The relentless pursuit of the elixir of youth has spurred anti-ageing research in attempts to achieve the triple goals of life extension, namely, the triumvirate of healthy lifespan, rejuvenation and longevity. Sirtuins are a family of cellular enzymes that are powered by a chemical compound called nicotinamide adenine dinucleotide (NAD). They play an important role in preventing diseases and even reversing some aspects of ageing. Studies have shown that increased sirtuin activity in mammals has been associated with a delayed onset of age related diseases and increased longevity.

Increased sirtuin activity appears to inhibit nerve degeneration and reduces the development of cardiovascular and metabolic diseases (such as diabetes mellitus and abnormal lipid levels). Hence, if sirtuin activity can be increased using compounds that can boost its activity (STACs or Sirtuin Activating Compounds), the use of STACs can potentially help a person stay healthy longer, even if longevity is not affected.

Resveratrol is a natural plant phenol STAC found in the skin of red grapes and other fruits such as blueberries and cranberries. Contrary to common belief, red wine contains very little of it. Resveratrol has been shown to have life-extending properties in studies on lower-order species such as yeast and nematodes, but this effect has marginal reliability in higher-order species. Nevertheless, it has been shown to have potentially beneficial effects. Before you start taking large doses of resveratrol, you may be surprised to know that it is a Janus-faced compound.

Low dietary doses may suffice to elicit the biological responses required to optimise the body’s defence mechanisms against incipient disease. But at high doses, it behaves in a contrarian manner. At low doses, resveratrol induces responses that overlap with the female hormone oestradiol. Low-dose effects seen in animal and human studies include beneficial metabolic effects such as more efficient glucose reduction in diabetics, reducing the development of obesity and non-alcoholic fatty liver disease, protecting against arterial degeneration, delaying development of neurodegeneration, and improving motor and cognitive functions.

At high doses, resveratrol has an anti-oestrogen effect which suggests that it may reduce the risk of oestrogen- dependent cancers. This Janusfaced hormetic effects of resveratrol may partly explain the French paradox, where there is a reduced incidence of cardiovascular diseases and certain types of cancer in some populations despite their consumption of high-fat diets.

NAD is an important molecule that is essential for over 500 enzyme reactions in the body which impact metabolism, ageing, cell death, DNA repair, and gene expression. Hence, NAD plays a pivotal role in human health span and longevity and is a necessary substrate for sirtuin enzymatic activity. In mammalian cells, NAD is mainly generated by the conversion of nicotinamide (a soluble form of Vitamin B3) into nicotinamide mononucleotide (NMN) followed by its combination with another molecule to form NAD. There is also another precursor, nicotinamide riboside (NR), that is converted by enzymes to NMN in the cells. As this pathway is safe and also the most efficient route for production of NAD, NMN or NR supplementation has been used to increase NAD levels.

Animal studies have shown that NMN supplementation can ameliorate the age-related reduction in NAD production in cells and improve the body’s cardiovascular response to ageing. Age-related decrease in arterial elasticity means that the aorta is less able to expand and buffer the increased blood pressure generated each time the heart pumps. With ageing, the production of a pressure-bearing protein, type 1 collagen, in the arterial wall increases, whereas the main protein responsible for the structural integrity and elastic properties of the arterial wall, elastin, decreases. Studies in mice have shown that NMN supplementation was able to reduce stiffness in large arteries by reversing the accumulation of type 1 collagen in arterial walls and improving elastin content.

From the age of 40 years onwards, there is a gradual decline in perfusion of the body tissues resulting in gradual deterioration in body function towards the last decades of life. A consequence of this is cognitive decline. Optimal brain function is dependent on adequate oxygen and nutrient delivery via minute brain blood vessels (cerebral microvascular circulation). This modulation of brain blood flow in response to increased brain activity is impaired with age, contributing to age related cognitive impairment. Studies in aged mice given NMN have demonstrated an improvement in the modulation of cerebral microvascular circulation. Animal studies have also shown that NMN can prevent age-related cognitive decline by reducing cell death in areas of the brain that control short and long-term memory.

Use of NMN was also associated with decrease in the neurodegenerative changes seen in Alzheimer’s disease and age-related retinal changes. This age-related decrease in the production of new vessels and a gradual decrease of blood vessels in the microcirculation also result in reduction in muscle mass and diminishing exercise capacity with age. Mice given NMN were able to demonstrate an increase in the production of new vessels in the muscle and an increase in density of small vessels, thereby improving exercise capacity.

Caloric restriction
Caloric restriction (CR) which involves calorie reduction without causing malnutrition, has been associated with an increase in lifespan in some animal studies. In these studies, dietary CR was associated with increased lifespan and reduced disease incidence,  specially cancers. However, some studies did not show benefit and, in some mouse strains, CR was associated with shortened lifespan. Observational studies on humans who have practised extreme CR over many years showed low levels of risk factors for cardiovascular disease and diabetes. Similarly, a human study on CR, the CALERIE study, found that CR participants had lower blood pressure and lower cholesterol. The study was too short to examine the impact of CR on lifespan. The current conclusion from the National Institute of Aging in the United States is that there is not enough evidence to recommend CR as a therapeutic measure for life extension.

Although CR was associated with lower risk factors for cardiovascular diseases and diabetes, caution is urged as in a study using mouse lemurs on prolonged CR, MRI studies showed that there was more widespread age-related grey matter atrophy in CR animals while only a few regions in the brain showed atrophy in those not on CR.

Life extension
Globally, heart disease and stroke are the two main causes of death in most high-middle and high-income countries. Hence, the first cardinal principle in life extension is to control the risk factors such as blood pressure elevation, cholesterol elevation, sugar elevation and smoking. The second principle is to have a healthy lifestyle such as keeping the weight within the healthy range and exercising regularly. Both physical exercise and dietary CR result in a significant increase in NAD production and increase sirtuin activity. CR may be an option as part of a weight-reduction regime to keep the weight optimal. The third principle is to see your doctor regularly to control risk factors.

Finally, among the supplement options, scientific studies favour the use of low-dose resveratrol or NMN as they may potentially provide many health benefits via increased sirtuin activity, although more studies will be required to understand their efficacy in human life extension.