Anti-Aging Therapeutics Volume XVI. A4M American Academy

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,