Promoting health and longevity
New and exciting information on NAD+ has given new meaning to the science of longevity, specifically though its role in energy metabolism, activation of Sirtuins and improving mitochondrial fitness. Increasing evidence in this field gives us compelling reasons to believe that increasing NAD+ levels in the body can help us achieve a long, healthy life with reduced risk of chronic degenerative diseases, such as type 2 diabetes, cancer, cardiovascular risk factors, and neuro-degenerative diseases like Alzheimer’s and Parkinson’s.
What is NAD?
Nicotinamide adenine dinucleotide (NAD) is an enzyme present in all living cells. It is made up of two cells attached to adenine and nicotinamide. NAD exists in two forms: NAD+ and NADH.
NAD+: Oxidized form of NAD
- Acts as an oxidizing agent, i.e. it accepts electrons from the oxidation of organic molecules, such as carbohydrates, proteins and fatty acids and is reduced to NADH
- Foundation of energy metabolism within the mitochondria, powerhouse of the cells.
- Plays central role in increasing life span by influencing pathways involved in aging (energy metabolism, optimizing mitochondrial functions, cellular response to oxidative stress and activation of Sirtuins.)
NADH: Reduced form of NAD
- Acts as a reducing agent, i.e. it donates electrons to create ATP molecules via oxidative phosphorylation.
- Recycled to NAD+ through NAD salvage pathways.
How NAD+ works?
NAD+ has two predominant roles to perform:
- Cofactor in redox and metabolic reactions
- Substrate for enzymes
NAD+ and energy metabolism in mitochondria
Cofactor in redox and metabolic reactions
Mitochondria are the epicentre of energy production in the cells. These tiny organelles specialize in generating ATP, energy currency required to perform every imaginable function involved in cellular growth and survival.
NAD+ plays a critical role in energy production within the mitochondria. NAD+ is converted to NADH during:
- Oxidation of fatty acids and amino acids in the mitochondria
- Four steps of the mitochondrial TCA cycle
- One of the steps of glycolysis, a pathway in which glucose is converted to pyruvate to release energy
NADH generated during these metabolic pathways donates electrons that are used in a complex series of reactions, resulting in ATP synthesis in the mitochondria via oxidative phosphorylation.
Besides playing a critical role in ATP synthesis, NAD+ is also important to maintaining mitochondrial health and overall functions. Recent studies have implicated mitochondrial dysfunction in over 40 major diseases and health conditions including type 2 diabetes, cancer, Alzheimer’s disease and other neurodegenerative diseases.
NAD+ and activation of Sirtuins
What are Sirtuins?
Sirtuins (SIR2 or silent information regulator 2 proteins), are the family of enzymes that are known to play an integral role in the aging process by regulating metabolic pathways. The Sirtuins family comprises of seven enzymes (SIRT1–7) and there is a special focus on SIRT1 proteins that have been extensively researched for their antiaging effects. SIRT1 is believed to increase life span by turning off certain genes that are known to accelerate aging, for example genes involved in triggering inflammatory processes, fat synthesis and storage, and in blood glucose management.
NAD+ as a substrate for Sirtuins and other enzymes
A substrate is a reactant molecule that enzymes act upon to catalyze a chemical reaction. Enzymes have active sites that bind to a specific substrate to form an unstable enzyme-substrate complex, that requires less amount of energy to carry out the chemical reaction. This intermediate compound quickly breaks down to form new products that eventually separate from the enzyme. The enzyme remains unchanged and is free to react with other substrates to catalyze or accelerate other reactions. The substrate, on the other hand, is completely utilized and transformed into a different product altogether.
NAD+ acts as a substrate for Sirtuins proteins, bacterial DNA ligase and also other classes of enzymes; Poly-ADP-ribose Polymerases (PARPs) and CD38. All these enzymes consume NAD+ to carry out their unique roles and functions, required to maintain cellular health. In these reactions, NAD+ is completely expended and not recycled. We can see that these other NAD+-consuming enzymes are in direct competition with the SIRT enzymes, leading to the declining levels of NAD+ as we age.
Exploring the functions of NAD+ dependent Sirtuins
This specialized class of NAD+ consuming enzymes is involved in multiple biological processes and their main functions can be summarized as:
- Remove acetyl groups from proteins, an essential process in gene regulation.
- Repair double-stranded DNA breaks (PARPs that also need NAD+ play an active role in repairing single-stranded DNA breaks.)
- Regulate physiological responses to metabolic disturbances and stress, two main factors that affect aging.
- Optimize mitochondrial functions and help mitochondria to respond efficiently to oxidative stress
- Inhibits pro-inflammatory processes
Sirtuins, NAD+ levels and cellular energy status
The activity of SIRT1 is generally increased in response to nutrition deprivation or environmental stressors, such as fasting, DNA damage or oxidative stress. NAD+ levels in the mitochondria indicates the energy status of the cell. SIRT1 basically functions as metabolic sensors that sense changes in intracellular NAD+ levels and help cells to regulate metabolic pathways to meet the energy requirements of the cell. NAD+ dependent SIRT1 activation thus helps to increase mitochondrial metabolism and protection against oxidative damage .
This suggests that interventions aimed to increase SIRT1 activity, such as increasing NAD+ levels, may turn out to be a useful, effective strategy to preventing and treating metabolic disorders.
NAD+ and nuclear-mitochondrial communication
NAD+ enables the communication between the nucleus and its mitochondria. Decline in NAD+ levels interrupts this nuclear-mitochondrial communication, contributing to weakening mitochondrial functions as we age .
Dr. David Sinclair, Harvard Medical School Professor of Genetics, compares this communication to that between 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 like with a couple, restoring communication solved the problem.”
Declining NAD+ Levels. What does it mean for our health?
NAD+ levels decline as we age. Other factors such as overeating, high-fat diet and sedentary lifestyles also contribute to the diminishing NAD+ levels. Low levels of nuclear NAD+ means number and density of mitochondria are also reduced, leading to the deterioration of mitochondrial functions.
Mitochondrial dysfunction means:
- Decline in ATP production
- Decline in heat production
- Excessive cellular free radical production
- Increased DNA damage
- Insufficient DNA repair
- Metabolic imbalance and associated consequences
- Inappropriate response to stressors (energy stress, oxidative stress and nutrient deprivation)
Insufficient levels of NAD+ are closely associated with major factors involved in aging and associated pathologies such as type 2 diabetes, cancer, cardiovascular risk factors, neuro-degenerative diseases like Alzheimer’s and Parkinson’s.
“NAD(+) levels decline during the aging process and may be an Achilles’ heel, causing defects in nuclear and mitochondrial functions and resulting in many age-associated pathologies. Restoring NAD(+) by supplementing NAD(+) intermediates can dramatically ameliorate these age-associated functional defects, counteracting many diseases of aging, including neurodegenerative diseases. Thus, the combination of sirtuin activation and NAD(+) intermediate supplementation may be an effective antiaging intervention, providing hope to aging societies worldwide.” 
Benefits of improving NAD+ levels
NAD+ is a mediator of several major biological processes and influence pathways associated with aging such as energy metabolism, mitochondrial functions, oxidative stress and Sirtuins activity. Increase in the bio-availability of NAD+ will boost the functions of mitochondria. NAD+ is thus emerging as a new strategy to delay the process of aging and treat a range of chronic diseases.
Maintaining NAD+ levels are important for:
- Energy and vitality
- Regulating metabolism and circadian rhythm
- Reducing inflammatory process
- Controlling factors involved in aging, promotes longevity
- Improved cognitive functions, improved memory
NAD+ shows substantial promise in preventing or managing many chronic, degenerative conditions:
- Neuro-degenerative diseases (Alzheimer’s, Parkinson’s, Dementia, Age-related memory loss)
- Conditions related to metabolic dysfunctions; Obesity, insulin resistance and type 2 diabetes
- Cardiovascular diseases
- Inherited mitochondrial disorders
- Cantó C, Auwerx J. Targeting Sirtuin 1 to improve metabolism: all you need is NAD(+)? Pharmacological Reviews 2012.
- Gomes et al. Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging. Cell. 2013.
- Imai et al. NAD+ and Sirtuins in Aging and Disease. Trends in Cell Biology. 2014.