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.
CONCLUDING REMARKS
If an anti-aging program is to be successful it needs to include therapies that will improve arterial health, enhance autophagy, and prevent premature senescence. Patients
