mTOR and the Science of Aging and Chronic Disease

By William H. Bestermann MD and Patricia Salber MD, MBA | Published 8/14/2020 0

Photo source: iStock

What if you could age slower and maintain your ability to be active and enjoy your family well into your 70’s or 80’s or beyond? What if you could delay the onset of chronic disease by almost a decade? Well, that is no longer a dream. Thanks to advances in the science of aging and chronic disease, we know that there are things that you can do now to impact your health and, perhaps, your longevity.

Let’s start our discussion by diving into some of the basic science related to prolongation of a healthy lifespan. Don’t worry, we are going to start with a video and it’s going to be fun.

What we can learn about aging and longevity from worms

First, check out this very entertaining short TED talk by Cynthia Kenyon who is a top scientist at the University of California at San Francisco Medical School. Then come back to this post for an expanded discussion.

The importance of Dr. Kenyon’s work and that of contemporary aging researchers is that they showed, for the first time, that aging and age-related chronic diseases aren’t things that “just happen” to us. [1] They are, in fact, related to an evolutionarily-conserved complex, highly regulated, and interconnected series of biochemical pathways.

Central to these pathways is a molecule called mTOR which stands for mechanistic Target of Rapamycin. It is so-named because rapamycin, a naturally occurring substance, inhibits the many of the activities of mTOR triggering a variety of metabolic and clinical outcomes. The most well-known of which is the extension of healthy lifespan.[2, 3]

mTOR: The master regulator of cell metabolism

mTOR exists as a complex of proteins called mTOR complex or mTORC. There are actually two different forms mTORC known as mTORC1 and mTORC2. Activation of the complexes occurs via different pathways. Once activated the mTOR complexes, in turn, activate or inhibit pathways critical to cell function. [2, 3]

mTORC1 and 2 are activated or inactivated depending on the availability of nutrients and certain other substances in the cell’s environment (e.g., glucose, amino acids, and various growth factors). In fact, you can think of mTORC as integrating and responding to the energy status of the cell’s environment.

mTORC1

When times are good and energy, oxygen, nutrients, and growth factors is plentiful, mTORC1 is activated and stimulates metabolic pathways that lead to growth. When times are tough, those pathways are suppressed and the pathways related to survival are activated.

Here are some of the cellular functions mTORC1 regulates [2,4]:

- - Mitochondrial biogenesis (building new mitochondria, organelles that generate energy)
  - Nucleotide biosynthesis (nucleotides are the building blocks of RNA and DNA)
  - Protein synthesis (creating new proteins)
  - Lipid biosynthesis (generation of lipids from precursors)
  - mRNA translation (decoding the genome on the way to creating new proteins)
  - Autophagy (cleaning out damaged or unnecessary cellular organelles. This frees up components to create new ones.
  - Lysosome biogenesis (creation of organelles involved in breakdown and waste removal in the cell. Lysosomes have been called the stomach of the cell.

The last two functions are inhibited when energy, nutrients, and growth factors are plentiful.

mTORC2

mTORC2 is activated by insulin and growth factors. [2,4] It regulates the following:

- - Cell proliferation
  - Cell survival
  - Apoptosis (cell death)
  - Cell metabolism
  - Cytoskeleton organization (maintaining cellular infrastructure)
Rapamycin

Rapamycin inhibits most but not all of the activities of mTORC1. However, it does not inhibit mTORC2 in the short run. There is some evidence that chronic administration of rapamycin, however, can inhibit mTORC2.[4] Further, there are important feedback pathways between mTORC1 and mTORC2.

mTOR acts as a nutrient sensor linking availability to various cell functions

Living organisms on our planet are subject to varying availability of nutrients and other sources of energy. In order to survive, they must be able to sample the energy availability in their surroundings and adjust accordingly.

mTOR-linked pathways provide that mechanism. Receptors found in cell membranes have both an external-facing component and an internal-facing component. The external component binds to nutrients, such as glucose, amino acids, oxygen, and various growth factors. As described above, this leads to the activation or inactivation of different intermediate proteins that ultimately activate or inhibit mTOR.

For example, during times of energetic stress, a protein known as AMPK is activated. This in turn inhibits mTORC1 and leads to activation or inhibition of other intermediate compounds. The result is a state of cellular activity that favors prolongation of lifespan.[5]

Although the pathways are incompletely understood, it is of note that dietary restriction – a self-induced famine in a way – is also associated with longevity.[5] We must remember, though, because of complex feedback loops, the ability to prolong lifespan via these mechanisms is not limitless.

On the other hand, during times of plenty, the availability of glucose increases. In addition to reducing the activation of AMPK, it also triggers the release of the hormone insulin and insulin-like growth factor). This leads to mTOR activation and the creation of a state that favors growth and development. Unfortunately, it can also lead to amongst other things, elevated lipid levels that favor the development of chronic diseases.

Practical applications of this complex molecular biology

Carbohydrate restriction

Understanding the molecular biology of the mTOR pathways has some very practical applications. For example, as we have already pointed out, restricting calories is associated with reduced levels of some factors that inhibit mTORC1. This, then, is associated with lifespan extension.[5] Intermittent fasting [6] and exercise [7] also reduce mTOR activity.

Also, restricting carbohydrates in people with Type 2 diabetes is known to lower blood glucose, insulin, and IGF-1 levels. The benefits of this type of diet do not require weight loss, although many do lose weight with carbohydrate restriction. In fact, some experts have called for dietary carbohydrate restriction to be the first intervention prescribed in Type 2 diabetes management.[8]

The prevailing American high-carbohydrate, high-fat fast-food diet, on the other hand, drives extra calorie intake and as well as higher levels of the factors that activate mTORC1. This, unfortunately, leads to metabolic conditions that accelerate the development of chronic diseases such as diabetes and heart artery problems.[9]

Metformin

Metformin is the most commonly prescribed drug for Type 2 diabetes. Multiple mechanisms of action, both direct and indirect have been proposed for this drug, including microbiome modification.[10]

However, it has also been shown to interfere with the same signaling pathways that we have been discussing. Specifically, it leads to the reduction of glucose, IGF-1, insulin levels, and the inhibition of mTORC1. [11]

This results in a metabolic state that favors important health outcomes, including the following:

- - reduces heart attacks in diabetes by about 40%
  - reduces cancer by about the same amount [12]
  - prolongs healthy life in several different animals [11]

Further, the drug has been proven to be safe with relatively few serious side effects. And, it is cheap, making it accessible even for people without health insurance.

Metformin is the also first drug approved by the FDA to enter a clinical trial to assess its effect on prolongation of a healthy lifespan. According to American Association for Aging Research, the Targeting Aging with Metformin (TAME) trials are a “series of nationwide, six-year clinical trials at 14 leading research institutions across the country that will engage over 3,000 individuals between the ages of 65-79.”

These trials will test whether those taking metformin experience delayed development or progression of age-related chronic diseases—such as heart disease, cancer, and dementia.

Rapamycin and rapalogs

As mentioned, the drug rapamycin inhibits mTORC1 activity and is associated with a prolonged lifespan. However, systemic rapamycin has unacceptable side effects, so its use is limited in humans.

It is used, however, for local applications. One example is the use of Sirolimus (the brand name of rapamycin) in early versions of drug-eluting stents (DES) used to treat coronary artery disease. [13]

More recently, scientists have modified rapamycin to create less toxic forms of the drug. They are known as rapalogs. These include everolimus, zotarolimus, and biolimus. Together with improved stent platform materials, the use of these DESs has been shown to lower thrombotic events related to the stents. [14]

Preventing chronic disease

There are a number of drugs that are used for cardiovascular disease that specifically impact the mTORC pathways by various mechanisms. For example, lisinopril (an ACE inhibitor), losartan, an angiotensin receptor blocker [15], atorvastatin, a statin [16], and eplerenone [17], a mineralocorticoid receptor blocker, all reduce oxidative particle formation. Indirectly, this leads to the inhibition of mTORC. [18]

This, as we know, leads to metabolic changes that favor healthy aging. These effects on the mTOR-related signaling pathways may be the reason why these medications lower the risk of heart attack and stroke more than they reduce the target risk factors of blood pressure, lipid, and glucose levels.

Interfering with this core signaling is a form of precision medicine that impacts the molecular biology that causes cardiovascular disease, cancer, and accelerated aging. These medications are antioxidants that work.

The language of life

Here is the most shocking insight. The same core signaling that causes accelerated aging, chronic disease, and ultimately death is essential to produce a perfectly developed newborn. At the moment of conception, there is a single cell that will ultimately become all the cells in the body with their vastly different functions.

The DNA for every cell in your body is the same. Epigenetic regulation determines which genes are turned on or off in a particular cell type. For example, normal EGFR function is necessary to establish pregnancy [19][successfully at the very beginning of life. However, it contributes to chronic disease development later in life.

Angiotensin II is required to form a normal fetal kidney [20], but inappropriate activation later in life contributes to developing hypertension, chronic kidney disease, and congestive heart failure.

mTOR activation via nutrient sensing and growth factor signaling in the fetus directs a master symphony [21] of switching genes on in just the right place, at just the right time, with just the right intensity for an exact amount of time to produce a perfect infant.

However, the same genes that are essential to coordinate normal development cause disease and death with chaotic activation later.

Summary

The human genome project did not give us the answers for accelerated aging and common chronic diseases. These problems are caused by normal genes that are inappropriately switched on later in life by things like aging, unhealthy diets, and tobacco smoke.

Specific highly effective generic medications with few side effects can block the signaling from those genes and lead to dramatically better clinical outcomes at a lower cost. Caloric restriction, intermittent fasting, exercise, and the specific medications mentioned all impact the same signaling pathways.

In order to fully unlock the potential of primary care, we need to move from management of risk factors (e.g., blood pressure, glucose levels) to manipulations of the metabolic pathways that are at the heart of many chronic diseases. We believe that “metabolic medicine” is the key to a healthier future

References:

Kenyon C. The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing. Philosophical Transactions of the Royal Society B. (2011) 366, 9-16.
https://royalsocietypublishing.org/doi/10.1098/rstb.2010.0276

2. Papadopoli D, Boulay K, Kazak L, et al. mTOR as a central regulator of lifespan and aging [version 1; peer-review: 3 approved] latest versions as of 07/27/20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611156/pdf/f1000research-8-18802.pdf

3. Weichhart T. mTOR as a regulator of lifespan, aging, and cellular senescence. Gerontology. (2018) 64(2):127-134. https://pubmed.ncbi.nlm.nih.gov/29190625/

4. Samidurai A, Kukreja R, Das A. Emerging role of mTOR signaling-related miRNAs in cardiovascular diseases. Oxidative Medicine and Cellular Longevity. Volume 2018, Article II6141902, 23 pages https://www.hindawi.com/journals/omcl/2018/6141902/

5. Longo V, Antebi A, Bartke A, et al. Interventions to Slow Aging in Humans: Are We Ready? Aging Cell (2015) 14, 497-510. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531065/

6. de Cabo R, Mattson M. Effects of intermittent fasting on health, aging, and disease. NEJM (2019) 381:2541-2551. https://www.nejm.org/doi/full/10.1056/NEJMra1905136

7. Dreyer H, Fujita S, Cadenas J, et al. Resistance exercise increases AMPK and reduces 4E-BP1 phosphorylation and protein synthesis in human skeletal muscle. J Physiol (2006) 576:2, 613-624. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1890364/

8. Feinman R, Pogozelski W, Astrup, A, et al. Dietary carbohydrate restriction as the first approach in diabetes management: Critical review and evidence base. Nutrition (2015) 31:1-13. https://www.sciencedirect.com/science/article/pii/S0899900714003323

9. Samidurai A, Kulreja R, Das A. Emerging Role of mTOR Signaling-Related miRNAs in Cardiovascular Diseases. Oxidative Medicine and Cellular Longevity (2018) Article ID 6141902. https://www.hindawi.com/journals/omcl/2018/6141902/

10. Rena G, Hardie D, Pearson E. The mechanisms of action of metformin. Diabetologia (2017) 60(9):1577-1585. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5552828/

11. Amin S, Lux A, O’Callaghan F. The journey of metformin from glycaemic control to mTOR inhibition and the suppression of tumor growth. Br. J. Clin Pharmacol (2019) Jan, 85(1):37-46. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303203/

12. Kasznicki J, Sliwinska A, Drzewoski J. Metformin in cancer prevention and therapy. Ann Trans Med (2014) June;2(6):57 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200668/

13. Serruys P, Regar E, Carter A. Rapamycin eluting stent: the onset of a new era in interventional cardiology. Heart (2002) 87:305-305. https://www.researchgate.net/publication/277539488_Rapamycin_eluting_stent_the_onset_of_a_new_era_in_interventional_cardiology

14. Im E, Hong, M-K. Drug-eluting stents to prevent stent thrombosis and restenosis. Expert Rev Cardiovasc Ther (2016) 14(1):87-104 https://pubmed.ncbi.nlm.nih.gov/26567863/

15. Ding G, Zhang A, Huang S et al. ANG II induces c-Jun NH2-terminal kinase activation and proliferation of human mesangial cells via redox-sensitive transactivation of the EGFR. AM J Physiology Renal Physiol (2007) 293:F1889-G1897 https://journals.physiology.org/doi/pdf/10.1152/ajprenal.00112.2007

16. Tanaka S, Fukumoto Y, Minami T. et al. Statins exert the pleiotropic effects through small GTP-binding protein dissociation stimulator upregulation with a resultant Rac1 degradation. Arterioscler Thromb Vasc Biol (2013) July;33(7). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3863549/pdf/nihms-536909.pdf

17. Huang S, Zhang A, Ding G et al. Aldosterone-induced mesangial cell proliferation is mediated by EGF receptor transactivation. Am J Physiol Renal Physiol (2009) 296: F1323-F1333 https://journals.physiology.org/doi/pdf/10.1152/ajprenal.90428.2008

18. Blagosklonny M. From rapalogs to anti-aging formula. Oncotarget (2017) 8(22) 35492-35507. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482593/pdf/oncotarget-08-35492.pdf

19. Large M, Wetendorf M, Lanz R et al. The Epidermal Growth Factor Receptor Critically Regulates Endometrial Function during Early Pregnancy. PLoS Genet (2014) 10(6):e1004451 https://doi.org/10.1371/journal.pgen.1004451

20. Gubler M, Antignac C. Renin-angiotensin system in kidney development: renal tubular dysgenesis. Kidney (2010) International 77(5): 400-406. https://www.sciencedirect.com/science/article/pii/S0085253815542646

21. Hennig M, Fiedler S, Jux C et al. Prenatal Mechanistic Target of Rapamycin Complex 1 (mTORC1) Inhibition by Rapamycin Treatment of Pregnant Mice Causes Intrauterin Growth Restriction and Alters Postnatal Cardiac Growth, Morphology, and Function. J Am Heart Assoc (2017) 6:e005506. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5586418/pdf/JAH3-6-e005506.pdf

Reviewed and updated with new references on 8/14/20.

William H. Bestermann MD and Patricia Salber MD, MBA

William H. Bestermann Jr., MD is a board-certified internist who has practiced preventive cardiology for more than 20 years. His core expertise is consistently producing optimal medical therapy (OMT) for cardiovascular and related conditions. He does this by using evidence-based care processes consistent with best practices.

He looks at OMT as a product. He understands how health care organizations can combine new systems, new science, and new payment models to produce that product much more consistently. That combination can be standardized, scaled, and industrialized. These new systems combine teams, protocols, population health tools, clinical/financial analytics, and provider training. Certain clinical interventions reduce clinical events more than they impact the target risk factor.

Dr. Bestermann has developed integrated protocols that combine those interventions which maximize impact on weight reduction, minimize drug interactions, and reduce side effects. When these systematic interventions are combined, they dramatically reduce the cost of care, prolong life, and delay cardiovascular events.

Dr. Bestermann wrote the first article on a systematic, integrated approach to the metabolic syndrome. He collaborated later with multiple academics and community leaders in a more detailed article on metabolic syndrome science and treatment. He proposed a new mechanism of action for metformin explaining its impact on cardiovascular, events, cancer, and aging.

He supervised an advanced medical home team within Holston Medical Group for cardiometabolic conditions that contained an ambulatory care residency for PharmDs. The team managed high-risk diabetic and hypertensive employees of Eastman Chemical Company.

He is also a senior clinical advisor for the Quality Blue Primary Care initiative at BCBS of Louisiana. That effort reduced hospital admissions, length of stay, and specialty referrals while lowering per member per month costs. He has personal experience producing OMT in multiple medical settings.

He has become convinced that only evidence, data, and transparency can deliver us from the low-value healthcare that prevails across the United States. There are many vendors making claims regarding their clinical and financial success. Most of those claims are not valid. Almost no one is consistently applying optimal medical therapy to patients with cardiovascular and related conditions in a way that prolongs life, delays cardiovascular events, and reduces costs. Dr. Bestermann submitted his approach to the Validation Institute and received their stamp of approval.

Patricia Salber, MD, MBA is the Founder and Editor-in-Chief of The Doctor Weighs In. Founded in 2005 as a single-author blog, it has evolved into a multiauthored, multi-media health news site with a global audience. She has been honored by LinkedIn as one of ten Top Voices in Healthcare in both 2017 and 2018.

Dr. Salber attended the University of California San Francisco for medical school, internal medicine residency, and endocrine fellowship. She also completed a Pew Fellowship in Health Policy at the affiliated Institute for Health Policy Studies. She earned an MBA with a health focus at the University of California Irvine.

She joined Kaiser Permanente (KP)where she practiced emergency medicine as a board-certified internist and emergency physician before moving into administration. She served as the first Physician Director for National Accounts at the Permanente Federation. She also served as the lead on a dedicated Kaiser Permanente-General Motors team to help GM with its managed care strategy. After leaving KP, she worked as a physician executive including serving as EVP and Chief Medical Officer at Universal American.

She has served as a consultant or advisor to a wide variety of organizations including digital start-ups such as CliniOps, My Safety Nest, Doctor Base. She currently consults with Duty First Consulting as well as Faegre, Drinker, Biddle, and Reath, LLP.

Pat serves on the Board of Trustees of MedShare, a global humanitarian organization. She is also Chair of MedShare's Western Regional Council.