nmnwiki - User contributions [en]

NR

2020-10-19T16:30:52Z

Judgesurreal777: Setting up redirect

#REDIRECT [[Nicotinamide Riboside]]

Nicotinamide Riboside

2020-10-19T16:22:27Z

Judgesurreal777: Categorizing

'''Nicotinamide Riboside (NR)''' is a natural organic compound found in trace amounts in foods such as dairy products and is a precursor to nicotinamide adenine dinucleotide ([[NAD+]])<ref name="pellagra"/>. Termed the ‘cousin’ of vitamin B3, this form of vitamin B3 also comes in variations known as nicotinamide and nicotinic acid/niacin (NA), niacin being most commonly used in fortifying foods such as flour and cereal particularly in the 1940s to ward off the fatal disease pellagra.<ref name="pellagra">[https://www.elysiumhealth.com/en-us/science-101/what-is-nicotinamide-riboside What Is Nicotinamide Riboside?] Written for Elysium Health.com. Published January 1, 2020; Accessed October 19, 2020</ref>

Previous research focused on the role of NAD+ on the body’s cellular health independently, however it is becoming known that NR may be more valuable than thought. NR supplementation has been proven to be effective in enhancing NAD+ when administered orally. The implications of using NR are so wide that there is an abundance of current research trials investigating the use of NR not only in prevention but also the treatment of many inflammatory disease states.

==History==
NR was first identified as a growth factor named Factor V in 1944, named so due to its ability to enhance the growth of Hemophilus influenzae, a bacterium that resides in the blood. When Factor V was extracted from blood and purified it was shown to exist in 3 forms: NAD+, NMN and NR. It became apparent that NR was responsible for the most rapid growth rate of the bacterium compared to that of NAD+ and NMN (2).

In 1963 Mandel and Colleagues identified a chemical reaction that broke NAD into 2 respective parts, nicotinamide and ADP-ribose (3).

Sirtuin enzymes, a family of proteins that regulate cellular health, were discovered in 2000. Biochemists investigating how yeast sirtuins affect longevity came across the findings that sirtuins used NAD to help keep specific genes “silent” so not to function. During this process sirtuin enzymes breakdown NAD and use parts of it to deacetylate or “remove acetyl groups” of proteins within the cell. Deacetylating histone proteins, proteins that provide structure and order to DNA, can change how the cell accesses nearby genes (4).

In 2004 advances were made in the implication of NR in the body other than just to ward off disease states. Biochemist Charles Brenner et al identified the NR kinase pathway leading to production of NAD+ (5). Follow up research showed that administering NR to yeast cells resulted in increased NAD levels and hence an extension in lifespan of the yeast (6).

Consequently, this paved the way for a more efficient pathway of producing NAD+, known to restore levels in the body and reduce the signs of the inflammatory and aging process internally at a cellular level. A crystal form of NR chloride, also known as Niagen is currently the only FDA-safety reviewed form (7). Dr Charles Brenner was the biochemist who not only discovered but also patented nicotinamide riboside as a cellular nutrient. Our cells are exposed to many stressors such as infections, poor diet, lack of sleep and exercise not to mention diminishing NAD+ levels as we age. NR allows the cells to become more resilient and super-charged.

==Structure==
Nicotinamide riboside is a nucleoside which is a combination for nicotinamide and riboside in a single chemical moiety.
1-(B-D-Ribofuranosyl)nicotinamide
Molecular formula C11H15N205
Molar mass of 255.25g/mol

==Biosynthesis==
NR is naturally occurring in milk, most recently it was found that cow’s milk contained approximately 12 micromole NAD+ precursor vitamin concentration, of this percentage 60% was nicotinamide and 40% present as NR. It was also found that the presence of Staphylococcus aureus resulted in lower concentrations of NR (9).

Most synthetic production of NR can be divided into 2 categories, firstly is a reaction between nicotinamide and a peracylated (halo)-D-ribofuranose resulting in an acylated (addition of an acyl group) intermediate that is then converted into NR. The second method is via condensation of a salt with derivatives of D-ribofuranosylamine. The first approach is the most commonly used as it produces NR with a greater yield and is more efficient (9).

This more commonly used approach requires synthetic glycosylation conditions, attachment of a carbohydrate molecule that depends on the type of sugar component used (8).

NR has also been synthesized enzymatically from NAD+ and NMN using many processes. Kaplan and Stolzenbach used snake venom phosphodiesterase to perform enzymatic cleavage or “breakdown” of NAD+ to form NMN followed by catalysis, otherwise known as acceleration of a reaction, with a prostatic monoesterase enzyme to form NR+ (8).

==Functions==
A precursor to NAD+, NR Is a building block essential to cellular processes such as DNA repair. NR is a nucleoside which provides researchers with a great tool to manipulate NAD+ levels and investigate the effects of NAD+ concentration on cellular processes (9).

The human body utilizes NR to boost levels of NAD which powers metabolism and protects cells during times of metabolic stress (10).

Nicotinamide phosphoribosyltransferase (Nampt) is an enzyme that catalyzes the conversion of nicotinamide to NAD+. There are also to forms of nicotinamide riboside kinsases (NRK1 and NRK2) that convert NR to NAD+ without the need for Nampt (5).

The kinase pathway is also found to be involved in assisting NR to raise NAD tissue concentrations in rodents and eliciting effects such as insulin sensitivity, mitochondrial biogenesis also depicted as the generation of more of the cell’s “powerhouse” and enhanced sirtuin functions (11).

Upregulation of NR, particularly through diet and oral administration has been shown to increase NAD+ concentrations which subsequently enhances mitochondrial function and supports the body by providing protection against damage from free radicals hence reducing the signs of aging. It has also become known that there are additional benefits to supplementing with oral NR such as neurological and cognitive support, metabolic support as well as liver and muscle support.

==Research==
The use of oral NR supplementation to treat an array of conditions is currently underway.

===Clinical trials timeline===
November 1st, 2018 – A pilot study aimed to test whether oral NR increase NAD+ levels or improves mitochondrial function in heart cells also known as cardiomyocytes. Previous studies have shown NR supplementation to increase myocardial levels of NAD+ in mice, this study aimed to test the same but in human cardiomyocytes of patients with advanced heart failure who are awaiting elective left ventricular assist device (LVAD) implantation (12).

December 28th, 2018 – Researchers conducted a study to see if NR may help improve muscle function and possibly improve exercising capacity via improved mitochondrial activity. Investigators aimed to study how skeletal muscle responds to NR in patients who have Li-Fraumeni syndrome (LFS), a rare hereditary disorder that increases an individual’s risk of developing many types of cancer and causes long-term fatigue and muscles weakness (13).

January 25th, 2019 – This piece of research recruited newly diagnosed, drug naïve Parkinson’s Disease (PD) patients who were treated with oral NR. The pilot aimed to determine if NR had any impact on the enzyme or neurometabolic profile of patients with PD. Secondly, to identify if high dose oral NR improves motor symptoms associated with PD. Finally, to determine whether high dose NR can restore NAD metabolism and subsequently elevate levels of NAD (14).

April 11th, 2019 – Evaluating the effects of NR in preventing experimentally induced small fiber nerve degeneration and promotion of nerve regeneration. A type of nerve disease or damage that affects signaling between the brain, spinal cord and the rest of the body termed as peripheral neuropathy. A particular form of peripheral neuropathy known as small fiber neuropathy (SFN) affects small unmyelinated fibers. Myelin is a lipid rich fatty-like substance that surrounds nerve cells and is likened to the insulation around wires in electrical systems. Myelin insulates the nerve/neuron hence increasing the speed of electronic signals called actional potentials through it. Unmyelinated nerves therefore lack the insulation and hence do not support a healthy environment for the generation of the electronic signals. Diabetes is known to be a common cause of neuropathy; however, half of the diagnosed cases have an unknown cause and are termed idiopathic. There is no current intervention that can prevent degeneration or promote regeneration, however, recent advances in molecular science illustrated the importance of key molecules such as NAD+. This study aims to evaluate NR’s ability to prevent degradation and promote regeneration of small sensory axons in the skins layer known as the epidermis. Such research may help pave the way in treatments for many types of peripheral neuropathies (15).

May 15th, 2019 – Mitochondrial synthesis and the use of oxygen to produce energy from carbohydrates known as oxidative metabolism in fatty skin or “adipose tissues” was found to be significantly impaired in obesity at a young adult stage. As a result, investigators aim to see if NR may activate dysfunctional mitochondria, particularly the SIRT/NAD+ pathway and help alleviate signs of obesity related illness (16).

May 23rd, 2019 – To establish any positive outcomes of NR on the disease course of patients suffering from Ataxia Telangiectasia (A-T), an inherited neurodegenerative disorder caused by mutation of the ATM gene which causes breakdown of nerve cells affects the immune and respiratory system. This disorder is coupled with a high cancer risk and currently treatment is limited to rehabilitation, screening and prevention. The ATM protein plays a vital role in processes such as cellular energy metabolism, cell signaling and DNA repair. NAD+ is known as an essential molecule in many cellular processes, particularly as a deficiency in it is linked to underlying DNA repair disorders as seen in A-T. Prior research using NR in animal models has proved beneficial, this studies aims to see if treatment for 6 months may have positive outcomes on disease progression of A-T (17).

August 1st, 2019 – Research to date has shown that NR supplementation lowered carotid-femoral pulse wave velocity (CFPWV), a measure of aortic stiffness and predictors of cardiovascular disease in patients with or without kidney disease. Additionally, NR was shown to decrease systolic blood pressure (SBP). As a ‘next-step’, the current study aims to assess the safety and efficacy of NR for decreasing aortic stiffness and SBP in patients with stage III and IV chronic kidney disease (CKD). It is hypothesized that NR will lower aortic stiffness and SBP due to increases in NAD+ bioavailability, influences on vascular smooth muscle tone and a decline in markers for inflammation and oxidative stress (18).

August 5th, 2019 – Investigators aim to determine metabolic improvements in Alzheimer’s and Parkinson’s disease patients by use of a cocktail of NR in combination with other co-factors such as N-acetylcysteine, L-carnitine tartrate and serine to activate mitochondria in the brain cells. Based on previous studies it is evident that each cofactor plays its own role in activating mitochondria, NR specifically, is known to boost hepatic (liver) B-oxidation (breakdown) of fatty acids in mitochondria hence stimulating the transfer of fatty acids from the cytosol to the mitochondria (19).

September 4th, 2019 – A clinical trial aimed at determining whether NR can improve cognitive function such as thinking/decision making, mood and daily activities in people suffering from Subjective Cognitive Decline (SCD) or Mild Cognitive Impairment (MCI). This would be measured using blood draws, EEG’s, cognitive testing and mood questionnaires (20).

October 1st, 2019 – Those suffering from acute illness often face long recovery times, of which the primary cause is not known, however many factors can contribute to this such as age and severity of illness. This study aims to determine whether NR can reduce the times taken to recover and improve outcomes in patients admitted to hospital with tissue damage (21).

October 2nd, 2019 – Niagen, the brand name for NR, was tested to observe its effects in improving persistent peripheral neuropathy in cancer survivors who have completed chemotherapy with taxane or platinum-complex compounds between 1 and 12 months prior. Outcomes will be measured based on changes in scores on sensory and motor subscale of quality of life questionnaire (22).

October 2nd, 2019 - Identified as an enhancer of exercise therapy in hypertensive (raised blood pressure) older adults, NR is therefore being investigated as a means of enhancing the effects of therapy in a population type that would otherwise struggle to exercise. This has great implications as a positive outcome may pave the way to reducing cardiovascular disease and death (23).

February 17th, 2020 – A pilot study to evaluate the effect of NR on immune activation in psoriasis, a skin disorder that causes skin cells to multiply ten times faster than normal resulting in dry scales on the skin. Psoriasis is linked with a subset of CD4 T cells, or “helper” cells that regulate the immune system named Th17 cells, these cells are characterized by the production of signaling proteins named cytokines such as IL-17. Currently it is known that NR diminishes Th1 and Th17 activation hence the pilot intends to further this hypothesis by measuring NR’s impact on Th17, neutrophils and whether it modulates skin cell or keratinocyte activation in skin lesions of psoriasis subjects (24).

April 2nd, 2020 – A study to find a safe and tolerable means to improve the transplant recovery process known as engraftment post-transplantation. Previous research studies have found that adding NR to donor cells can increase blood stem cell quantities and reduces time to engraftment. This study aims to evaluate the safety and tolerability of NR as well as observe white blood cell and platelet count post-transplantation (25).

June 1st, 2020 – Well aware that a decline in NAD+ with increasing age can have major implications in this proinflammatory states, researchers advance on previous research that shows even short-term treatment with NR is sufficient to reduce the impact of this aging process. NR is therefore under test to see if it can attenuate the severity of SARS-CoV-2 infection in elderly patients aged 70 years or older (26).

==References==
<references/>

(1)Gingrich, W; Schlenk, F (June 1944). "Codehydrogenase I and Other Pyridinium Compounds as V-Factor for Hemophilus influenzae and H. parainfluenzae". Journal of Bacteriology. 47 (6): 535–50. PMC 373952. PMID 16560803

(2)CHAMBON, P., ET AL., NICOTINAMIDE MONONUCLEOTIDE ACTIVATION OF NEW DNA-DEPENDENT POLYADENYLIC ACID SYNTHESIZING NUCLEAR ENZYME. BIOCHEM BIOPHYS RES COMMUN, 1963. 11(1): P. 39-43.

(3) IMAI, S., ET AL., TRANSCRIPTIONAL SILENCING AND LONGEVITY PROTEIN SIR2 IS AN NAD-DEPENDENT HISTONE DEACETYLASE. NATURE, 2000. 403(6771): P. 795-800.

(4)Bieganowski, P; Brenner, C (2004). "Discoveries of Nicotinamide Riboside as a Nutrient and Conserved NRK Genes Establish a Preiss-Handler Independent Route to NAD+ in Fungi and Humans". Cell. 117 (4): 495–502. doi:10.1016/S0092-8674(04)00416-7. PMID 15137942

(5)BELENKY, P., ET AL., NICOTINAMIDE RIBOSIDE PROMOTES SIR2 SILENCING AND EXTENDS LIFESPAN VIA NRK AND URH1/PNP1/MEU1 PATHWAYS TO NAD+. CELL, 2007. 129(3): P. 473-84.

(6) https://www.chromadex.com/ingredient/niagen/

(7) https://www.beilstein-journals.org/bjoc/articles/15/36

(8) https://pubmed.ncbi.nlm.nih.gov/27052539/

(9) https://www.biospace.com/article/releases/new-study-demonstrates-a-unique-role-of-nicotinamide-riboside-over-other-nad-precursors/

(10) https://pubmed.ncbi.nlm.nih.gov/24071780/

(11) https://clinicaltrials.gov/ct2/show/record/NCT03727646?term=nicotinamide+riboside

(12) https://clinicaltrials.gov/ct2/show/record/NCT03789175?term=nicotinamide+riboside

(13) https://clinicaltrials.gov/ct2/show/record/NCT03816020?term=nicotinamide+riboside

(14) https://clinicaltrials.gov/ct2/show/record/NCT03912220?term=nicotinamide+riboside

(15) https://clinicaltrials.gov/ct2/show/record/NCT03951285?term=nicotinamide+riboside

(16) https://clinicaltrials.gov/ct2/show/record/NCT03962114?term=nicotinamide+riboside

(17) https://clinicaltrials.gov/ct2/show/record/NCT04040959?term=nicotinamide+riboside&rank=4

(18) https://clinicaltrials.gov/ct2/show/record/NCT04044131?term=nicotinamide+riboside

(19) https://clinicaltrials.gov/ct2/show/record/NCT04078178?term=nicotinamide+riboside

(20) https://clinicaltrials.gov/ct2/show/record/NCT04110028?term=nicotinamide+riboside

(21) https://clinicaltrials.gov/ct2/show/record/NCT04112641?term=nicotinamide+riboside

(22) https://clinicaltrials.gov/ct2/show/record/NCT04112043?term=nicotinamide+riboside

(23) https://clinicaltrials.gov/ct2/show/record/NCT04271735?term=nicotinamide+riboside&draw=2

(24) https://clinicaltrials.gov/ct2/show/NCT04332341?term=nicotinamide+riboside&draw=2&rank=7

(25) https://clinicaltrials.gov/ct2/show/record/NCT04407390

[[Category:Compounds]]

Nicotinamide Riboside

2020-10-19T16:01:30Z

Judgesurreal777: /* Clinical trials timeline */ commas

Nicotinamide Riboside

2020-10-19T15:57:28Z

Judgesurreal777: Fixes

'''Nicotinamide Riboside (NR)''' is a natural organic compound found in trace amounts in foods such as dairy products and is a precursor to nicotinamide adenine dinucleotide ([[NAD+]])<ref name="pellagra"/>. Termed the ‘cousin’ of vitamin B3, this form of vitamin B3 also comes in variations known as nicotinamide and nicotinic acid/niacin (NA), niacin being most commonly used in fortifying foods such as flour and cereal particularly in the 1940s to ward off the fatal disease pellagra.<ref name="pellagra">[https://www.elysiumhealth.com/en-us/science-101/what-is-nicotinamide-riboside What Is Nicotinamide Riboside?] Written for Elysium Health.com. Published January 1, 2020; Accessed October 19, 2020</ref>

Previous research focused on the role of NAD+ on the body’s cellular health independently, however it is becoming known that NR may be more valuable than thought. NR supplementation has been proven to be effective in enhancing NAD+ when administered orally. The implications of using NR are so wide that there is an abundance of current research trials investigating the use of NR not only in prevention but also the treatment of many inflammatory disease states.

==History==
NR was first identified as a growth factor named Factor V in 1944, named so due to its ability to enhance the growth of Hemophilus influenzae, a bacterium that resides in the blood. When Factor V was extracted from blood and purified it was shown to exist in 3 forms: NAD+, NMN and NR. It became apparent that NR was responsible for the most rapid growth rate of the bacterium compared to that of NAD+ and NMN (2).

In 1963 Mandel and Colleagues identified a chemical reaction that broke NAD into 2 respective parts, nicotinamide and ADP-ribose (3).

Sirtuin enzymes, a family of proteins that regulate cellular health, were discovered in 2000. Biochemists investigating how yeast sirtuins affect longevity came across the findings that sirtuins used NAD to help keep specific genes “silent” so not to function. During this process sirtuin enzymes breakdown NAD and use parts of it to deacetylate or “remove acetyl groups” of proteins within the cell. Deacetylating histone proteins, proteins that provide structure and order to DNA, can change how the cell accesses nearby genes (4).

In 2004 advances were made in the implication of NR in the body other than just to ward off disease states. Biochemist Charles Brenner et al identified the NR kinase pathway leading to production of NAD+ (5). Follow up research showed that administering NR to yeast cells resulted in increased NAD levels and hence an extension in lifespan of the yeast (6).

Consequently, this paved the way for a more efficient pathway of producing NAD+, known to restore levels in the body and reduce the signs of the inflammatory and aging process internally at a cellular level. A crystal form of NR chloride, also known as Niagen is currently the only FDA-safety reviewed form (7). Dr Charles Brenner was the biochemist who not only discovered but also patented nicotinamide riboside as a cellular nutrient. Our cells are exposed to many stressors such as infections, poor diet, lack of sleep and exercise not to mention diminishing NAD+ levels as we age. NR allows the cells to become more resilient and super-charged.

==Structure==
Nicotinamide riboside is a nucleoside which is a combination for nicotinamide and riboside in a single chemical moiety.
1-(B-D-Ribofuranosyl)nicotinamide
Molecular formula C11H15N205
Molar mass of 255.25g/mol

==Biosynthesis==
NR is naturally occurring in milk, most recently it was found that cow’s milk contained approximately 12 micromole NAD+ precursor vitamin concentration, of this percentage 60% was nicotinamide and 40% present as NR. It was also found that the presence of Staphylococcus aureus resulted in lower concentrations of NR (9).

Most synthetic production of NR can be divided into 2 categories, firstly is a reaction between nicotinamide and a peracylated (halo)-D-ribofuranose resulting in an acylated (addition of an acyl group) intermediate that is then converted into NR. The second method is via condensation of a salt with derivatives of D-ribofuranosylamine. The first approach is the most commonly used as it produces NR with a greater yield and is more efficient (9).

This more commonly used approach requires synthetic glycosylation conditions, attachment of a carbohydrate molecule that depends on the type of sugar component used (8).

NR has also been synthesized enzymatically from NAD+ and NMN using many processes. Kaplan and Stolzenbach used snake venom phosphodiesterase to perform enzymatic cleavage or “breakdown” of NAD+ to form NMN followed by catalysis, otherwise known as acceleration of a reaction, with a prostatic monoesterase enzyme to form NR+ (8).

==Functions==
A precursor to NAD+, NR Is a building block essential to cellular processes such as DNA repair. NR is a nucleoside which provides researchers with a great tool to manipulate NAD+ levels and investigate the effects of NAD+ concentration on cellular processes (9).

The human body utilizes NR to boost levels of NAD which powers metabolism and protects cells during times of metabolic stress (10).

Nicotinamide phosphoribosyltransferase (Nampt) is an enzyme that catalyzes the conversion of nicotinamide to NAD+. There are also to forms of nicotinamide riboside kinsases (NRK1 and NRK2) that convert NR to NAD+ without the need for Nampt (5).

The kinase pathway is also found to be involved in assisting NR to raise NAD tissue concentrations in rodents and eliciting effects such as insulin sensitivity, mitochondrial biogenesis also depicted as the generation of more of the cell’s “powerhouse” and enhanced sirtuin functions (11).

Upregulation of NR, particularly through diet and oral administration has been shown to increase NAD+ concentrations which subsequently enhances mitochondrial function and supports the body by providing protection against damage from free radicals hence reducing the signs of aging. It has also become known that there are additional benefits to supplementing with oral NR such as neurological and cognitive support, metabolic support as well as liver and muscle support.

==Research==
The use of oral NR supplementation to treat an array of conditions is currently underway.

===Clinical trials timeline===
November 1st 2018 – A pilot study aimed to test whether oral NR increase NAD+ levels or improves mitochondrial function in heart cells also known as cardiomyocytes. Previous studies have shown NR supplementation to increase myocardial levels of NAD+ in mice, this study aimed to test the same but in human cardiomyocytes of patients with advanced heart failure who are awaiting elective left ventricular assist device (LVAD) implantation (12).

December 28th 2018 – Researchers conducted a study to see if NR may help improve muscle function and possibly improve exercising capacity via improved mitochondrial activity. Investigators aimed to study how skeletal muscle responds to NR in patients who have Li-Fraumeni syndrome (LFS), a rare hereditary disorder that increases an individual’s risk of developing many types of cancer and causes long-term fatigue and muscles weakness (13).

January 25th 2019 – This piece of research recruited newly diagnosed, drug naïve Parkinson’s Disease (PD) patients who were treated with oral NR. The pilot aimed to determine if NR had any impact on the enzyme or neurometabolic profile of patients with PD. Secondly, to identify if high dose oral NR improves motor symptoms associated with PD. Finally, to determine whether high dose NR can restore NAD metabolism and subsequently elevate levels of NAD (14).

April 11th 2019 – Evaluating the effects of NR in preventing experimentally induced small fiber nerve degeneration and promotion of nerve regeneration. A type of nerve disease or damage that affects signaling between the brain, spinal cord and the rest of the body termed as peripheral neuropathy. A particular form of peripheral neuropathy known as small fiber neuropathy (SFN) affects small unmyelinated fibers. Myelin is a lipid rich fatty-like substance that surrounds nerve cells and is likened to the insulation around wires in electrical systems. Myelin insulates the nerve/neuron hence increasing the speed of electronic signals called actional potentials through it. Unmyelinated nerves therefore lack the insulation and hence do not support a healthy environment for the generation of the electronic signals. Diabetes is known to be a common cause of neuropathy; however, half of the diagnosed cases have an unknown cause and are termed idiopathic. There is no current intervention that can prevent degeneration or promote regeneration, however, recent advances in molecular science illustrated the importance of key molecules such as NAD+. This study aims to evaluate NR’s ability to prevent degradation and promote regeneration of small sensory axons in the skins layer known as the epidermis. Such research may help pave the way in treatments for many types of peripheral neuropathies (15).

May 15th 2019 – Mitochondrial synthesis and the use of oxygen to produce energy from carbohydrates known as oxidative metabolism in fatty skin or “adipose tissues” was found to be significantly impaired in obesity at a young adult stage. As a result, investigators aim to see if NR may activate dysfunctional mitochondria, particularly the SIRT/NAD+ pathway and help alleviate signs of obesity related illness (16).

May 23rd 2019 – To establish any positive outcomes of NR on the disease course of patients suffering from Ataxia Telangiectasia (A-T), an inherited neurodegenerative disorder caused by mutation of the ATM gene which causes breakdown of nerve cells affects the immune and respiratory system. This disorder is coupled with a high cancer risk and currently treatment is limited to rehabilitation, screening and prevention. The ATM protein plays a vital role in processes such as cellular energy metabolism, cell signaling and DNA repair. NAD+ is known as an essential molecule in many cellular processes, particularly as a deficiency in it is linked to underlying DNA repair disorders as seen in A-T. Prior research using NR in animal models has proved beneficial, this studies aims to see if treatment for 6 months may have positive outcomes on disease progression of A-T (17).

August 1st 2019 – Research to date has shown that NR supplementation lowered carotid-femoral pulse wave velocity (CFPWV), a measure of aortic stiffness and predictors of cardiovascular disease in patients with or without kidney disease. Additionally, NR was shown to decrease systolic blood pressure (SBP). As a ‘next-step’, the current study aims to assess the safety and efficacy of NR for decreasing aortic stiffness and SBP in patients with stage III and IV chronic kidney disease (CKD). It is hypothesized that NR will lower aortic stiffness and SBP due to increases in NAD+ bioavailability, influences on vascular smooth muscle tone and a decline in markers for inflammation and oxidative stress (18).

August 5th 2019 – Investigators aim to determine metabolic improvements in Alzheimer’s and Parkinson’s disease patients by use of a cocktail of NR in combination with other co-factors such as N-acetylcysteine, L-carnitine tartrate and serine to activate mitochondria in the brain cells. Based on previous studies it is evident that each cofactor plays its own role in activating mitochondria, NR specifically, is known to boost hepatic (liver) B-oxidation (breakdown) of fatty acids in mitochondria hence stimulating the transfer of fatty acids from the cytosol to the mitochondria (19).

September 4th 2019 – A clinical trial aimed at determining whether NR can improve cognitive function such as thinking/decision making, mood and daily activities in people suffering from Subjective Cognitive Decline (SCD) or Mild Cognitive Impairment (MCI). This would be measured using blood draws, EEG’s, cognitive testing and mood questionnaires (20).

October 1st 2019 – Those suffering from acute illness often face long recovery times, of which the primary cause is not known, however many factors can contribute to this such as age and severity of illness. This study aims to determine whether NR can reduce the times taken to recover and improve outcomes in patients admitted to hospital with tissue damage (21).

October 2nd 2019 – Niagen, the brand name for NR, was tested to observe its effects in improving persistent peripheral neuropathy in cancer survivors who have completed chemotherapy with taxane or platinum-complex compounds between 1 and 12 months prior. Outcomes will be measured based on changes in scores on sensory and motor subscale of quality of life questionnaire (22).

October 2nd 2019 - Identified as an enhancer of exercise therapy in hypertensive (raised blood pressure) older adults, NR is therefore being investigated as a means of enhancing the effects of therapy in a population type that would otherwise struggle to exercise. This has great implications as a positive outcome may pave the way to reducing cardiovascular disease and death (23).

February 17th 2020 – A pilot study to evaluate the effect of NR on immune activation in psoriasis, a skin disorder that causes skin cells to multiply ten times faster than normal resulting in dry scales on the skin. Psoriasis is linked with a subset of CD4 T cells, or “helper” cells that regulate the immune system named Th17 cells, these cells are characterized by the production of signaling proteins named cytokines such as IL-17. Currently it is known that NR diminishes Th1 and Th17 activation hence the pilot intends to further this hypothesis by measuring NR’s impact on Th17, neutrophils and whether it modulates skin cell or keratinocyte activation in skin lesions of psoriasis subjects (24).

April 2nd 2020 – A study to find a safe and tolerable means to improve the transplant recovery process known as engraftment post-transplantation. Previous research studies have found that adding NR to donor cells can increase blood stem cell quantities and reduces time to engraftment. This study aims to evaluate the safety and tolerability of NR as well as observe white blood cell and platelet count post-transplantation (25).

June 1st 2020 – Well aware that a decline in NAD+ with increasing age can have major implications in this proinflammatory states, researchers advance on previous research that shows even short-term treatment with NR is sufficient to reduce the impact of this aging process. NR is therefore under test to see if it can attenuate the severity of SARS-CoV-2 infection in elderly patients aged 70 years or older (26).

==References==
<references/>

(1)Gingrich, W; Schlenk, F (June 1944). "Codehydrogenase I and Other Pyridinium Compounds as V-Factor for Hemophilus influenzae and H. parainfluenzae". Journal of Bacteriology. 47 (6): 535–50. PMC 373952. PMID 16560803

(2)CHAMBON, P., ET AL., NICOTINAMIDE MONONUCLEOTIDE ACTIVATION OF NEW DNA-DEPENDENT POLYADENYLIC ACID SYNTHESIZING NUCLEAR ENZYME. BIOCHEM BIOPHYS RES COMMUN, 1963. 11(1): P. 39-43.

(3) IMAI, S., ET AL., TRANSCRIPTIONAL SILENCING AND LONGEVITY PROTEIN SIR2 IS AN NAD-DEPENDENT HISTONE DEACETYLASE. NATURE, 2000. 403(6771): P. 795-800.

(4)Bieganowski, P; Brenner, C (2004). "Discoveries of Nicotinamide Riboside as a Nutrient and Conserved NRK Genes Establish a Preiss-Handler Independent Route to NAD+ in Fungi and Humans". Cell. 117 (4): 495–502. doi:10.1016/S0092-8674(04)00416-7. PMID 15137942

(5)BELENKY, P., ET AL., NICOTINAMIDE RIBOSIDE PROMOTES SIR2 SILENCING AND EXTENDS LIFESPAN VIA NRK AND URH1/PNP1/MEU1 PATHWAYS TO NAD+. CELL, 2007. 129(3): P. 473-84.

(6) https://www.chromadex.com/ingredient/niagen/

(7) https://www.beilstein-journals.org/bjoc/articles/15/36

(8) https://pubmed.ncbi.nlm.nih.gov/27052539/

(9) https://www.biospace.com/article/releases/new-study-demonstrates-a-unique-role-of-nicotinamide-riboside-over-other-nad-precursors/

(10) https://pubmed.ncbi.nlm.nih.gov/24071780/

(11) https://clinicaltrials.gov/ct2/show/record/NCT03727646?term=nicotinamide+riboside

(12) https://clinicaltrials.gov/ct2/show/record/NCT03789175?term=nicotinamide+riboside

(13) https://clinicaltrials.gov/ct2/show/record/NCT03816020?term=nicotinamide+riboside

(14) https://clinicaltrials.gov/ct2/show/record/NCT03912220?term=nicotinamide+riboside

(15) https://clinicaltrials.gov/ct2/show/record/NCT03951285?term=nicotinamide+riboside

(16) https://clinicaltrials.gov/ct2/show/record/NCT03962114?term=nicotinamide+riboside

(17) https://clinicaltrials.gov/ct2/show/record/NCT04040959?term=nicotinamide+riboside&rank=4

(18) https://clinicaltrials.gov/ct2/show/record/NCT04044131?term=nicotinamide+riboside

(19) https://clinicaltrials.gov/ct2/show/record/NCT04078178?term=nicotinamide+riboside

(20) https://clinicaltrials.gov/ct2/show/record/NCT04110028?term=nicotinamide+riboside

(21) https://clinicaltrials.gov/ct2/show/record/NCT04112641?term=nicotinamide+riboside

(22) https://clinicaltrials.gov/ct2/show/record/NCT04112043?term=nicotinamide+riboside

(23) https://clinicaltrials.gov/ct2/show/record/NCT04271735?term=nicotinamide+riboside&draw=2

(24) https://clinicaltrials.gov/ct2/show/NCT04332341?term=nicotinamide+riboside&draw=2&rank=7

(25) https://clinicaltrials.gov/ct2/show/record/NCT04407390

Nicotinamide Riboside

2020-10-19T15:56:34Z

Judgesurreal777: Started referencing

'''Nicotinamide Riboside (NR)''' is a natural organic compound found in trace amounts in foods such as dairy products and is a precursor to nicotinamide adenine dinucleotide ([[NAD+]]) (1). Termed the ‘cousin’ of vitamin B3, this form of vitamin B3 also comes in variations known as nicotinamide and nicotinic acid/niacin (NA), niacin being most commonly used in fortifying foods such as flour and cereal particularly in the 1940s to ward off the fatal disease pellagra.<ref name="pellagra">[https://www.elysiumhealth.com/en-us/science-101/what-is-nicotinamide-riboside What Is Nicotinamide Riboside?] Written for Elysium Health.com. Published January 1, 2020; Accessed October 19, 2020</ref>

Previous research focused on the role of NAD+ on the body’s cellular health independently, however it is becoming known that NR may be more valuable than thought. NR supplementation has been proven to be effective in enhancing NAD+ when administered orally. The implications of using NR are so wide that there is an abundance of current research trials investigating the use of NR not only in prevention but also the treatment of many inflammatory disease states.

==History==
NR was first identified as a growth factor named Factor V in 1944, named so due to its ability to enhance the growth of Hemophilus influenzae, a bacterium that resides in the blood. When Factor V was extracted from blood and purified it was shown to exist in 3 forms: NAD+, NMN and NR. It became apparent that NR was responsible for the most rapid growth rate of the bacterium compared to that of NAD+ and NMN (2).

In 1963 Mandel and Colleagues identified a chemical reaction that broke NAD into 2 respective parts, nicotinamide and ADP-ribose (3).

Sirtuin enzymes, a family of proteins that regulate cellular health, were discovered in 2000. Biochemists investigating how yeast sirtuins affect longevity came across the findings that sirtuins used NAD to help keep specific genes “silent” so not to function. During this process sirtuin enzymes breakdown NAD and use parts of it to deacetylate or “remove acetyl groups” of proteins within the cell. Deacetylating histone proteins, proteins that provide structure and order to DNA, can change how the cell accesses nearby genes (4).

In 2004 advances were made in the implication of NR in the body other than just to ward off disease states. Biochemist Charles Brenner et al identified the NR kinase pathway leading to production of NAD+ (5). Follow up research showed that administering NR to yeast cells resulted in increased NAD levels and hence an extension in lifespan of the yeast (6).

Consequently, this paved the way for a more efficient pathway of producing NAD+, known to restore levels in the body and reduce the signs of the inflammatory and aging process internally at a cellular level. A crystal form of NR chloride, also known as Niagen is currently the only FDA-safety reviewed form (7). Dr Charles Brenner was the biochemist who not only discovered but also patented nicotinamide riboside as a cellular nutrient. Our cells are exposed to many stressors such as infections, poor diet, lack of sleep and exercise not to mention diminishing NAD+ levels as we age. NR allows the cells to become more resilient and super-charged.

==Structure==
Nicotinamide riboside is a nucleoside which is a combination for nicotinamide and riboside in a single chemical moiety.
1-(B-D-Ribofuranosyl)nicotinamide
Molecular formula C11H15N205
Molar mass of 255.25g/mol

==Biosynthesis==
NR is naturally occurring in milk, most recently it was found that cow’s milk contained approximately 12 micromole NAD+ precursor vitamin concentration, of this percentage 60% was nicotinamide and 40% present as NR. It was also found that the presence of Staphylococcus aureus resulted in lower concentrations of NR (9).

Most synthetic production of NR can be divided into 2 categories, firstly is a reaction between nicotinamide and a peracylated (halo)-D-ribofuranose resulting in an acylated (addition of an acyl group) intermediate that is then converted into NR. The second method is via condensation of a salt with derivatives of D-ribofuranosylamine. The first approach is the most commonly used as it produces NR with a greater yield and is more efficient (9).

This more commonly used approach requires synthetic glycosylation conditions, attachment of a carbohydrate molecule that depends on the type of sugar component used (8).

NR has also been synthesized enzymatically from NAD+ and NMN using many processes. Kaplan and Stolzenbach used snake venom phosphodiesterase to perform enzymatic cleavage or “breakdown” of NAD+ to form NMN followed by catalysis, otherwise known as acceleration of a reaction, with a prostatic monoesterase enzyme to form NR+ (8).

==Functions==
A precursor to NAD+, NR Is a building block essential to cellular processes such as DNA repair. NR is a nucleoside which provides researchers with a great tool to manipulate NAD+ levels and investigate the effects of NAD+ concentration on cellular processes (9).

The human body utilizes NR to boost levels of NAD which powers metabolism and protects cells during times of metabolic stress (10).

Nicotinamide phosphoribosyltransferase (Nampt) is an enzyme that catalyzes the conversion of nicotinamide to NAD+. There are also to forms of nicotinamide riboside kinsases (NRK1 and NRK2) that convert NR to NAD+ without the need for Nampt (5).

The kinase pathway is also found to be involved in assisting NR to raise NAD tissue concentrations in rodents and eliciting effects such as insulin sensitivity, mitochondrial biogenesis also depicted as the generation of more of the cell’s “powerhouse” and enhanced sirtuin functions (11).

Upregulation of NR, particularly through diet and oral administration has been shown to increase NAD+ concentrations which subsequently enhances mitochondrial function and supports the body by providing protection against damage from free radicals hence reducing the signs of aging. It has also become known that there are additional benefits to supplementing with oral NR such as neurological and cognitive support, metabolic support as well as liver and muscle support.

==Research==
The use of oral NR supplementation to treat an array of conditions is currently underway.

===Clinical trials timeline===
November 1st 2018 – A pilot study aimed to test whether oral NR increase NAD+ levels or improves mitochondrial function in heart cells also known as cardiomyocytes. Previous studies have shown NR supplementation to increase myocardial levels of NAD+ in mice, this study aimed to test the same but in human cardiomyocytes of patients with advanced heart failure who are awaiting elective left ventricular assist device (LVAD) implantation (12).

December 28th 2018 – Researchers conducted a study to see if NR may help improve muscle function and possibly improve exercising capacity via improved mitochondrial activity. Investigators aimed to study how skeletal muscle responds to NR in patients who have Li-Fraumeni syndrome (LFS), a rare hereditary disorder that increases an individual’s risk of developing many types of cancer and causes long-term fatigue and muscles weakness (13).

January 25th 2019 – This piece of research recruited newly diagnosed, drug naïve Parkinson’s Disease (PD) patients who were treated with oral NR. The pilot aimed to determine if NR had any impact on the enzyme or neurometabolic profile of patients with PD. Secondly, to identify if high dose oral NR improves motor symptoms associated with PD. Finally, to determine whether high dose NR can restore NAD metabolism and subsequently elevate levels of NAD (14).

April 11th 2019 – Evaluating the effects of NR in preventing experimentally induced small fiber nerve degeneration and promotion of nerve regeneration. A type of nerve disease or damage that affects signaling between the brain, spinal cord and the rest of the body termed as peripheral neuropathy. A particular form of peripheral neuropathy known as small fiber neuropathy (SFN) affects small unmyelinated fibers. Myelin is a lipid rich fatty-like substance that surrounds nerve cells and is likened to the insulation around wires in electrical systems. Myelin insulates the nerve/neuron hence increasing the speed of electronic signals called actional potentials through it. Unmyelinated nerves therefore lack the insulation and hence do not support a healthy environment for the generation of the electronic signals. Diabetes is known to be a common cause of neuropathy; however, half of the diagnosed cases have an unknown cause and are termed idiopathic. There is no current intervention that can prevent degeneration or promote regeneration, however, recent advances in molecular science illustrated the importance of key molecules such as NAD+. This study aims to evaluate NR’s ability to prevent degradation and promote regeneration of small sensory axons in the skins layer known as the epidermis. Such research may help pave the way in treatments for many types of peripheral neuropathies (15).

May 15th 2019 – Mitochondrial synthesis and the use of oxygen to produce energy from carbohydrates known as oxidative metabolism in fatty skin or “adipose tissues” was found to be significantly impaired in obesity at a young adult stage. As a result, investigators aim to see if NR may activate dysfunctional mitochondria, particularly the SIRT/NAD+ pathway and help alleviate signs of obesity related illness (16).

May 23rd 2019 – To establish any positive outcomes of NR on the disease course of patients suffering from Ataxia Telangiectasia (A-T), an inherited neurodegenerative disorder caused by mutation of the ATM gene which causes breakdown of nerve cells affects the immune and respiratory system. This disorder is coupled with a high cancer risk and currently treatment is limited to rehabilitation, screening and prevention. The ATM protein plays a vital role in processes such as cellular energy metabolism, cell signaling and DNA repair. NAD+ is known as an essential molecule in many cellular processes, particularly as a deficiency in it is linked to underlying DNA repair disorders as seen in A-T. Prior research using NR in animal models has proved beneficial, this studies aims to see if treatment for 6 months may have positive outcomes on disease progression of A-T (17).

August 1st 2019 – Research to date has shown that NR supplementation lowered carotid-femoral pulse wave velocity (CFPWV), a measure of aortic stiffness and predictors of cardiovascular disease in patients with or without kidney disease. Additionally, NR was shown to decrease systolic blood pressure (SBP). As a ‘next-step’, the current study aims to assess the safety and efficacy of NR for decreasing aortic stiffness and SBP in patients with stage III and IV chronic kidney disease (CKD). It is hypothesized that NR will lower aortic stiffness and SBP due to increases in NAD+ bioavailability, influences on vascular smooth muscle tone and a decline in markers for inflammation and oxidative stress (18).

August 5th 2019 – Investigators aim to determine metabolic improvements in Alzheimer’s and Parkinson’s disease patients by use of a cocktail of NR in combination with other co-factors such as N-acetylcysteine, L-carnitine tartrate and serine to activate mitochondria in the brain cells. Based on previous studies it is evident that each cofactor plays its own role in activating mitochondria, NR specifically, is known to boost hepatic (liver) B-oxidation (breakdown) of fatty acids in mitochondria hence stimulating the transfer of fatty acids from the cytosol to the mitochondria (19).

September 4th 2019 – A clinical trial aimed at determining whether NR can improve cognitive function such as thinking/decision making, mood and daily activities in people suffering from Subjective Cognitive Decline (SCD) or Mild Cognitive Impairment (MCI). This would be measured using blood draws, EEG’s, cognitive testing and mood questionnaires (20).

October 1st 2019 – Those suffering from acute illness often face long recovery times, of which the primary cause is not known, however many factors can contribute to this such as age and severity of illness. This study aims to determine whether NR can reduce the times taken to recover and improve outcomes in patients admitted to hospital with tissue damage (21).

October 2nd 2019 – Niagen, the brand name for NR, was tested to observe its effects in improving persistent peripheral neuropathy in cancer survivors who have completed chemotherapy with taxane or platinum-complex compounds between 1 and 12 months prior. Outcomes will be measured based on changes in scores on sensory and motor subscale of quality of life questionnaire (22).

October 2nd 2019 - Identified as an enhancer of exercise therapy in hypertensive (raised blood pressure) older adults, NR is therefore being investigated as a means of enhancing the effects of therapy in a population type that would otherwise struggle to exercise. This has great implications as a positive outcome may pave the way to reducing cardiovascular disease and death (23).

February 17th 2020 – A pilot study to evaluate the effect of NR on immune activation in psoriasis, a skin disorder that causes skin cells to multiply ten times faster than normal resulting in dry scales on the skin. Psoriasis is linked with a subset of CD4 T cells, or “helper” cells that regulate the immune system named Th17 cells, these cells are characterized by the production of signaling proteins named cytokines such as IL-17. Currently it is known that NR diminishes Th1 and Th17 activation hence the pilot intends to further this hypothesis by measuring NR’s impact on Th17, neutrophils and whether it modulates skin cell or keratinocyte activation in skin lesions of psoriasis subjects (24).

April 2nd 2020 – A study to find a safe and tolerable means to improve the transplant recovery process known as engraftment post-transplantation. Previous research studies have found that adding NR to donor cells can increase blood stem cell quantities and reduces time to engraftment. This study aims to evaluate the safety and tolerability of NR as well as observe white blood cell and platelet count post-transplantation (25).

June 1st 2020 – Well aware that a decline in NAD+ with increasing age can have major implications in this proinflammatory states, researchers advance on previous research that shows even short-term treatment with NR is sufficient to reduce the impact of this aging process. NR is therefore under test to see if it can attenuate the severity of SARS-CoV-2 infection in elderly patients aged 70 years or older (26).

==References==
<references/>

(1)Gingrich, W; Schlenk, F (June 1944). "Codehydrogenase I and Other Pyridinium Compounds as V-Factor for Hemophilus influenzae and H. parainfluenzae". Journal of Bacteriology. 47 (6): 535–50. PMC 373952. PMID 16560803

(2)CHAMBON, P., ET AL., NICOTINAMIDE MONONUCLEOTIDE ACTIVATION OF NEW DNA-DEPENDENT POLYADENYLIC ACID SYNTHESIZING NUCLEAR ENZYME. BIOCHEM BIOPHYS RES COMMUN, 1963. 11(1): P. 39-43.

(3) IMAI, S., ET AL., TRANSCRIPTIONAL SILENCING AND LONGEVITY PROTEIN SIR2 IS AN NAD-DEPENDENT HISTONE DEACETYLASE. NATURE, 2000. 403(6771): P. 795-800.

(4)Bieganowski, P; Brenner, C (2004). "Discoveries of Nicotinamide Riboside as a Nutrient and Conserved NRK Genes Establish a Preiss-Handler Independent Route to NAD+ in Fungi and Humans". Cell. 117 (4): 495–502. doi:10.1016/S0092-8674(04)00416-7. PMID 15137942

(5)BELENKY, P., ET AL., NICOTINAMIDE RIBOSIDE PROMOTES SIR2 SILENCING AND EXTENDS LIFESPAN VIA NRK AND URH1/PNP1/MEU1 PATHWAYS TO NAD+. CELL, 2007. 129(3): P. 473-84.

(6) https://www.chromadex.com/ingredient/niagen/

(7) https://www.beilstein-journals.org/bjoc/articles/15/36

(8) https://pubmed.ncbi.nlm.nih.gov/27052539/

(9) https://www.biospace.com/article/releases/new-study-demonstrates-a-unique-role-of-nicotinamide-riboside-over-other-nad-precursors/

(10) https://pubmed.ncbi.nlm.nih.gov/24071780/

(11) https://clinicaltrials.gov/ct2/show/record/NCT03727646?term=nicotinamide+riboside

(12) https://clinicaltrials.gov/ct2/show/record/NCT03789175?term=nicotinamide+riboside

(13) https://clinicaltrials.gov/ct2/show/record/NCT03816020?term=nicotinamide+riboside

(14) https://clinicaltrials.gov/ct2/show/record/NCT03912220?term=nicotinamide+riboside

(15) https://clinicaltrials.gov/ct2/show/record/NCT03951285?term=nicotinamide+riboside

(16) https://clinicaltrials.gov/ct2/show/record/NCT03962114?term=nicotinamide+riboside

(17) https://clinicaltrials.gov/ct2/show/record/NCT04040959?term=nicotinamide+riboside&rank=4

(18) https://clinicaltrials.gov/ct2/show/record/NCT04044131?term=nicotinamide+riboside

(19) https://clinicaltrials.gov/ct2/show/record/NCT04078178?term=nicotinamide+riboside

(20) https://clinicaltrials.gov/ct2/show/record/NCT04110028?term=nicotinamide+riboside

(21) https://clinicaltrials.gov/ct2/show/record/NCT04112641?term=nicotinamide+riboside

(22) https://clinicaltrials.gov/ct2/show/record/NCT04112043?term=nicotinamide+riboside

(23) https://clinicaltrials.gov/ct2/show/record/NCT04271735?term=nicotinamide+riboside&draw=2

(24) https://clinicaltrials.gov/ct2/show/NCT04332341?term=nicotinamide+riboside&draw=2&rank=7

(25) https://clinicaltrials.gov/ct2/show/record/NCT04407390

Nicotinamide Riboside

2020-10-19T15:26:26Z

Judgesurreal777: Link

'''Nicotinamide Riboside (NR)''' is a natural organic compound found in trace amounts in foods such as dairy products and is a precursor to nicotinamide adenine dinucleotide ([[NAD+]]) (1). Termed the ‘cousin’ of vitamin B3, this form of vitamin B3 also comes in variations known as nicotinamide and nicotinic acid/niacin (NA), niacin being most commonly used in fortifying foods such as flour and cereal particularly in the 1940s to ward off the fatal disease pellagra (1).

Previous research focused on the role of NAD+ on the body’s cellular health independently, however it is becoming known that NR may be more valuable than thought. NR supplementation has been proven to be effective in enhancing NAD+ when administered orally. The implications of using NR are so wide that there is an abundance of current research trials investigating the use of NR not only in prevention but also the treatment of many inflammatory disease states.

==History==
NR was first identified as a growth factor named Factor V in 1944, named so due to its ability to enhance the growth of Hemophilus influenzae, a bacterium that resides in the blood. When Factor V was extracted from blood and purified it was shown to exist in 3 forms: NAD+, NMN and NR. It became apparent that NR was responsible for the most rapid growth rate of the bacterium compared to that of NAD+ and NMN (2).

In 1963 Mandel and Colleagues identified a chemical reaction that broke NAD into 2 respective parts, nicotinamide and ADP-ribose (3).

Sirtuin enzymes, a family of proteins that regulate cellular health, were discovered in 2000. Biochemists investigating how yeast sirtuins affect longevity came across the findings that sirtuins used NAD to help keep specific genes “silent” so not to function. During this process sirtuin enzymes breakdown NAD and use parts of it to deacetylate or “remove acetyl groups” of proteins within the cell. Deacetylating histone proteins, proteins that provide structure and order to DNA, can change how the cell accesses nearby genes (4).

In 2004 advances were made in the implication of NR in the body other than just to ward off disease states. Biochemist Charles Brenner et al identified the NR kinase pathway leading to production of NAD+ (5). Follow up research showed that administering NR to yeast cells resulted in increased NAD levels and hence an extension in lifespan of the yeast (6).

Consequently, this paved the way for a more efficient pathway of producing NAD+, known to restore levels in the body and reduce the signs of the inflammatory and aging process internally at a cellular level. A crystal form of NR chloride, also known as Niagen is currently the only FDA-safety reviewed form (7). Dr Charles Brenner was the biochemist who not only discovered but also patented nicotinamide riboside as a cellular nutrient. Our cells are exposed to many stressors such as infections, poor diet, lack of sleep and exercise not to mention diminishing NAD+ levels as we age. NR allows the cells to become more resilient and super-charged.

==Structure==
Nicotinamide riboside is a nucleoside which is a combination for nicotinamide and riboside in a single chemical moiety.
1-(B-D-Ribofuranosyl)nicotinamide
Molecular formula C11H15N205
Molar mass of 255.25g/mol

==Biosynthesis==
NR is naturally occurring in milk, most recently it was found that cow’s milk contained approximately 12 micromole NAD+ precursor vitamin concentration, of this percentage 60% was nicotinamide and 40% present as NR. It was also found that the presence of Staphylococcus aureus resulted in lower concentrations of NR (9).

Most synthetic production of NR can be divided into 2 categories, firstly is a reaction between nicotinamide and a peracylated (halo)-D-ribofuranose resulting in an acylated (addition of an acyl group) intermediate that is then converted into NR. The second method is via condensation of a salt with derivatives of D-ribofuranosylamine. The first approach is the most commonly used as it produces NR with a greater yield and is more efficient (9).

This more commonly used approach requires synthetic glycosylation conditions, attachment of a carbohydrate molecule that depends on the type of sugar component used (8).

NR has also been synthesized enzymatically from NAD+ and NMN using many processes. Kaplan and Stolzenbach used snake venom phosphodiesterase to perform enzymatic cleavage or “breakdown” of NAD+ to form NMN followed by catalysis, otherwise known as acceleration of a reaction, with a prostatic monoesterase enzyme to form NR+ (8).

==Functions==
A precursor to NAD+, NR Is a building block essential to cellular processes such as DNA repair. NR is a nucleoside which provides researchers with a great tool to manipulate NAD+ levels and investigate the effects of NAD+ concentration on cellular processes (9).

The human body utilizes NR to boost levels of NAD which powers metabolism and protects cells during times of metabolic stress (10).

Nicotinamide phosphoribosyltransferase (Nampt) is an enzyme that catalyzes the conversion of nicotinamide to NAD+. There are also to forms of nicotinamide riboside kinsases (NRK1 and NRK2) that convert NR to NAD+ without the need for Nampt (5).

The kinase pathway is also found to be involved in assisting NR to raise NAD tissue concentrations in rodents and eliciting effects such as insulin sensitivity, mitochondrial biogenesis also depicted as the generation of more of the cell’s “powerhouse” and enhanced sirtuin functions (11).

Upregulation of NR, particularly through diet and oral administration has been shown to increase NAD+ concentrations which subsequently enhances mitochondrial function and supports the body by providing protection against damage from free radicals hence reducing the signs of aging. It has also become known that there are additional benefits to supplementing with oral NR such as neurological and cognitive support, metabolic support as well as liver and muscle support.

==Research==
The use of oral NR supplementation to treat an array of conditions is currently underway.

===Clinical trials timeline===
November 1st 2018 – A pilot study aimed to test whether oral NR increase NAD+ levels or improves mitochondrial function in heart cells also known as cardiomyocytes. Previous studies have shown NR supplementation to increase myocardial levels of NAD+ in mice, this study aimed to test the same but in human cardiomyocytes of patients with advanced heart failure who are awaiting elective left ventricular assist device (LVAD) implantation (12).

December 28th 2018 – Researchers conducted a study to see if NR may help improve muscle function and possibly improve exercising capacity via improved mitochondrial activity. Investigators aimed to study how skeletal muscle responds to NR in patients who have Li-Fraumeni syndrome (LFS), a rare hereditary disorder that increases an individual’s risk of developing many types of cancer and causes long-term fatigue and muscles weakness (13).

January 25th 2019 – This piece of research recruited newly diagnosed, drug naïve Parkinson’s Disease (PD) patients who were treated with oral NR. The pilot aimed to determine if NR had any impact on the enzyme or neurometabolic profile of patients with PD. Secondly, to identify if high dose oral NR improves motor symptoms associated with PD. Finally, to determine whether high dose NR can restore NAD metabolism and subsequently elevate levels of NAD (14).

April 11th 2019 – Evaluating the effects of NR in preventing experimentally induced small fiber nerve degeneration and promotion of nerve regeneration. A type of nerve disease or damage that affects signaling between the brain, spinal cord and the rest of the body termed as peripheral neuropathy. A particular form of peripheral neuropathy known as small fiber neuropathy (SFN) affects small unmyelinated fibers. Myelin is a lipid rich fatty-like substance that surrounds nerve cells and is likened to the insulation around wires in electrical systems. Myelin insulates the nerve/neuron hence increasing the speed of electronic signals called actional potentials through it. Unmyelinated nerves therefore lack the insulation and hence do not support a healthy environment for the generation of the electronic signals. Diabetes is known to be a common cause of neuropathy; however, half of the diagnosed cases have an unknown cause and are termed idiopathic. There is no current intervention that can prevent degeneration or promote regeneration, however, recent advances in molecular science illustrated the importance of key molecules such as NAD+. This study aims to evaluate NR’s ability to prevent degradation and promote regeneration of small sensory axons in the skins layer known as the epidermis. Such research may help pave the way in treatments for many types of peripheral neuropathies (15).

May 15th 2019 – Mitochondrial synthesis and the use of oxygen to produce energy from carbohydrates known as oxidative metabolism in fatty skin or “adipose tissues” was found to be significantly impaired in obesity at a young adult stage. As a result, investigators aim to see if NR may activate dysfunctional mitochondria, particularly the SIRT/NAD+ pathway and help alleviate signs of obesity related illness (16).

May 23rd 2019 – To establish any positive outcomes of NR on the disease course of patients suffering from Ataxia Telangiectasia (A-T), an inherited neurodegenerative disorder caused by mutation of the ATM gene which causes breakdown of nerve cells affects the immune and respiratory system. This disorder is coupled with a high cancer risk and currently treatment is limited to rehabilitation, screening and prevention. The ATM protein plays a vital role in processes such as cellular energy metabolism, cell signaling and DNA repair. NAD+ is known as an essential molecule in many cellular processes, particularly as a deficiency in it is linked to underlying DNA repair disorders as seen in A-T. Prior research using NR in animal models has proved beneficial, this studies aims to see if treatment for 6 months may have positive outcomes on disease progression of A-T (17).

August 1st 2019 – Research to date has shown that NR supplementation lowered carotid-femoral pulse wave velocity (CFPWV), a measure of aortic stiffness and predictors of cardiovascular disease in patients with or without kidney disease. Additionally, NR was shown to decrease systolic blood pressure (SBP). As a ‘next-step’, the current study aims to assess the safety and efficacy of NR for decreasing aortic stiffness and SBP in patients with stage III and IV chronic kidney disease (CKD). It is hypothesized that NR will lower aortic stiffness and SBP due to increases in NAD+ bioavailability, influences on vascular smooth muscle tone and a decline in markers for inflammation and oxidative stress (18).

August 5th 2019 – Investigators aim to determine metabolic improvements in Alzheimer’s and Parkinson’s disease patients by use of a cocktail of NR in combination with other co-factors such as N-acetylcysteine, L-carnitine tartrate and serine to activate mitochondria in the brain cells. Based on previous studies it is evident that each cofactor plays its own role in activating mitochondria, NR specifically, is known to boost hepatic (liver) B-oxidation (breakdown) of fatty acids in mitochondria hence stimulating the transfer of fatty acids from the cytosol to the mitochondria (19).

September 4th 2019 – A clinical trial aimed at determining whether NR can improve cognitive function such as thinking/decision making, mood and daily activities in people suffering from Subjective Cognitive Decline (SCD) or Mild Cognitive Impairment (MCI). This would be measured using blood draws, EEG’s, cognitive testing and mood questionnaires (20).

October 1st 2019 – Those suffering from acute illness often face long recovery times, of which the primary cause is not known, however many factors can contribute to this such as age and severity of illness. This study aims to determine whether NR can reduce the times taken to recover and improve outcomes in patients admitted to hospital with tissue damage (21).

October 2nd 2019 – Niagen, the brand name for NR, was tested to observe its effects in improving persistent peripheral neuropathy in cancer survivors who have completed chemotherapy with taxane or platinum-complex compounds between 1 and 12 months prior. Outcomes will be measured based on changes in scores on sensory and motor subscale of quality of life questionnaire (22).

October 2nd 2019 - Identified as an enhancer of exercise therapy in hypertensive (raised blood pressure) older adults, NR is therefore being investigated as a means of enhancing the effects of therapy in a population type that would otherwise struggle to exercise. This has great implications as a positive outcome may pave the way to reducing cardiovascular disease and death (23).

February 17th 2020 – A pilot study to evaluate the effect of NR on immune activation in psoriasis, a skin disorder that causes skin cells to multiply ten times faster than normal resulting in dry scales on the skin. Psoriasis is linked with a subset of CD4 T cells, or “helper” cells that regulate the immune system named Th17 cells, these cells are characterized by the production of signaling proteins named cytokines such as IL-17. Currently it is known that NR diminishes Th1 and Th17 activation hence the pilot intends to further this hypothesis by measuring NR’s impact on Th17, neutrophils and whether it modulates skin cell or keratinocyte activation in skin lesions of psoriasis subjects (24).

April 2nd 2020 – A study to find a safe and tolerable means to improve the transplant recovery process known as engraftment post-transplantation. Previous research studies have found that adding NR to donor cells can increase blood stem cell quantities and reduces time to engraftment. This study aims to evaluate the safety and tolerability of NR as well as observe white blood cell and platelet count post-transplantation (25).

June 1st 2020 – Well aware that a decline in NAD+ with increasing age can have major implications in this proinflammatory states, researchers advance on previous research that shows even short-term treatment with NR is sufficient to reduce the impact of this aging process. NR is therefore under test to see if it can attenuate the severity of SARS-CoV-2 infection in elderly patients aged 70 years or older (26).

==References==
(1)https://www.elysiumhealth.com/en-us/science-101/what-is-nicotinamide-riboside

(2)Gingrich, W; Schlenk, F (June 1944). "Codehydrogenase I and Other Pyridinium Compounds as V-Factor for Hemophilus influenzae and H. parainfluenzae". Journal of Bacteriology. 47 (6): 535–50. PMC 373952. PMID 16560803

(3)CHAMBON, P., ET AL., NICOTINAMIDE MONONUCLEOTIDE ACTIVATION OF NEW DNA-DEPENDENT POLYADENYLIC ACID SYNTHESIZING NUCLEAR ENZYME. BIOCHEM BIOPHYS RES COMMUN, 1963. 11(1): P. 39-43.

(4) IMAI, S., ET AL., TRANSCRIPTIONAL SILENCING AND LONGEVITY PROTEIN SIR2 IS AN NAD-DEPENDENT HISTONE DEACETYLASE. NATURE, 2000. 403(6771): P. 795-800.

(5)Bieganowski, P; Brenner, C (2004). "Discoveries of Nicotinamide Riboside as a Nutrient and Conserved NRK Genes Establish a Preiss-Handler Independent Route to NAD+ in Fungi and Humans". Cell. 117 (4): 495–502. doi:10.1016/S0092-8674(04)00416-7. PMID 15137942

(6)BELENKY, P., ET AL., NICOTINAMIDE RIBOSIDE PROMOTES SIR2 SILENCING AND EXTENDS LIFESPAN VIA NRK AND URH1/PNP1/MEU1 PATHWAYS TO NAD+. CELL, 2007. 129(3): P. 473-84.

(7) https://www.chromadex.com/ingredient/niagen/

(8) https://www.beilstein-journals.org/bjoc/articles/15/36

(9) https://pubmed.ncbi.nlm.nih.gov/27052539/

(10) https://www.biospace.com/article/releases/new-study-demonstrates-a-unique-role-of-nicotinamide-riboside-over-other-nad-precursors/

(11) https://pubmed.ncbi.nlm.nih.gov/24071780/

(12) https://clinicaltrials.gov/ct2/show/record/NCT03727646?term=nicotinamide+riboside

(13) https://clinicaltrials.gov/ct2/show/record/NCT03789175?term=nicotinamide+riboside

(14) https://clinicaltrials.gov/ct2/show/record/NCT03816020?term=nicotinamide+riboside

(15) https://clinicaltrials.gov/ct2/show/record/NCT03912220?term=nicotinamide+riboside

(16) https://clinicaltrials.gov/ct2/show/record/NCT03951285?term=nicotinamide+riboside

(17) https://clinicaltrials.gov/ct2/show/record/NCT03962114?term=nicotinamide+riboside

(18) https://clinicaltrials.gov/ct2/show/record/NCT04040959?term=nicotinamide+riboside&rank=4

(19) https://clinicaltrials.gov/ct2/show/record/NCT04044131?term=nicotinamide+riboside

(20) https://clinicaltrials.gov/ct2/show/record/NCT04078178?term=nicotinamide+riboside

(21) https://clinicaltrials.gov/ct2/show/record/NCT04110028?term=nicotinamide+riboside

(22) https://clinicaltrials.gov/ct2/show/record/NCT04112641?term=nicotinamide+riboside

(23) https://clinicaltrials.gov/ct2/show/record/NCT04112043?term=nicotinamide+riboside

(24) https://clinicaltrials.gov/ct2/show/record/NCT04271735?term=nicotinamide+riboside&draw=2

(25) https://clinicaltrials.gov/ct2/show/NCT04332341?term=nicotinamide+riboside&draw=2&rank=7

(26) https://clinicaltrials.gov/ct2/show/record/NCT04407390

Nicotinamide Riboside

2020-10-19T14:55:14Z

Judgesurreal777: Formatting

'''Nicotinamide Riboside (NR)''' is a natural organic compound found in trace amounts in foods such as dairy products and is a precursor to nicotinamide adenine dinucleotide (NAD+) (1). Termed the ‘cousin’ of vitamin B3, this form of vitamin B3 also comes in variations known as nicotinamide and nicotinic acid/niacin (NA), niacin being most commonly used in fortifying foods such as flour and cereal particularly in the 1940s to ward off the fatal disease pellagra (1).

Previous research focused on the role of NAD+ on the body’s cellular health independently, however it is becoming known that NR may be more valuable than thought. NR supplementation has been proven to be effective in enhancing NAD+ when administered orally. The implications of using NR are so wide that there is an abundance of current research trials investigating the use of NR not only in prevention but also the treatment of many inflammatory disease states.

==History==
NR was first identified as a growth factor named Factor V in 1944, named so due to its ability to enhance the growth of Hemophilus influenzae, a bacterium that resides in the blood. When Factor V was extracted from blood and purified it was shown to exist in 3 forms: NAD+, NMN and NR. It became apparent that NR was responsible for the most rapid growth rate of the bacterium compared to that of NAD+ and NMN (2).

In 1963 Mandel and Colleagues identified a chemical reaction that broke NAD into 2 respective parts, nicotinamide and ADP-ribose (3).

Sirtuin enzymes, a family of proteins that regulate cellular health, were discovered in 2000. Biochemists investigating how yeast sirtuins affect longevity came across the findings that sirtuins used NAD to help keep specific genes “silent” so not to function. During this process sirtuin enzymes breakdown NAD and use parts of it to deacetylate or “remove acetyl groups” of proteins within the cell. Deacetylating histone proteins, proteins that provide structure and order to DNA, can change how the cell accesses nearby genes (4).

In 2004 advances were made in the implication of NR in the body other than just to ward off disease states. Biochemist Charles Brenner et al identified the NR kinase pathway leading to production of NAD+ (5). Follow up research showed that administering NR to yeast cells resulted in increased NAD levels and hence an extension in lifespan of the yeast (6).

Consequently, this paved the way for a more efficient pathway of producing NAD+, known to restore levels in the body and reduce the signs of the inflammatory and aging process internally at a cellular level. A crystal form of NR chloride, also known as Niagen is currently the only FDA-safety reviewed form (7). Dr Charles Brenner was the biochemist who not only discovered but also patented nicotinamide riboside as a cellular nutrient. Our cells are exposed to many stressors such as infections, poor diet, lack of sleep and exercise not to mention diminishing NAD+ levels as we age. NR allows the cells to become more resilient and super-charged.

==Structure==
Nicotinamide riboside is a nucleoside which is a combination for nicotinamide and riboside in a single chemical moiety.
1-(B-D-Ribofuranosyl)nicotinamide
Molecular formula C11H15N205
Molar mass of 255.25g/mol

==Biosynthesis==
NR is naturally occurring in milk, most recently it was found that cow’s milk contained approximately 12 micromole NAD+ precursor vitamin concentration, of this percentage 60% was nicotinamide and 40% present as NR. It was also found that the presence of Staphylococcus aureus resulted in lower concentrations of NR (9).

Most synthetic production of NR can be divided into 2 categories, firstly is a reaction between nicotinamide and a peracylated (halo)-D-ribofuranose resulting in an acylated (addition of an acyl group) intermediate that is then converted into NR. The second method is via condensation of a salt with derivatives of D-ribofuranosylamine. The first approach is the most commonly used as it produces NR with a greater yield and is more efficient (9).

This more commonly used approach requires synthetic glycosylation conditions, attachment of a carbohydrate molecule that depends on the type of sugar component used (8).

NR has also been synthesized enzymatically from NAD+ and NMN using many processes. Kaplan and Stolzenbach used snake venom phosphodiesterase to perform enzymatic cleavage or “breakdown” of NAD+ to form NMN followed by catalysis, otherwise known as acceleration of a reaction, with a prostatic monoesterase enzyme to form NR+ (8).

==Functions==
A precursor to NAD+, NR Is a building block essential to cellular processes such as DNA repair. NR is a nucleoside which provides researchers with a great tool to manipulate NAD+ levels and investigate the effects of NAD+ concentration on cellular processes (9).

The human body utilizes NR to boost levels of NAD which powers metabolism and protects cells during times of metabolic stress (10).

Nicotinamide phosphoribosyltransferase (Nampt) is an enzyme that catalyzes the conversion of nicotinamide to NAD+. There are also to forms of nicotinamide riboside kinsases (NRK1 and NRK2) that convert NR to NAD+ without the need for Nampt (5).

The kinase pathway is also found to be involved in assisting NR to raise NAD tissue concentrations in rodents and eliciting effects such as insulin sensitivity, mitochondrial biogenesis also depicted as the generation of more of the cell’s “powerhouse” and enhanced sirtuin functions (11).

Upregulation of NR, particularly through diet and oral administration has been shown to increase NAD+ concentrations which subsequently enhances mitochondrial function and supports the body by providing protection against damage from free radicals hence reducing the signs of aging. It has also become known that there are additional benefits to supplementing with oral NR such as neurological and cognitive support, metabolic support as well as liver and muscle support.

==Research==
The use of oral NR supplementation to treat an array of conditions is currently underway.

===Clinical trials timeline===
November 1st 2018 – A pilot study aimed to test whether oral NR increase NAD+ levels or improves mitochondrial function in heart cells also known as cardiomyocytes. Previous studies have shown NR supplementation to increase myocardial levels of NAD+ in mice, this study aimed to test the same but in human cardiomyocytes of patients with advanced heart failure who are awaiting elective left ventricular assist device (LVAD) implantation (12).

December 28th 2018 – Researchers conducted a study to see if NR may help improve muscle function and possibly improve exercising capacity via improved mitochondrial activity. Investigators aimed to study how skeletal muscle responds to NR in patients who have Li-Fraumeni syndrome (LFS), a rare hereditary disorder that increases an individual’s risk of developing many types of cancer and causes long-term fatigue and muscles weakness (13).

January 25th 2019 – This piece of research recruited newly diagnosed, drug naïve Parkinson’s Disease (PD) patients who were treated with oral NR. The pilot aimed to determine if NR had any impact on the enzyme or neurometabolic profile of patients with PD. Secondly, to identify if high dose oral NR improves motor symptoms associated with PD. Finally, to determine whether high dose NR can restore NAD metabolism and subsequently elevate levels of NAD (14).

April 11th 2019 – Evaluating the effects of NR in preventing experimentally induced small fiber nerve degeneration and promotion of nerve regeneration. A type of nerve disease or damage that affects signaling between the brain, spinal cord and the rest of the body termed as peripheral neuropathy. A particular form of peripheral neuropathy known as small fiber neuropathy (SFN) affects small unmyelinated fibers. Myelin is a lipid rich fatty-like substance that surrounds nerve cells and is likened to the insulation around wires in electrical systems. Myelin insulates the nerve/neuron hence increasing the speed of electronic signals called actional potentials through it. Unmyelinated nerves therefore lack the insulation and hence do not support a healthy environment for the generation of the electronic signals. Diabetes is known to be a common cause of neuropathy; however, half of the diagnosed cases have an unknown cause and are termed idiopathic. There is no current intervention that can prevent degeneration or promote regeneration, however, recent advances in molecular science illustrated the importance of key molecules such as NAD+. This study aims to evaluate NR’s ability to prevent degradation and promote regeneration of small sensory axons in the skins layer known as the epidermis. Such research may help pave the way in treatments for many types of peripheral neuropathies (15).

May 15th 2019 – Mitochondrial synthesis and the use of oxygen to produce energy from carbohydrates known as oxidative metabolism in fatty skin or “adipose tissues” was found to be significantly impaired in obesity at a young adult stage. As a result, investigators aim to see if NR may activate dysfunctional mitochondria, particularly the SIRT/NAD+ pathway and help alleviate signs of obesity related illness (16).

May 23rd 2019 – To establish any positive outcomes of NR on the disease course of patients suffering from Ataxia Telangiectasia (A-T), an inherited neurodegenerative disorder caused by mutation of the ATM gene which causes breakdown of nerve cells affects the immune and respiratory system. This disorder is coupled with a high cancer risk and currently treatment is limited to rehabilitation, screening and prevention. The ATM protein plays a vital role in processes such as cellular energy metabolism, cell signaling and DNA repair. NAD+ is known as an essential molecule in many cellular processes, particularly as a deficiency in it is linked to underlying DNA repair disorders as seen in A-T. Prior research using NR in animal models has proved beneficial, this studies aims to see if treatment for 6 months may have positive outcomes on disease progression of A-T (17).

August 1st 2019 – Research to date has shown that NR supplementation lowered carotid-femoral pulse wave velocity (CFPWV), a measure of aortic stiffness and predictors of cardiovascular disease in patients with or without kidney disease. Additionally, NR was shown to decrease systolic blood pressure (SBP). As a ‘next-step’, the current study aims to assess the safety and efficacy of NR for decreasing aortic stiffness and SBP in patients with stage III and IV chronic kidney disease (CKD). It is hypothesized that NR will lower aortic stiffness and SBP due to increases in NAD+ bioavailability, influences on vascular smooth muscle tone and a decline in markers for inflammation and oxidative stress (18).

August 5th 2019 – Investigators aim to determine metabolic improvements in Alzheimer’s and Parkinson’s disease patients by use of a cocktail of NR in combination with other co-factors such as N-acetylcysteine, L-carnitine tartrate and serine to activate mitochondria in the brain cells. Based on previous studies it is evident that each cofactor plays its own role in activating mitochondria, NR specifically, is known to boost hepatic (liver) B-oxidation (breakdown) of fatty acids in mitochondria hence stimulating the transfer of fatty acids from the cytosol to the mitochondria (19).

September 4th 2019 – A clinical trial aimed at determining whether NR can improve cognitive function such as thinking/decision making, mood and daily activities in people suffering from Subjective Cognitive Decline (SCD) or Mild Cognitive Impairment (MCI). This would be measured using blood draws, EEG’s, cognitive testing and mood questionnaires (20).

October 1st 2019 – Those suffering from acute illness often face long recovery times, of which the primary cause is not known, however many factors can contribute to this such as age and severity of illness. This study aims to determine whether NR can reduce the times taken to recover and improve outcomes in patients admitted to hospital with tissue damage (21).

October 2nd 2019 – Niagen, the brand name for NR, was tested to observe its effects in improving persistent peripheral neuropathy in cancer survivors who have completed chemotherapy with taxane or platinum-complex compounds between 1 and 12 months prior. Outcomes will be measured based on changes in scores on sensory and motor subscale of quality of life questionnaire (22).

October 2nd 2019 - Identified as an enhancer of exercise therapy in hypertensive (raised blood pressure) older adults, NR is therefore being investigated as a means of enhancing the effects of therapy in a population type that would otherwise struggle to exercise. This has great implications as a positive outcome may pave the way to reducing cardiovascular disease and death (23).

February 17th 2020 – A pilot study to evaluate the effect of NR on immune activation in psoriasis, a skin disorder that causes skin cells to multiply ten times faster than normal resulting in dry scales on the skin. Psoriasis is linked with a subset of CD4 T cells, or “helper” cells that regulate the immune system named Th17 cells, these cells are characterized by the production of signaling proteins named cytokines such as IL-17. Currently it is known that NR diminishes Th1 and Th17 activation hence the pilot intends to further this hypothesis by measuring NR’s impact on Th17, neutrophils and whether it modulates skin cell or keratinocyte activation in skin lesions of psoriasis subjects (24).

April 2nd 2020 – A study to find a safe and tolerable means to improve the transplant recovery process known as engraftment post-transplantation. Previous research studies have found that adding NR to donor cells can increase blood stem cell quantities and reduces time to engraftment. This study aims to evaluate the safety and tolerability of NR as well as observe white blood cell and platelet count post-transplantation (25).

June 1st 2020 – Well aware that a decline in NAD+ with increasing age can have major implications in this proinflammatory states, researchers advance on previous research that shows even short-term treatment with NR is sufficient to reduce the impact of this aging process. NR is therefore under test to see if it can attenuate the severity of SARS-CoV-2 infection in elderly patients aged 70 years or older (26).

==References==
(1)https://www.elysiumhealth.com/en-us/science-101/what-is-nicotinamide-riboside

(2)Gingrich, W; Schlenk, F (June 1944). "Codehydrogenase I and Other Pyridinium Compounds as V-Factor for Hemophilus influenzae and H. parainfluenzae". Journal of Bacteriology. 47 (6): 535–50. PMC 373952. PMID 16560803

(3)CHAMBON, P., ET AL., NICOTINAMIDE MONONUCLEOTIDE ACTIVATION OF NEW DNA-DEPENDENT POLYADENYLIC ACID SYNTHESIZING NUCLEAR ENZYME. BIOCHEM BIOPHYS RES COMMUN, 1963. 11(1): P. 39-43.

(4) IMAI, S., ET AL., TRANSCRIPTIONAL SILENCING AND LONGEVITY PROTEIN SIR2 IS AN NAD-DEPENDENT HISTONE DEACETYLASE. NATURE, 2000. 403(6771): P. 795-800.

(5)Bieganowski, P; Brenner, C (2004). "Discoveries of Nicotinamide Riboside as a Nutrient and Conserved NRK Genes Establish a Preiss-Handler Independent Route to NAD+ in Fungi and Humans". Cell. 117 (4): 495–502. doi:10.1016/S0092-8674(04)00416-7. PMID 15137942

(6)BELENKY, P., ET AL., NICOTINAMIDE RIBOSIDE PROMOTES SIR2 SILENCING AND EXTENDS LIFESPAN VIA NRK AND URH1/PNP1/MEU1 PATHWAYS TO NAD+. CELL, 2007. 129(3): P. 473-84.

(7) https://www.chromadex.com/ingredient/niagen/

(8) https://www.beilstein-journals.org/bjoc/articles/15/36

(9) https://pubmed.ncbi.nlm.nih.gov/27052539/

(10) https://www.biospace.com/article/releases/new-study-demonstrates-a-unique-role-of-nicotinamide-riboside-over-other-nad-precursors/

(11) https://pubmed.ncbi.nlm.nih.gov/24071780/

(12) https://clinicaltrials.gov/ct2/show/record/NCT03727646?term=nicotinamide+riboside

(13) https://clinicaltrials.gov/ct2/show/record/NCT03789175?term=nicotinamide+riboside

(14) https://clinicaltrials.gov/ct2/show/record/NCT03816020?term=nicotinamide+riboside

(15) https://clinicaltrials.gov/ct2/show/record/NCT03912220?term=nicotinamide+riboside

(16) https://clinicaltrials.gov/ct2/show/record/NCT03951285?term=nicotinamide+riboside

(17) https://clinicaltrials.gov/ct2/show/record/NCT03962114?term=nicotinamide+riboside

(18) https://clinicaltrials.gov/ct2/show/record/NCT04040959?term=nicotinamide+riboside&rank=4

(19) https://clinicaltrials.gov/ct2/show/record/NCT04044131?term=nicotinamide+riboside

(20) https://clinicaltrials.gov/ct2/show/record/NCT04078178?term=nicotinamide+riboside

(21) https://clinicaltrials.gov/ct2/show/record/NCT04110028?term=nicotinamide+riboside

(22) https://clinicaltrials.gov/ct2/show/record/NCT04112641?term=nicotinamide+riboside

(23) https://clinicaltrials.gov/ct2/show/record/NCT04112043?term=nicotinamide+riboside

(24) https://clinicaltrials.gov/ct2/show/record/NCT04271735?term=nicotinamide+riboside&draw=2

(25) https://clinicaltrials.gov/ct2/show/NCT04332341?term=nicotinamide+riboside&draw=2&rank=7

(26) https://clinicaltrials.gov/ct2/show/record/NCT04407390

Nicotinamide Riboside

2020-10-19T14:53:25Z

Judgesurreal777: Starting new article

'''Nicotinamide Riboside''' is a natural organic compound found in trace amounts in foods such as dairy products and is a precursor to nicotinamide adenine dinucleotide (NAD+) (1). Termed the ‘cousin’ of vitamin B3, this form of vitamin B3 also comes in variations known as nicotinamide and nicotinic acid/niacin (NA), niacin being most commonly used in fortifying foods such as flour and cereal particularly in the 1940s to ward off the fatal disease pellagra (1).

Previous research focused on the role of NAD+ on the body’s cellular health independently, however it is becoming known that NR may be more valuable than thought. NR supplementation has been proven to be effective in enhancing NAD+ when administered orally. The implications of using NR are so wide that there is an abundance of current research trials investigating the use of NR not only in prevention but also the treatment of many inflammatory disease states.

==History==
NR was first identified as a growth factor named Factor V in 1944, named so due to its ability to enhance the growth of Hemophilus influenzae, a bacterium that resides in the blood. When Factor V was extracted from blood and purified it was shown to exist in 3 forms: NAD+, NMN and NR. It became apparent that NR was responsible for the most rapid growth rate of the bacterium compared to that of NAD+ and NMN (2).

In 1963 Mandel and Colleagues identified a chemical reaction that broke NAD into 2 respective parts, nicotinamide and ADP-ribose (3).

Sirtuin enzymes, a family of proteins that regulate cellular health, were discovered in 2000. Biochemists investigating how yeast sirtuins affect longevity came across the findings that sirtuins used NAD to help keep specific genes “silent” so not to function. During this process sirtuin enzymes breakdown NAD and use parts of it to deacetylate or “remove acetyl groups” of proteins within the cell. Deacetylating histone proteins, proteins that provide structure and order to DNA, can change how the cell accesses nearby genes (4).

In 2004 advances were made in the implication of NR in the body other than just to ward off disease states. Biochemist Charles Brenner et al identified the NR kinase pathway leading to production of NAD+ (5). Follow up research showed that administering NR to yeast cells resulted in increased NAD levels and hence an extension in lifespan of the yeast (6).

Consequently, this paved the way for a more efficient pathway of producing NAD+, known to restore levels in the body and reduce the signs of the inflammatory and aging process internally at a cellular level. A crystal form of NR chloride, also known as Niagen is currently the only FDA-safety reviewed form (7). Dr Charles Brenner was the biochemist who not only discovered but also patented nicotinamide riboside as a cellular nutrient. Our cells are exposed to many stressors such as infections, poor diet, lack of sleep and exercise not to mention diminishing NAD+ levels as we age. NR allows the cells to become more resilient and super-charged.

==Structure==
Nicotinamide riboside is a nucleoside which is a combination for nicotinamide and riboside in a single chemical moiety.
1-(B-D-Ribofuranosyl)nicotinamide
Molecular formula C11H15N205
Molar mass of 255.25g/mol

==Biosynthesis==
NR is naturally occurring in milk, most recently it was found that cow’s milk contained approximately 12 micromole NAD+ precursor vitamin concentration, of this percentage 60% was nicotinamide and 40% present as NR. It was also found that the presence of Staphylococcus aureus resulted in lower concentrations of NR (9).

Most synthetic production of NR can be divided into 2 categories, firstly is a reaction between nicotinamide and a peracylated (halo)-D-ribofuranose resulting in an acylated (addition of an acyl group) intermediate that is then converted into NR. The second method is via condensation of a salt with derivatives of D-ribofuranosylamine. The first approach is the most commonly used as it produces NR with a greater yield and is more efficient (9).

This more commonly used approach requires synthetic glycosylation conditions, attachment of a carbohydrate molecule that depends on the type of sugar component used (8).

NR has also been synthesized enzymatically from NAD+ and NMN using many processes. Kaplan and Stolzenbach used snake venom phosphodiesterase to perform enzymatic cleavage or “breakdown” of NAD+ to form NMN followed by catalysis, otherwise known as acceleration of a reaction, with a prostatic monoesterase enzyme to form NR+ (8).

==Functions==
A precursor to NAD+, NR Is a building block essential to cellular processes such as DNA repair. NR is a nucleoside which provides researchers with a great tool to manipulate NAD+ levels and investigate the effects of NAD+ concentration on cellular processes (9).

The human body utilizes NR to boost levels of NAD which powers metabolism and protects cells during times of metabolic stress (10).

Nicotinamide phosphoribosyltransferase (Nampt) is an enzyme that catalyzes the conversion of nicotinamide to NAD+. There are also to forms of nicotinamide riboside kinsases (NRK1 and NRK2) that convert NR to NAD+ without the need for Nampt (5).

The kinase pathway is also found to be involved in assisting NR to raise NAD tissue concentrations in rodents and eliciting effects such as insulin sensitivity, mitochondrial biogenesis also depicted as the generation of more of the cell’s “powerhouse” and enhanced sirtuin functions (11).

Upregulation of NR, particularly through diet and oral administration has been shown to increase NAD+ concentrations which subsequently enhances mitochondrial function and supports the body by providing protection against damage from free radicals hence reducing the signs of aging. It has also become known that there are additional benefits to supplementing with oral NR such as neurological and cognitive support, metabolic support as well as liver and muscle support.

==Research==
The use of oral NR supplementation to treat an array of conditions is currently underway.

===Clinical trials timeline===
November 1st 2018 – A pilot study aimed to test whether oral NR increase NAD+ levels or improves mitochondrial function in heart cells also known as cardiomyocytes. Previous studies have shown NR supplementation to increase myocardial levels of NAD+ in mice, this study aimed to test the same but in human cardiomyocytes of patients with advanced heart failure who are awaiting elective left ventricular assist device (LVAD) implantation (12).

December 28th 2018 – Researchers conducted a study to see if NR may help improve muscle function and possibly improve exercising capacity via improved mitochondrial activity. Investigators aimed to study how skeletal muscle responds to NR in patients who have Li-Fraumeni syndrome (LFS), a rare hereditary disorder that increases an individual’s risk of developing many types of cancer and causes long-term fatigue and muscles weakness (13).

January 25th 2019 – This piece of research recruited newly diagnosed, drug naïve Parkinson’s Disease (PD) patients who were treated with oral NR. The pilot aimed to determine if NR had any impact on the enzyme or neurometabolic profile of patients with PD. Secondly, to identify if high dose oral NR improves motor symptoms associated with PD. Finally, to determine whether high dose NR can restore NAD metabolism and subsequently elevate levels of NAD (14).

April 11th 2019 – Evaluating the effects of NR in preventing experimentally induced small fiber nerve degeneration and promotion of nerve regeneration. A type of nerve disease or damage that affects signaling between the brain, spinal cord and the rest of the body termed as peripheral neuropathy. A particular form of peripheral neuropathy known as small fiber neuropathy (SFN) affects small unmyelinated fibers. Myelin is a lipid rich fatty-like substance that surrounds nerve cells and is likened to the insulation around wires in electrical systems. Myelin insulates the nerve/neuron hence increasing the speed of electronic signals called actional potentials through it. Unmyelinated nerves therefore lack the insulation and hence do not support a healthy environment for the generation of the electronic signals. Diabetes is known to be a common cause of neuropathy; however, half of the diagnosed cases have an unknown cause and are termed idiopathic. There is no current intervention that can prevent degeneration or promote regeneration, however, recent advances in molecular science illustrated the importance of key molecules such as NAD+. This study aims to evaluate NR’s ability to prevent degradation and promote regeneration of small sensory axons in the skins layer known as the epidermis. Such research may help pave the way in treatments for many types of peripheral neuropathies (15).

May 15th 2019 – Mitochondrial synthesis and the use of oxygen to produce energy from carbohydrates known as oxidative metabolism in fatty skin or “adipose tissues” was found to be significantly impaired in obesity at a young adult stage. As a result, investigators aim to see if NR may activate dysfunctional mitochondria, particularly the SIRT/NAD+ pathway and help alleviate signs of obesity related illness (16).

May 23rd 2019 – To establish any positive outcomes of NR on the disease course of patients suffering from Ataxia Telangiectasia (A-T), an inherited neurodegenerative disorder caused by mutation of the ATM gene which causes breakdown of nerve cells affects the immune and respiratory system. This disorder is coupled with a high cancer risk and currently treatment is limited to rehabilitation, screening and prevention. The ATM protein plays a vital role in processes such as cellular energy metabolism, cell signaling and DNA repair. NAD+ is known as an essential molecule in many cellular processes, particularly as a deficiency in it is linked to underlying DNA repair disorders as seen in A-T. Prior research using NR in animal models has proved beneficial, this studies aims to see if treatment for 6 months may have positive outcomes on disease progression of A-T (17).

August 1st 2019 – Research to date has shown that NR supplementation lowered carotid-femoral pulse wave velocity (CFPWV), a measure of aortic stiffness and predictors of cardiovascular disease in patients with or without kidney disease. Additionally, NR was shown to decrease systolic blood pressure (SBP). As a ‘next-step’, the current study aims to assess the safety and efficacy of NR for decreasing aortic stiffness and SBP in patients with stage III and IV chronic kidney disease (CKD). It is hypothesized that NR will lower aortic stiffness and SBP due to increases in NAD+ bioavailability, influences on vascular smooth muscle tone and a decline in markers for inflammation and oxidative stress (18).

August 5th 2019 – Investigators aim to determine metabolic improvements in Alzheimer’s and Parkinson’s disease patients by use of a cocktail of NR in combination with other co-factors such as N-acetylcysteine, L-carnitine tartrate and serine to activate mitochondria in the brain cells. Based on previous studies it is evident that each cofactor plays its own role in activating mitochondria, NR specifically, is known to boost hepatic (liver) B-oxidation (breakdown) of fatty acids in mitochondria hence stimulating the transfer of fatty acids from the cytosol to the mitochondria (19).

September 4th 2019 – A clinical trial aimed at determining whether NR can improve cognitive function such as thinking/decision making, mood and daily activities in people suffering from Subjective Cognitive Decline (SCD) or Mild Cognitive Impairment (MCI). This would be measured using blood draws, EEG’s, cognitive testing and mood questionnaires (20).

October 1st 2019 – Those suffering from acute illness often face long recovery times, of which the primary cause is not known, however many factors can contribute to this such as age and severity of illness. This study aims to determine whether NR can reduce the times taken to recover and improve outcomes in patients admitted to hospital with tissue damage (21).

October 2nd 2019 – Niagen, the brand name for NR, was tested to observe its effects in improving persistent peripheral neuropathy in cancer survivors who have completed chemotherapy with taxane or platinum-complex compounds between 1 and 12 months prior. Outcomes will be measured based on changes in scores on sensory and motor subscale of quality of life questionnaire (22).

October 2nd 2019 - Identified as an enhancer of exercise therapy in hypertensive (raised blood pressure) older adults, NR is therefore being investigated as a means of enhancing the effects of therapy in a population type that would otherwise struggle to exercise. This has great implications as a positive outcome may pave the way to reducing cardiovascular disease and death (23).

February 17th 2020 – A pilot study to evaluate the effect of NR on immune activation in psoriasis, a skin disorder that causes skin cells to multiply ten times faster than normal resulting in dry scales on the skin. Psoriasis is linked with a subset of CD4 T cells, or “helper” cells that regulate the immune system named Th17 cells, these cells are characterized by the production of signaling proteins named cytokines such as IL-17. Currently it is known that NR diminishes Th1 and Th17 activation hence the pilot intends to further this hypothesis by measuring NR’s impact on Th17, neutrophils and whether it modulates skin cell or keratinocyte activation in skin lesions of psoriasis subjects (24).

April 2nd 2020 – A study to find a safe and tolerable means to improve the transplant recovery process known as engraftment post-transplantation. Previous research studies have found that adding NR to donor cells can increase blood stem cell quantities and reduces time to engraftment. This study aims to evaluate the safety and tolerability of NR as well as observe white blood cell and platelet count post-transplantation (25).

June 1st 2020 – Well aware that a decline in NAD+ with increasing age can have major implications in this proinflammatory states, researchers advance on previous research that shows even short-term treatment with NR is sufficient to reduce the impact of this aging process. NR is therefore under test to see if it can attenuate the severity of SARS-CoV-2 infection in elderly patients aged 70 years or older (26).

==References==

(1)https://www.elysiumhealth.com/en-us/science-101/what-is-nicotinamide-riboside

(2)Gingrich, W; Schlenk, F (June 1944). "Codehydrogenase I and Other Pyridinium Compounds as V-Factor for Hemophilus influenzae and H. parainfluenzae". Journal of Bacteriology. 47 (6): 535–50. PMC 373952. PMID 16560803

(3)CHAMBON, P., ET AL., NICOTINAMIDE MONONUCLEOTIDE ACTIVATION OF NEW DNA-DEPENDENT POLYADENYLIC ACID SYNTHESIZING NUCLEAR ENZYME. BIOCHEM BIOPHYS RES COMMUN, 1963. 11(1): P. 39-43.

(4) IMAI, S., ET AL., TRANSCRIPTIONAL SILENCING AND LONGEVITY PROTEIN SIR2 IS AN NAD-DEPENDENT HISTONE DEACETYLASE. NATURE, 2000. 403(6771): P. 795-800.

(5)Bieganowski, P; Brenner, C (2004). "Discoveries of Nicotinamide Riboside as a Nutrient and Conserved NRK Genes Establish a Preiss-Handler Independent Route to NAD+ in Fungi and Humans". Cell. 117 (4): 495–502. doi:10.1016/S0092-8674(04)00416-7. PMID 15137942

(6)BELENKY, P., ET AL., NICOTINAMIDE RIBOSIDE PROMOTES SIR2 SILENCING AND EXTENDS LIFESPAN VIA NRK AND URH1/PNP1/MEU1 PATHWAYS TO NAD+. CELL, 2007. 129(3): P. 473-84.

(7) https://www.chromadex.com/ingredient/niagen/

(8) https://www.beilstein-journals.org/bjoc/articles/15/36

(9) https://pubmed.ncbi.nlm.nih.gov/27052539/

(10) https://www.biospace.com/article/releases/new-study-demonstrates-a-unique-role-of-nicotinamide-riboside-over-other-nad-precursors/

(11) https://pubmed.ncbi.nlm.nih.gov/24071780/

(12) https://clinicaltrials.gov/ct2/show/record/NCT03727646?term=nicotinamide+riboside

(13) https://clinicaltrials.gov/ct2/show/record/NCT03789175?term=nicotinamide+riboside

(14) https://clinicaltrials.gov/ct2/show/record/NCT03816020?term=nicotinamide+riboside

(15) https://clinicaltrials.gov/ct2/show/record/NCT03912220?term=nicotinamide+riboside

(16) https://clinicaltrials.gov/ct2/show/record/NCT03951285?term=nicotinamide+riboside

(17) https://clinicaltrials.gov/ct2/show/record/NCT03962114?term=nicotinamide+riboside

(18) https://clinicaltrials.gov/ct2/show/record/NCT04040959?term=nicotinamide+riboside&rank=4

(19) https://clinicaltrials.gov/ct2/show/record/NCT04044131?term=nicotinamide+riboside

(20) https://clinicaltrials.gov/ct2/show/record/NCT04078178?term=nicotinamide+riboside

(21) https://clinicaltrials.gov/ct2/show/record/NCT04110028?term=nicotinamide+riboside

(22) https://clinicaltrials.gov/ct2/show/record/NCT04112641?term=nicotinamide+riboside

(23) https://clinicaltrials.gov/ct2/show/record/NCT04112043?term=nicotinamide+riboside

(24) https://clinicaltrials.gov/ct2/show/record/NCT04271735?term=nicotinamide+riboside&draw=2

(25) https://clinicaltrials.gov/ct2/show/NCT04332341?term=nicotinamide+riboside&draw=2&rank=7

(26) https://clinicaltrials.gov/ct2/show/record/NCT04407390

Shin-ichiro Imai

2020-06-01T21:22:44Z

Judgesurreal777: Adding back references

{{Infobox
| title = Shin-ichiro Imai, MD, PhD
| image = [[File:Shin-Ichiro Imai.jpg|350px|Shin-Ichiro Imai]]

| data1 = {{Infobox | subbox = yes
| headerstyle = background:#ddd;
| header1 = Personal information
| label2 = Born | data2 = 1962 (age 58) Tokyo, Japan
| label3 = Nationality | data3 = Japanese
| label4 = Education | data4 = Keio University School of Medicine (PhD, MD)
| label5 = Field of study | data5 = Molecular mechanism of aging and longevity
| label6 = Occupation | data6 = Researcher, professor
| label7 = Affiliation | data7 = Washington University School of Medicine in St. Louis
| label8 = Position | data8 = Professor of Developmental Biology and Medicine
}}
}}

'''Shin-ichiro Imai''' is a researcher and physician at the Washington University School of Medicine where he is a professor of developmental biology specializing in anti-aging. After an early childhood interest in the sciences, Imai went on to pursue a medical degree at Keio University in Tokyo. Over half way through, however, Imai became torn over his increasing desire to be a researcher into cellular senescence, which is the study of how cells age and break down.

After joining with Massachusetts Institute of Technology researcher Leonard Guarentes lab, he and fellow researchers went on to make significant progress in the study of anti-aging, starting in the 1999 discovery of the role of sirtuins in the metabolic regulation of cells. His work has continued to focus on the physiological processes that cause living cells to stay young and healthy, and focus on discovering supplementation that could reinforce the delivery and creation of anti-aging compounds within the human body.

==Early life and research==
Shin-ichiro Imai was often told the story of his birth by his parents: because of his mothers partially detached placenta, his chance of surviving birth was lower than normal, and his parents had to find a doctor willing to take on the risk.<ref name=placenta>[https://source.wustl.edu/2015/02/washington-people-shinichiro-imai/ Washington People: Shin-ichiro Imai] Written by Julia Evangelou Strait for Washington University in Saint Louis. Published February 2, 2015; Accessed April 3, 2020</ref> This story influenced him in later life to want to become a doctor.<ref name=placenta/> A self-described “active child”, he was given many biology projects by his history-teaching father, including one that involved tracking the height and petal sizes of sunflowers, which they grew and recorded.<ref name=placenta/> Imai attended Keio University in Tokyo with the intention of becoming a medical doctor, but in year four of six of his studies, he began to take an interest in research.<ref name=placenta/> After much questioning of which path to take, Imai finished his medical degree and began his doctoral work while working full time at the laboratory he had been volunteering at for years.<ref name=placenta/>

Imai was fascinated by the relatively un-researched area of cellular immortality, which asked how cells have, and then lose, the ability to endlessly self-replicate, and how this ability might relate to both human lifespans and health risks like cancer.<ref name=placenta/> After a difficult start over the next two years setting up complex experiments to track the activation of different genes, he successfully discovered a protein called collagenase, later found to be part of a group of proteins that are involved in cellular senescence.<ref name=placenta/> Through his work, he met Leonard Guarente from the Massachusetts Institute of Technology at a scientific conference, and thereafter joined Guarente’s lab at MIT as a post-doctoral student. Imai met and worked with David Andrew Sinclair, a fellow anti-aging researcher and writer, at Leonard Guarentes lab.<ref name=sinclair>[https://www.bostonmagazine.com/health/2019/10/29/david-sinclair/ Has Harvard’s David Sinclair Found the Fountain of Youth?] Written by Catherine Elton for Boston Magazine. Published October 29, 2019; Accessed April 3, 2020</ref> In 1999, Imai, Guarente, Sinclair, and others discovered how certain metabolic regulation proteins in cells, called sirtuins, silence certain genes when cells are young, and cease this ability when they grow old. This function was found to be dependent on the levels of energy in cells, and greatly influences cellular longevity.

==Research==
In 2001, Imai joined the faculty of Washington University in Saint Louis. Imai’s research into the nature of aging continued there, and in 2011 he published a study showing that giving female type 2 diabetic mice a compound called nicotinamide mono nucleotide (NMN) helped restore them to a healthy metabolism.<ref name=diabeto>[https://source.wustl.edu/2011/10/natural-compound-helps-reverse-diabetes-in-mice/ Natural compound helps reverse diabetes in mice] Written by Julia Evangelou Strait for Washington University in Saint Louis. Published October 4, 2011; Accessed April 4, 2020</ref> The chemical compound also helped with other age-related conditions. Imai believes that the chemical NMN, which is derived from Vitamin B3, is used in the production of “NAM”, the loss of which is theorized to cause aging. Foods thought to be high in NMN include broccoli, edamame, cucumber, cabbage, and avocado, though Imai doesn’t believe that any of the foods would affect your rate of aging significantly.<ref name=broccoli>[https://time.com/4547919/this-compound-in-broccoli-can-slow-aging/ How This Broccoli Enzyme Can Slow Aging] Written by Alice Park for Time Magazine. Published October 27, 2016; Accessed April 3, 2020</ref>

Imai did further research in 2013 on sirtuins, and found that supplementing the compound NMN did not stop the aging process, but helped extend the period of youth in mice.<ref name=sirtuinz>[https://medicine.wustl.edu/news/young-mouse-blood-delays-aging-in-older-mice/ Aging delayed in older mice given blood component from young mice] Written by Julia Evangelou Strait for Washington University in Saint Louis. Published June 13, 2019; Accessed April 3, 2020</ref> He also discovered that a sirtuin protein found in the brain, named “Sirti1”, was responsible for, and seemed to replicate, the effects of low-calorie diets.<ref name=aging>[https://source.wustl.edu/2013/09/aging-really-is-in-your-head/ Aging really is ‘in your head’] Written by Lee Phillion for Washington University in Saint Louis. Published September 3, 2013; Accessed April 3, 2020</ref> Many age-related health issues, such as declines in physical activity, body temperature, and other issues were also delayed by supplementation with this protein.<ref name=delays>[https://www.scientificamerican.com/gallery/protein-found-to-extend-youth/ Protein Found to Extend Youth] Written by Julianne Chiaet for Scientific American. Published September 6, 2013; Accessed April 3, 2020</ref>

Imai also explored the question of optimal levels of fat the human body should have, and found that as humans grew older, being slightly overweight was more desirable than being at “healthy” fat levels.<ref name=fatty>[https://www.dailymail.co.uk/health/article-3067515/How-slightly-overweight-GOOD-health-Fat-tissue-boosts-brain-s-energy-levels-affects-metabolism-ageing.html How being slightly overweight is GOOD for your health: Fat tissue 'boosts brain's energy levels and affects metabolism and ageing'] Written by Madlen Davies for the Daily Mail. Published May 4, 2015; Accessed April 4, 2020</ref> Imai has hypothesized that fat cells somehow effect the regulation of the body’s physiology, possibly through the hypothalamus. In one study, mice that had low levels of “NAMPT” in their fatty tissues also had low levels of “fuel” in their hypothalamus, followed by worse measurements in their physical activity. Imai latter commented on a study involving stem cell injections into the hypothalamus of mice that caused a reduction in their memory loss, stating that the hypothalamus may control the aging and longevity of mammals.<ref name=hypothalamuses>[https://www.statnews.com/2017/07/26/aging-brain-hypothalamus-mice/ A tiny part of the brain appears to orchestrate the whole body’s aging] Written by Jonathan Wosen for Stat News. Published July 26, 2017; Accessed April 3, 2020</ref><ref name=slowly>[https://www.scientificamerican.com/article/brains-stem-cells-slow-aging-in-mice/ Brain’s Stem Cells Slow Aging in Mice] Written by Sarah Reardon for Scientific American. Published July 26, 2017; Accessed April 3, 2020</ref>

In 2016, Imai partnered with researchers in Japan to study the bio-availability and safety of NMN supplementation in humans.<ref name=longevity>[https://www.asianscientist.com/2018/08/print/nmn-metformin-longevity-pill/ Longevity In A Bottle] Written by Jeremy Chan for Asian Scientist. Published August 15, 2018; Accessed April 3, 2020</ref> The idea behind this study was to try and “re-energize” the bodies cells and stimulate the restocking of the NAM supply, thereby disrupting the aging process.<ref name=reverse>[https://www.newscientist.com/article/dn24784-turning-back-time-ageing-reversed-in-mice/ Turning back time: ageing reversed in mice] Written by Laasya Samhita for the New Scientist. Published December 19, 2013; Accessed April 3, 2020</ref> Imai has explained that, in ways science does not yet entirely understand, sirtuins, along with chemicals like metformin and rapamycin, are all involved in creating cellular energy, but when the process of creating and delivering NAM breaks down, aging is the result.

In 2019, Imai worked on a study involving the injection of young mouse blood into older mice which caused increased longevity.<ref name=elderly>[https://www.techtimes.com/articles/244344/20190617/scientists-discover-a-protein-in-the-blood-of-young-mice-that-prolongs-life-of-older-mice.htm Scientists Discover A Protein In The Blood Of Young Mice That Prolongs Life Of Older Mice] Written by Naia Carlos for Tech Times. Published June 17, 2019; Accessed April 3, 2020</ref> Imai and his team hypothesized that the increased presence of a protein enzyme called “eNAMPT” in younger blood, which helps cells make energy, may have been the cause.<ref name=enzyme>[https://www.medicaldaily.com/secret-immortality-scientists-find-enzyme-prolongs-life-436831 Secret To Immortality? Scientists Find Enzyme That Prolongs Life] Written by Johnny Vatican for Medical Daily. Published June 17, 2019; Accessed April 3, 2020</ref> Previous studies had focused on giving whole blood to older mice, whereas this study focused just on the enzyme.<ref name=slashes>[https://www.slashgear.com/researchers-made-old-mice-live-longer-using-blood-from-young-mice-15580509/ Researchers made old mice live longer using blood from young mice] Written by Brittany Roston for Slashgear. Published June 15, 2019; Accessed April 3, 2020</ref> This chemical had the effect of mimicking calorie restriction without actually having to consume fewer calories. The mice in the study given eNAMPT supplements lived on average sixteen percent longer.

Imai has also studied how the bodies cells react to the loss of the “fuel” that is “NAM”, and how the body attempts to summon more of it when their supply starts to run out.<ref name=summon>[https://medicine.wustl.edu/news/scientists-identify-new-fuel-delivery-route-for-cells/ Scientists identify new fuel-delivery route for cells] Written Julia Evangelou Strait for Washington University in Saint Louis. Published January 7, 2019; Accessed April 3, 2020.</ref> Imai’s research was able to show compound Slc12a8 is the NMN transporter, which had not previously been identified.<ref name=Slc12a8>[https://www.futurity.org/cell-fuel-delivery-aging-1973572/ CAN EXTRA FUEL DELIVERY RECHARGE AGING CELLS?] Written by Julia Evangelou Straight-Wusl for Futurity. Published February 4, 2019; Accessed April 3, 2020</ref> Imai has noted that the human body ends up in a kind of “bottleneck” as it ages, as the body can no longer produce enough NAD, and yet it needs more than before, which Imai speculates is due to chronic inflammation.<ref name=not>[https://www.washingtonpost.com/lifestyle/wellness/do-nad-boosting-supplements-fight-aging-not-according-to-current-research/2019/11/26/ffc95704-07c4-11ea-818c-fcc65139e8c2_story.html Do NAD-boosting supplements fight aging? Not according to current research.] Written by Carrie Dennett for the Washington Post. Published November 26, 2019; Accessed April 3, 2020</ref> He is working with Washington University’s Office of Technology Management and a Japanese company called Teijin Limited to use this knowledge to create therapies both increasing NAD production and helping in the transportation of it throughout the body. Because increased production of NAD can sometimes be used by virulent cancerous tumors, studies in mice continuously look for any rise in the rate of cancer.<ref name=cancer>[https://www.sciencedaily.com/releases/2016/10/161027122047.htm Natural compound reduces signs of aging in healthy mice] Written by the Washington University School of Medicine for Science Daily. Published October 27, 2016; Accessed April 3, 2020.</ref> Imai has also cautioned that longevity and health are sometimes at odds, and continued low calorie anti-aging can lead to fragility, meaning higher susceptibility to disease, as was demonstrated in studies done on nematodes in 2019.<ref name=nematodes>[https://www.sciencenews.org/article/gene-may-help-worms-live-longer-not-healthier This gene may help worms live longer, but not healthier] Written by Tina Hesman Saey for Science News. Published July 17, 2019; Accessed April 3, 2020</ref> eNAMPT levels will also be examined during the study to see if they can serve as a biomarker for age.<ref name=markers>[https://www.futurity.org/enampt-aging-blood-protein-2083352/ ENZYME IN BLOOD OF YOUNG MICE SLOWS AGING IN OLDER ONES] Written by Julia Evangelou Straight—Wusl for Futurity. Published June 16, 2019; Accessed April 3, 2020</ref> Research is ongoing in older humans to see if the levels of eNAMPT are different in people who have experienced illness, and if the compound could be used for anti-aging supplementation.

==References==
<references />

[[Category:Key Figures]]
[[Category:Full index]]

David Sinclair

2020-06-01T21:20:43Z

Judgesurreal777: Adding back cites

{{Infobox
| title = David Sinclair, PhD
| image = [[File:Sinclair-image2.jpg|350px|Sinclair in his lab at Harvard Medical School (2017)]]

| data1 = {{Infobox | subbox = yes
| headerstyle = background:#ddd;
| header1 = Personal information
| label2 = Born | data2 = June 26, 1969 (age 50) Sydney, Australia
| label3 = Nationality | data3 = Australian
| label4 = Education | data4 = University of New South Wales (BS, PhD)
| label5 = Field of study | data5 = Molecular genetics
| label6 = Occupation | data6 = Professor, author, entrepreneur
| label7 = Position | data7 = co-Director of the Paul F. Glenn Center for the Biology of Aging at Harvard Medical School
}}
}}

'''David Andrew Sinclair''' is an Australian teacher of genetics at Harvard University who specializes in the study of anti-aging. After meeting researcher Leonard Guarente, Sinclair worked with him as a post-doctoral student and began to study the genetic and non-genetic reasons for aging. After years of research, Sinclair founded Sirtris Pharmaceuticals in 2004 to research the re-activation of molecules that supposedly prevent aging, known as sirtuins.

The research he did suggested that the compound resveratrol would help reverse aging and was found primarily in red wine. In studies he had done, he was able to extend the life of small animals, though later studies on humans did not yield a medical product. In the last decade, Sinclair has founded or been a part of several startups focused on different aspects of anti-aging. These startups range from replicating the effects of cardiovascular exercise, or the effects of a healthy diet, as well as attempting to disrupt the aging process itself. He has become a well-known expert in the field, often being interviewed, and noted for his research.

==Biography==
===Early Life and Education===

Sinclair grew up in Saint Ives, Australia. From a young age, he actively explored his vast backyard and studied birds, plants, and reptiles, and was fascinated with how things work.<ref name=lifespaning>[https://www.amazon.com/Lifespan-Why-Age_and-Dont-Have/dp/1501191977 Lifespan: Why We Age―and Why We Don't Have To] Written by David Andrew Sinclair and Matthew D. LaPlante for Atria Books. Published September 10, 2019; Accessed April 13, 2020</ref> Sinclair stated that since the age of four, he has been "obsessed" with "the gravity of life."<ref name=enthusiastic/> Interested in science from an early age, he experimented with making bombs from chlorine or gunpowder.<ref name=enthusiastic>[https://www.technologyreview.com/s/408433/the-enthusiast/ The Enthusiast] written by David Ewing Duncan for the Massachusetts Institute of Technology Review. Published August 15, 2007; Accessed March 3, 2020</ref>

Sinclair's grandmother, his greatest inspiration, was a bohemian, who ran a hotel in Hungary until the Nazis converted it into a headquarters for the SS.<ref name=lifespaning/> Sinclair's great grandmother tried to cross the Soviet borders of Hungary in the mid-1950s, and was sentenced to two years in prison, and died shortly after release.<ref name=lifespaning>[https://www.amazon.com/Lifespan-Why-Age_and-Dont-Have/dp/1501191977 Lifespan: Why We Age―and Why We Don't Have To] Written by David Andrew Sinclair and Matthew D. LaPlante for Atria Books. Published September 10, 2019; Accessed April 13, 2020</ref> His grandmother was an anti-Soviet activist, but after the failed uprising in 1956, she fled to Australia.<ref name=lifespaning/> She impressed upon Sinclair and his sibling that six was the best age to be and to keep the feeling of youth as long as he lived.<ref name=lifespaning/>

Later he attended the University of New South Wales and studied gene regulation in yeast. While attending college, he attended a lecture by a visiting researcher named Leonard Guarente, whose area of focus was in molecular biology at the Massachusetts Institute of Technology. Sinclair ended up joining Guarente's lab as a post-doctoral student in 1995.<ref name =thecut>[https://www.thecut.com/2016/08/is-elysium-healths-basis-the-fountain-of-youth.html Is Elysium Health’s Basis the Fountain of Youth?] written by Benjamin Wallace for New York Magazine. Published August 22, 2016; Accessed March 3, 2020</ref> After four years, Sinclair was offered a position with Elixir Pharmaceuticals, which his colleague and mentor Guarente had co-founded.

==Career==
===Sirtris Pharmaceuticals===
In 2004, Sinclair convinced philanthropist Paul Glenn to donate five million dollars to start an institute to study aging at Harvard, which Sinclair became director of. That same year, Sinclair cofounded a biotechnology company called Sirtris Pharmaceuticals with the assistance of Kevin Bitterman, a researcher at Harvard Medical School who had studied under Sinclair.<ref name=founding>[https://www.nytimes.com/2007/07/08/business/yourmoney/08stream.html An Age-Defying Quest (Red Wine Included)] Written by Jason Pontin for the New York Times. Published July 8, 2007; Accessed April 2, 2020</ref><ref name=bitter>[https://www.bizjournals.com/boston/blog/mass-high-tech/2008/05/polaris-bitterman-is-humble-about-his-early.html Polaris' Bitterman is humble about his early VC success] Written by Ryan McBride for the Boston Business Journal. Published May 1, 2008; Accessed on April 2, 2020</ref> In May 2007, Sirtris completed its initial public offering and raised 62 million dollars.

Sinclair’s company became one of the biggest in anti-aging research largely due to their work on a compound called resveratrol and their attempt at an anti-aging product called SRT501. This compound contained molecules that the lab claimed was a thousand times as potent as resveratrol, and would be able to activate sirtuins which would reverse the aging process.<ref name= athousandtimes>[https://www.technologyreview.com/s/409112/the-longevity-pill/ The Longevity Pill?] written by Emily Singer for the Massachusetts Institute of Technology Review. Published November 28, 2007; Accessed on April 1, 2020</ref><ref name=thousand>[https://techcrunch.com/2019/08/15/elysium-and-the-quest-to-bottle-the-fountain-of-youth/ Elysium and the quest to bottle the fountain of youth] Written by Alice Lloyd George for Tech Crunch. Published August 15, 2019; Accessed April 3, 2020</ref> Animal testing had shown their was potential for the formula to treat diabetes and neurological disorders, and human trials were planned to see if it affected Melas disease, which caused accelerated again as well as brain and muscle deterioration.

Sirtris Pharmaceuticals had to deal with lower federal funding in the late two-thousands, with Sinclair’s lab being reduced from eighteen personnel to four.<ref name=funding>[https://www.the-scientist.com/careers/follow-the-funding-35541 Follow the Funding] Written for Bob Grant for The Scientist Magazine. Published April 30, 2015; Accessed April 2, 2020</ref> The company was sold in 2008 for 720 million to GlaxoSmithKline, of which Sinclair received eight million.<ref name=purchase>[https://www.fiercebiotech.com/r-d/updated-gsk-moves-to-shutter-sirtris-cambridge-office-integrate-r-d Updated:GSK moves to shutter Sirtris’ Cambridge office, integrate R&D] Written by John Carroll and Ryan McBridge for FierceBiotech. Published March 12, 2013; Accessed April 2, 2020</ref> A drug using resveratrol and other compounds were tested by Sirtris in clinical trials over several years, but a drug that would help with diabetes or other diseases was not identified. GlaxoSmithKline ended research into resveratrol in 2010 because of its low efficacy and side effects. Sirtris’s existence as an independent unit ended in 2013 when it was absorbed into GlaxoSmithKline.<ref name =independence>[http://blogs.nature.com/news/2013/03/gsk-absorbs-controversial-longevity-company.html GSK absorbs controversial ‘longevity’ company] Written for Nature.com. Published March 13, 2013, Accessed April 2, 2020</ref>

===Other Endeavors===
During his time before and after his involvement with Sirtris Pharmaceuticals, Sinclair was regularly involved with other scientific startups and research groups. In 2008, he was invited to join the scientific advisory board of Shaklee, a supplement company selling a product called “Vivix”, a grape-flavored anti-aging supplement.<ref name=grape>[https://blogs.wsj.com/health/2008/12/26/harvard-researcher-tied-to-shaklee-anti-aging-tonic-vivix/ Harvard Researcher Tied to Shaklee ‘Anti-Aging Tonic’ Vivix] Written by Jacob Goldstein for The Wall Street Journal. Published Decebember 26, 2008; Accessed April 3, 2020</ref> In 2015, Sinclair was funded by the United States Department of Defense to research survival and recovery of soldiers on the battlefield and three years later he started “Arc Bio”, a tech startup with researchers from Harvard University and Stanford University, to develop a disease database to help stop outbreaks and reduce laboratory testing time.<ref name=fierce>[https://www.fiercebiotech.com/medtech/illumina-scientist-s-startup-aims-to-rapidly-detect-drug-resistance-bacterial-dna Illumina scientist’s startup aims to rapidly detect drug resistance in bacterial DNA] written by Conor Hale for Fierce BioTech. Published July 25, 2018; Accessed March 3, 2020</ref><ref name=also>[https://www.bizjournals.com/boston/news/2018/07/24/harvard-stanford-geneticists-launch-biotech-to.html Harvard, Stanford geneticists launch biotech to fight deadly bacteria] Written by Allison DeAngelis for the Boston Business Journal. Published July 24, 2018; Accessed April 2, 2020</ref><ref name=defense>[https://www.smh.com.au/lifestyle/never-say-die-david-sinclairs-antiageing-quest-20150916-gjocnm.html Never say die: David Sinclair's anti-ageing quest] Written by John Zubrzycki for the Sydney Morning Herald. Published October 1, 2015; Accessed April 2, 2020</ref> Sinclair co-founded a company called Life Biosciences in 2017 and raised over seventy-five million dollars in its first two years.<ref name=pepsi>[https://www.fastcompany.com/90314848/pepsicos-top-scientist-is-joining-the-fight-to-help-you-live-forever PepsiCo’s top scientist is joining the fight to help you live forever] Written by Rina Raphael for Fast Company. Published March 4, 2019; Accessed April 6, 2020</ref> In 2018, he worked with “Rejuvenate Bio”, a startup working to extend the life of, and cure diseases found in, dogs.<ref name=dogs>[https://www.technologyreview.com/s/611018/a-stealthy-harvard-startup-wants-to-reverse-aging-in-dogs-and-humans-could-be-next/ A stealthy Harvard startup wants to reverse aging in dogs, and humans could be next] Written by Antonio Regalado for the Massachusetts Institute of Technology Review. Published May 9, 2018; Accessed April 2, 2020</ref> Sinclair is also an investor in a company called “InsideTracker”, which attempts to measure peoples lifespans.<ref name=fountain>[https://khn.org/news/a-fountain-of-youth-pill-sure-if-youre-a-mouse/ A ‘Fountain of Youth’ Pill? Sure, If You’re A Mouse] written by Marisa Taylor for Kaiser Health News. Published February 11, 2020; Accessed March 3, 2020.</ref>

==Research==
One of the main focus’s of Sinclair’s research has been his work on a compound called resveratrol, with which he was able to extend the life of mice by twenty-four percent, and fifty-nine percent in flies and worms.<ref name = worms>[https://www.nytimes.com/2018/11/19/health/human-life-span.html How Long Can People Live?] Written by Nicholas Bakalar for the New York Times. Published November 19, 2018; Accessed April 2, 2020</ref> The mice used in this study were overweight, yet their longevity was as long as the mice of normal weight, most likely due to increased insulin sensitivity.<ref name =never>[https://www.forbes.com/forbes/2009/0608/022-harvard-pharmaceutical-science-ideas-opinions.html#954f93e74efc Never Say Die] written by Robert Langreth for Forbes Magazine. Published May 21, 2009; Accessed April 2, 2020</ref> Mice, along with other animals with shorter lifespans such as worms and fruit flies are often used in Sinclair’s research as human trails of medicines can take decades for results. Early in his research, Sinclair screened many food products to see which held the highest amounts of resveratrol, finally settling on red wine. That the chemical is found in red wine was at least initially thought to help explain the “French Paradox”, which is shorthand for the observation that French life expectancies are not lower than normal despite a generally heavy diet of fatty foods.<ref name= french>[https://www.nytimes.com/2003/08/24/health/lifeextending-chemical-is-found-in-certain-red-wines.html Life-Extending Chemical Is Found in Certain Red Wines] Written by Nicholas Wade for the New York Times. Published August 24, 2003; Accessed March 18, 2020</ref>

Sinclair’s work has also focused upon calorie restriction, and during his research, he identified genes that made yeast consume fewer calories, yet live 30% longer. Sinclair has stated his belief that calorie restrictive diets cause the body to focus on self repair, and that a compound found in cells called nicotinamide adenine dinucleotide (NAD) could be used to induce this repair state in the body even without calorie restriction.<ref name=Harv>[https://harvardmagazine.com/2017/09/anti-aging-breakthrough Anti-Aging Approaches] Written by Marina Bolotnikova for Harvard Magazine. Published for the September-October 2017 Issue; Accessed April 3, 2020</ref> In 2013, Sinclair published a study claiming that a family of proteins called sirtuins, which help regulate other cells, became overwhelmed with DNA repair work over time, and were then unable to read genetic information due to a lack of NAD, leading to aging.<ref name=fountains>[https://www.bostonmagazine.com/health/2019/10/29/david-sinclair/ Has Harvard’s David Sinclair Found the Fountain of Youth?] Written by Catherine Elton for Boston Magazine. Published October 29, 2019; Accessed April 3, 2020</ref> To test this theory, one experiment involved “breaking” mouse DNA to see if it accelerated aging.<ref name = breaking>[https://www.thestar.com/life/health_wellness/opinion/2020/03/03/what-if-the-way-we-think-about-aging-is-wrong.html What if the way we think about aging is wrong?] Written by Christine Sismondo for The Star. Published March 3, 2020; Accessed April 2, 2020</ref> As humans age, they produce less and less NAD, and Sinclair believes that NAD supplementation could reverse aging caused by this process.<ref name =lessandless> [http://www.slate.com/articles/health_and_science/prudential_living_longer_project/2014/07/could_a_pill_slow_aging_geneticist_david_sinclair_thinks_so.html Could A Pill Slow Aging? Geneticist David Sinclair Thinks So] written by Jordan Teicher for Slate. Published December 31, 2014; Accessed March 3, 2020</ref> A 2017 study conducted on mice being given “NAD+” in their water resulted in the mice acting and looking younger.<ref name=water>[https://time.com/5159879/is-an-anti-aging-pill-on-the-horizon/ Is an Anti-Aging Pill on the Horizon?] Written by Alexandra Sifferlin for Time Magazine. Published February 15, 2018; Accessed April 3, 2020</ref> Sinclair has tried to commercialize molecules known as “NAD boosters” which he claims help with life span extension. In 2018, NASA granted Sinclair and a colleague a Post-Doctoral Award for his proposal to study the boosting of NAD to protect against the loss of musculature around the bones while in space.<ref name=finalfrontier>[https://www.nasa.gov/feature/nasa-selects-29-proposals-for-space-biology-research NASA Selects 29 Proposals for Space Biology Research] Written for NASA. Published October 5, 2018; Accessed April 6, 2020</ref>

Sinclair has also used a compound called nicotinamide mononucleotide (NMN) to help promote the creation of blood vessels near muscles and organs, causing a sixty percent increase in the treadmill running ability of the test mice.<ref name = NMN>[https://time.com/5209427/aging-nicotinamide-mononucleotide-nmn/ This Compound Can Reverse Aging in Mice. Will It Work in People?] Written by Alice Park for Time Magazine. Published March 22, 2018, Accessed April 2, 2020</ref> As resveratrol attempted to replicate a healthy diet, NMN is seemingly attempting to chemically replicate the effects of increased cardiovascular health.

Sinclair believes that aging should be labeled a “disease”, not only in order to free up funding in the medical community that reserves most research for the study of disease, but to treat the many disorders and diseases that are occurring due to what Sinclair views is their root cause; aging.<ref name=diseases>[https://www.themonthly.com.au/issue/2018/september/1535724000/ceridwen-dovey/can-david-sinclair-cure-old-age Can David Sinclair cure old age?] Written by Ceridwen Dovey for The Monthly. Published for the September 2018 Issue; Accessed April 2, 2020</ref> In this way, instead of treating many diseases in a “whack a mole” fashion, Sinclair believes that scientists can go right to the source and make it possible for humans to live to 150 years old.<ref name=fifty>[https://www.thetimes.co.uk/article/david-sinclair-nmn-the-anti-ageing-scientist-who-thinks-we-could-all-live-to-150-c0rnnppl3 David Sinclair, the anti-ageing scientist who thinks we could all live to 150] Written by Damian Whitworth for the Times. Published September 30, 2019; Accessed April 3, 2020</ref><ref name=disease-ish>[https://www.technologyreview.com/s/614080/what-if-aging-werent-inevitable-but-a-curable-disease/ What if aging weren’t inevitable, but a curable disease?] Written by David Adam for the Technology Review. Published August 19, 2019; Accessed April 3, 2020</ref> In the meantime however, Sinclair’s focus is to deal with illnesses such as heart disease, cancer, diabetes, and dementia through his NAD treatment.<ref name=ill>[https://www.washingtonpost.com/national/health-science/this-serious-scientist-is-working-on-an-anti-aging-pill--and-taking-it-himself/2015/08/17/07628214-3179-11e5-8f36-18d1d501920d_story.html This serious scientist is working on an anti-aging pill — and taking it himself] Written by Emily Mullin for the Washington Post. Published August 17, 2015; Accessed April 2, 2020</ref>

==Personal Life and Diet==
Some of his colleagues regard Sinclair as very persuasive, but sometimes lacking the patience and having too much passion for a scientist. His mentor Leonard Guarente has called him a "bold scientist," who is willing to take chances and try risky experiments." Sinclair's mother fell ill, having already lost her joy of life, and experienced suffering before dying. Sinclair became more determined than ever to extend not only the length of life but the youthful portion of life.<ref name=lifespaning/>

Sinclair's diet has changed because of his research; he eats more vegetables than meat, and takes supplements, including resveratrol and a NAD compound.<ref name=diet>[https://www.inc.com/jessica-stillman/slow-aging-tips-harvard-longevity-researcher.html This Harvard Researcher Studied How to Slow Aging for 20 Years. He's Made These 3 Changes to His Own Routine] Written by Jessica Stillman for INC. Published on August 27, 2019; Accessed April 2, 2020</ref> He believes in a practice called "hormesis," which involves introducing metabolic stress by intermittent fasting and metabolic stress.<ref name=best/> He has summed up this approach as "Every day, try to be hungry and out of breath."<ref name=best>[https://www.newyorker.com/magazine/2019/05/20/can-we-live-longer-but-stay-younger Can We Live Longer but Stay Younger?] Written by Adam Gopnik for The New Yorker. Published May 13, 2019; Accessed April 2, 2020</ref> With his medical products, Sinclair believes he has extended his biological clock by two decades.<ref name=decades>[https://www.tampabay.com/health/medical-news/scientists-may-be-closer-than-you-think-to-an-anti-aging-pill-but-beware-of-the-hype-20190212/ Scientists may be closer than you think to an anti-aging pill. But beware of the hype.] Written by Marisa TaylorKaiser for the Tampa Bay Times. Published February 11, 2019; Accessed April 6, 2020.</ref> He also estimates that at least a third of his colleagues are taking experimental anti-aging molecules.

==Publications==
*[https://genetics.med.harvard.edu/sinclair/publications.php 148 Publications produced by The Sinclair Lab]
In 2018, Sinclair became an officer of the Order of Australia.<ref name=order>[https://www.abc.net.au/radio/programs/national-mornings/david-sinclair/9365076 Anti-ageing with Officer of The Order of Australia David Sinclair] Written by Josh Szeps for ABC AU. Published January 26, 2018; Accessed April 6, 2020</ref> In 2019, Sinclair and journalist Matthew LaPlante released a book entitled Lifespan: Why We Age - and Why We Don't Have To. This book discusses not just the ways medicine could extend human lifespans, but the societal and ethical implications of such an occurrence.<ref name=enlightenment>[https://www.nature.com/articles/d41586-019-02667-5 The enlightenment of age] Written by Toren Finkel for Nature.com. Published September 10, 2019; Accessed April 2, 2020</ref> Sinclair calls aging a "disease" in the book, a concept not widely agreed with among the medical community. This designation has restricted funding for anti-aging research, according to Sinclair. On October 6, 2019, Lifespan was number twelve on the New York Times Best Seller List under "Hardcover Nonfiction" books.<ref name=hardcover>[https://www.nytimes.com/books/best-sellers/2019/10/05/hardcover-nonfiction/ Hardcover Nonfiction] Written for the New York Times. Published October 6, 2019; Accessed April 2, 2020</ref>

==Media==
Sinclair has appeared on many television and radio shows, as well as podcasts such as "The Joe Rogan Experience."<ref name=rogan>[https://www.maxim.com/news/rewind-epigenetic-clock-study-2019-9 JOE ROGAN INTRIGUED BY NEW STUDY THAT HINTS 'BIOLOGICAL AGE' CAN BE REVERSED] Written by Zeynep Yenisey for Maxim Magazine. Published September 11, 2019; Accessed April 6, 2020</ref>

==Awards==
Sinclair has received honors for his research, such as inclusion as one of Time Magazines 100 Most Influential People of 2014, and as part of their "Healthcare 50" in 2018.<ref name= healthy>[https://time.com/collection/health-care-50/5425092/david-sinclair/ David Sinclair: Fighting Old Age] Written for Time Magazine. Published December 1, 2018; Accessed March 18, 2020.</ref><ref name=onehundred>[https://time.com/collection-post/70863/david-sinclair-2014-time-100/ David Sinclair] Written by David Agus for Time Magazine. Published April 23, 2014; Accessed April 3, 2020</ref>

==References==
<references />

==External links==
*[https://twitter.com/davidasinclair Twitter]
*[https://www.facebook.com/davidsinclairphd Facebook]
*[https://www.instagram.com/davidsinclairphd/ Instagram]
*[https://www.linkedin.com/in/sinclairda/ LinkedIn]
*[https://orcid.org/0000-0002-9936-436X ORCHID]
*[https://connects.catalyst.harvard.edu/Profiles/display/Person/17959 Harvard Catalyst]
*[https://genetics.med.harvard.edu/sinclair/ The Sinclair Lab]
*[https://lifespanbook.com/ Life Span (Book)]
*[https://genetics.med.harvard.edu/sinclair/publications.php Sinclair Lab Publications]
*[https://genetics.med.harvard.edu/sinclair/people/sinclair.php Harvard Medical Biography]
*[https://genetics.hms.harvard.edu/faculty-staff/david-andrew-sinclair Scholarly Publications]

[[Category:Key Figures]]
[[Category:Full index]]