Читать книгу Anti-Aging Therapeutics Volume XVI - A4M American Academy - Страница 22

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 reduces the risk of heart attack. However, when you look at the study in detail neither Mediterranean diet arm actually did that. Both arms of the Mediterranean diet significantly reduced the risk of stroke – by 34% in those assigned to the diet supplemented with olive oil and 49% in those assigned to the diet with extra nuts – and when you put statistics like those together in a “major cardiovascular events” category the result looks impressive. But what the authors did not report was that neither of the Mediterranean diets had any impact whatsoever on longevity compared to the low-fat diet. So, yes the Mediterranean diet does seem to be beneficial for the arterial system, and longevity requires arterial health. However, maintaining the health of the arteries alone does not guarantee longevity. If you want to live longer, you have got to follow a much more comprehensive anti-aging program, and CR should be a major component of it.

Physical exercise also enhances autophagy.^8,9 In studies on mice, He et al demonstrated that the beneficial effects of exercise on glucose and lipid metabolism are mediated by autophagy.⁸ But Galluzzi and Kroemer ask an important question: “Does physical exercise extend lifespan (at least in part) by activating autophagy?”⁹ In their review, Galluzzi and Kroemer conclude that the answer to this question is “unresolved”, however they add that “autophagy constitutes a crucial anti-aging (and anticancer) process.” I don’t think that the answer to their question remains unresolved as there is evidence to show that exercise reduces all-cause mortality risk. Wen et al found that people who exercised for 15-minutes a day had a 14% reduced risk of all-cause mortality, and had a 3-year longer life expectancy, compared to people who did no exercise. Furthermore, every additional 15-minutes of daily exercise beyond the minimum amount of 15-minutes a day further reduced all-cause mortality by 4% and all-cancer mortality by 1%.¹⁰ Exercise is an essential ingredient for longevity, and one of the main reasons why it is so beneficial is that it enhances autophagy.

It is also possible to enhance autophagy by decreasing signals that inhibit it. One such signal is insulin-like growth factor (IGF1), which inhibits autophagy when it binds to insulin-like growth factor receptors (IGF1R). Insulin increases IGF1 levels. Insulin resistance increases insulin levels. Thus avoiding insulin resistance will keep insulin and IGF1 levels low and enhance autophagy. How do we prevent insulin resistance? By avoiding metabolic syndrome, remaining physically active, and decreasing BMI (but remembering to keep BMI in the optimal range of 20.0-24.9). Ben Ounis et al randomly assigned 28 obese children (age 13.2 +/- 0.7-years, BMI 30.9 +/- 1.3) to a diet/training group or a control group for 2-months.¹¹ Results showed that children in the diet/training lost a significant about of body weight and exhibited significant decreases in levels of IGF1 and other inflammatory markers. The results of this study go to show that restricting calories and exercising can have a positive effect on IGF1 levels, thereby helping to maintain insulin sensitivity and enhancing autophagy. What happens if insulin resistance is left unchecked? Type 2 diabetes is the end result of loss of insulin sensitivity. Franco et al found that having type 2 diabetes significantly increased the risk of developing and dying from cardiovascular disease.¹² Furthermore, becoming diabetic at age 50 results in an average 7.5 (men) and 8.2-years (women) earlier death in comparison to nondiabetic men and women. So, we can see that keeping IGF1 levels under control and maintaining insulin sensitivity is vital for anti-aging.

To date, there are 3 substances – resveratrol, rapamycin, and spermidine – that are known to enhance autophagy. However, it is very important to realize that if you start to utilize supplements or pharmaceuticals there is also the potential for harm. Resveratrol, rapamycin, and spermidine all have off-target effects, meaning that they also affect biologic processes independently of autophagy activation.⁹

Most people in the anti-aging community are familiar with resveratrol, a plant compound claimed to be responsible for the apparent cardioprotective benefits of red wine. Resveratrol is a sirtuin (SIRT1)-activating compound (STAC), and activation of SIRT1 is known to enhance autophagy. Results of a recently published study by Hubbard supports the theory that activation of SIRT1 by STACs remains a viable strategy for anti-aging.¹³ However, research on resveratrol is still in its infancy and the long-term effects of supplementation in humans are not known. What is known is that there are a number of issues surrounding resveratrol. From a pharmacokinetic point of view resveratrol is not a good candidate for therapeutic use, as although it is well absorbed (~70%), its bioavailability is very poor (~1%), with only trace amounts (below 5 ng/ml) being detectable in the blood after a 25 mg oral dose.¹⁴ Research has shown that you can start detecting clinically relevant amounts of resveratrol in the blood if you increase the dose to 2000 mg dose twice a day.¹⁵ However at this dosage you also start to see adverse effects, including diarrhea and significant but not clinically relevant changes from baseline in serum potassium and total bilirubin levels. So, we are starting to see the potential for harm. It is also important to note that GlaxoSmithKline (GSK) stopped a small clinical trial of SRT501, a proprietary form of resveratrol, back in December 2010 due to safety concerns. The company has now abandoned research on resveratrol and is focusing its efforts on more potent and selective STACs. Despite resveratrol falling out of favor with GSK, there are still many research teams that are concentrating their attention on it, and some of the results are promising. Carrizzo et al recently demonstrated that resveratrol has beneficial effects on the atherosclerotic vessels of hypertensive patients.¹⁶ Results of this study showed that resveratrol induced vasorelaxation and reduced endothelial dysfunction through the modulation of nitric oxide (NO) metabolism. Endothelial dysfunction is an early pathophysiological feature of cardiovascular disease and is an independent predictor of poor prognosis in most instances. The authors of this study conclude: “Our findings strongly indicate that a diet rich in resveratrol and healthy lifestyle changes can be useful in patients with atherosclerosis and hypertension because resveratrol exerts a protective action on the vascular, regardless of concomitant classical drug therapy.” Note that the authors are recommending that resveratrol is obtained from eating resveratrol-rich foods not from taking supplementary resveratrol.

Rapamycin (sirolimus) is an FDA-approved antibiotic and immunosuppressive drug. It is known to enhance autophagy by inhibiting the mammalian target of rapamycin (mTOR), a protein that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription. Rapamycin is currently being investigated in phase II and III clinical cancer studies for its apparent anti-tumor activity. Harrison et al studied the effects of rapamycin on mice.¹⁷ Results showed that the lifespan of mice (equivalent in age to 60-year-old humans) fed rapamycin increased by approximately 30%. This suggests that effective anti-aging treatment could be delivered at an older age. Rapamycin also holds promise as a treatment for the cardiovascular diseases familial supravalvular aortic stenosis (SVAS) and Williams Syndrome (WS), which are caused by the genetic loss of elastin. Patients who suffer from these diseases develop obstructive arteriopathy, due to increased proliferation of smooth muscle cells (SMC) together with an increased number of thinner-than-normal elastic lamellae. Li et al¹⁸ found that mTOR signaling in vessel wall is increased by the genetic loss of elastin and that mTOR inhibition by rapamycin reduced SMC proliferation and aortic obstruction in elastin-deficient mice in vivo. They also found that rapamycin was able to decrease the excessive growth of cultured cells from patients with SVAS and WS in vitro. The authors concluded that their results suggest that mTOR “represents a promising pharmacological strategy to treat severe and diffuse arterial obstructive disease attributable to elastin deficiency.” Meanwhile Chen et al¹⁹ found that rapamycin therapy decreased myocardial apoptosis by 23% and myocardial infarction area by 45% in ischemic murine hearts. Study results demonstrated that this benefit was derived from enhanced autophagy by rapamycin. It is important to remember that there is always the potential for harm with pharmaceutical intervention. Rapamycin is known to cause lung toxicity,²⁰ is thought to actually increase the risk of cancer,²¹ and has also been linked to insulin insensitivity.²² These issues obviously need to be overcome, thus it is too early to say whether rapamycin will prove to be useful in anti-aging medicine.

Spermidine enhances autophagy by upregulating the expression of the autophagy-related protein (ATG) genetic pathway. Spermidine can be obtained from food and, as its name suggests, from semen. In terms of food, the best available food sources of spermidine are legumes (soybeans, beans, sunflower seeds, and peas). Other sources include cereals (maize, oats, and rye), mussels, tree nuts, tea leaf, and some fruits.²³ It is possible to obtain spermidine from semen (at concentrations on a par with tree nuts), however the concentration of spermidine in legumes is 6-times greater than that obtainable from semen.

Senescence

Cell senescence is the irreversible loss of the ability of cells to divide. There are 2 types of senescence:

1.Replicative senescence – exhaustion of proliferative lifespan over time (aging), shortened telomeres induce DNA damage;

2.Stress-induced premature senescence (SIPS) – triggered by external stimuli, including oxidizing agents and radiation. SIPS is not usually characterized by telomere shortening.

Due to the mechanism of DNA replication, telomeres shorten with each cell division. Although some cells (e.g. adult germ cells) contain specific enzymes, such as telomerase, that maintain telomere length. Increasing evidence suggests that telomere integrity rather than telomere length may be responsible for controlling cell longevity. However, there is also plenty of research documenting the importance of telomere length for longevity. For example, Carlquist et al found that telomere length predicted survival in patients referred for an angiogram.²⁴ The researchers studied data from 3,569 patients with a mean age of 63-years, approximately two-thirds were male and approximately two-thirds had coronary artery disease. Patients were followed for a total of 9-years, during which 1,122 died, 530 had a myocardial infarction, and 232 had a stroke. Study results showed that while telomere length was not associated with myocardial infarction or stroke, longer telomere length was associated with a decreased risk of death, even after adjustment for age and other risk factors. The researchers concluded: “Telomere length is a strong univariable predictor of survival that is not eliminated by adjustment for age and other risk factors.” So, we can see that telomere length is obviously important, however it is not the only issue with senescence. Oxidative stress causes premature senescence, but has absolutely nothing to do with telomere shortening. Senescence triggered by oxidative stress has numerous deleterious effects upon the cardiovascular system, including:

•Endothelial senescence is associated with loss of function and a shift toward a proinflammatory and proapoptotic state²⁵;

•Vascular smooth muscle cell (VSMC) senescence generates a proinflammatory environment, and VSMCs have a diminished ability to repair plaques²⁵;

•Monocyte senescence generates a greater proinflammatory environment.²⁵

We can see that premature senescence is clearly linked to arterial inflammation. Thus, premature senescence is bad news for our arteries and bad news if you want to live a long time. But can we do anything about it? Fortunately, we can.

The best way to prevent premature senescence is to prevent oxidative stress. So, the first and foremost thing anyone should do if they want to prevent premature senescence is avoid nicotine as it increases oxidative stress.²⁶ Jha found that current smokers were 3-times more likely to die than people who had never smoked. Smokers were also found to lose at least 1 decade of life expectancy.²⁷ Thus, nicotine is not compatible with longevity. Exercise, CR, and antioxidants may also be helpful. Some medications, e.g. statins, angiotensin receptor blockers (ARBs), angiotensin-converting-enzyme (ACE) inhibitors, and possibly chloroquine, can also reduce oxidative stress, but again they have the potential for harm as well.