Nicotinamide riboside and longevity

Throughout the modern age, life expectancy has been steadily increasing, driven by advances in health care, and improvements in living and working conditions. Since approximately 2011 it has started to slow and current estimates are that now life expectancy has reduced to levels seen a decade earlier, suggesting we are becoming less healthy than we were. Modern science, medicine and technology have allowed us to live longer but are we living better?

The definition of longevity is living a longer and healthier life. It defines not only how long a person is going to live, but how healthy their later life will be. Longevity takes our wellbeing into old age into account and is a better a definition of health ageing than life expectancy.

Nicotinamide riboside (NR) is a nutrient which has gained much interest for supporting longevity. In this blog we will explore the functions of NR, how they impact longevity and look at some of the research behind its use for conditions associated with ageing.

What is Nicotinamide Riboside?

Nicotinamide riboside (NR) is a compound that has gained attention for its potential role in promoting longevity and overall health. NR is a form of niacin (vitamin B3) which consists of nicotinamide (NAM) and ribose as its fundamental components. It is a precursor to nicotinamide adenine dinucleotide (NAD+), which is an essential component of energy production. During glycolysis and the citric acid cycle NAD+ becomes NADH, which is then converted via the electron transport chain in the mitochondria into the body’s usable form of energy, adenosine triphosphate (ATP). ¹

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What is NAD+?

B3 and hence NAD+ deficiency was first noted in 1735 by Gaspar Casal, who spotted a bizarre malady in poor peasants from the region of Oviedo (Spain). These people displayed dermatitis lesions, generally manifested as rashes in exposed skin areas, such as the neck, hands, and feet. This was also seen in French peasants who ate mainly a maize-based diet. It was thought the condition may be due to toxicity in maize and was named as pellagra. It wasn’t until 1915 Joseph Goldberger had performed a series of careful experiments in human patients unequivocally demonstrating that pellagra was not due to a toxic element in maize, but to a nutritional deficiency in maize-based diets. In the 1930s B3 and NAD+ were discovered, and pellagra was attribute to a nutritional deficiency of B3.²

In today’s society, B3 deficiency as pellagra is incredibly rare and is a dramatic manifestation of severe, chronic NAD+ depletion. However, recent evidence in model organisms indicates that more modest decreases in NAD+ levels are enough to alter cellular metabolism and function, and that lower intracellular NAD+ content is a hallmark of physiological decline.

NAD+ levels will decline when NAD+ synthesis rates cannot match NAD+ degradation rates. Multiple factors can play in this balance, including dietary deficiencies for NAD+ precursors, changes in the expression levels of enzymes that transform dietary precursors to NAD+, or changes in the activity of enzymes that break down NAD+.¹

What is noted is that declines in NAD+ levels are associated with may symptoms of ageing and chronic disease including:

• Reduced mitochondrial respiratory capacity
• Liver dysfunction and damage
• Kidney disease
• Cardiovascular disease
• Neurodegeneration¹

In many tissues (e.g., brain, muscle, skin, liver, pancreas, and adipose tissue), the level of NAD+ decreases with age, which has an effect of reduced cellular energy production. Consequently, healthy aging and longevity are thought to be related to NAD+ metabolism, which can be regulated through NR (as well as nicotinamide mononucletoide (NMN)). One argument for nicotinamide related dietary supplements (e.g. NR or NMN) is that these can have prophylactic and therapeutic impacts on functional decline, improving age-associated neurodegenerative, cardiovascular, and metabolic diseases and conditions, and promoting the beneficial effects of calorie restriction.^1,3

It has been shown that NAD+ declines with age and that it can be restored or elevated by supplementation with NAD+ precursors including nicotinamide riboside (NR).⁴

What are sirtuins?

Sirtuins are a family of enzymes which are dependent on the presence of NAD+. They play key roles in responding to nutritional and environmental perturbations, such as fasting, dietary restriction, DNA damage, and oxidative stress. Their activation is strongly associated with resistance to oxidative stress and mitochondrial metabolism and hence longevity. Many studies have shown that sirtuins promote longevity in animal models, and can mitigate many diseases of ageing in models, such as type 2 diabetes, cancer, cardiovascular diseases, neurodegenerative diseases, and pro-inflammatory diseases.^3,5

Sirtuins have also been shown to decline with age, and much of this is attributed to the decline in NAD+. The restoration of NAD+ via supplementation of NR is associated with an amelioration of age-associated pathologies. This is thought to be mainly by its influence on sirtuin activity.^2,3,5

It is therefore thought that nicotinamide riboside has an influence on longevity both directly by supporting normal energy production by making NAD+ available, but also via promotion of sirtuin activity, which requires adequate availability of NAD+ and elicits multiple effects to attenuate the ageing process.

How we age

Before we discuss the effects of NR on ageing, it is important to look at why and how we age. Firstly, ageing is a natural process and one that is evolutionarily beneficial. To put it rather crudely, we pass on our genes to a new generation during reproduction. After these reproductive years our vitality wanes and we eventually die allowing for more resources to be available to the younger generation. We can now live a long way past our reproductive years which has also been a benefit to the evolution of our civilisation. As we are no longer preoccupied with finding a mate and reproducing, humans have developed philosophically and socially leading to advancements in knowledge and understanding which is passed this on down the generations allowing for societal evolution.

Even though we are living longer than our reproductive years our body cells cannot be immortal and they go through the process of ageing. There is no one mechanism associated with ageing, but multiple factors which contribute to the ageing process, these include:

Oxidative stress

Occurs when there is an imbalance between the production of free radicals or reactive oxygen species (ROS) and the ability of the body to counteract or detoxify their harmful effects using antioxidants. ROS play a critical role in alterations of the dermal extracellular matrix, both in the case of intrinsic and photo (extrinsic) ageing.^6–8

Mitochondrial dysfunction

Mitochondria produce ROS during energy production. This activates antioxidant enzymes (such as superoxide dismutase) and mitophagy (the breaking down of damaged mitochondria) and therefore mitochondrial biogenesis (generation of new mitochondria). Over time, our antioxidant systems become overwhelmed, and we are less able to maintain a balance between mitophagy and mitochondrial biogenesis. Therefore, old mitochondria endure but are less efficient at producing energy and produce more oxidative stress, further damaging the mitochondria and the cell. Leading to poor energy production, poor cell function and high levels of oxidative stress. This accelerates the ageing process.^8–10

Inflammation

Chronic, low-grade inflammation is recognised as a major characteristic of the ageing process and is often referred to as ‘inflammaging’. It plays a role in the initiation and progression of age-related diseases such as type II diabetes, Alzheimer’s disease and cardiovascular disease.⁸

Cell cycle dysfunction

In all organ systems of the body there is cell turnover, where there is a balance between apoptosis (cell death) and cellular regeneration or mitosis. As we age, many factors influence this balance and drive them further towards cell degeneration, i.e. increased apoptosis and endurance of dysfunctional cells and a loss of cell regeneration. This leads to cell loss and can also allow an excess of damaged cells, which can increase the risk of cancer formation.⁸

DNA damage

DNA is more protected from damage than the mitochondria as it resides in the nucleus. However, over time DNA becomes more damaged via oxidative stress, exposure to toxins, pollutants, radiation etc., which means that the cell cycle doesn’t work effectively, and the cell can no longer divide. These cells become senescent, where they are at a reduced ability to function but are not destroyed by apoptosis. This means the cells, tissue and organ systems are functioning sub-optimally but also there is an increased risk of uncontrolled cell division, which is a cornerstone of cancer development.

Telomere shortening

Telomeres act as buffers at the end of our chromosomes, protecting our genes from damage during cell division. UV radiation leads to excessive ROS production, resulting in telomere mutations and further cell death, or senescence. With eachcell cycle, telomeres get slightly shorter, although they can be extended or repaired by the action of the enzyme telomerase. As we age and go through more cell cycles our telomeres become shorter and shorter. Telomere length is a strong indication of ageing. Slowing telomer shortening and increasing telomerase activation are intervention to help maintain longevity.^8,11

Mechanisms of NR on ageing

As mentioned above, NR has multiple influences on healthy ageing. Firstly, due to the maintenance of normal energy production by the mitochondria. Mitochondrial function is essential for the function and activity of the cell and therefore the tissue, organ system and ultimately the whole body. Poor energy production and mitochondrial dysfunction are essential factors in accelerated ageing and progression of chronic disease.

The other main influence NR has on longevity is by increasing the activation of sirtuins via supporting the availability of NAD+. We know that sirtuins are associated with longevity by mechanisms including:

• Supporting mitochondrial function and biogenesis
• Attenuating oxidative stress
• Attenuating inflammation
• Increasing lipolysis (production of energy from fat)
• Supporting DNA repair
• Regulating the cell cycle
• May improve insulin sensitivity^1,4

Studies have suggested:¹

• • NR significantly reduced apoptosis and the generation of reactive oxygen species (ROS), increased cell viability, and improved levels of superoxide dismutase (SOD), catalase (CAT), total glutathione (GSH), and mitochondrial membrane potential.
  • NR promotes thermogenesis, (burning of fat to produce energy as heat).
  • NR supports energy production mitochondrial function
  • NR has involvement in the activation of sirtuins

• NR increases NAD+ production
• NAD+ is involved in an extensive spectrum of pathologies, including neurodegenerative disorders, cardiomyopathy, obesity, and diabetes.
• Healthy aging and longevity appear to be closely related to NAD+ and its related metabolites, including through NR and NMN.
• NR has prophylactic and therapeutic value in improving age-associated neurodegenerative, cardiovascular, and metabolic diseases and conditions.

NR v NMN v Niacin

NR enters cells and is then converted to nicotinamide mononucleotide (NMN) which is then converted to NAD+, so NMN is further down the conversion pathway than NR. However, in order to enter the cell it needs to be in the form of NR. NMN has been recently discovered to be converted extracellularly to NR, which is then transported into cells. It may be more efficient to supplement in the form of NR as opposed to NMN. Studies have considered the merits of both, and both forms support the production of NAD+ adequately. However, among the NAD+ precursors, NR may be preferred, as it produces fewer reported unfavourable side effects.^5,12,13

Niacin generically refers to two molecules, nicotinic acid (NA) and nicotinamide (NAM), this is the standard form of B3. Niacin has many other functions within the body and hence when scarce may not raise NAD+ as potently at the NAD+ precursors NR and NMN. Additionally, niacin has to go through further enzymatic steps in order to generate NAD+, so is therefore less efficient. Studies have shown that NA can act as a potent NAD⁺ precursor in liver and kidney however, NA is a poor NAD⁺ precursor beyond these tissues. Niacin in the form of nicotinic acid also can cause unpleasant side effects such as flushing.¹³

If wishing to supplement in order to improve NAD+ production it is suggested that nicotinamide riboside may be the preferred form.

References

1. Biţă A, Scorei IR, Ciocîlteu MV, et al. Nicotinamide Riboside, a Promising Vitamin B3 Derivative for Healthy Aging and Longevity: Current Research and Perspectives. Molecules. 2023;28(16). doi:10.3390/MOLECULES28166078
2. Cercillieux A, Ciarlo E, Carles Canto ·. Balancing NAD + deficits with nicotinamide riboside: therapeutic possibilities and limitations. Cellular and Molecular Life Sciences. 2022;79:463. doi:10.1007/s00018-022-04499-5
3. Grabowska Ewa Sikora Anna Bielak-Zmijewska W. Sirtuins, a promising target in slowing down the ageing process. doi:10.1007/s10522-017-9685-9
4. Martens CR, Denman BA, Mazzo MR, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD + in healthy middle-aged and older adults. doi:10.1038/s41467-018-03421-7
5. Imai SI, Guarente L. NAD + and Sirtuins in Aging and Disease. Trends Cell Biol. 2014;24(8):464-471. doi:10.1016/j.tcb.2014.04.002
6. Ames BN. Prolonging healthy aging: Longevity vitamins and proteins. Proceedings of the National Academy of Sciences. 2018;115(43):10836-10844. doi:10.1073/pnas.1809045115
7. Liu X, Yuen M, Yuen T, Yuen H, Wang M, Peng Q. Anti‐skin aging effect of sea buckthorn proanthocyanidins in D‐galactose‐induced aging mice. Food Sci Nutr. 2024;12(2):1082. doi:10.1002/FSN3.3823
8. DiLoreto R, Murphy CT. The cell biology of aging. Mol Biol Cell. 2015;26(25):4524. doi:10.1091/MBC.E14-06-1084
9. Marzetti E, Calvani R, Cesari M, et al. Mitochondrial dysfunction and sarcopenia of aging: from signaling pathways to clinical trials. Int J Biochem Cell Biol. 2013;45(10):2288-2301. doi:10.1016/J.BIOCEL.2013.06.024
10. Krutmann J, Bouloc A, Sore G, Bernard BA, Passeron T. The skin aging exposome. J Dermatol Sci. 2017;85(3):152-161. doi:10.1016/j.jdermsci.2016.09.015
11. Galiè S, Canudas S, Muralidharan J, García-Gavilán J, Bulló M, Salas-Salvadó J. Impact of Nutrition on Telomere Health: Systematic Review of Observational Cohort Studies and Randomized Clinical Trials. Advances in Nutrition. 2020;11(3):576. doi:10.1093/ADVANCES/NMZ107
12. Imai S ichiro, Guarente L. NAD+ and Sirtuins in Aging and Disease. Trends Cell Biol. 2014;24(8):464. doi:10.1016/J.TCB.2014.04.002
13. Cercillieux A, Ciarlo E, Canto C. Balancing NAD+ deficits with nicotinamide riboside: therapeutic possibilities and limitations. Cell Mol Life Sci. 2022;79(8):463. doi:10.1007/S00018-022-04499-5

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Last updated on 25th October 2024 by cytoffice