The Enhancement of Cardiovascular Health and Longevity
The French paradox was first discovered from epidemiology data in the late 1980s, It describes the apparently paradoxical epidemiological observation that French people have a relatively low incidence of coronary heart disease (CHD), while having a diet rich in meat, fat and dairy product.
In 1990s, researchers concluded that a diet based on southwestern Mediterranean cuisine; which is high in omega-3 oils, antioxidants and includes “moderate consumption” of red wine; created lower cases of cancer, myocardial infarction and cardiovascular disease; partly through increasing HDL cholesterol whilst reducing LDL cholesterol.
The beneficial effect of red wine was later found to be attributable to the presence of polyphenols called resveratrol. Resveratrol is now known for its antioxidant and anti-inflammatory properties and for its ability to upregulate endothelial nitric oxide synthase (eNOS). Resveratrol is able to scavenge •OH/O2•− and peroxyl free oxygen radicals, which can limit the lipid peroxidation processes. The resveratrol was found in a small concentration in red grapes and Japanese knot weed. It protects these plants against fungal infections and enhances survival in hostile environment. Resveratrol can enhance cardiovascular health owing to its protective action of vascular walls towards oxidation, inflammation, platelet oxidation and thrombus formation. One of my earlier translational studies had demonstrated the beneficial effect of resveratrol in reducing atrial fibrillation and myocardial fibrosis and improving systolic function in ischemic heart failure animal models via enhancement of Pi3K / APK / eNOS pathway. I also conducted a NMRC granted study using resveratrol 500mg in heart patients with symptomatic ventricular arrhythmias, the cardiac symptoms were improved in patients after resveratrol therapy and ventricular ectopic load was reduced in some patients.
The discovery of resveratrol was attributable to the pioneer work of Professor David Sinclair in 2003. Sinclair was an Harvard geneticist and was named one of the 100 most influential people by Times Magazine in 2014 for his discovery and research on longevity gene Sirtuin 1 (SIRT1) and upregulation of Sirtuin activity by resveratrol. SIRT1 enhancement slows aging in yeast by reducing the accumulation of extra chromosomal rDNA circles. Sirtuins are hypothesized to play a key role in an organism’s response to stresses such as heat and starvation and is responsible for the lifespan-extending effects similar to that of calorie restriction. Caloric restriction has long been well documented for lifespan extension in human and animals. Sirtuins are activated during calorie restriction and artificially stimulating Sirtuins with drugs can mimic the biochemical effects of calorie restriction. Sirtuins genes are able to protect the chromosomes, protect stem cells from being lost, and protect cells from becoming chronic inflammation-producing senescent cells. Sirtuin-1 can be activated by calorie restriction, resveratrol, restricting amino acids or sugar, or by increasing NAD (nicotinamide dinucleotide) levels.
In 2003, Sinclair discovered that polyphenols including resveratrol could activate Sirtuin, By enhancing the Sirtuins gene, the lifespan of yeast cells increased by 70% and small animals increased by 30%. Resveratrol treatment also made rodents healthier and younger. In 2004 Sinclair, founded Sirtris Pharmaceuticals. Sirtris was focused on developing activators of Sirtuins, which focused mainly on resveratrol and derivatives as activators of the SIRT1 enzyme. The theory behind resveratrol in human disease prevention was that by enhancing the longevity genes and by reducing the physiological age, common aging related diseases such as heart disease, stroke, and cancer can be significantly prevented. The analogy was that a person with younger physiological age and enhanced longevity genes would be much healthier than an older person or person with aged genes, and hence less likely to develop cardiovascular disease, cancers and Alzheimer’s disease. As most human diseases increase with age, antiaging therapy could be a promising strategy for lifespan extension and disease prevention. If the animal data of 30% life expansion can be replicated in human, average human lifespan could reach 120 years. Sinclair’s Sirtris company went public in 2007 and was subsequently purchased and made a subsidiary of GlaxoSmithKline in 2008 for US$720 million.
In 2010s, there was further research data released on the mitochondrial theory of aging. Researchers discovered the potential fountain of youth. Nicotinamide adenine dinucleotide (NAD) is naturally present in mitochondrial cells of our body and plays significant role in a myriad of cellular processes, most notably the one controlling DNA repair. NAD keeps our bodies built-in DNA repair machinery working smoothly. However, our NAD levels decline by about 50 percent as we age, which in turn, weakens the body’s defenses against age-related diseases such as diabetes, heart disease, cancer, and Alzheimer’s. The scientists found that DBC1, one of the human body’s most abundant proteins, binds itself to the protein that is in charge of mending damaged DNA, impairing the DNA repair process. In addition, researchers found that NAD blocks DBC1 and other proteins from hindering DNA repair. Having lower levels of NAD as we age allows DBC1 to interfere with the DNA repair process. Boosting cellular NAD levels improved DNA repair and function. Further data showed that NAD has a broad range of healthful effects in the human body as it also stimulates Sirtuins.
Research data demonstrated that NAD supplementation with Nicotinamide Mononucleotide (NMN) mimic the longevity beneficial effect of calorie restriction and has extended the lifespan and improved health in animals it has been tested in so far, from mice to monkeys. The old mice taking NAD regrew a lustrous coat of fur, had improved kidney function and were able to run twice as fast as the untreated aging mice. The muscles of the treated mice looked and behaved like those of a young mouse. Human trials of a therapy that could increase NAD levels have already begun in Harvard Medical School. NASA has also signed a contract to test the protective effect of NAD compound from cosmic radiation in Astronauts.
Lastly, the anti-diabetic drug metformin is currently considered to be a potential anti-aging drug which have been used for longevity clinical trials in the UK for non-diabetic elderly patients. Epidemiology data showed that diabetes patient on metformin were healthier and have longer lifespan than those on other diabetic medications. Data also showed well controlled diabetes patients on metformin live longer with lower cardiovascular events than non-diabetes patient. Researchers have already proven that metformin extends the life span of animals. The Food and Drug Administration in the US has now given the green light for a trial to see if the same effects can be replicated in humans.
In conclusion, the available health enhancement interventions for disease prevention and longevity include dietary restriction, moderate exercise, red wine, metformin, NAD precursors (NMN) and sirtuin activators (i.e. Resveratrol). Up and coming therapeutic interventions may also include modifiers of senescence and telomere dysfunction, hormonal and circulating factors, mechanistic target of rapamycin (mTOR) inhibitors and mitochondria-targeted therapeutics, I hope to update our readers on these new interventions in future. Among them, dietary restriction (calorie restriction) and exercise are the current realistic interventions, but both requires modest lifestyle modification which may be difficult for some individuals to implement. Sirtuin activators as well as mitochondrial function enhancers, can be good practical targets. We are living in an exciting era of longevity and genetic medicine.
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comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes Obes Metab 2014 Nov;16(11):1165-73. doi: 10.1111/ dom.12354.
A Specialist’s Point of View – Written by Dr Eric Silvio Chong
Dr Eric Silvio Chong is currently a senior consultant interventional and cardiac device cardiologist at the Farrer Park Hospital. He has previously undergone overseas translational research fellowship in antiaging therapy for cardiovascular disease.
Dr Chong is subspecialised in and accredited in interventional cardiology and cardiac device procedures. He has conducted clinical and translational research in coronary angioplasty, coronary stents, protective kidney therapy during contrast procedure, heart rhythm disorders, atrial fibrillation and cardiac device management. His current research and clinical interest is in longevity enhancement treatment for patients with severe heart disease.
He is a elected fellow of several cardiology societies such as the Academy of Medicine of Singapore, European Society of Cardiology, American College of Cardiology, ASEAN Federation of Cardiology, Asia Pacific Society of Interventional Cardiology and Society of Cardiovascular Angiography and Interventions USA and European Heart Rhythm Society.
Dr Chong underwent advanced subspecialty training under world famous cardiologists in internationally renowned cardiac centers in Singapore National University Hospital, Taiwan Veterans General Hospital and London St Thomas Hospital in the past.