity¹⁹ is thought to set off a cascade of pathological processes that include:

1. Decreased autophagy (removal of cellular debris)
2. Abnormal blood lipid profiles (cholesterol/triglycerides)
3. Increased C-reactive protein (chronic inflammation)
4. Increased abdominal fat storage (especially visceral fat)

Boosting AMPK activity using nutrients like Gynostemma and hesperidin has been demonstrated to mitigate some of these deleterious mechanisms of aging while helping to reduce belly fat.

Do You Need to Suppress mTOR?

Not everyone should consider aggressive suppression of mTOR and turning up autophagy (cellular housecleaning).

If mTOR is excessively and constantly turned down, it could worsen sarcopenia and other frailty-associated conditions.

Western diets are increasingly putting Americans at risk of chronically elevated mTOR activity that contributes to metabolic disorders and unwanted fat accumulation.

There are people today who cycle between aggressively suppressing mTOR via calorie restriction and/or high-dose AMPK activators, and then eating balanced protein-rich diets. This enables mTOR to rebuild muscle mass while suppressing the undesirable impact of pathological mTOR activation.

When it comes to optimal health, balance is key.

Summary

Anyone contemplating a weight-loss program that involves reducing calorie intake along with greater physical activity should ensure they get maximum results by increasing their cellular AMPK activity.

AMPK activation can be accomplished with prescription drugs like metformin or by using a once-daily nutrient combination of standardized extracts of Gynostemma pentaphyllum and hesperidin.

Convenient dosing of just one tablet daily will enable more maturing individuals to boost their cellular AMPK.

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

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