Caloric restriction and nicotinamide riboside

Caloric restriction or CR is the practice of long-term calorie reduction with the aim of improving health, delaying ageing and even extending longevity. Research in animals, ranging from nematodes, mice and rats to Rhesus monkeys, has shown benefits to health and longevity of restricting calories, without malnutrition, by 25% to 50%. Some believe this may also work for humans and there are followers and advocates of this dietary regime. This blog explores the effects of caloric restriction and refers to an exciting pilot study on nicotinamide riboside which is being researched as a possible caloric restriction mimetic.

“Caloric restriction without malnutrition is the most studied and robust … experimental intervention for extending healthspan and lifespan in multiple animal models”

Most et al 2017¹

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The Minnesota Semi-Starvation Experiment

Obviously, there are dangers associated with caloric restriction as illustrated in the Minnesota Semi-Starvation Experiment. This study was conducted during World War II by Ancel Keys on a group of lean men who restricted their calorie intake by 40% for 6 months. The experiment was instigated as there was concern about food availability during the war and so Ancel Keys undertook to investigate the effects of starvation followed by re-feeding. The participants reduced their calorie intake from 3,200 calories per day to 1,800 calories per day and were required to walk 22 miles per week and expend 3000 kcal/day. The diet quality was poor, to reflect a wartime diet, and in the main comprised starchy carbohydrates, without good sources of protein or micronutrients. Thus, as well as weight loss, the men suffered malnutrition and the experiment resulted in severe negative physical and psychological effects including anaemia, muscle wasting, hair loss, dizziness, lethargy, depression and obsession with food. Nevertheless, the study did also report some beneficial changes to body fat, blood pressure and cholesterol². 

Caloric Restriction Studies without Malnutrition

Studies in animals have shown that caloric restriction (without malnutrition) can delay the onset of many chronic diseases and extend lifespan dramatically, for example by 2-3 times in fruit flies and nematodes and up to 50% in mice and rats¹.

In non-human primates, caloric restriction of 30% improves blood glucose parameters, slows down age related sarcopenia (muscle loss) and brain atrophy (shrinkage). Improvements to longevity have been seen in some studies and not in others, and some researchers question whether the longevity effects seen in, for example, mice and rats are relevant to humans¹.

The CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) trials were initiated by the US National Institute of Aging to provide the first controlled clinical trials of CR, with adequate nutrient provision, in healthy, non-obese humans. Caloric restriction of 20 – 30% was run over 6 months, 12 months and 2 years.

The short trials (6 and 12 months) showed improvements in insulin sensitivity, glucose homeostasis, cardiovascular disease risk factors (blood pressure, LDL, HDL, fibrinogen, homocysteine) and markers of oxidative stress. In addition, the expression of genes encoding proteins involved in mitochondrial function, including SIRT1, was increased. However, some metabolic adaptations seen in animal studies, such as inflammatory markers and factors associated with ageing were unchanged in these CALERIE trials^1,3,4,5.

As the 6 month and 1-year trials were not sufficient to induce many of the metabolic and hormonal adaptations in humans that are thought to increase longevity in rodents, a 2-year study was also undertaken. During this 2-year period (25% CR), further metabolic adaptations were observed, including improvements to inflammatory parameters such as CRP and TNFα. Some adaptations that are seen in rodents were not observed and it was suggested that this might be because the caloric restriction was insufficient^1,6,7

The Caloric Restriction with Optimal Nutrition (CRON)

Members of the Caloric Restriction Society follow a CR regime of around 1800 kcal/day with optimal nutrition, i.e. around 30% less energy than individuals following a regular Western diet, with the goal of prolonging healthspan and lifespan. They are very lean (BMI 19.7 +/- 1.8) and have been restricting their caloric intake for between 3 and 15 years. The CRON diet is of good quality comprising low glycaemic foods; it is high in vegetable fibre and phytonutrients.

Studies of CRON individuals indicate that long-term moderate/severe CR in humans results in the same metabolic and molecular adaptations typical of long lived CR animals (although it is recognised that the high quality of the CRON diet will also be contributing to the metabolic health effects seen, independently of caloric intake)⁸.

Cardiometabolic risk factors in the members of the CR society are low^8,9 – blood pressure, cholesterol, inflammatory markers (CRP, TNFα, IL6), fasting glucose and fasting insulin. As a result, members suffer lower levels of atherosclerosis⁹ and heart rate variability is comparable with healthy men and women 20 years younger¹⁰.

At a molecular level, certain pathways and genes associated with longevity were altered by CR and were similar to younger individuals. Thus CRON studies have shown that long-term CR results in similar metabolic adaptations to long lived rodents⁸.

Searching for a caloric restriction mimetic

Of course, long-term severe CR is not practical, feasible or sustainable for most people and can come with undesirable side effects such as extreme leanness, reduced bone density, sensitivity to cold, risk of malnutrition and other unpleasant effects. Therefore, the aim of CR research is to understand the mechanisms and how similar benefits might be achieved with fewer restrictions.  Areas being researched include intermittent fasting, protein restriction and the use of selected nutrients such as nicotinamide riboside or nicotinamide adenine dinucleotide (NAD) – referred to as CR mimetics.

Nicotinamide riboside is a form of vitamin B3 that functions as a precursor to NAD, which has two important functions:

• NAD boosts mitochondrial function. Animal studies have shown that restoring mitochondrial function slows ageing and extends longevity¹¹
• NAD is a rate limiting co-substrate for the family of sirtuin enzymes – increasing levels of the co-substrate NAD increases the activity of these enzymes; and oral supplementation with nicotinamide riboside has been shown to increase levels of NAD¹².

Sirtuins play an important role in maintaining cellular homeostasis by regulating energy status (mitochondrial function), gene expression, repair of DNA and stress resistance to prevent metabolic disease (and CR increases the activity of sirtuin enzymes by increasing available NAD).

However, the cellular bioavailability of NAD declines during normal ageing¹². Therefore, a substance which has the same effect as CR (i.e. increasing available NAD and thus the activity of sirtuin enzymes) might be termed a CR mimetic.

Canto et al (2012) showed that NR supplementation in mammalian cells and mouse tissues increases NAD⁺ levels and activates sirtuin enzymes providing protection against metabolic abnormalities induced from a high fat diet. They concluded that “nicotinamide riboside could be used as a nutritional supplement to ameliorate metabolic and age-related disorders characterised by defective mitochondrial function”¹³.

There is also interest in relation to brain health as evidence, again from mice models, suggests NAD might play important roles in metabolic processes in the brain, with effects on brain functioning such as neurotransmission, learning and memory.¹⁴

Interestingly, promising results have also been shown in humans – a, randomised, double-blind, crossover, 6 week, pilot trial (24 subjects) earlier this year demonstrated that a regular dose of nicotinamide riboside (500 mg, 2x per day) activated some of the same biological pathways seen in people who are fasting. It showed improvements in patients’ blood pressure and arterial health and was well tolerated.¹⁵

The authors concluded:

“We provide the first insight into the effects of NR supplementation on physiological function in humans and identify systolic blood pressure and aortic stiffness as promising cardiovascular outcomes to be assessed in larger-scale clinical trials”

Martens (2018)

If you have any questions regarding the topics that have been raised, or any other health matters, please do contact me (Clare) by email at any time (clare@cytoplan.co.uk)

Clare Daley and the Cytoplan Editorial Team

Related Cytoplan Product

Nicotinamide Riboside – A very unique member of the vitamin B3 family. The body converts NR into Nicotinamide Adenine Dinucleotide (NAD+) which is an essential molecule found in every living cell.

References

1. Most, J. et al. (2017) ‘Caloric restriction in humans: an update’. Ageing Research Reviews, 30, pp. 36-45.
2. Kalm, L.M. and Semba, R.D. (2005) ‘They starved so that others be better fed: remembering Ancel Keys and the Minnesota Experiment’. The Journal of Nutrition, Volume 135, Issue 6, 1 June 2005, Pages 1347–1352.
3. Das, S.K. et al. (2007) ‘Long-term effects of 2 energy-restricted diets differing in glycemic load on dietary adherence, body composition, and metabolism in CALERIE: a 1-y randomized controlled trial. American Journal of Clinical Nutrition, 85, 1023-1030.
4. Heilbronn, L.K. et al. (2006) ‘Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA : the Journal of the American Medical Association, 295, 1539-1548.
5. Racette, S.B. et al. (2006). One year of caloric restriction in humans: feasibility and effects on body composition and abdominal adipose tissue. The Journals of Gerontology. Series A, Biological sciences and medical sciences, 61, 943-950.
6. Rickman, A.D. et al. (2011) ‘The CALERIE Study: design and methods of an innovative 25% caloric restriction intervention. Contemporary Clinical Trials 32, 874-881
7. Rochon, J. et al. (2011) ‘Design and conduct of the CALERIE study: comprehensive assessment of the long-term effects of reducing intake of energy. The Journals of Gerontology. Series A, Biological sciences and medical sciences 66, 97108.
8. Fontana, L. et al. (2004) ‘Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans’. Proc Natl Acad Sci USA, 101, 6659-6663.
9. Fontana, L. et al. (2010) ‘Effects of long-term calorie restriction and endurance exercise on glucose tolerance, insulin action, and adipokine production’. Age 32, 97-108.
10. Stein, P.K. et al. (2012) ‘Caloric restriction may reverse age-related autonomic decline in humans’. Aging Cell 11, 644-650.
11. Zhang, H. et al. (2016) ‘NAD(+) repletion improves mitochondrial and stem cell function and enhances life span in mice.’ Science. 2016;352(6292):1436-43.
12. Belenky, P. et al. (2007) ‘Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/MeuI pathway to NAD+’. Cell, 4, 129, 3, 473-84.
13. Mouchiroud, L. (2013) ‘NAD(+) metabolism: a therapeutic target for age-related metabolic disease’. Crit Rev Biochem Mol Biol, 48, 397-408.
14. Gong, B. et al. (2013) ‘Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-ϒ coactivator 1α regulated β-secretase I degradation and mitochondrial gene expression in Alzheimer’s mouse models’. Neurobiol Aging, 34, 6, 1581-8.
15. Martens, C.R. et al. (2018) ‘Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy and middle-aged and older adults’. Nature Communications, 9, 1286.

Last updated on 2nd May 2018 by cytoffice