NAD+ is creating quite a buzz in scientific circles.
Nicotinamide Adenine Dinucleotide, or NAD+ for short, is used by every cell in the body. NAD+ is important because it is a big player in the energy production process within the mitochondria. Sirtuins, a class of enzymes well known for their role in regulating ageing, need NAD+ to do their job. And, research tells us that the tight integration between NAD+ availability and sirtuins activity is the major driver in controlling ageing factors and promoting longevity.
NAD+: A co-enzyme used by every living cell
NAD exists in two forms: NAD+ and NADH. NAD+ is the oxidized form of NAD. NAD+ levels decrease as we age, and scientists have established a solid inverse relationship between NAD+ levels and ageing.
How does NAD+ work?
NAD+ sits at the heart of the energy production process that occurs within the mitochondria – aptly called the ‘powerhouse of the cells’. How does it help in maintaining overall health and promoting longevity?
- NAD+ improves mitochondrial functions
- NAD+ activates Sirtuins, family of enzymes linked with regulating lifespan
Let’s explore the role of NAD+ in more detail.
NAD+ improves mitochondrial health
The cells in our body go through cycles of reproduction growth, repair and survival – and require tremendous energy to perform these myriad functions. Every cell in our body produces its own energy with all the action taking place in the mitochondria – tiny organelles within the cells. The energy is produced in a complex series of redox reactions, where NAD+ keeps shuttling between two forms; NAD+ and NADH.
NAD+ accepts electrons that are released during the burning or oxidation of organic fuels (fats, glucose), and in turn is reduced to NADH. NADH transfers the electrons in this ongoing chain of redox reactions – eventually resulting in ATP synthesis in a complicated yet highly organized process called oxidative phosphorylation. Clearly, NAD+ drives this process forward – that is, it facilitates the transfer of energy from the food to our cells – and thereby helps cells carry out their numerous functions that are so critical to our sustenance, physical and mental well-being, and survival.
What happens when NAD+ levels decline?
Reduced levels of NAD+ means the energy transfer takes a massive hit – resulting in impaired mitochondrial functions and increased oxidative stress, which in turn manifest as:
- Reduced energy (ATP) production
- Reduced heat production
- Increased generation of damaging free radicals, causing damage to DNA, proteins and lipids
- Reduced cellular ability to perform basic functions: healthy division, growth and repair damage triggered by oxidative stress
- Disturbed metabolic pathways (causing metabolic imbalance, insulin resistance, unbalanced sugar levels)
- Chronic inflammation
- Cognitive dysfunction
Mitochondrial dysfunction is believed to be one of the main reasons behind the symptoms of ageing, such as physical and cognitive decline, loss of energy and fatigue. Not surprisingly, with the mitochondria not working as smoothly and efficiently, cells become vulnerable to oxidative stress, hence trailed by premature ageing and age associated diseases such as heart failure, type 2 diabetes, insulin resistance, obesity, hearing loss, vision loss, Alzheimer’s disease and cancer.
NAD+ and Sirtuins: NAD+ activates Sirtuins
Playing important roles in the process of ageing and mitochondrial fitness are sirtuins – SIR2 or silent information regulator 2 proteins. This family, so far as current research has identified, consists of seven enzymes (SIRT1–7). In mammals, Sirtuins control how the body responds to energy metabolism and stress – two factors at the core of the ageing process.
While sirtuins are found in different compartments of a cell, such as nucleus, cytoplasm and mitochondria, and may have unique functions, the predominant role of Sirtuins can still be summed up as:
- To protect cells from stress and,
- Enhance cellular capacity to develop resistance against stressors, survive and self-preserve, thus contributing to increasing life span.
And Sirtuins are dependent on NAD+ for their activity. In fact, Sirtuins also act as a substrate for other enzymes including bacterial DNA ligase, Poly-ADP-ribose Polymerases (PARPs) and CD38, with all these enzymes playing important role in cell survival. This competitive use of NAD+ among so many related ‘consumer’ enzymes is also one of the factors why NAD+ levels decline as we age.
Sirtuins: The magic behind the effects of calorie restriction (CR)
A low-calorie diet is one of most effective and proven strategies to keep ageing at bay. Even long before modern scientific studies, many traditional systems of medicine, such as Ayurveda, have long believed that calorie restriction (CR) is the road to achieve a long, healthy life. So, what is the mystery behind CR and anti-ageing benefits? How come depriving the body of calories can make you live longer?
It seems that Sirtuins hold the key to this puzzle. Of course, one of the theories backing the CR effect is that it reduces the formation of free radicals, invariably formed when our cells use nutrients and oxygen to create energy during the oxidative phosphorylation process. It is something like when a vehicle burns fuel and releases smoke as a by-product. With reduced generation of free radicals, cellular structures experience less oxidative damage, and function better.
However, more and more studies indicate there is something more interesting happening at the backend. It appears that CR drives some very targeted bio-chemical responses, which helps cells preserve themselves and survive under unfavorable conditions. And no points for guessing, sirtuins are believed to drive these biological responses.
CR achieves the anti-ageing effect by activating sirtuins. To be precise, CR increases the expression of SIRT1, SIRT3 and SIRT5, enzymes that are known to regulate the expressions of genes associated with ageing. So, increasing the bio-availability of cellular NAD+ and increasing Sirtuins activity to extend the lifespan (that mimics CR mechanism) makes complete sense as a strategy to combat ageing and diseases of ageing.
NAD+ and Sirtuins: The Complex Relationship
In the mitochondria, NAD+ levels mirror the energy status of the cell. And sirtuins function as sensors; detecting the variations in the NAD+ levels and processing this information to help cells adapt and survive fluctuating energy requirements. NAD+ availability decreases as we age, negatively impacting Sirtuin activity.
The complex relationship between NAD+ and Sirtuins helps in controlling metabolic and longevity pathways. Studies show that this tight integration between the availability of NAD+ and Sirtuins activity helps to:
- Maintain the communication between the nucleus and mitochondria at a cellular level and;
- Maintain the inter-tissue communication, more specifically between the hypothalamus and adipose tissue at a systemic level.
The integration of NAD+ and sirtuins orchestrates this important communication, both at cellular as well as systemic level. If this orchestration works smoothly, the result is melodious harmony that keeps cells healthy. However, with low NAD+ levels, this communication gets disrupted. Cells lose their ability to create sufficient energy and the process of ageing accelerates. Dr. David Sinclair, Harvard Medical School Professor of Genetics commented that “this communication network is like a married couple—when they are young, they communicate well, but over time, living in close quarters for many years, communication breaks down. And just as with a married couple, restoring communication solved the problem.”
Overall, NAD+ dependent Sirtuins protects against premature ageing and associated diseases through various mechanisms, such as:
- Deacetylation of proteins like histones
- Regulating metabolism and circadian rhythm
- DNA repair
- Boosting mitochondrial functions and response in the face of external or internal stress, for example fasting and oxidative damage
- Reducing inflammation in the body
Boosts energy and fights premature ageing
Improves mitochondrial efficiency. Enhances energy metabolism. Reduces Oxidative stress.
Emerging research and scientific studies are all pointing to the role of NAD+ in improving human lifespan, quality of life and all-inclusive health. The evidence is promising and shows that boosting NAD+ levels can help us achieve a healthy and disease free life. Since oxidative stress and mitochondrial dysfunction are implicated in ageing and most heath conditions, NAD+ indeed is fast emerging as a real possibility to prevent and even reverse a wide range of chronic ailments, including:
- Metabolic disorders, such as obesity, insulin resistance, type 2 diabetes
- Neuro-degenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, dementia
- Cardiovascular disorders
- Inherited mitochondrial diseases
- Vision loss
- Hearing loss
- Imai et al. NAD+ and Sirtuins in Ageing and Disease. Trends in Cell Biology. 2014.
- Akiko Satoh, Liana Stein, Shin Imai. The Role of Mammalian Sirtuins in the Regulation of Metabolism, Ageing, and Longevity. Handb Exp Pharmacol. 2011; 206: 125–162.
- Gomes et al. Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Ageing. Cell. 2013.
- Shin-ichiro Imai, Leonard Guarente. It takes two to tango: NAD+ and sirtuins in ageing/longevity control. Nature. Ageing and Mechanisms of Disease. August 2016