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all play key roles in both aging and cardiovascular disease. The aim of this paper is to discuss these roles and to consider ways in which we can help our patients to prevent and reduce arterial inflammation, enhance autophagy, and avoid premature senescence.

      RELATIONSHIP TO AGING AND CARDIOVASCULAR DISEASE

      Arterial Inflammation

      Living long and living well is dependent on a healthy vascular system. Vascular health is vital because our micro and macro health requires an adequate supply of nutrients, and without arterial support our cells and organs perish quickly. Thus, an essential element of anti-aging is maintaining the wellness of the 60,000 miles of vessels that deliver nutrients to our cells and our organs to keep them healthy.

      In order to know how to keep the vascular system healthy, we need to know what leads to damage. Inflammation has long been thought to play a key role in the development and progression of arterial disease.¹ This hypothesis is supported by observational and experimental studies in humans and animals, however until the publication of 2 landmark studies in 2012^2,3 causality had not been established. These 2 studies demonstrated that inflammation is responsible for the inception of cardiovascular disease, the progression of cardiovascular disease, and the eventual cardiovascular event. Both of these studies were concerned with interleukin-6 receptors (IL6R), which are found in the membrane of hepatocytes and leukocytes. If the cytokine interleukin-6 (IL-6) attaches to an IL6R a pro-inflammatory cascade of events is triggered, including increased levels of C-reactive protein (CRP), fibrinogen, and other acute phase reactants.

      The meta-analysis led by the IL6R Genetics Consortium Emerging Risk Factors Collaboration² investigated Asp358Ala (rs2228145), a genetic variant that reduces IL6R membrane-bound numbers. The researchers hypothesized that if inflammation is causal of arterial disease, there should be a direct relationship between the Asp358Ala variant and heart attack risk – possession of 1 or 2 Asp358Ala alleles should reduce heart attack risk as the number of membrane-bound IL6R should be lower. Analysis of 51,441 heart attack victims and 136,226 controls revealed that for each allele for Asp358Ala carried there was indeed a significant 3.4% reduced risk of heart attack. Thus, people who are homozygous for Asp 358Ala (meaning that they carry 2 Asp358Ala alleles) have a 6.8% reduced risk of heart attack.

      The second study, led by the Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortiumm,³ adds further support to the theory that inflammation is the root cause of arterial disease. In this study researchers investigated IL6R SNP (rs7529229), another genetic variant that decreases IL6R numbers. Data from a total of 25,458 heart attack victims and 100,740 controls was analyzed, and results showed that IL6R SNP was associated with a 5% decreased risk of heart attack per allele. So, if you are lucky enough to have inherited 2 copies of the allele, your risk of heart attack is 10% lower than that of someone who has not inherited any copies of the IL6R SNP variant. Together, these studies provide extremely strong evidence that inflammation is the cause of arterial disease.

      Figure 1 illustrates the relationship between inflammation and arterial disease. The trunk of the tree is inflamed, and that is what generates the atherosclerosis on the tree limbs. Numerous pathologies can drive arterial inflammation. So, in order to put out the inflammatory flames that fuel arterial disease it is vital to adopt a holistic approach. Conventional medicine has focused all of its attention on lipids. Yes, hyperlipidemia is certainly one of the root potential causes of arterial inflammation, but it is only one of many. Obstructive sleep apnea will generate inflammation, and so will periodontal disease, psychosocial issues, rheumatoid arthritis, infectious disease, nicotine, and many other factors. All of these are extremely important, and if you want to prevent the development or progression of arterial disease you have got to address all of these issues in order to make sure that you put the inflammatory fire out.

      Figure 1. Extinguishing arterial ‘fire’ requires a holistic approach.

      There are 2 very important factors missing from Figure 1: autophagy and senescence. If we are to live a long and healthy life it is very important that we consider both of these factors, as in addition to driving arterial inflammation, they also play a vital role in determining longevity.

      Autophagy

      Autophagy (“self-eating”) is critical for cell health. In a recent review of the role of autophagy in human health and disease, Choi et al stated: “Autophagy primarily acts as a protective mechanism that may prevent cell death.”⁴ Autophagy is the ability of an individual cell to maintain its health or homeostasis by recycling long-lived proteins and removing damaged organelles (e.g. mitochondria) and cellular debris. Without autophagy, you are not going to live very long and you are going to have a lot of problems. One of which will be arterial disease. Autophagy helps to reduce the risk of arterial disease and many other diseases (as well as cancer) in a number of ways, including:

      •The removal of dysfunctional mitochondria which can release apoptotic mediators and reactive oxygen species (ROS)⁵;

      •The removal of harmful proteins associated with insulin resistance⁵;

      •Enhancing the degradation of infectious agents⁵;

      •Suppressing inflammation⁴ – the root cause of arterial disease.

      Thus we can see that autophagy is important both for longevity and a healthy arterial system. The good news is that it is possible to rejuvenate cells by enhancing autophagy. This is even possible in elderly people. Therefore, it is never too late to begin helping your patients to enhance their autophagy. The important question here is: How can we enhance autophagy?

      We are now aware of the biochemistry of autophagy, and we are beginning to understand how we can enhance it. At present this is mainly with lifestyle changes, but in the future it is likely that pharmaceutical intervention will play a key role in autophagy enhancement.

      Calorie restriction (CR) without starvation has been shown to extend lifespan in almost all of the animals in which it has been tested, including rhesus monkeys. It has also been shown to reduce the incidence of diabetes, cardiovascular disease, cancer, and brain atrophy. So, it is not too surprising that CR has also been shown to enhance autophagy.⁵ CR enhances autophagy in order for the body to generate the energy requirements of a cell, which it does by recycling cytoplasmic macromolecules. The problem that we have with CR in humans is, of course, compliance. Very few patients are likely to wish to follow such a strict diet, and of the few people that may initially try CR, virtually none will continue with it for a significant period of time. However, research in rodents has shown that CR in the form of intermittent fasts, and without a major decrease in body mass index (BMI), can also increase lifespan.⁵ Intermittent fasting, as opposed to chronic CR, is much more palatable to patients, and compliance is much more likely. Furthermore, this technique also avoids the negative effects on bone density that are associated with chronic CR. Do we have any human data to support this? Yes. Results of a study by Berrington de Gonzales⁶ showed that all-cause mortality was lowest in people with a BMI of 20.0 to 24.49 – maintaining a BMI between 20.0 and 24.9 requires some CR, especially in today’s society. However, another key point from this study is that it is important not to overdo CR, because a BMI below 20.0 is associated with an increased risk of all-cause mortality. Therefore, the BMI data certainly supports CR without starvation as a way to promote longevity.

      It is important to note a recent study by Estruch.⁷ The purpose of this research was to determine the impact of eating a Mediterranean diet on cardiovascular risk. A total of 7,447 participants who were at high cardiovascular risk, but did not have cardiovascular disease at enrollment, were randomly assigned to 1 of 3 diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). The trial was halted after 4.8-years because of very positive results on cardiovascular events in both of the Mediterranean diet arms. Shortly afterwards we started to see headlines claiming that the Mediterranean diet

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