Fatty liver disease

Many common chronic disease conditions are strongly associated with increased insulin resistance.  This is because insulin resistance is a surrogate marker for an inefficient metabolism, leading to increased chronic low-level inflammation and a growing population of senescent cells that accelerate aging throughout the body.  The biological consequences of increased insulin resistance can be attenuated, if not reversed, by Metabolic Engineering™.

Metabolic Engineering™ is a defined dietary program to reduce insulin resistance and its associated chronic low-level inflammation that increases cellular senescence.  At the molecular level, Metabolic Engineering™ activates the master switch of metabolism, AMPK.  The power of Metabolic Engineering™ is the ability to keep AMPK within a zone in each of your 30 trillion cells.  The result is an increased healthspan, defined as longevity minus years of disability caused by chronic disease.

There is no magic bullet (drug or supplement) to achieve this dynamic metabolic balance of AMPK in every cell.  However, there is a synergistic balance of three unique interrelated dietary strategies that can. 

The first strategy is calorie restriction but without hunger or fatigue.  This is only feasible if the calorie restriction is accomplished without hunger or fatigue.  The Zone diet is a patented technology that achieves this goal by balancing protein-to-glycemic load.  The Zone diet is the foundation for Metabolic Engineering™ as it is the most potent dietary approach to activate AMPK that no current drug or supplement can match.  The second dietary strategy you also need is the adequate intake of omega-3 fatty acids to provide the building blocks for a powerful group of hormones (i.e., resolvins) that turn off chronic low-level inflammation that drives all chronic diseases.  It is difficult to achieve adequate intake of omega-3 fatty acids by diet alone, so supplementation is often needed.  Finally, the third dietary strategy is the requirement for an adequate intake of polyphenols.  These are chemicals that give vegetables and fruits their color.  They are also critical to the repair of damaged tissue caused by insulin resistance. Like omega-3 fatty acids, it is often difficult to consume adequate intake of polyphenols, so supplementation is also usually required. In addition, omega-3 fatty acids and polyphenols indirectly activate AMPK.  Thus, all dietary components work together as an integrated team to keep AMPK in the appropriate zone to extend healthspan.

Equally important, Metabolic Engineering™ can be personalized to the individual based on blood testing to determine the correct balance of its three dietary components to generate optimal results in reducing insulin resistance.  The more consistently you follow the dietary guidelines of Metabolic Engineering™,  the more likely you will reduce the underlying cause of most chronic health conditions, which is the growing population of senescent cells associated with increasing levels of insulin resistance. 

The ultimate goal of Metabolic Engineering™ is to reduce the number of senescent cells throughout the body to slow down your rate of aging.  Thus, the real benefit of Metabolic Engineering™ is an increased healthspan.  This should be the primary goal of medicine instead of using more drugs to treat the symptoms of chronic disease.

The various chronic disease conditions that can benefit from consistent use of Metabolic Engineering™ are shown below.

The Problem                                                                                                 The constriction of air passages in the lungs causes asthma. This is primarily driven by increased inflammation in the airway passages.  There is a strong link between asthma and insulin resistance (1,2).   At the molecular level, insulin resistance is caused by inhibiting AMPK, the master regulator of metabolism (3).  One of the consequences of AMPK inhibition is the reduction of the ability of the cell to reduce the overproduction of pro-inflammatory hormones known as eicosanoids.

The Traditional Drug Approach
The primary drug treatments for long-term asthma control are anti-inflammatory drugs such as corticosteroids and leukotriene inhibitors.  Corticosteroids relieve asthma symptoms quickly.  Unfortunately, this short-term relief comes at a significant metabolic cost.  Corticosteroids also inhibit overall eicosanoid formation, removing your first line of defense against infection or tissue injury.  Furthermore, long-term use of corticosteroids also leads to increased insulin resistance that accelerates aging by accelerating the population of senescent cells. Leukotriene inhibitors are more focused drugs acting on only one subclass of eicosanoids (i.e., leukotrienes), thus creating less generalized suppression of your immune system than corticosteroids but having a lower efficacy than corticosteroids.  This is because these leukotriene inhibitors will have little effect on other eicosanoids (such as PGD₂) that also drive the symptoms of asthma.

The Metabolic Engineering™ Approach
The effectiveness of either of these drug treatments can be enhanced by increasing AMPK activity, which decreases insulin resistance (4).  As AMPK activity increases, the production of pro-inflammatory hormones decreases.  Thus, combining a standard drug therapy with Metabolic Engineering™ can reduce the inflammation, thus helping to reduce flare-ups in the airway passages of the lung.

Metabolic Engineering™ offers a more sophisticated dietary approach because it is a systems-based approach to reducing the underlying cause of asthma.  The Zone diet component of Metabolic Engineering™ increases AMPK activity, which decreases the activation of the gene transcription factor NF-κB.  Inhibition of NF-κB activity reduces eicosanoids, leukotrienes, and other pro-inflammatory inflammatory mediators such as cytokines.  The omega-3 fatty acid component of Metabolic Engineering™ is an inhibitor of eicosanoids and leukotriene formation without causing immunosuppression.  Furthermore, omega-3 fatty acids are the building blocks to make resolvins, the hormones critical in resolving the inflammation in the damaged airway passages caused by an asthma attack.  Resolvins also indirectly stimulate AMPK activity.  Finally, the polyphenol component of Metabolic Engineering™ indirectly activates AMPK and increases the activity of the gene transcription factor, Nrf2, which reduces oxidative stress.  Only when these three dietary components are working together as an integrated system to increase AMPK activity will you get the full benefit of Metabolic Engineering™  to increase your healthspan

Thus, Metabolic Engineering™ works with any drug therapy for asthma treatment to help reduce airway constriction without associated side effects such as immunosuppression.  This makes the asthmatic drug work better or allows the physician to potentially decrease the amount of the medications needed to manage asthma with fewer side effects.

References
1. Roshan Lal, Cechinel, LR, Freishtat R, Rastogi, D.  Metabolic contributions to pathobiology of asthma.   2023, 13:212. doi.org/10.3390/metabo13020212 

2. Wu TD.  Diabetes, insulin resistance, and asthma: a review of potential links. Curr Opin Pulm Med. 2021, 27:29-36. doi: 10.1097/MCP.0000000000000738.

3. Ruderman NB, Carling D, Prentki M, Cacicedo JM. AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest. 2013; 123:2764-72. doi: 10.1172/JCI67227.

4. Sears B and Saha AK.Dietary control of inflammation and resolution. Front Nutr. 2021; 8:709435. doi: 10.3389/fnut.2021.709435. 

The Problem
Auto-immune conditions occur when the immune system begins to attack normal tissue.  Some of these conditions include classic auto-immune diseases such as rheumatoid arthritis, lupus, and irritable bowel syndrome, as well as psoriasis and multiple sclerosis.  The underlying cause of auto-immune disease is poorly understood. However,  it appears to involve the breakdown of the body’s immune system to recognize a cell as “foreign” instead of “self,” thus targeting that cell for inflammatory attack by the immune system.   Many auto-immune conditions are also associated with increased insulin resistance (1).

The Traditional Medical Approach
The primary drug treatments are anti-inflammatory drugs.  These drugs can include non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or monoclonal antibodies.  However, these same drugs can reduce the immune system’s efficiency to fight off microbial infections or reduce healing from physical injuries.  Although the cause of auto-immunity is unknown, it is associated with increased insulin resistance.

The Metabolic Engineering™ Approach
Metabolic Engineering™ offers a sophisticated dietary approach to reduce the side effects of standard anti-inflammatory drugs used to treat auto-immune conditions. The goal of Metabolic Engineering™ is to activate AMPK, which in turn reduces inflammation in the cells (2,3).    The Zone diet component of Metabolic Engineering™ increases AMPK activity via calorie restriction without hunger or fatigue that, in turn, decreases the activation of the gene transcription factor NF-κB.  Reducing NF-κB activity decreases pro-inflammatory eicosanoids (prostaglandins and leukotrienes) and other pro-inflammatory inflammatory mediators such as cytokines (such as TNF-α).  The omega-3 fatty acid component of Metabolic Engineering™ is a far more precise inhibitor of eicosanoid and leukotriene formation without causing immunosuppression.  Furthermore, omega-3 fatty acids are the building blocks to make resolvins, the hormones critical in repairing the damaged airway passages caused by an asthma attack.  Finally, the polyphenol component indirectly activates AMPK to increase the activity of the gene transcription factor, Nrf2, which reduces oxidative stress. 

The consistent use of Metabolic Engineering™ results in an overall decrease of inflammation, which helps the immune system better recognize normal cells as being “self” instead of perceived as being “foreign.”     

Thus, Metabolic Engineering™ works to help reprogram the metabolism to reduce inflammation.  This makes anti-inflammatory drugs used to treat auto-immunity either perform better or allow the physician to decrease the amount of drug to manage inflammation associated with their auto-immune disorder to have fewer side effects.

References
1. Uddin J, Tran K, Hannan A, Rahman A, Lam A, Ngoc TN, Chu D. Autoimmune diseases and metabolic disorders: Molecular connections and potential therapeutic targets. Translational Autoimmunity. Elsevier (2002)

2. Noor HB, Mou NA, Salem L, Shimul MFA, Biswas S, Akther R, Khan S, Raihan S, Mohib MM, Sagor MAT. Anti-inflammatory property of AMP-activated protein kinase.  Antiinflamm Antiallergy Agents Med Chem. 2020; 19: 2-41. doi: 10.2174/1871523018666190830100022.

3. Sears B and Saha AK. Dietary control of inflammation and resolution. Front Nutr. 2021; 8:709435. doi: 10.3389/fnut.2021.709435. 

The Problem
Cancer can be considered a “wound that never heals,” meaning it represents a continuing inflammatory state.  Cancer causes a significant reprogramming of the cell’s metabolism to maintain increased cellular growth and metastatic spread to other organs.   

The Traditional Medical Approach
Cancer drugs work by either causing the death of the cancer cell, thus creating cell debris at the tumor site. The cellular debris from the dead cancer cell often becomes a smoldering site of a new source of inflammation.  Cancer drugs also cause normal cells exposed to the cancer treatment to become senescent, thereby increasing the acceleration of aging in every organ in the body.

The Metabolic Engineering™ Approach
The goal of Metabolic Engineering™ is to reduce inflammation at the cellular level by activating AMPK, which reduces the activity of other gene transcription factors (such as mTOR) that accelerate tumor growth (1). 

The foundation of Metabolic Engineering™ is the Zone diet, which restricts calories without hunger or fatigue.  Calorie restriction is receiving more attention in cancer treatment (2). Recent research has demonstrated the resolvins generated from omega-3 fatty acids can speed up the removal of cell debris from cancer treatments in animals (3,4).  Likewise, the role of polyphenols in the modulation of oxidative stress in cancer is being recognized (5). 

Cancer drugs, unfortunately, cause the side-effect of generating a large number of senescent cells as a consequence of any treatment (6).  Thus, after any cancer treatment, using Metabolic Engineering™ can minimize the inflammatory damage caused by the cancer treatment and enhance the repair of damaged tissue caused by the cancer treatment.  Thus,  Metabolic Engineering™ should be considered a lifelong dietary system to help minimize the acceleration of aging associated with existing cancer treatments.

References
1. Populo H, Lopes JM, Soares P. IntThe mTOR signaling pathway in human cancer. J Mol Sci. 2012; 13:1886-1918. doi: 10.3390/ijms13021886.

2. Vidoni C, Ferraresi A, Esposito A, Maheshwari C, Dhanasekaran DN, Mollace V, Isidoro C.J Calorie restriction for cancer prevention and therapy: Mechanisms, expectations, and efficacy.  Cancer Prev. 2021; 26:224-236. doi: 10.15430/JCP.2021.26.4.224.

3. Sulciner ML, Serhan CN, Gilligan MM, Mudge DK, Chang J, Gartung A, Lehner KA, Bielenberg DR, Schmidt B, Dalli J, Greene ER, Gus-Brautbar Y, Piwowarski J, Mammoto T, Zurakowski D, Perretti M, Sukhatme VP, Kaipainen A, Kieran MW, Huang S, Panigrahy D.J Resolvins suppress tumor growth and enhance cancer therapy. Exp Med. 2018; 215:115-140. doi: 10.1084/jem.20170681.

4. Fishbein A, Hammock BD, Serhan CN, Panigrahy D. Carcinogenesis:  Failure of resolution of inflammation?  Pharmacol Ther. 2021; 218:107670.doi: 10.1016/j.pharmthera.2020.107670.

5. Mileo AM and Miccadei S. Polyphenols as a modulator of oxidative stress in cancer disease: New therapeutic strategies.  Oxid Med Cell Longev. 2016; 2016:6475624. doi: 10.1155/2016/6475624.

6. Xiao S, Qin D, Hou X, Tian L, Yu Y, Zhang R, Lyu H, Guo D, Chen XZ, Zhou C, Tang J.Cellular senescence: A double-edged sword in cancer therapy.  Front Oncol. 2023; 13:1189015. doi: 10.3389/fonc.2023.1189015.

The Problem
Cardiovascular disease is caused by chronic low-level inflammation (1, 2).  The ultimate cause is a pro-inflammatory diet.  The consequences of such a pro-inflammatory diet leads to the build-up of atherosclerotic lesions, the rupture of those lesions, and an inability to repair damaged tissue to maintain an efficient cardiovascular system. 

The Traditional Medical Approach
Drugs (such as statins) that lower cholesterol are the primary drugs currently used to treat heart disease.  Statins are known to activate AMPK, which also inhibits cholesterol synthesis (3,4).  Thus, statins could be considered to be AMPK-activating drugs.  Cardiovascular disease is also correlated with increased oxidative stress (5).  Finally, cardiovascular disease is highly associated with insulin resistance (6).

The Metabolic Engineering™ Approach
The molecular drivers of cardiovascular disease can be attenuated by consistent use of Metabolic Engineering™.  The Zone diet component activates AMPK due to calorie restriction (7).  The omega-3 fatty acid component reduces inflammation and increases its resolution (8).  Finally, the polyphenols reduce oxidative stress (5). 

Thus, Metabolic Engineering™ works in concert with any drug therapy for cardiovascular treatment to help reprogram your metabolism by activating AMPK.  Activation of AMPK decreases cholesterol synthesis, reduces inflammation, increases resolution, and decreases oxidative stress by increasing Nrf2 activity.  The overall effect is a decrease in insulin resistance as well as the level of cellular senescence. These benefits of Metabolic Engineering™ either make a cardiovascular drug work better or allow the physician to potentially reduce the amount of drug to manage their patient’s cardiovascular disorder with fewer side effects.

References
1. Libby P, Ridker PM, Maseri A.Inflammation and atherosclerosis.Circulation. 2002; 105(9):1135-43. doi: 10.1161/hc0902.104353.

2. Soehnlein O and Libby P.Targeting inflammation in atherosclerosis – from experimental insights to the clinic.  Nat Rev Drug Discov. 2021; 20:589-610.doi: 10.1038/s41573-021-00198-1. 

3. Dehnavi S, Kiani A, Sadeghi M, Biregani AF, Banach M, Atkin SL, Jamialahmadi T, Sahebkar A.Targeting AMPK by Statins: A potential therapeutic approach.Drugs. 2021; 81:923-933. doi: 10.1007/s40265-021-01510-4.\

4. Foretz M, Viollet B. Measurement of AMPK-induced inhibition of lipid synthesis flux in cultured cells. Methods Mol Biol. 2018; 1732:363-371. doi: 10.1007/978-1-4939-7598-3_23.

5. Cheng YC, Sheen JM, Hu WL, Hung YC Polyphenols and oxidative stress in atherosclerosis-related ischemic heart disease and stroke.  Oxid Med Cell Longev. 2017; 2017:8526438. doi: 10.1155/2017/8526438. 

6.  Kosmas CE, Bousvarou MD, Kostara CE, Papakonstantinou EJ, Salamou E, Guzman E.  Insulin resistance and cardiovascular disease.   J Int Med Res. 2023; 51: 3000605231164548. doi: 10.1177/03000605231164548.

7. Guo Z, Wang M, Ying X, Yuan J, Wang C, Zhang W, Tian S, Yan X.Caloric restriction increases the resistance of aged heart to myocardial ischemia/reperfusion injury via modulating AMPK-SIRT₁-PGC_1a energy metabolism pathway.  Sci Rep. 2023, 13:2045. doi: 10.1038/s41598-023-27611-6.

8. Omega-3 fatty acids, cardiovascular risk, and the resolution of inflammation. Back M, Hansson GK.  FASEB J. 2019; 33:1536-1539. doi: 10.1096/fj.201802445R.

The Problem
Type 2 diabetes is the primary chronic disease associated with increased insulin resistance.  Currently, about 30 million Americans have type 2 diabetes, and another 100 million Americans have pre-diabetes.  High levels of insulin resistance characterize both conditions.  Insulin resistance represents the inability of a cell to remove glucose from the blood. About 50 percent of this action is orchestrated by AMPK.  Thus, any decrease in AMPK activity will increase insulin resistance (1). 

The Traditional Medical Approach
The primary drug used in treating type 2 diabetes is metformin, which is known to activate AMPK (2, 3).  More potent drugs to treat type 2 diabetes, such as thiazolidinediones (TZDs), also work by increasing AMPK activity (4).  Newer medications, such as injectable GLP-1 agonists, also increase AMPK activity (5).  However, these drugs also have numerous side effects associated with long-term use.

The Metabolic Engineering™ Approach
Many drugs used to treat type 2 diabetes work through AMPK activation.  Thus, the consistent use of Metabolic Engineering™ works in concert with any drug therapy for type 2 diabetes treatment to help reprogram your metabolism by activating AMPK.  Using only the Zone diet as a single dietary intervention resulted in significant reductions of HbA1c (the primary marker of the severity of type 2 diabetes) and a significant decrease in the use of their diabetic medications in 12 weeks (6).  Adding the omega-3 fatty acids and polyphenols only adds to the AMPK-activating benefit of the Zone diet, as they are indirect activators of AMPK (7).

References

1  Saha AK, Xu XJ, Balon TW, Brandon A, Kraegen EW, Ruderman NB.  Insulin resistance due to nutrient excess: Is it a consequence of AMPK downregulation? 

Cell Cycle.  2011; 10:3447-51. doi: 10.4161/cc.10.20.17886.

• Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action.  J Clin Invest. 2001; 108:1167-74. doi: 10.1172/JCI13505.

• Goel S, Singh R, Singh V, Singh H, Kumari P, Chopra H, Sharma R, Nepovimova E, Valis M, Kuca K, Emran TB. Metformin: Activation of 5′ AMP-activated protein kinase and its emerging potential beyond anti-hyperglycemic action.  Front Genet. 2022; 13:1022739. doi: 10.3389/fgene.2022.1022739. 

• LeBrasseur NK, Kelly M, Tsao TS, Farmer SR, Saha AK, Ruderman NB, Tomas E. Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues.  Am J Physiol Endocrinol Metab. 2006; 291:E175-81. doi: 10.1152/ajpendo.00453.2005. 

• Reis-Barbosa PH, Marcondes-de-Castro IA, Marinho TS, Aguila MB, Mandarim-de-Lacerda CA. The mTORC1/AMPK pathway plays a role in the beneficial effects of semaglutide (GLP-1 receptor agonist) on the liver of obese mice.  Clin Res Hepatol Gastroenterol. 2022; 46:101922. doi: 10.1016/j.clinre.2022.101922. 

• Hamdy O and Carver C. The Why WAIT program: improving clinical outcomes through weight management in type 2 diabetes.  Curr Diab Rep. 2008; 8:413-20. doi: 10.1007/s11892-008-0071-5.

• Sears B and Saha AK.  Dietary control of inflammation and resolution.  Front Nutr. 2021; 8:709435. doi: 10.3389/fnut.2021.709435.

References
1. Insulin resistance due to nutrient excess: Is it a consequence of AMPK downregulation?  Saha AK, Xu XJ, Balon TW, Brandon A, Kraegen EW, Ruderman NB. Cell Cycle. 2011; 10:3447-51. doi: 10.4161/cc.10.20.17886.

2. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action.  J Clin Invest. 2001; 108:1167-74. doi: 10.1172/JCI13505.

3. Goel S, Singh R, Singh V, Singh H, Kumari P, Chopra H, Sharma R, Nepovimova E, Valis M, Kuca K, Emran TB. Metformin: Activation of 5′ AMP-activated protein kinase and its emerging potential beyond anti-hyperglycemic action.  Front Genet. 2022; 13:1022739. doi: 10.3389/fgene.2022.1022739.

4. LeBrasseur NK, Kelly M, Tsao TS, Farmer SR, Saha AK, Ruderman NB, Tomas E. Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues.  Am J Physiol Endocrinol Metab. 2006; 291:E175-81. doi: 10.1152/ajpendo.00453.2005. 

5. Reis-Barbosa PH, Marcondes-de-Castro IA, Marinho TS, Aguila MB, Mandarim-de-Lacerda CA. The mTORC1/AMPK pathway plays a role in the beneficial effects of semaglutide (GLP-1 receptor agonist) on the liver of obese mice.  Clin Res Hepatol Gastroenterol. 2022; 46:101922. doi: 10.1016/j.clinre.2022.101922.

6. Hamdy O and Carver C. The Why WAIT program: improving clinical outcomes through weight management in type 2 diabetes.  Curr Diab Rep. 2008; 8:413-20. doi: 10.1007/s11892-008-0071-5.

7. Sears B and Saha AK.  Dietary control of inflammation and resolution.  Front Nutr. 2021; 8:709435. doi: 10.3389/fnut.2021.709435.

The Problem
Fatty liver disease occurs when excess fat builds up in the liver, causing metabolic complications.  Fatty liver disease is becoming an epidemic, with nearly 80 million Americans having this condition (1).  Not surprisingly, this number is similar to the number of Americans having pre-diabetes, as both conditions are strongly associated with increased insulin resistance (2).    

The Traditional Medical Approach
Fatty liver disease can be classified as alcohol-induced or metabolically-induced.  There are no approved drugs to treat either type of fatty liver disease.  For alcohol-induced fatty liver disease, the recommendation is to stop drinking.  For metabolically-induced fatty liver disease, the recommendation is to lose weight.

The Metabolic Engineering™ Approach
Since there is no approved drug for treating either type of fatty liver disease, using Metabolic Engineering™ is the most appropriate approach to reduce stored fat in the liver for increasing AMPK activity to increase the metabolic oxidation of stored fat in the liver for energy production (2).  The Zone diet component of Metabolic Engineering™ is the most potent method to activate AMPK because of its ability to restrict calories without hunger or fatigue.  The omega-3 fatty acid component of Metabolic Engineering™ will directly reduce inflammation and promote resolution of the damaged liver tissue.  The polyphenol dietary component of Metabolic Engineering™ will reduce the oxidative stress associated with fatty liver disease. Furthermore, omega-3 fatty acids and polyphenols are indirect activators of AMPK, thus making the Zone diet work more effectively (3).

References
1. Cotter TG, Rinella M. Gastroenterology. Nonalcoholic fatty liver disease 2020: The state of the disease.  2020; 158:1851-1864. doi:10.1053/j.gastro.2020.01.052. 

2. The AMPK pathway in fatty liver disease. Fang C, Pan J, Qu N, Lei Y, Han J, Zhang J, Han D.  Front Physiol. 2022; 13:970292. doi: 10.3389/fphys.2022.970292. 

3. Sears B and Saha AK. Dietary control of inflammation and resolution.Front Nutr. 2021; 8:709435. doi: 10.3389/fnut.2021.709435. 

Successful conception is one of the more complex tasks of human metabolism and, not surprisingly, is under robust dietary control.  This is especially true for infertility problems germane to both males and females.

Polycystic Ovary Syndrome (PCOS)

The Problem
The most common condition associated with female infertility is polycystic ovarian syndrome (PCOS).  PCOS is also strongly associated with increased insulin resistance (1,2).  

The Traditional Medical Approach
There is no cure for PCOS.  Thus, the best approach is the dietary reduction of insulin resistance.

The Metabolic Engineering™ Approach
The best strategy is to reduce insulin resistance by activating AMPK (3).  Metabolic Engineering™ is a proven dietary technology to reduce existing insulin resistance.  Using the Zone diet component of Metabolic Engineering™ to restrict calories without hunger or fatigue is the most powerful dietary approach for lowering insulin resistance because of its direct impact on increasing AMPK activity.  The omega-3 fatty acid and polyphenol components of Metabolic Engineering™ are indirect activators of AMPK activity. Thus, combining all three dietary interventions in Metabolic Engineering™ provides the optimal approach to maximizing AMPK activity to reduce insulin resistance.

In-vitro Fertilization

The Problem
Considering the complex metabolic changes that are required to take place in successful conception, it is not surprising that increased insulin resistance is strongly associated with female infertility, even for females who do not have PCOS (4).  This includes decreased quality of the egg and ovulation as well as increased associated pregnancy-induced complications such as gestational diabetes (5).   For males, increased insulin resistance translates into a reduction in semen quality (6,7). 

The Traditional Medical Approach
In-vitro fertilization is the traditional approach to overcome infertility.  However, it requires two to tango, meaning it requires good quality eggs from the female and healthy sperm quality from the male.  Both are adversely affected by insulin resistance (4).

The Metabolic Engineering™ Approach
The goal of Metabolic Engineering™ is to reduce insulin resistance by increasing AMPK activity.  Using the Zone diet component of Metabolic Engineering™ to restrict calories without hunger or fatigue is the most powerful dietary approach for lowering insulin resistance because of its direct impact on increasing AMPK activity.  The omega-3 fatty acid and polyphenol components of Metabolic Engineering™ are indirect activators of AMPK activity. Thus, combining all three dietary interventions in Metabolic Engineering™ provides the optimal approach to maximizing AMPK activity to reduce insulin resistance.

Thus, for both males and females seeking the use of IVF for a successful pregnancy, following Metabolic Engineering™ should be considered a dietary requirement to help support better IVF success. 

References
1. Zhao, H., Zhang, J., Cheng, X. et al. Insulin resistance in polycystic ovary syndrome across various tissues: an updated review of pathogenesis, evaluation, and treatment. J Ovarian Res. 2023; 16:9. org/10.1186/s13048-022-01091-0

2. Li M, Chi X, Wang Y, Setrerrahmane S, Xie W, Xu H.  Trends in insulin resistance: Insights into mechanisms and therapeutic strategy.  Signal Transduct Target Ther. 2022; 7:216. doi: 10.1038/s41392-022-01073-0.

3. Sears B, Saha AK.  Dietary control of inflammation and resolution.Front Nutr. 2021; 8:709435. doi: 10.3389/fnut.2021.709435. 

4. Lei R, Chen S, Li W.Advances in the study of the correlation between insulin resistance and infertility.  Front Endocrinol. 2024; 15:1288326. doi: 10.3389/fendo.2024.1288326.

5. Ferrazzi E. and Sears B. eds.  Metabolic Syndrome and Complications of Pregnancy. Springer.  Heidelburg, Germany (2015)

6. Bertoldo MJ, Faure M, Dupont J, Froment P.  AMPK: A master energy regulator for gonadal function.  Front Neurosci. 2015; 9:235. doi: 10.3389/fnins.2015.00235. 

7. Zańko A, Siewko K, Krętowski AJ, Milewski R. Lifestyle, insulin resistance and semen quality as co-dependent factors of male infertility.  Int J Environ Res Public Health. 2022; 20:732. doi: 10.3390/ijerph20010732.

The Problem
The kidney removes much of the body’s waste products generated by metabolism.  The inability to consistently accomplish this goal results in kidney disease.  Kidney disease is strongly associated with insulin resistance (1). 

The underlying cause of kidney disease is fibrosis (i.e., scar formation) in the kidney tubules, which reduces the ability of the kidneys to remove waste products from the blood into the urine.  In severe cases of kidney disease, the patient requires dialysis to remove waste products from the blood. It has been shown that activation of AMPK in reverses many complications associated with kidney disease (2). 

The Traditional Medical Approach
The leading drugs to treat kidney disease are sodium-glucose co-transporter-2 inhibitors (SGLT2i).  The tradenames of these drugs include Farxiga and Jardiance.  SGLT2 inhibitors work by increasing AMPK levels (3,4).

The Metabolic Engineering™ Approach
Many of the drugs used to treat the symptoms of kidney disease can be enhanced by consistent use of Metabolic Engineering™ to reduce insulin resistance by activating AMPK activity.  

The goal of Metabolic Engineering™ is to reduce insulin resistance by increasing AMPK activity.  Using the Zone diet component of Metabolic Engineering™ to restrict calories without hunger or fatigue is the most powerful dietary approach for lowering insulin resistance because of its direct impact on increasing AMPK activity.  The omega-3 fatty acid and polyphenol components of Metabolic Engineering™ are indirect activators of AMPK activity.  Thus, combining all three dietary interventions in Metabolic Engineering™ provides the optimal approach to maximizing AMPK activity to reduce insulin resistance.

Thus, Metabolic Engineering™ works in concert with drug therapy for kidney treatment to help reprogram kidney function by activating AMPK.  This means that Metabolic Engineering™ either makes the drug used to improve kidney function work better or allows the physician to potentially decrease the amount of drug used to manage their patient’s kidney disease, resulting in fewer side effects. 

Although Metabolic Engineering™ can quickly reduce insulin resistance, eliminating scar tissue caused by prolonged diet-induced inflammation and replacing it with new healthy tissue takes considerably longer.

References
1. Xu, H. and Carrero, J. Insulin resistance in chronic kidney disease. Nephrology, 2017; 22: 31-34. https://doi.org/10.1111/nep.13147

2. Juszczak F, Caron N, Mathew AV, Declèves AE.Critical role for AMPK in metabolic disease-induced chronic kidney disease.  Int J Mol Sci.  2020; 21:7994.doi: 10.3390/ijms21217994.

3. Packer M. Interplay of adenosine monophosphate-activated protein kinase/sirtuin-1 activation and sodium influx inhibition mediates the renal benefits of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes: A novel conceptual framework. Diabetes Obes Metab. 2020; 22:734-742. doi: 10.1111/dom.13961.

4. Safaie N, Masoumi S, Alizadeh S, et al. SGLT2 inhibitors and AMPK: The road to cellular housekeeping? Cell Biochem Funct. 2024; 42:e3922. doi:10.1002/cbf.3922

The brain is the organ most susceptible to the consequences of insulin resistance.   The brain is a relative energy hog as it accounts for two percent of the body’s mass, but it uses 20 percent of metabolic energy produced by the body.  The reason is to maintain nerve conduction requires massive amounts of energy.  The primary fuel source for the brain’s energy needs is glucose.  Thus, any insulin resistance in the brain will decrease energy production, leading to diminished capacity in terms of mental fatigue or the inability to control neurotransmitters, or in more extreme cases of neurological disease to address the loss of mitochondrial function that causes the loss of cognitive and locomotive function.    Thus, a broad spectrum of neurological diseases may be better understood as an umbrella of conditions related to disrupted metabolism in the brain.

ADHD

The Problem
Attention deficient hyperactivity disorder (ADHD) is a condition characterized by the inability to focus attention coupled with hyperactivity. Although ADHD is often associated with only children, it can affect one at any age. 

The Traditional Medical Approach
The primary pharmacological treatment for ADHD consists of drugs that are stimulants that increase the levels of dopamine and norepinephrine,  The primary drugs include methylphenidate (Concerta, Ritalin, and others) or amphetamine (Adderall or Adderall XR)

The Metabolic Engineering™ Approach
One published clinical research indicates that high-dose omega-3 fatty acids combined with the Zone diet had a significant impact had a significant benefit in better managing this condition in children (1).  Another study using only high-dose omega-3 fatty acids had a benefit, but not to the same extent as combining the omega-3 fatty acids with the Zone diet (2).   Not surprisingly, there is also an association between adult ADHD and insulin resistance (3). 

The goal of Metabolic Engineering™ is to reduce insulin resistance by increasing AMPK activity.  Using the Zone diet component of Metabolic Engineering™ to restrict calories without hunger or fatigue is the most powerful dietary approach for lowering insulin resistance because of its direct impact on increasing AMPK activity.  The omega-3 fatty acid and polyphenol components of Metabolic Engineering™ are indirect activators of AMPK activity.   Thus, combining all three dietary interventions in Metabolic Engineering™ provides the optimal approach to maximizing AMPK activity to reduce insulin resistance and improve the symptoms of ADHD.

This suggests that using the full spectrum of Metabolic Engineering™ may significantly impact managing ADHD at any stage of life by reducing insulin resistance in the brain by increasing omega-3 fatty acid content in the brain.

References
1. Sorgi PJ, Hallowell EM, Hutchins HL, Sears B.Effects of an open-label pilot study with high-dose EPA/DHA concentrates on plasma phospholipids and behavior in children with attention deficit hyperactivity disorder.  Nutr J. 2007; 6:16. doi: 10.1186/1475-2891-6-16.

2. Germano M, Meleleo D, Montorfano G, Adorni L, Negroni M, Berra B, Rizzo AM. Plasma, red blood cells phospholipids, and clinical evaluation after long chain omega-3 supplementation in children with attention deficit hyperactivity disorder (ADHD). Nutr Neurosci. 2007; 10:1-9. doi: 10.1080/10284150601153801.

3. di Girolamo G, Bracco IF, Portigliatti Pomeri A, Puglisi S, Oliva F.Prevalence of metabolic syndrome and insulin resistance in a sample of adult ADHD outpatients.  Front Psychiatry. 2022; 13:891479. doi: 10.3389/fpsyt.2022.891479.

Alzheimer’s

The Problem
Alzheimer’s disease is often referred to as “type 3 diabetes”  because of its strong association with insulin resistance (4,5).  Any insulin resistance in the brain decreases the ability of the brain to generate sufficient cellular energy from glucose to maintain cellular activity.  As a result, the cell’s ability to remove the aggregated proteins associated with Alzheimer’s disease is compromised (6).  These aggregated proteins promote neuroinflammation by increasing oxidative stress. This leads to the death of the nerve cell.  When enough nerve cells are destroyed, cognitive memory is lost.

The Traditional Medical Approach
There is no approved drug for treating Alzheimer’s.  Thus, your best prevention is the reduction of insulin resistance.

The Metabolic Engineering™ Approach
The molecular mechanism that links insulin resistance and oxidative stress to Alzheimer’s may be decreased AMPK activity (7). 

The goal of Metabolic Engineering™ is to reduce insulin resistance by increasing AMPK activity.  Using the Zone diet component of Metabolic Engineering™ to restrict calories without hunger or fatigue is the most powerful dietary approach for lowering insulin resistance because of its direct impact on increasing AMPK activity.  The omega-3 fatty acid dietary component of Metabolic Engineering™ reduces neuroinflammation and promotes resolution.  The polyphenol dietary component of Metabolic Engineering™ reduces oxidative stress.  Equally important is that the omega-3 fatty acid and polyphenol components of Metabolic Engineering™ are also indirect activators of AMPK activity.   Thus, combining all three dietary interventions in Metabolic Engineering™ provides the optimal approach to maximizing AMPK activity to reduce insulin resistance.

Since the development of insulin resistance precedes the development of Alzheimer’s by more than a decade, using Metabolic Engineering™ to reduce insulin resistance becomes your best dietary therapy to reduce the likelihood of developing cognitive dysfunction later in life.

References
4. Kandimalla R, Thirumala V, Reddy PH.Is Alzheimer’s disease a type 3 diabetes? A critical appraisal.  Biochim Biophys Acta Mol Basis Dis. 2017; 1863:1078-1089. doi: 10.1016/j.bbadis.2016.08.018.

5. Michailidis M, Moraitou D, Tata DA, Kalinderi K, Papamitsou T, Papaliagkas V.Alzheimer’s disease as type 3 diabetes: Common pathophysiological mechanisms between Alzheimer’s disease and type 2 diabetes.  Int J Mol Sci. 2022; 23:2687.doi: 10.3390/ijms23052687.

6. Dewanjee S, Chakraborty P, Bhattacharya H, Chacko L, Singh B, Chaudhary A, Javvaji K, Pradhan SR, Vallamkondu J, Dey A, Kalra RS, Jha NK, Jha SK, Reddy PH, Kandimalla R. Altered glucose metabolism in Alzheimer’s disease:  Role of mitochondrial dysfunction and oxidative stress. Free Radic Biol Med. 2022; 193(Pt 1):134-157. doi: 10.1016/j.freeradbiomed.2022.09.032.

7. Yang L, Jiang Y, Shi L, Zhong D, Li Y, Li J, Jin R. AMPK: Potential therapeutic target for Alzheimer’s disease. Curr Protein Pept Sci. 2020; 21:66-77.doi: 10.2174/1389203720666190819142746.

Brain trauma

The Problem
Brain trauma can be classified either as severe (comatose patients) or traumatic (head injuries without the loss of consciousness).  In both cases, the brain damage causes ongoing neuroinflammation.  The survival chances of those with severe brain trauma are limited.

On the other hand, those suffering with traumatic brain trauma often have lifetime complications due to chronic low-level neuroinflammation caused by the injury.  Unless the inflammation is stopped and the injury’s resolution quickly begins, the inflammatory damage spreads to nearby nerve cells to compromise their activity.  As time progresses, neurological dysfunction in the person becomes more apparent, leading to an inability to control emotions. 

The Traditional Medical Approach
There has been minimal advancement in brain trauma treatment except for rest and psychological counseling. Neither represents an advanced therapy in reducing the neuroinflammation generated by brain trauma.

The Metabolic Engineering™ Approach
Metabolic Engineering™ can decrease this spread of neuroinflammation by activating AMPK in the brain.  Using the Zone diet component of Metabolic Engineering™ to restrict calories without hunger or fatigue is the most powerful dietary approach for increasing AMPK activity.  The omega-3 fatty acid dietary component of Metabolic Engineering™ reduces neuroinflammation and promotes its resolution.  Finally, the polyphenol dietary component of Metabolic Engineering™ reduces oxidative stress that drives neuroinflammation.  Equally important is that the omega-3 fatty acid and polyphenol components of Metabolic Engineering™ are also indirect activators of AMPK activity.   Thus, combining all three dietary interventions in Metabolic Engineering™ provides the optimal dietary approach to maximizing AMPK activity to reduce neuroinflammation. 

It has been shown that the immediate use of high-dose omega-3 fatty acids after severe brain trauma can significantly improve clinical outcomes in patients with severe brain trauma if the supplementation is started after the injury (8, 9).  Pre-treatment with high levels of omega-3 fatty acids dramatically reduces the neurological damage caused by head injury in animal models of TBI (10).

Thus, using the full spectrum of dietary interventions that comprise Metabolic Engineering™, may significantly speed up the repair rate of damaged brain tissue (11,12). It also suggests that following Metabolic Engineering™ may serve as a prophylactic dietary approach to reduce the severity of any potential cause of brain trauma,

References
8. Roberts L, Bailes J, Dedhia H, Zikos A, Singh A, McDowell D, Failinger C, Biundo R, Petrick J, Carpenter J. Surviving a mine explosion.  J Am Coll Surg. 2008;  207:276-83. doi: 10.1016/j.jamcollsurg.2008.02.015.

9. Bailes JE, Abusuwwa R, Arshad M, Chowdhry SA, Schleicher D, Hempeck N, Gandhi YN, Jaffa Z, Bokhari F, Karahalios D, Barkley J, Patel V, Sears B. Omega-3 fatty acid supplementation in severe brain trauma: Case for a large multicenter trial.  J Neurosurg. 2020:1-5. doi: 10.3171/2020.3.JNS20183.

10. Mills JD, Bailes JE, Sedney CL, Hutchins H, Sears B.J   Omega-3 fatty acid supplementation and reduction of traumatic axonal injury in a rodent head injury model.  2011; 114:77-84. doi: 10.3171/2010.5.JNS08914. 

11. Sears B, Perry M, Saha AK. Dietary technologies to optimize healing from injury-induced inflammation.   Antiinflamm Antiallergy Agents Med Chem. 2021; 20:123-131. doi: 10.2174/1871523019666200512114210.

12. Sears B and Saha AK. Dietary control of inflammation and resolution.Front Nutr. 2021;8: 709435. doi: 10.3389/fnut.2021.709435.

Depression

The Problem
Depression is commonly thought of being due to decreased serotonin levels.  However, depression is strongly associated with both increased inflammation (13,14) and insulin resistance (15)

The Traditional Medical Approach
The primary approach to treating depression has been the use of drugs that enhance serotonin levels in the brain.  Before such drug therapy was introduced, the primary treatment for depression was electroshock therapy.  Recent research indicates that electroshock therapy increases AMPK levels (16)

The Metabolic Engineering™ Approach
Both inflammation and insulin resistance are reduced by Metabolic Engineering™ because it activates AMPK.  As an example, both bipolar and unipolar depression respond well to high-dose omega-3 fatty acids (17,18).  In treating unipolar depression, the improvement in symptoms were correlated with an increase in resolvins formation (19).  Finally, there is an association between depression and increased oxidative stress (20).

The goal of Metabolic Engineering™ is to activate AMPK in the brain.  Using the Zone diet component of Metabolic Engineering™ to restrict calories without hunger or fatigue is the most powerful dietary approach for increasing AMPK activity.  The omega-3 fatty acid dietary component of Metabolic Engineering™ reduces neuroinflammation and promotes its resolution.  The polyphenol dietary component of Metabolic Engineering™ reduces oxidative stress.  Equally important is that the omega-3 fatty acid and polyphenol components of Metabolic Engineering™ are also indirect activators of AMPK activity.   Thus, combining all three dietary interventions in Metabolic Engineering™ provides the optimal dietary approach to maximizing AMPK activity to reduce neuroinflammation. 

This suggests that Metabolic Engineering™ may play a significant role in the reduction of the symptoms associated with depression.  These benefits would include the reduction of insulin resistance, an increase in the production of resolvins (the hormones that turn off neuroinflammation) and decreased oxidative stress.  All these benefits are mediated by increased activation of AMPK (21).

References
13. Kiecolt-Glaser JK, Derry HM, Fagundes CP. Inflammation: Depression fans the flames and feasts on the heat. Am J Psychiatry. 2015; 172:1075-91. doi: 10.1176/appi.ajp.2015.15020152.

14. Beurel E, Toups M, Nemeroff CB.The bidirectional relationship of depression and inflammation:  Double trouble.  Neuron. 2020; 107:234-256.doi: 10.1016/j.neuron.2020.06.002.

15. Fernandes BS, Salagre E, Enduru N, Grande I, Vieta E, Zhao Z. Insulin resistance in depression:  A large meta-analysis of metabolic parameters and variation.  Neurosci Biobehav Rev. 2022;139: 104758. doi: 10.1016/j.neubiorev.2022.104758.

16. Kim SH, Yu HS, Huh S, Kang UG, Kim YS.Electroconvulsive seizure inhibits the mTOR signaling pathway via AMPK in the rat frontal cortex.  Psychopharmacology.  2022; 239: 443-454. doi: 10.1007/s00213-021-06015-2.

17. Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, Cress KK, Marangell LB.Omega 3 fatty acids in bipolar disorder: A preliminary double-blind, placebo-controlled trial.  Arch Gen Psychiatry. 1999; 56:407-12.doi: 10.1001/archpsyc.56.5.407.

18. Mischoulon D, Dunlop BW, Kinkead B, Schettler PJ, Lamon-Fava S, Rakofsky JJ, Nierenberg AA, Clain AJ, Mletzko Crowe T, Wong A, Felger JC, Sangermano L, Ziegler TR, Cusin C, Fisher LB, Fava M, Rapaport MH.  Omega-3 fatty acids for major depressive disorder with high inflammation:  A randomized dose-finding clinical trial. J Clin Psychiatry. 2022; 8:21m14074. doi: 10.4088/JCP.21m14074.

19. Lamon-Fava S, Liu M, Dunlop BW, Kinkead B, Schettler PJ, Felger JC, Ziegler TR, Fava M, Mischoulon D, Rapaport MH.Clinical response to EPA supplementation in patients with major depressive disorder is associated with higher plasma concentrations of pro-resolving lipid mediators.  Neuropsychopharmacology. 2023; 48:929-935. doi: 10.1038/s41386-022-01527-7.

20. Sipahi H, Mat AF, Ozhan Y, Aydin A.The interrelation between oxidative stress, depression, and inflammation through the kynurenine pathway.  Curr Top Med Chem. 2023; 23:415-425. doi: 10.2174/1568026623666221223111309.

21. Sears B and Saha AK.Dietary control of inflammation and resolution.Front Nutr. 2021; 8:709435. doi: 10.3389/fnut.2021.709435.

Parkinson’s

The Problem
Parkinson’s disease is like Alzheimer’s disease in that it is associated with aggregated proteins in the brain, but now initially affecting motor skills instead of loss of memory.  Furthermore, like Alzheimer’s disease, there appears to be a link between insulin resistance and Parkinson’s (22).  In addition, the relationship between decreased AMPK activity and Parkinson’s is also quite strong  (23).  Finally, disruption of AMPK activity in dopamine-associated neurons promotes Parkinson’s-like symptoms (24).

The longer the Parkinson’s patient survives, their mental skills begin to erode as the neuroinflammation spreads to the cognitive areas of the brain.  Also, like Alzheimer’s disease, advanced Parkinson’s disease is associated with aggregated protein clumps known as Lewy bodies. The removal of such protein aggregates is mediated by autophagy, which is controlled by AMPK activity (24).  In essence, the progression of Parkinson’s disease may be better understood as an AMPK inhibition condition. 

The Traditional Medical Approach
The primary drug used to treat Parkinson’s is L-dopa, which is the precursor to dopamine.  Unfortunately, the benefits of L-dopa fall off after a few years, and the progression of Parkinson’s continues.

The Metabolic Engineering™ Approach
The best way to increase the energy production of mitochondria in the brain (as well as every cell in the body) is to activate AMPK. The most effective tool to do that is following Metabolic Engineering™ at the first sign of increasing insulin resistance. 

The goal of Metabolic Engineering™ is to activate AMPK in the brain.  Using the Zone diet component of Metabolic Engineering™ to restrict calories without hunger or fatigue is the most powerful dietary approach for increasing AMPK activity.  The omega-3 fatty acid dietary component of Metabolic Engineering™ reduces neuroinflammation and promotes its resolution.  The polyphenol dietary component of Metabolic Engineering™ reduces oxidative stress.  Equally important is that the omega-3 fatty acid and polyphenol components of Metabolic Engineering™ are also indirect activators of AMPK activity.   Thus, combining all three dietary interventions in Metabolic Engineering™ provides the optimal dietary approach to maximizing AMPK activity to reduce neuroinflammation. 

As with Alzheimer’s, the increase in insulin resistance will occur years ahead of the development of the symptoms of Parkinson’s disease. Thus, the best way to reduce the likelihood of developing Parkinson’s disease is to reduce, if not eliminate, insulin resistance as early as possible.

References 
22. Sharma T, Kaur D, Grewal AK, Singh TG.Therapies modulating insulin resistance in Parkinson’s disease: A cross-talk.  Neurosci Lett. 2021 Apr 1;749:135754.doi: 10.1016/j.neulet.2021.135754.

23. Curry DW, Stutz B, Andrews ZB, Elsworth JD.Targeting AMPK signaling as a neuroprotective strategy in Parkinson’s disease.  J Parkinsons Dis. 2018; 8:161-181. doi: 10.3233/JPD-171296.

24. Parekh P, Sharma N, Sharma M, Gadepalli A, Sayyed AA, Chatterjee S, Kate A, Khairnar A.AMPK-dependent autophagy activation and alpha-Synuclein clearance: a putative mechanism behind alpha-mangostin’s neuroprotection in a rotenone-induced mouse model of Parkinson’s disease.  Metab Brain Dis. 2022; 37:2853-2870. doi: 10.1007/s11011-022-01087-1.

The Problem
Obesity has become a worldwide epidemic.  Excess body fat is usually the first physical sign that your metabolism is disrupted and that your level of insulin resistance is rising, however about 16 percent of normal weight individuals have severe insulin resistance (1).  Not only is obesity a chronic inflammatory condition, but it also increases the production of senescent cells that drive the aging process (2). 

The physiological foundation of obesity is insulin resistance caused by decreased AMPK activity (3,4).  If AMPK activity is inhibited, the burning of excess body fat in every organ is compromised, and fat stores continue to increase.  However, that same inhibition of AMPK activity will also have negative consequences on your immune system, the ability to resolve inflammation, the expression of your genes, and the acceleration of aging.

The Traditional Medical Approach
The search for weight loss drugs has continued for nearly a century and has yet to generate sustainable results.  The current generation of injectable weight loss drugs stops hunger and reduces calorie intake, thus leading to weight loss.  Unfortunately, much weight loss comes from losing lean body mass (5).  This loss of lean body mass reduces the metabolic efficacy of every organ in the body.

The Metabolic Engineering™ Approach
Metabolic Engineering™ is a more comprehensive dietary technology to improve metabolic efficiency and repair damaged tissue by activating AMPK (6).  Increased AMPK activity also stimulates the oxidation of stored fat in every cell in the body. 

The goal of Metabolic Engineering™ is to activate AMPK in the adipose tissue.  Using the Zone diet component of Metabolic Engineering™ to restrict calories without hunger or fatigue is the most powerful dietary approach for increasing AMPK activity.  The omega-3 fatty acid dietary component of Metabolic Engineering™ reduces neuroinflammation and promotes its resolution.  The polyphenol dietary component of Metabolic Engineering™ reduces oxidative stress.  Equally important is that the omega-3 fatty acid and polyphenol components of Metabolic Engineering™ are also indirect activators of AMPK activity.   Thus, combining all three dietary interventions in Metabolic Engineering™ provides the optimal dietary approach to maximizing AMPK activity to metabolize stored excess body fat for energy. 

An added benefit of the benefit of following Metabolic Engineering™ to reduce excess body fat is that you will also reduce cellular senescence (7).   That is the true benefit of fat loss as it leads to a longer healthspan.

References1. 
1. McLaughlin T, Allison G, Abbasi F, Lamendola C, Reaven G.Prevalence of insulin resistance and associated cardiovascular disease risk factors among normal weight, overweight, and obese individuals.  Metabolism. 2004; 53:495-9. doi: 10.1016/j.metabol.2003.10.032.

2. Burton DGA and Faragher RGA. Obesity and type-2 diabetes as inducers of premature cellular senescence and ageing.  Biogerontology. 2018; 19(6): 447-459.doi: 10.1007/s10522-018-9763-7. 

3. Ruderman NB, Carling D, Prentki M, Cacicedo JM. AMPK, insulin resistance, and the metabolic syndrome.  J Clin Invest. 2013; 123:2764-72. doi: 10.1172/JCI67227.

4. Saha AK, Xu XJ, Balon TW, Brandon A, Kraegen EW, Ruderman NB. Insulin resistance due to nutrient excess:  Is it a consequence of AMPK downregulation?Cell Cycle. 2011; 10: 3447-51. doi: 10.4161/cc.10.20.17886.

5. Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, Tran MTD, Wadden TA, Wharton S, Yokote K, Zeuthen N, Kushner RF; STEP 1 Study Group.Once-weekly semaglutide in adults with overweight or obesity.  N Engl J Med. 2021; 384: 989-1002. doi: 10.1056/NEJMoa2032183.

6. Sears B and Saha AK.Dietary control of inflammation and resolution. Front Nutr. 2021;8: 709435. doi: 10.3389/fnut.2021.709435.

7. List EO, Jensen E, Kowalski J, Buchman M, Berryman DE, Kopchick JJ. Diet-induced weight loss is sufficient to reduce senescent cell number in white adipose tissue of weight-cycled mice.  Nutr Healthy Aging.  2016 4:95-99. doi: 10.3233/NHA-1614.

The Problem
The primary ocular disease associated with aging is age-related macular degeneration (AMD).  When you begin to develop AMD, you begin to lose your central vision in the retina.  You cannot see fine details, whether you are looking at something close or far. But your peripheral vision can still be normal. Nonetheless, as your central vision decreases to the extent you are likely to become legally blind.  AMD is the primary cause of blindness after age 50. 

The Traditional Medical Approach
There are two types of AMD: wet and dry.  Wet AMD accounts for only 10% of AMD cases, and its progression can be minimized by injections of monoclonal antibodies indirectly into the eye. However, the condition rarely improves, and once the monthly injections are stopped, the progression of the disease continues, leading to functional blindness.  The other type of AMD is known as dry AMD, which accounts for 90 percent of the cases of AMD.  There is no drug treatment for dry AMD.

The Metabolic Engineering™ Approach
AMD is strongly associated with insulin resistance and cellular senescence (1,2).  Both conditions are associated with decreased AMPK activity.   

The goal of Metabolic Engineering™ is to activate AMPK in every organ, including the eye.  Using the Zone diet component of Metabolic Engineering™ to restrict calories without hunger or fatigue is the most powerful dietary approach for increasing AMPK activity.  The omega-3 fatty acid dietary component of Metabolic Engineering™ reduces inflammation and promotes its resolution.  The polyphenol dietary component of Metabolic Engineering™ reduces oxidative stress.  Equally important is that the omega-3 fatty acid and polyphenol components of Metabolic Engineering™ are also indirect activators of AMPK activity.   Thus, combining all three dietary interventions in Metabolic Engineering™ provides the optimal dietary approach to maximizing AMPK activity to metabolize stored excess body fat for energy. 

A preliminary trial has demonstrated that high-dose omega-3 fatty acids per day significantly improve vision in patients with dry AMD (3).  This clinical result suggests that  Metabolic Engineering™ with adequate levels of omega-3 fatty acids may significantly reduce insulin resistance and cellular senescence in the retina by increasing AMPK activity. 

References
1. Roddy GW.Metabolic syndrome and the aging retina.  Curr Opin Ophthalmol. 2021; 32: 280-287. doi: 10.1097/ICU.0000000000000747.

2. Lee KS, Lin S, Copland DA, Dick AD, Liu J.Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration.J Neuroinflammation. 2021; 18: 32. doi: 10.1186/s12974-021-02088-0.

3. Georgiou T, Neokleous A, Nicolaou D, Sears B.Pilot study for treating dry age-related macular degeneration (AMD) with high-dose omega-3 fatty acids, PharmaNutrition 2014 2:8-11. doi.org/10.1016/j.phanu.2013.10.001.

The Problem
The skin is the one organ constantly visible to the signs of aging and unresolved inflammation.  The obvious external signs of skin aging are the loss of skin elasticity and thinning of the skin.  These visual signs result from increased cellular senescence in the skin (1-3).    

The Traditional Medical Approach
Retinol treatment, laser resurfacing, and collagen injections are the primary treatments to make the skin appear to look younger.  However, they don’t treat the underlying cause of aging skin, which is increased cellular senescence.

The Metabolic Engineering™ Approach
The goal of Metabolic Engineering™ is to activate AMPK in every organ, including the skin.  Using the Zone diet component of Metabolic Engineering™ to restrict calories without hunger or fatigue is the most powerful dietary approach for increasing AMPK activity.  The omega-3 fatty acid dietary component of Metabolic Engineering™ reduces inflammation and promotes its resolution.  The polyphenol dietary component of Metabolic Engineering™ reduces oxidative stress.  Equally important is that the omega-3 fatty acid and polyphenol components of Metabolic Engineering™ are also indirect activators of AMPK activity.   Thus, combining all three dietary interventions in Metabolic Engineering™ provides the optimal dietary approach to maximizing AMPK activity to metabolize stored excess body fat for energy. 

Metabolic Engineering™ works by activating AMPK.  Once AMPK is activated, it is the key to reducing the rate of aging (4,5).  AMPK activation reduces the release of pro-inflammatory cytokines by inhibiting the inflammatory gene transcription factor NF-κB (6).  Simultaneously, AMPK activation also enhances the activity of another gene transcription factor (Nrf2), increasing the production of anti-oxidative enzymes that reduce free radical damage (7).  This is why activating AMPK is the key to slowing the aging process in every organ, including the skin.

References
1. Chin T, Lee XE, Ng PY, Lee Y, Dreesen O.  The role of cellular senescence in skin aging and age-related skin pathologies.  Front Physiol. 2023; 14:1297637.doi: 10.3389/fphys.2023.1297637.

2. Wlaschek M, Maity P, Makrantonaki E, Scharffetter-Kochanek K. Connective tissue and fibroblast senescence in skin aging.  J Invest Dermatol.  2021; 141:985-992. doi: 10.1016/j.jid.2020.11.010.

3. Wyles SP, Carruthers JD, Dashti P, Yu G, Yap JQ, Gingery A, Tchkonia T, Kirkland J.Cellular senescence in human skin aging: Leveraging senotherapeutics. Gerontology. 2024; 70: 7-14. doi: 10.1159/000534756.

4. Salminen A and Kaarniranta K.AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network.  Ageing Res Rev. 2012; 11: 230-41. doi: 10.1016/j.arr.2011.12.005.

5. Ge Y, Zhou M, Chen C, Wu X, Wang X.Role of AMPK mediated pathways in autophagy and aging.  Biochimie. 2022; 195: 100-113. doi: 10.1016/j.biochi.2021.11.008.

6. Salminen, A., Hyttinen, J.M.T. & Kaarniranta, K. AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan. J Mol Med. 2011. 89: 667–676. doi.org/10.1007/s00109-011-0748-0

7. Manuel Matzinger, Katrin Fischhuber, Daniel Poloske, Karl Mechtler, Elke H. Heiss. AMPK leads to phosphorylation of the transcription factor Nrf2, tuning transactivation of selected target genes. Redox Biology.  2020: 29:101393. doi.org/10.1016/j.redox.2019.101393.