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AI tunnel of 1s and 0s to assess anti-aging

Combating Aging via Artificial Intelligence

Aging disrupts youthful cell- signaling pathways leading to whole-body degeneration. Seeking to mitigate this cellular deficit, researchers used artificial intelligence (A.I.) to assess tens of thousands of signaling pathways. Their findings uncovered three nutrients that can modulate many of the same anti-aging pathways as the drug metformin, and help restore youthful cell signaling.

Scientifically reviewed by Dr. Gary Gonzalez, MD, in October 2024. Written 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.

What you need to know

  • Science has progressed to the point that we understand aging as a risk factor for chronic diseases, which in turn can now be viewed as symptoms of aging.
  • Seven fundamental processes, or pillars of aging, have been identified by a consortium organized with the National Institutes of Health as holding the keys to why our bodies age.
  • Combating the age-accelerating signaling pathways that promote the pillars of aging, and enhancing those that decelerate aging, is therefore emerging as potentially the most powerful tool for extending both quantity and quality of life.
  • Until quite recently, severe calorie restriction was seen as the leading candidate to favorably alter many of the pathways that contribute to the pillars of aging.
  • Recent work shows that metformin, originally an antidiabetic drug, alters those same pathways in a fashion similar to calorie restriction.
  • Groundbreaking work by Life Extension scientists using artificial intelligence networks has led to the discovery of a three-natural extract formulation with more than 78% of the pathway-modifying actions of metformin.
  • Withaferin A, ginsenoside, and gamma linolenic acid modulate pathways that contribute to all seven pillars of aging, and are predicted to have a similar age-decelerating effect as metformin, including protection against neurodegeneration, obesity, diabetes, cancer, and cardiovascular disease.
  • Unlike other therapies and supplement regimens that target a specific disease, this formulation is intended for regular use by healthy people interested in an across-the-board protection from age-accelerating processes, with the anticipated result of lower rates of chronic, age-related disorders.

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

The Seven Deadly “Pillars of Aging”
The Seven Deadly Pillars of Aging

Figure 1. Each of the independent factors above contributes to what we see as aging of the entire individual.

To one extent or another, all seven processes are active in every chronic disorder that threatens human longevity and health.1

Control over these aging processes can be better achieved via compounds that “turn on” beneficial cell signaling pathways while “turning off” degenerative factors.

Deep-learning artificial intelligence is helping identify interventions that enable the restoration of more youthful cell signaling.

 

 

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.

The Seven “Pillars of Aging” Drive Healthspan
Pillar Definition/Role in Aging
Macromolecular Damage Damage to large functional molecules (macromolecules) that increases with age. This damage to proteins, DNA, lipids, and other macromolecules is an important factor in specific age-related diseases.62
Epigenetics Modifications of gene expression can be induced by the environment, altering which genes are either activated or suppressed.63
Inflammation Chronic inflammation is a pervasive feature of age-related diseases.64
Cellular Stress The rate of biological aging is modulated in part by genes interacting with environmental stressors.65
Proteostasis Loss of proper regulation of protein structure and function, known as “proteostasis,” is a common feature of aging and disease that is characterized by the appearance of dysfunctional or destructive protein aggregates in various tissues.66
Stem Cell Dysfunction Stem cells (capable of maturing into specialized, tissue-specific cells) normally provide sources of new tissue when regeneration is called for. Loss of stem cells or their ability to regenerate, contributes to the age-related decline in tissue function.67
Metabolic Disorders The aging process is characterized by changes in response to insulin (e.g., resistance), changes in body composition (e.g., increased fat, decreased muscle mass), and physiological declines in specific metabolic signaling molecules, e.g., growth hormone (GH), and sex steroids.68

Each pillar in this box is comprised of complex biochemical pathways that modulate the aging process at the whole organism level. Pathways that drive each pillar are capable of being modified to reduce impact on overall aging, with calorie restriction and metformin treatment being the best-studied to date.1,69,70

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.

Three Ingredients Cover Pathways in all Seven Pillars of Aging
Three Ingredients Cover Pathways in all Seven Pillars of Aging

Figure 2. Insilico Medicine’s analysis revealed how three natural ingredients work together to combat the pillars of aging. This diagram shows how each of the ingredients—withaferin A (red), ginsenoside (green), gamma linolenic acid (purple)—work together and independently to address each of the aging pillars and the biochemical signaling pathways they each represent.2

 

 

 

 

 

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.

Seven Pillars, Many Pathways to Aging
Seven Pillars, Many Pathways to Aging

Communications within and between cells are vital to the function of the entire organism. The molecular systems that produce those communications are called signaling pathways, because they involve multiple molecular signals, each triggering a new sequence of events until a final result is achieved.

Pathways associated with the pillars are associated with protecting cells from chemical and environmental stress, adverse gene expression, inflammatory changes, protein degradation, DNA damage and repair, control over cell replication, and many others. Each pillar involves many pathways, which overlap and reinforce one another, as shown in Figure 2.

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

Artificial Intelligence Identifies Natural Extracts With the Anti-Aging Capacity of Metformin
Anti-Aging Capacity of Metformin

Until recently, conducting a comprehensive review of anti-aging pathways would have taken human researchers a decade or more.

Now, Artificial Intelligence (A.I.) is being utilized to accelerate this process so that more and more life-extending therapeutics can be brought to the public in a shorter time span.

In a first, Life Extension scientists teamed up with Insilico Medicine, Inc., to apply Insilico’s “deep learning” A.I. technology in order to identify known natural compounds that activate similar anti-aging pathways as metformin. A paper detailing Insilico’s unique discovery was published in the prestigious journal Aging.2

This process yielded more than 3,000 pathways that metformin actively modulates in living cells. Of those, 99 pathways were identified as comprising the “anti-aging pathway cloud,” and were placed on the map.

The researchers conducted a similar process on more than 800 natural compounds, identifying their relevant metabolic pathways.

Comparing results of these exhaustive searches, the researchers ranked the natural compounds in order of their “pathway similarity” to metformin, and identified the three that most emulated metformin’s actions on the anti-aging pathways.

What they found is depicted in Figure 2. Withaferin A, ginseng and GLA – all with established safety records in humans – between them influenced the same aging pathways as metformin.

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

Introducing Proteostasis—Major New Anti-Aging Target
Introducing Proteostasis—Major New Anti-Aging Target

Many of the structural elements that hold cells and tissue together are made of proteins, as are all of the enzymes that carry out essential chemical reactions in our bodies.

A major activity of most cells in the body is regeneration of new proteins to replace those lost to age-inducing damage.

That constant protein manufacture and recycling process requires ongoing quality control, a process called proteostasis.

As a major pillar of aging, deficiencies in proteostasis can produce conditions we recognize as independent, age-related disorders, e.g., diabesity, cancer, cardiovascular diseases, and neurodegenerative diseases.17

There is now growing interest in attacking poor proteostasis as an anti-aging target, which offers the potential to prevent a host of different disorders involving poor protein quality control.71

For example, in healthy cells, a pathway called the unfolded protein response naturally supports the essential folding that long protein molecules require to achieve their normal functions. A defective unfolded protein response leads to proteins that fail to attain their functional structure, leading to cellular dysfunction and progression of aging-associated diseases.

Withaferin A has strong proteostasis-improving properties. It has been shown to attenuate the abnormal unfolded protein response that develops in high-fat-fed mice, which restores normal signaling by the anti-obesity protein hormone leptin, in turn resulting in weight loss and fat-mass reduction.26

GLA Slows Cancer, Prevents Diabetes, Fights Obesity, Lowers Cardiovascular Risk

GLA  

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

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.

Summary

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.

References

  1. Kennedy BK, Berger SL, Brunet A, et al. Geroscience: linking aging to chronic disease. Cell. 2014;159(4):709-13.
  2. Aliper A, Jellen L, Cortese F, et al. Towards natural mimetics of metformin and rapamycin. Aging (Albany NY). 2017;9(11):2245-68.
  3. van der Aa MP, Hoving V, van de Garde EM, et al. The Effect of Eighteen-Month Metformin Treatment in Obese Adolescents: Comparison of Results Obtained in Daily Practice with Results from a Clinical Trial. J Obes. 2016;2016:7852648.
  4. Christodoulou MI, Scorilas A. Metformin and Anti-Cancer Therapeutics: Hopes for a More Enhanced Armamentarium Against Human Neoplasias? Curr Med Chem. 2017;24(1):14-56.
  5. Gong Z, Aragaki AK, Chlebowski RT, et al. Diabetes, metformin and incidence of and death from invasive cancer in postmenopausal women: Results from the women’s health initiative. Int J Cancer. 2016;138(8):1915-27.
  6. Kaya MG, Yildirim S, Calapkorur B, et al. Metformin improves endothelial function and carotid intima media thickness in patients with PCOS. Gynecol Endocrinol. 2015;31(5):401-5.
  7. Markowicz-Piasecka M, Sikora J, Szydlowska A, et al. Metformin - a Future Therapy for Neurodegenerative Diseases : Theme: Drug Discovery, Development and Delivery in Alzheimer’s Disease Guest Editor: Davide Brambilla. Pharm Res. 2017;34(12):2614-27.
  8. Skov V, Cangemi C, Gram J, et al. Metformin, but not rosiglitazone, attenuates the increasing plasma levels of a new cardiovascular marker, fibulin-1, in patients with type 2 diabetes. Diabetes Care. 2014;37(3):760-6.
  9. Available at: https://clinicaltrials.gov/ct2/show/nct02432287. Accessed 27 December, 2017.
  10. Available at: http://learn.genetics.utah.edu/content/basics/proteins. Accessed January 31, 2018.
  11. Milisav I, Suput D, Ribaric S. Unfolded Protein Response and Macroautophagy in Alzheimer’s, Parkinson’s and Prion Diseases. Molecules. 2015;20(12):22718-56.
  12. Prell T, Lautenschlager J, Witte OW, et al. The unfolded protein response in models of human mutant G93A amyotrophic lateral sclerosis. Eur J Neurosci. 2012;35(5):652-60.
  13. Rinella ME, Siddiqui MS, Gardikiotes K, et al. Dysregulation of the unfolded protein response in db/db mice with diet-induced steatohepatitis. Hepatology. 2011;54(5):1600-9.
  14. Scheper W, Nijholt DA, Hoozemans JJ. The unfolded protein response and proteostasis in Alzheimer disease: preferential activation of autophagy by endoplasmic reticulum stress. Autophagy. 2011;7(8):910-1.
  15. Varma D, Sen D. Role of the unfolded protein response in the pathogenesis of Parkinson’s disease. Acta Neurobiol Exp (Wars). 2015;75(1):1-26.
  16. Shah D, Romero F, Guo Z, et al. Obesity-Induced Endoplasmic Reticulum Stress Causes Lung Endothelial Dysfunction and Promotes Acute Lung Injury. Am J Respir Cell Mol Biol. 2017;57(2):204-15.
  17. Balch WE, Morimoto RI, Dillin A, et al. Adapting proteostasis for disease intervention. Science. 2008;319(5865):916-9.
  18. Tao S, Tillotson J, Wijeratne EMK, et al. Withaferin A Analogs That Target the AAA+ Chaperone p97. ACS Chem Biol. 2015;10(8):1916-24.
  19. Li X, Zhu F, Jiang J, et al. Simultaneous inhibition of the ubiquitin-proteasome system and autophagy enhances apoptosis induced by ER stress aggravators in human pancreatic cancer cells. Autophagy. 2016;12(9):1521-37.
  20. Medinas DB, Valenzuela V, Hetz C. Proteostasis disturbance in amyotrophic lateral sclerosis. Hum Mol Genet. 2017;26(R2):R91-R104.
  21. Rozas P, Bargsted L, Martinez F, et al. The ER proteostasis network in ALS: Determining the differential motoneuron vulnerability. Neurosci Lett. 2017;636:9-15.
  22. Ruegsegger C, Saxena S. Proteostasis impairment in ALS. Brain Res. 2016;1648(Pt B):571-9.
  23. Patel P, Julien JP, Kriz J. Early-stage treatment with Withaferin A reduces levels of misfolded superoxide dismutase 1 and extends lifespan in a mouse model of amyotrophic lateral sclerosis. Neurotherapeutics. 2015;12(1):217-33.
  24. Cavadas C, Aveleira CA, Souza GF, et al. The pathophysiology of defective proteostasis in the hypothalamus - from obesity to ageing. Nat Rev Endocrinol. 2016;12(12):723-33.
  25. Yan Y, Wang H, Hu M, et al. HDAC6 Suppresses Age-Dependent Ectopic Fat Accumulation by Maintaining the Proteostasis of PLIN2 in Drosophila. Dev Cell. 2017;43(1):99-111 e5.
  26. Lee J, Liu J, Feng X, et al. Withaferin A is a leptin sensitizer with strong antidiabetic properties in mice. Nat Med. 2016;22(9):1023-32.
  27. Pan H, Guo J, Su Z. Advances in understanding the interrelations between leptin resistance and obesity. Physiol Behav. 2014;130:157-69.
  28. Ozcan L, Ergin AS, Lu A, et al. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab. 2009;9(1):35-51.
  29. Patel SB, Rao NJ, Hingorani LL. Safety assessment of Withania somnifera extract standardized for Withaferin A: Acute and sub-acute toxicity study. J Ayurveda Integr Med. 2016;7(1):30-7.
  30. Lee IS, Uh I, Kim KS, et al. Anti-Inflammatory Effects of Ginsenoside Rg3 via NF-kappaB Pathway in A549 Cells and Human Asthmatic Lung Tissue. J Immunol Res. 2016;2016:7521601.
  31. Weber DA, Wheat JM, Currie GM. Cancer stem cells and the impact of Chinese herbs, isolates and other complementary medical botanicals: a review. Zhong Xi Yi Jie He Xue Bao. 2012;10(5):493-503.
  32. Lee JW, Choi YR, Mok HJ, et al. Characterization of the changes in eicosanoid profiles of activated macrophages treated with 20(S)-ginsenoside Rg3. J Chromatogr B Analyt Technol Biomed Life Sci. 2017;1065-1066:14-9.
  33. Park SM, Choi MS, Sohn NW, et al. Ginsenoside Rg3 attenuates microglia activation following systemic lipopolysaccharide treatment in mice. Biol Pharm Bull. 2012;35(9):1546-52.
  34. Zhang LP, Jiang YC, Yu XF, et al. Ginsenoside Rg3 Improves Cardiac Function after Myocardial Ischemia/Reperfusion via Attenuating Apoptosis and Inflammation. Evid Based Complement Alternat Med. 2016;2016:6967853.
  35. Kim JH, Cho SY, Lee JH, et al. Neuroprotective effects of ginsenoside Rg3 against homocysteine-induced excitotoxicity in rat hippocampus. Brain Res. 2007;1136(1):190-9.
  36. Poon PY, Kwok HH, Yue PY, et al. Cytoprotective effect of 20S-Rg3 on benzo[a]pyrene-induced DNA damage. Drug Metab Dispos. 2012;40(1):120-9.
  37. Oh J, Jeon SB, Lee Y, et al. Fermented red ginseng extract inhibits cancer cell proliferation and viability. J Med Food. 2015;18(4):421-8.
  38. Tian L, Shen D, Li X, et al. Ginsenoside Rg3 inhibits epithelial-mesenchymal transition (EMT) and invasion of lung cancer by down-regulating FUT4. Oncotarget. 2016;7(2):1619-32.
  39. Sun HY, Lee JH, Han YS, et al. Pivotal Roles of Ginsenoside Rg3 in Tumor Apoptosis Through Regulation of Reactive Oxygen Species. Anticancer Res. 2016;36(9):4647-54.
  40. Sun M, Huang C, Wang C, et al. Ginsenoside Rg3 improves cardiac mitochondrial population quality: mimetic exercise training. Biochem Biophys Res Commun. 2013;441(1):169-74.
  41. Tian J, Fu F, Geng M, et al. Neuroprotective effect of 20(S)-ginsenoside Rg3 on cerebral ischemia in rats. Neurosci Lett. 2005;374(2):92-7.
  42. Gonzalez-Freire M, de Cabo R, Bernier M, et al. Reconsidering the Role of Mitochondria in Aging. J Gerontol A Biol Sci Med Sci. 2015;70(11):1334-42.
  43. Kong Y, Trabucco SE, Zhang H. Oxidative stress, mitochondrial dysfunction and the mitochondria theory of aging. Interdiscip Top Gerontol. 2014;39:86-107.
  44. Shin WH, Ri Y, Do SG, et al. 13-week subchronic toxicity study of a novel ginsenoside composition from ginseng leaves in rats. Lab Anim Res. 2014;30(3):112-22.
  45. Chang CS, Sun HL, Lii CK, et al. Gamma-linolenic acid inhibits inflammatory responses by regulating NF-kappaB and AP-1 activation in lipopolysaccharide-induced RAW 264.7 macrophages. Inflammation. 2010;33(1):46-57.
  46. Park JH, Lee MK, Yoon J. Gamma-linolenic acid inhibits hepatic PAI-1 expression by inhibiting p38 MAPK-dependent activator protein and mitochondria-mediated apoptosis pathway. Apoptosis. 2015;20(3):336-47.
  47. Chen PY, Wang J, Lin YC, et al. 18-carbon polyunsaturated fatty acids ameliorate palmitate-induced inflammation and insulin resistance in mouse C2C12 myotubes. J Nutr Biochem. 2015;26(5):521-31.
  48. Kapoor R, Huang YS. Gamma linolenic acid: an antiinflammatory omega-6 fatty acid. Curr Pharm Biotechnol. 2006;7(6):531-4.
  49. Vang K, Ziboh VA. 15-lipoxygenase metabolites of gamma-linolenic acid/eicosapentaenoic acid suppress growth and arachidonic acid metabolism in human prostatic adenocarcinoma cells: possible implications of dietary fatty acids. Prostaglandins Leukot Essent Fatty Acids. 2005;72(5):363-72.
  50. Pham H, Banerjee T, Nalbandian GM, et al. Activation of peroxisome proliferator-activated receptor (PPAR)-gamma by 15S-hydroxyeicosatrienoic acid parallels growth suppression of androgen-dependent prostatic adenocarcinoma cells. Cancer Lett. 2003;189(1):17-25.
  51. Chen SC, Brooks R, Houskeeper J, et al. Metformin suppresses adipogenesis through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms. Mol Cell Endocrinol. 2017;440:57-68.
  52. Jiang WG, Redfern A, Bryce RP, et al. Peroxisome proliferator activated receptor-gamma (PPAR-gamma) mediates the action of gamma linolenic acid in breast cancer cells. Prostaglandins Leukot Essent Fatty Acids. 2000;62(2):119-27.
  53. Mills DE, Summers MR, Ward RP. Gamma linolenic acid attenuates cardiovascular responses to stress in borderline hypertensive rats. Lipids. 1985;20(9):573-7.
  54. Mills DE, Ward R. Attenuation of psychosocial stress-induced hypertension by gamma-linolenic acid (GLA) administration in rats. Proc Soc Exp Biol Med. 1984;176(1):32-7.
  55. Cameron NE, Cotter MA. Interaction between oxidative stress and gamma-linolenic acid in impaired neurovascular function of diabetic rats. Am J Physiol. 1996;271(3 Pt 1):E471-6.
  56. Ravindran S, Kuruvilla V, Wilbur K, et al. Nephroprotective Effects of Metformin in Diabetic Nephropathy. J Cell Physiol. 2017;232(4):731-42.
  57. Nesti L, Natali A. Metformin effects on the heart and the cardiovascular system: A review of experimental and clinical data. Nutr Metab Cardiovasc Dis. 2017;27(8):657-69.
  58. Fiocchi A, Sala M, Signoroni P, et al. The efficacy and safety of gamma-linolenic acid in the treatment of infantile atopic dermatitis. J Int Med Res. 1994;22(1):24-32.
  59. Jamal GA, Carmichael H. The effect of gamma-linolenic acid on human diabetic peripheral neuropathy: a double-blind placebo-controlled trial. Diabet Med. 1990;7(4):319-23.
  60. Zurier RB, Rossetti RG, Jacobson EW, et al. gamma-Linolenic acid treatment of rheumatoid arthritis. A randomized, placebo-controlled trial. Arthritis Rheum. 1996;39(11):1808-17.
  61. Pastor-Villaescusa B, Canete MD, Caballero-Villarraso J, et al. Metformin for Obesity in Prepubertal and Pubertal Children: A Randomized Controlled Trial. Pediatrics. 2017;140(1).
  62. Richardson AG, Schadt EE. The role of macromolecular damage in aging and age-related disease. J Gerontol A Biol Sci Med Sci. 2014;69 Suppl 1(Suppl_1):S28-32.
  63. Brunet A, Berger SL. Epigenetics of aging and aging-related disease. J Gerontol A Biol Sci Med Sci. 2014;69 Suppl 1:S17-20.
  64. Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci. 2014;69 Suppl 1:S4-9.
  65. Epel ES, Lithgow GJ. Stress biology and aging mechanisms: toward understanding the deep connection between adaptation to stress and longevity. J Gerontol A Biol Sci Med Sci. 2014;69 Suppl 1:S10-6.
  66. Labbadia J, Morimoto RI. The biology of proteostasis in aging and disease. Annu Rev Biochem. 2015;84:435-64.
  67. Oh J, Lee YD, Wagers AJ. Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nat Med. 2014;20(8):870-80.
  68. Barzilai N, Huffman DM, Muzumdar RH, et al. The critical role of metabolic pathways in aging. Diabetes. 2012;61(6):1315-22.
  69. Thomas I, Gregg B. Metformin; a review of its history and future: from lilac to longevity. Pediatr Diabetes. 2017;18(1):10-6.
  70. Sinclair DA. Toward a unified theory of caloric restriction and longevity regulation. Mech Ageing Dev. 2005;126(9):987-1002.
  71. Morimoto RI, Cuervo AM. Proteostasis and the aging proteome in health and disease. J Gerontol A Biol Sci Med Sci. 2014;69 Suppl 1(Suppl 1):S33-8.

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