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
