Combating Aging via Artificial IntelligenceApril 2018
By Gene Hastings
In youth, cells communicate by emitting precise signals that enable healthy tissue function.
Aging causes disruption of cell-signaling pathways that leads to whole-body degeneration.
Restoration of youthful cell signaling is a critical part of a healthy longevity strategy.
In the March 1995 issue of Life Extension Magazine®, we advised readers to consider an antidiabetic drug called metformin to combat degenerative alterations.
We did so at great personal risk, as the FDA insisted we not do this.
We nonetheless continued extolling the use of metformin by normal aging persons because the drug protected against so many degenerative factors.
A significant number of people, however, cannot tolerate metformin’s gastrointestinal side effects. Many others cannot persuade their doctors to prescribe metformin because they are not type II diabetic.
There are also newly identified signaling pathways that metformin itself might not adequately target.
These facts motivated Life Extension® to ally with an A.I. group called Insilico Medicine. The strategy involved using advanced artificial intelligence (A.I.) to assess tens of thousands of signaling pathways and how they can be youthfully restored.
The result is the discovery of concentrated natural compounds that can modulate many of the same anti-aging pathways as metformin. These landmark findings were recently published in a prestigious scientific journal.2
Never before has there been a targeted combination of natural compounds that can mimic so many longevity benefits via modulation of cell-signaling pathways.
Restoring youthful functionality is expected to help protect against age-related maladies, including cognitive decline, heart-muscle weakness, excess weight, metabolic disorders, and DNA gene mutations.
This research arena is accelerating because of proprietary artificial intelligence that analyzes complex biological activities and identifies natural compounds to reinstate more youthful functionality.
Why Mimic Metformin?
Metformin is a widely prescribed drug, first developed to lower blood sugar in people with type II diabetes.
It was approved in England in 1957, but did not gain FDA approval until 1994.
Increasingly, scientists are discovering that metformin provides multiple beneficial effects that extend beyond glucose control.
It turns out that metformin can inhibit key aspects of degenerative aging, which in turn can boost protection against diabetes, obesity, cardiovascular diseases, neurodegeneration, and cancer.3-8
Scientists have long known that metformin mimics many of the anti-aging pathways activated by calorie restriction (CR).
CR works in a number of ways to modulate aging. It impacts how the body manages energy, how it controls cell replication, and how it recycles basic building blocks to prevent intracellular pollution and conserve resources.
Metformin’s potential anti-aging benefits are so profound that the FDA approved a clinical trial in 2015 to assess its impact against aging. This study will determine whether metformin can restore the gene expression profile of older adults to more closely resemble that of young, healthy subjects.9
Natural Extracts With Metformin’s Anti-Aging Impact
In reviewing massive amounts of data, artificial intelligence analyses identified a combination of three natural extracts that can impact many of the beneficial pathways targeted by metformin.2
These three highly concentrated plant extracts are:
- Withaferin A (from ashwagandha)
- Ginsenoside (from ginseng)
- Gamma linolenic acid (from borage seed oil)
In combination, these three natural extracts are likely to provide broad-spectrum protection against underlying causes of age-related disorders.
To create a more comprehensive longevity strategy, Life Extension scientists expanded their search beyond metformin. They also incorporated the model of the seven pillars of aging, proposed by a consortium organized with the National Institutes of Health.1
Life Extension believes the seven pillars of aging provide a framework for science-based interventions to extend both lifespan and healthspan.
Using this concept, Life Extension characterized the compounds identified by Insilico based on how they beneficially modulate each of the seven pillars of aging, thereby modulating critical factors related to systemic degeneration.
An abundance of published data reveals how each of these natural extracts can provide a similar level of protection as metformin and also modulate the seven pillars of aging to protect against the key destructive forces of aging.
Withaferin A Protects Against Neurodegeneration, Obesity, and Dysfunctional Proteins
In their research, Life Extension and Insilico Medicine scientists found that withaferin A, a component of the herb ashwagandha, was the closest in its predicted gene-regulating effects to metformin.2
Ashwagandha, an herb used in traditional Ayurvedic medicine, has important anti-aging properties that include: antidiabetic, anti-obesity, anticancer, anti-inflammatory, and appetite-regulating.
What has scientists so excited about withaferin A is the multiple beneficial roles it demonstrates in peer-reviewed, published studies.
Protect Your Body’s Proteins
Proteins make up about 42% of the dry weight of our bodies. The protein collagen—which holds our skin, tendons, muscles, and bones together—makes up about a quarter of your body’s total protein.10
Proteins play many critical roles in the body. They do most of the work in cells and are required for the structure, function, and regulation of the body’s tissues and organs.
Recent scientific evidence has identified loss of protein homeostasis (protein quality control network) as a causative factor in age-related disorders, including cancer and heart disease, as well as neurodegenerative disorders such as Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis (ALS), and even obesity.11-16
Withaferin A has shown the ability to activate the protein quality-control network in human cells, also known as proteostasis, loss of which can lead to many destructive diseases of aging.17-19
One can think of proteostasis as the cellular protein quality-control network that removes damaged proteins and helps maintain healthy proteins.
When the cell accumulates excessive amounts of damaged or improperly folded proteins, degenerative disease often sets in. The goal is to prevent production of misfolded proteins and encourage elimination of damaged proteins.
Protecting Nerve Cells From Degeneration
ALS or Lou Gehrig’s disease causes progressive loss of motor control, leading to weakness, tremors, and, eventually, difficulties with speaking, swallowing, and breathing. It is one of the neurodegenerative diseases associated with poor proteostasis,20-22 making it a highly attractive first target for withaferin A.
Researchers treated mice genetically engineered to develop ALS with withaferin A or a placebo control solution to study the effects on ALS.23
The study found that mice supplemented with withaferin A showed reduced inflammation, a 39% reduction in damaged proteins in the spinal cord, a more than 60% reduction in loss of motor nerve cells (cells that transmit movement signals from brain to spinal cord to muscles), and increases of lifespan (5.6% in animals with rapidly-progressing ALS, and 4.7% in a slowly-progressing disease model).23
In other words, treatment of animals with withaferin A reduced many of the underlying factors that result in the paralysis of ALS – most importantly the loss of motor nerve cells, which triggers the rapidly progressive weakness associated with ALS, eventually leading to death.
Withaferin A Fights Obesity
Obesity may be connected with loss of proteostasis.24,25
A group of scientists decided to study the benefit of withaferin A on obesity resulting from excess calorie intake. Obesity is not just a cosmetic problem but a powerful accelerator of aging itself, so all efforts to fight obesity can lead to a reduction in aging.
In this study, obese mice were fed a high-fat diet and given withaferin A for 21 days. Other mice were fed the same diet but administered a control solution.26
The mice supplemented with withaferin A experienced significant weight loss. By the end of the study they had nearly a 23% reduction in weight from baseline.26 This weight reduction did not occur in the placebo group.
The weight loss appeared to be largely driven by a significant reduction in food intake by more than 60%.
Interestingly, these mice—with their reduced food intake—also showed higher sensitivity to leptin,26 a hormone that inhibits hunger.27 In obese animals with poor proteostasis, scientists found an overall insensitivity to leptin that contributes to obesity.28
The mice that were supplemented with withaferin A showed significantly lower leptin levels after treatment.26 This indicated that their bodies had recovered their normal sensitivity to leptin, producing the decreased appetite and food intake that in turn resulted in lower body weight.
Biochemical analysis showed that withaferin A-supplemented mice also had a significant reduction in the harmful unfolded protein response.
This reduction is credited with restoring leptin sensitivity and the observed reductions in food intake and body-fat mass.26 By contrast, untreated leptin-resistant mice maintained much higher levels of leptin, but failed to suppress their appetites because of their resistance to the leptin hormone.26
These two studies are a clear indicator of the effectiveness of withaferin A at modulating proteostasis to help fight neurodegenerative diseases and obesity, two conditions that account for a considerable share of degenerative aging.
Safety studies have shown that withaferin A has no adverse effects at doses up to 2,000 mg/kg in rats—roughly equivalent to about 22 grams in humans, vastly higher than the recommended doses.29
Ginsenoside Protects Against Neurodegeneration, Cancer, Cardiovascular Disease
Ginsenoside is a steroid-like molecule from ginseng. It was identified by the Insilico Medicine team as having an overlap with many of the age-decelerating pathways that metformin regulates.2
They found that ginsenoside concentrate modulates pathways related to the pillars of aging.
Ginsenoside favorably impacts inflammation, and has moderate effects related to macromolecular degeneration, metabolism, stem cells, and regeneration.2 It addresses mechanisms both separately and with some overlap with withaferin A.
Previous studies have shown that ginsenoside can reduce the inflammatory changes that underlie many of the consequences of aging, contributing to neurodegenerative diseases, cancer, and cardiovascular disease.30-34
Ginsenoside also works to prevent damage to DNA and other large molecules, which contributes to cancer development while inhibiting normal repairs in neurodegenerative disorders.35,36
Ginsenoside also suppresses cancer stem cells that manage to survive both natural anticancer protections and chemotherapy, and are a major risk in cancer development and severity.31,37-39
And ginsenoside prevents loss of energy-generating mitochondria that contributes to poor heart function and brain deterioration.40,41 Improving the quality and quantity of mitochondria is an innovative approach to the deceleration of aging.42,43
The impressive results of these animal studies are supported by the safety profile of ginsenoside, which, in rat studies, was found to be tolerated at doses up to the equivalent of about 18 grams/day in humans, without adverse effects.44
GLA Slows Cancer, Prevents Diabetes, Fights Obesity, Lowers Cardiovascular Risk
Gamma Linolenic Acid (GLA), a fatty acid found in evening primrose, borage, and black currant oils, was found by the Insilico Medicine researchers to activate many pathways triggered by metformin, in many cases with greater potency.2
Specifically, GLA beneficially modifies pathways related to the seven pillars of aging, including inflammation and stress adaptation, with moderate impact on the metabolism and stem cells/regeneration pillars, and even a mild effect on epigenetics (regulation of gene expression).2
GLA is a fatty acid long associated with health benefits.45 GLA is best known for its anti-inflammatory properties, with studies showing favorable impact on the body’s overall inflammatory status through activation of many pathways in common with metformin.45-48
Regulation of inflammation gives GLA effects that can influence body weight, diabetes risk, cancer development, and brain function.
Like metformin, GLA also activates the metabolic regulator complex called PPAR, a group of biochemical receptors involved in everything from energy sensing in obesity and diabetes, to control of cell replication and controlled cell death in cancer.49-52
A healthy adaptation to stress, both environmental and biochemical, is essential for fighting aging’s effects on health. In animal studies, GLA has demonstrated its ability to fight such stresses and preserve more youthful functions.
For example, GLA supplementation reduced the blood pressure elevation and heart-rate increases in rats confronted with psychosocial stress.53,54 GLA also improved nerve function in diabetic rats by attenuating the oxidative stress associated with the disease.55 Metformin also fights such oxidative stress to protect against diabetic and nondiabetic age-accelerating processes.56,57
These properties of GLA, and its sizable overlap with metformin in terms of aging pathways, make it an ideal component of a new metformin-mimicking formulation.
Like the other natural compounds identified by Insilico Medicine as having powerful metformin-like effects on aging, GLA has a proven safety record, including a lengthy history of human clinical trials.58-60
How A.I.-identified Natural Extracts Compare to Metformin
A study published last year in the journal Aging was titled:
“Towards natural mimetics of metformin and rapamycin.”
Source: Aging (Albany NY). 2017;9(11):2245-68.
This publication reported on the artificial intelligence algorithm that detected withaferin A, ginsenoside, and gamma linolenic acid (GLA). It showed that these three concentrated plant extracts support more than 78% of the beneficial anti-aging pathways activated by metformin.2
The race to develop natural mimetics to metformin and rapamycin is being fueled by consistent research findings showing these drugs delay onset and may reverse common age-related disorders.
The A.I. process led to a metformin-mimic formula, predicted to offer a large portion of the aging-decelerating actions of metformin.
This prediction is supported by a long record of independent studies showing that, by modulating pathways in common with metformin:
- Withaferin A restores proteostasis, protects against neurodegeneration, and can prevent obesity;
- Ginsenoside can protect against neurodegeneration, cancer, and cardiovascular disease, and;
- GLA can slow cancer growth, prevents experimentally induced diabetes, fights weight gain, and lowers blood pressure and other cardiovascular risk factors.
As it relates to what may be metformin’s most important mechanism, which is activation of the cellular enzyme AMPK, these compounds appear to have a modest effect.2
So those using metformin to control their blood sugar levels should continue doing so, with the knowledge that these three A.I.-identified compounds may provide additive protection against the effects of aging.
All maturing individuals should continue efforts to maintain youthful levels of activated AMPK.
Metformin is a multitargeted drug that confers protection against many age-related disorders.4-8,61
It has been approved for the first-ever study of aging in healthy humans.
Metformin was selected for this human study because of its close overlap with the pathways activated by calorie restriction, which is still the only definitive way to extend lifespan in all species in which it has been tested.
Based on its known benefits, Life Extension scientists combed through thousands of data points to identify the crucial biochemical signaling pathways modulated by metformin utilizing proprietary artificial intelligence.
Findings from this meticulous analysis were published last year in a prestigious scientific journal.2
The results of Life Extension’s A.I.-driven study make it possible to recommend the three compounds reported here for daily use in healthy adults who wish to decelerate their own cellular aging processes, by modulating the same group of biochemical pathways modulated by metformin.
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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