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. Source
