Natural communication breakdown in aging

A naturally produced compound rewinds aspects of age-related demise in mice.

Researchers have discovered a cause of aging in mammals that may be reversible.

The essence of this finding is a series of molecular events that enable communication inside cells between the nucleus and mitochondria. As communication breaks down, aging accelerates. By administering a molecule naturally produced by the human body, scientists restored the communication network in older mice. Subsequent tissue samples showed key biological hallmarks that were comparable to those of much younger animals.

This image shows and labels the mitochondria.

“The aging process we discovered is like a married couple—when they are young, they communicate well, but over time, living in close quarters for many years, communication breaks down,” said Harvard Medical School Professor of Genetics David Sinclair, senior author on the study. “And just like with a couple, restoring communication solved the problem.”

This study was a joint project between Harvard Medical School, the National Institute on Aging, and the University of New South Wales, Sydney, Australia, where Sinclair also holds a position.

The findings are published Dec. 19 in Cell.

Communication breakdown

Mitochondria are often referred to as the cell’s “powerhouse,” generating chemical energy to carry out essential biological functions. These self-contained organelles, which live inside our cells and house their own small genomes, have long been identified as key biological players in aging. As they become increasingly dysfunctional overtime, many age-related conditions such as Alzheimer’s disease and diabetes gradually set in.

Researchers have generally been skeptical of the idea that aging can be reversed, due mainly to the prevailing theory that age-related ills are the result of mutations in mitochondrial DNA—and mutations cannot be reversed.

Sinclair and his group have been studying the fundamental science of aging—which is broadly defined as the gradual decline in function with time—for many years, primarily focusing on a group of genes called sirtuins. Previous studies from his lab showed that one of these genes, SIRT1, was activated by the compound resveratrol, which is found in grapes, red wine and certain nuts.

The is the SIRT1 protein.

Ana Gomes, a postdoctoral scientist in the Sinclair lab, had been studying mice in which this SIRT1 gene had been removed. While they accurately predicted that these mice would show signs of aging, including mitochondrial dysfunction, the researchers were surprised to find that most mitochondrial proteins coming from the cell’s nucleus were at normal levels; only those encoded by the mitochondrial genome were reduced.

“This was at odds with what the literature suggested,” said Gomes.

As Gomes and her colleagues investigated potential causes for this, they discovered an intricate cascade of events that begins with a chemical called NAD and concludes with a key molecule that shuttles information and coordinates activities between the cell’s nuclear genome and the mitochondrial genome. Cells stay healthy as long as coordination between the genomes remains fluid. SIRT1’s role is intermediary, akin to a security guard; it assures that a meddlesome molecule called HIF-1 does not interfere with communication.

For reasons still unclear, as we age, levels of the initial chemical NAD decline. Without sufficient NAD, SIRT1 loses its ability to keep tabs on HIF-1. Levels of HIF-1 escalate and begin wreaking havoc on the otherwise smooth cross-genome communication. Over time, the research team found, this loss of communication reduces the cell’s ability to make energy, and signs of aging and disease become apparent.

“This particular component of the aging process had never before been described,” said Gomes.

While the breakdown of this process causes a rapid decline in mitochondrial function, other signs of aging take longer to occur. Gomes found that by administering an endogenous compound that cells transform into NAD, she could repair the broken network and rapidly restore communication and mitochondrial function. If the compound was given early enough—prior to excessive mutation accumulation—within days, some aspects of the aging process could be reversed.

This is a diagram which shows what happens when the nucleus breaks down.

Cancer connection

Examining muscle from two-year-old mice that had been given the NAD-producing compound for just one week, the researchers looked for indicators of insulin resistance, inflammation and muscle wasting. In all three instances, tissue from the mice resembled that of six-month-old mice. In human years, this would be like a 60-year-old converting to a 20-year-old in these specific areas.

One particularly important aspect of this finding involvesHIF-1. More than just an intrusive molecule that foils communication, HIF-1 normally switches on when the body is deprived of oxygen. Otherwise, it remains silent. Cancer, however, is known to activate and hijack HIF-1. Researchers have been investigating the precise role HIF-1 plays in cancer growth.

“It’s certainly significant to find that a molecule that switches on in many cancers also switches on during aging,” said Gomes. “We’re starting to see now that the physiology of cancer is in certain ways similar to the physiology of aging. Perhaps this can explain why the greatest risk of cancer is age.”

“There’s clearly much more work to be done here, but if these results stand, then certain aspects of aging may be reversible if caught early,” said Sinclair.

The researchers are now looking at the longer-term outcomes of the NAD-producing compound in mice and how it affects the mouse as a whole. They are also exploring whether the compound can be used to safely treat rare mitochondrial diseases or more common diseases such as Type 1 and Type 2 diabetes. Longer term, Sinclair plans to test if the compound will give mice a healthier, longer life.

Notes about this neurogenetics and aging research

The Sinclair lab is funded by the National Institute on Aging (NIA/NIH), the Glenn Foundation for Medical Research, the Juvenile Diabetes Research Foundation, the United Mitochondrial Disease Foundation and a gift from the Schulak family.

Written by David Cameron
Contact: David Cameron – Harvard University
Source: Harvard University press release
Image Source: The images are credited to Ana Gomes and are adapted from the Harvard press release.
Original Research: Abstract for “Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging” by Ana P. Gomes, Nathan L. Price, Alvin J.Y. Ling, Javid J. Moslehi, Magdalene K. Montgomery, Luis Rajman, James P. White, João S. Teodoro, Christiane D. Wrann, Basil P. Hubbard, Evi M. Mercken, Carlos M. Palmeira, Rafael de Cabo, Anabela P. Rolo, Nigel Turner, Eric L. Bell, and David A. Sinclair in Cell. Published online December 19 2013 doi:10.1016/j.cell.2013.11.037


Here are four foods that are good sources of resveratrol

Red Grapes

Grapes don’t have to be fermented to contain this antioxidant. It’s actually found in the skin of red grapes along with other nutrients, such as minerals manganese and potassium and vitamins K, C and B1.

Peanut Butter

Peanut butter is great for dressing up apples and celery, but it also contains some resveratrol (up to .13 mg per cup). Peanut butter is a great source of niacin and manganese.

Dark Chocolate

In dark chocolate, resveratrol blends nicely with other antioxidants and also minerals, such as iron, copper and manganese. Who doesn’t like chocolate?

Blueberries

Blueberries don’t have quite as much resveratrol as grapes, but they are also a great source of other antioxidants, dietary fiber, vitamins C and K and manganese.


NAD

Nicotinamide adenine dinucleotide (NADH) supplements can be used by people struggling with clinical depression, those affected by Alzheimer’s disease and Parkinson’s disease as well as people with long term chronic fatigue syndrome. The beneficial effects of nicotinamide adenine dinucleotide (NADH) will best be felt after supplementation goes on for some period of time. Each patient may respond to the supplement in a different way.

Some condition specific uses of NADH are discussed below in brief.

Nicotinamide adenine dinucleotide (NADH) facilitates in providing relief from a health condition known as chronic fatigue syndrome.

The nicotinamide adenine dinucleotide (NADH) is primarily found in the foods like fish, all poultry, and cattle, and in yeast containing food products.

Though it may be a little hard to find, NADH supplements can be found in some health food stores.

Nevertheless, it is yet to be ascertained whether the body is able to effectively take up or make use of the NADH obtained from the above mentioned sources. In addition to the sources mentioned above, NADH is also available in the form of a dietary supplement.

Deficiencies and susceptibility

A deficiency of nicotinamide adenine dinucleotide (NADH) can only happen if the diet is deficient in vitamin B3, and except in long term alcoholics, deficiencies of the vitamin B3 is almost unknown in the modern western world.

Tryptophan – Niacin – NAD = Anti-aging

tryp foodtryptryptophan and niacin

Chocolate, oats, dried dates, milk, yogurt, cottage cheese, red meat, eggs, fish, poultry, sesame, chickpeas, almonds, sunflower seeds, pumpkin seeds, buckwheat, spirulina, bananas, and peanuts.

Tryptophan

For many organisms (including humans), tryptophan is needed to prevent illness or death, but cannot be synthesized by the organism and must be ingested; in short, it is an essential amino acid. Amino acids, including tryptophan, act as building blocks in protein biosynthesis, and proteins are required to sustain life. In addition, tryptophan functions as a biochemical precursor for the following compounds (see also figure to the right):

  • Serotonin (a neurotransmitter), synthesized via tryptophan hydroxylase.[9][10] Serotonin, in turn, can be converted to melatonin (a neurohormone), via N-acetyltransferase and 5-hydroxyindole-O-methyltransferase activities.[11]
  • Niacin, also known as vitamin B3, is synthesized from tryptophan via kynurenine and quinolinic acids as key biosynthetic intermediates.[12]
  • Auxins (a class of phytohormones) are synthesized from tryptophan.[13]
  • The disorder fructose malabsorption causes improper absorption of tryptophan in the intestine, reduced levels of tryptophan in the blood,[14] and depression.[15] Some studies did not find reduced tryptophan in cases of lactose maldigestion.[14]
  • Niacin and its derivative nicotinamide are dietary precursors of nicotinamide adenine dinucleotide (NAD), which can be phosphorylated (NADP) and reduced (NADH and NADPH). NAD functions in oxidation-reduction (redox) reactions and non-redox reactions. (More information)
  • Pellagra is the disease of severe niacin deficiency. It is characterized by symptoms affecting the skin, the digestive system, and the nervous system and can lead to death if left untreated. (More information)
  • Dietary tryptophan can be converted to niacin, although the efficiency of conversion is low in humans and affected by deficiencies in other nutrients. (More information)
  • Causes of niacin deficiency include inadequate oral intake, poor bioavailability from unlimed grains, defective tryptophan absorption, metabolic disorders, and the long-term use of chemotherapeutic treatments. (More information)
  • The requirements for niacin are based on the urinary excretion of niacin metabolites. (More information)
  • NAD is the sole substrate for PARP enzymes involved in DNA repair activity in response to DNA strand breaks; thus, NAD is critical for genome stability. Several studies, mostly using in vitro and animal models, suggest a possible role for niacin in cancer prevention. Nevertheless, large studies are needed to investigate the association between niacin deficiency and cancer risk in human populations. (More information)
  • Despite promising initial results, nicotinamide administration has failed to prevent or delay the onset of type 1 diabetes in high-risk relatives of type 1 diabetics. Future research might explore the use of nicotinamide in combined therapy and evaluate activators of NAD-dependent enzymes. (More information)
  • At pharmacologic doses, niacin, but not nicotinamide, improves the lipid profile and reduces coronary events and total mortality in patients at high risk for coronary heart disease. Several clinical trials have explored the cardiovascular benefit of niacin in combination with other lipid-lowering medications. (More information)
  • Elevated tryptophan breakdown and niacin deficiency have been reported in HIV-positive people. This population is also at high risk for cardiovascular disease, and current data show that they could benefit from niacin supplementation. (More information)
  • The tolerable upper intake level (UL) for niacin is based on skin flushing, niacin’s most prominent side effect. A new drug, laropiprant, has been developed to reduce skin flushing. Adverse effects have also been reported with pharmacologic doses of niacin administrated alone or in combination with other lipid-lowering medications. (More information)
  • Niacin is a water-soluble vitamin, which is also known as nicotinic acid or vitamin B3. Nicotinamide is the derivative of niacin and used by the body to form the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The chemical structures of the various forms of niacin are shown (Figure 1). None of the forms are related to the nicotine found in tobacco, although their names are similar (1).

Function

  • Oxidation-reduction (redox) reactions
  • Living organisms derive most of their energy from oxidation-reduction (redox) reactions, which are processes involving the transfer of electrons. Over 400 enzymes require the niacin coenzymes, NAD and NADP, mainly to accept or donate electrons for redox reactions (2). NAD functions most often in energy-producing reactions involving the degradation (catabolism) of carbohydrates, fats, proteins, and alcohol. NADP functions more often in biosynthetic (anabolic) reactions, such as in the synthesis of all macromolecules, including fatty acids and cholesterol (1, 3).

Non-redox reactions

  • The niacin coenzyme, NAD, is the substrate (reactant) for at least four classes of enzymes that separate the nicotinamide moiety from NAD and transfer ADP-ribose to acceptors.
  • Mono-ADP-ribosyltransferase enzymes were first discovered in certain bacteria, where they mediate the action of toxins, such as cholera and diptheria. In mammalian cells, these enzymes transfer an ADP-ribose residue from NAD to a specific amino acid of a target protein, with the creation of an ADP-ribosylated protein and the release of nicotinamide. Mono ADP-ribosylation reactions reversibly modify the activity of acceptor proteins, such as G-proteins that bind guanosine-5′-triphosphate (GTP) and act as intermediaries in a number of cell-signaling pathways (4).
  • Poly-ADP-ribose polymerases (PARPs) are enzymes that catalyze the transfer of polymers of ADP-ribose from NAD to acceptor proteins. PARPs appear to function in DNA repair and stress responses, cell signaling, transcription, regulation, apoptosis, chromatin structure, and cell differentiation, suggesting a role for NAD in cancer prevention (3). At least six different PARPs have been identified, and although their functions are not yet fully understood, their existence indicates a potential for considerable consumption of NAD (5, 6).
  • A new nomenclature has been proposed for enzymes catalyzing ADP-ribosylation: The PARP family was renamed ARTD, while ARTC designates the mono ADP-ribosyltransferase family (6).
  • ADP-ribosylcyclases catalyze the formation of cyclic ADP-ribose from ADP-ribose. Cyclic ADP-ribose works within cells to provoke the release of calcium ions from internal storage sites and probably also plays a role in cell signaling (1).
  • Sirtuins are a class of NAD-dependent deacetylase enzymes that remove acetyl groups from the acetylated lysine residues of target proteins. During the deacetylation process, an ADP-ribose is added to the acetyl group to produce O-acetyl-ADP-ribose. Both acetylation and ADP-ribosylation are known post-translational modifications that affect protein activities. The initial interest in sirtuins followed the discovery that their activation could mimic calorie restriction, which has been shown to increase lifespan in lower organisms. Such a role in mammals is controversial, although sirtuins are energy-sensing regulators involved in signaling pathways that could play important roles in delaying the onset of age-related diseases (e.g., cardiovascular disease, cancer, dementia, arthritis). To date, the spectrum of their biological functions include gene silencing, DNA damage repair, cell cycle regulation, and cell differentiation (7).

Summary

  • Niacin and its derivative nicotinamide are dietary precursors of nicotinamide adenine dinucleotide (NAD), which can be phosphorylated (NADP) and reduced (NADH and NADPH). NAD functions in oxidation-reduction (redox) reactions and non-redox reactions. (More information)
  • Pellagra is the disease of severe niacin deficiency. It is characterized by symptoms affecting the skin, the digestive system, and the nervous system and can lead to death if left untreated. (More information)
  • Dietary tryptophan can be converted to niacin, although the efficiency of conversion is low in humans and affected by deficiencies in other nutrients. (More information)
  • Causes of niacin deficiency include inadequate oral intake, poor bioavailability from unlimed grains, defective tryptophan absorption, metabolic disorders, and the long-term use of chemotherapeutic treatments. (More information)
  • The requirements for niacin are based on the urinary excretion of niacin metabolites. (More information)
  • NAD is the sole substrate for PARP enzymes involved in DNA repair activity in response to DNA strand breaks; thus, NAD is critical for genome stability. Several studies, mostly using in vitro and animal models, suggest a possible role for niacin in cancer prevention. Nevertheless, large studies are needed to investigate the association between niacin deficiency and cancer risk in human populations. (More information)
  • Despite promising initial results, nicotinamide administration has failed to prevent or delay the onset of type 1 diabetes in high-risk relatives of type 1 diabetics. Future research might explore the use of nicotinamide in combined therapy and evaluate activators of NAD-dependent enzymes. (More information)
  • At pharmacologic doses, niacin, but not nicotinamide, improves the lipid profile and reduces coronary events and total mortality in patients at high risk for coronary heart disease. Several clinical trials have explored the cardiovascular benefit of niacin in combination with other lipid-lowering medications. (More information)
  • Elevated tryptophan breakdown and niacin deficiency have been reported in HIV-positive people. This population is also at high risk for cardiovascular disease, and current data show that they could benefit from niacin supplementation. (More information)
  • The tolerable upper intake level (UL) for niacin is based on skin flushing, niacin’s most prominent side effect. A new drug, laropiprant, has been developed to reduce skin flushing. Adverse effects have also been reported with pharmacologic doses of niacin administrated alone or in combination with other lipid-lowering medications. (More information)
  • Niacin is a water-soluble vitamin, which is also known as nicotinic acid or vitamin B3. Nicotinamide is the derivative of niacin and used by the body to form the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The chemical structures of the various forms of niacin are shown (Figure 1). None of the forms are related to the nicotine found in tobacco, although their names are similar (1).
  • Figure 1. Chemical Structures of Niacin and Related Compounds. Niacin is also known as nicotinic acid or vitamin B3. nicotinamide is the derivative of niacin that is used to form the coenzymes NAD and NADP.

Function

  • Oxidation-reduction (redox) reactions
  • Living organisms derive most of their energy from oxidation-reduction (redox) reactions, which are processes involving the transfer of electrons. Over 400 enzymes require the niacin coenzymes, NAD and NADP, mainly to accept or donate electrons for redox reactions (2). NAD functions most often in energy-producing reactions involving the degradation (catabolism) of carbohydrates, fats, proteins, and alcohol. NADP functions more often in biosynthetic (anabolic) reactions, such as in the synthesis of all macromolecules, including fatty acids and cholesterol (1, 3).

Non-redox reactions

  • The niacin coenzyme, NAD, is the substrate (reactant) for at least four classes of enzymes that separate the nicotinamide moiety from NAD and transfer ADP-ribose to acceptors.
  • Mono-ADP-ribosyltransferase enzymes were first discovered in certain bacteria, where they mediate the action of toxins, such as cholera and diptheria. In mammalian cells, these enzymes transfer an ADP-ribose residue from NAD to a specific amino acid of a target protein, with the creation of an ADP-ribosylated protein and the release of nicotinamide. Mono ADP-ribosylation reactions reversibly modify the activity of acceptor proteins, such as G-proteins that bind guanosine-5′-triphosphate (GTP) and act as intermediaries in a number of cell-signaling pathways (4).
  • Poly-ADP-ribose polymerases (PARPs) are enzymes that catalyze the transfer of polymers of ADP-ribose from NAD to acceptor proteins. PARPs appear to function in DNA repair and stress responses, cell signaling, transcription, regulation, apoptosis, chromatin structure, and cell differentiation, suggesting a role for NAD in cancer prevention (3). At least six different PARPs have been identified, and although their functions are not yet fully understood, their existence indicates a potential for considerable consumption of NAD (5, 6).
  • A new nomenclature has been proposed for enzymes catalyzing ADP-ribosylation: The PARP family was renamed ARTD, while ARTC designates the mono ADP-ribosyltransferase family (6).
  • ADP-ribosylcyclases catalyze the formation of cyclic ADP-ribose from ADP-ribose. Cyclic ADP-ribose works within cells to provoke the release of calcium ions from internal storage sites and probably also plays a role in cell signaling (1).
  • Sirtuins are a class of NAD-dependent deacetylase enzymes that remove acetyl groups from the acetylated lysine residues of target proteins. During the deacetylation process, an ADP-ribose is added to the acetyl group to produce O-acetyl-ADP-ribose. Both acetylation and ADP-ribosylation are known post-translational modifications that affect protein activities. The initial interest in sirtuins followed the discovery that their activation could mimic calorie restriction, which has been shown to increase lifespan in lower organisms. Such a role in mammals is controversial, although sirtuins are energy-sensing regulators involved in signaling pathways that could play important roles in delaying the onset of age-related diseases (e.g., cardiovascular disease, cancer, dementia, arthritis). To date, the spectrum of their biological functions include gene silencing, DNA damage repair, cell cycle regulation, and cell differentiation (7).

Deficiency: Pellagra

  • The late stage of severe niacin deficiency is known as pellagra. Early records of pellagra followed the widespread cultivation of corn in Europe in the 1700s (1). The disease is generally associated with poorer social classes whose chief dietary staple consisted of cereals like corn or sorghum. Pellagra was also common in the southern United States during the early 1900s where income was low and corn products were a major dietary staple (8).
  • Interestingly, pellagra was not known in Mexico, where corn was also an important dietary staple and much of the population was also poor. In fact, corn contains appreciable amounts of niacin, but it is present in a bound form that is not nutritionally available to humans. The traditional preparation of corn tortillas in Mexico involves soaking the corn in a lime (calcium oxide) solution, prior to cooking. Heating the corn in an alkaline solution results in the release of bound niacin, increasing its bioavailability (9).
  • The most common symptoms of niacin deficiency involve the skin, the digestive system, and the nervous system (3). The symptoms of pellagra are commonly referred to as the three D’s: dermatitis, diarrhea, and dementia. A fourth D, death, occurs if pellagra is left untreated (10). In the skin, a thick, scaly, darkly pigmented rash develops symmetrically in areas exposed to sunlight. In fact, the word “pellagra” comes from “pelle agra,” the Italian phrase for rough or raw skin. Symptoms related to the digestive system include inflammation of the mouth and tongue (“bright red tongue”), vomiting, constipation, abdominal pain, and ultimately, diarrhea.
  • Gastrointestinal disorders and diarrhea contribute to the ongoing malnourishment of the subjects. Neurologic symptoms include headache, apathy, fatigue, depression, disorientation, and memory loss and are more consistent with delirium than with the historically described dementia (11). Disease presentations vary in appearance since the classic triad rarely presents in its entirety. The absence of dermatitis, for example, is known as pellagra sine pellagra.

Treatment of pellagra

  • To treat pellagra, the World Health Organization (WHO) recommends administering nicotinamide to avoid the flushing commonly caused by niacin (see Safety). Treatment guidelines suggest using 300 mg nicotinamide per day orally in divided doses, or 100 mg per day parenterally in divided doses, for three to four weeks (12, 13). Because patients with pellagra often display additional vitamin deficiencies, administration of a vitamin B-complex preparation is advised.

Tryptophan metabolism

  • In addition to its synthesis from dietary niacin, NAD can be synthesized from the dietary amino acid tryptophan via the kynurenine pathway (see Figure 2 below). The relative ability to make this conversion varies greatly from mice to humans. The first step is catalyzed by the extrahepatic enzyme indoleamine 2,3-dioxygenase (IDO), which is responsible for the oxidative cleavage of tryptophan. The chronic stimulation of tryptophan oxidation, mediated by an increased activity of IDO and/or inadequate niacin levels, is observed in a number of diseases, including human immunodeficiency virus (HIV) infection (see HIV/AIDS). In healthy individuals, less than 2% of dietary tryptophan is converted to NAD by this tryptophan oxidation pathway (14).
  • Tryptophan metabolism plays an essential regulatory role by mediating immunological tolerance of the fetus during pregnancy (15). It is now understood that tryptophan oxidation in the placenta drives a physiologic tryptophan depletion that impairs the function of nearby maternal T-lymphocytes and prevents the rejection of the fetus. However, the synthesis of niacin from tryptophan is a fairly inefficient pathway that depends on enzymes requiring vitamin B6 and riboflavin, as well as an enzyme containing heme (iron). On average, 1 milligram (mg) of niacin can be synthesized from the ingestion of 60 mg of tryptophan. The term “niacin equivalent” (NE) is used to describe the contribution to dietary intake of all the forms of niacin that are available to the body.
  • Thus, 60 mg of tryptophan are considered to be 1 mg NE. However, studies of pellagra in the southern US during the early twentieth century indicated that the diets of many individuals who suffered from pellagra contained enough NE to prevent pellagra (10), challenging the idea that 60 mg of dietary tryptophan are equivalent to 1 mg of niacin. In particular, one study in young men found that the tryptophan content of the diet had no effect on the decrease in red blood cell niacin content that resulted from low dietary niacin (16).

Causes of niacin deficiency

  • Niacin deficiency or pellagra may result from inadequate dietary intake of niacin and/or tryptophan. As mentioned above, other nutrient deficiencies may also contribute to the development of niacin deficiency. Niacin deficiency, often associated with malnutrition, is observed in the homeless population, in individuals suffering from anorexia nervosa or obesity, and in consumers of diets high in maize and poor in animal proteins (17-20).
  • Patients with Hartnup’s disease, a hereditary disorder resulting in defective tryptophan absorption, have developed pellagra (3). Other malabsorptive states that can lead to pellagra include Crohn’s disease and megaduodenum (21, 22). Carcinoid syndrome, a condition of increased secretion of serotonin and other catecholamines by carcinoid tumors, may also result in pellagra due to increased utilization of dietary tryptophan for serotonin rather than niacin synthesis. Further, prolonged treatment with the anti-tuberculosis drug Isoniazid has resulted in niacin deficiency (23).
  • Other pharmaceutical agents, including the immunosuppressive drugs Azathioprine and 6-Mercaptopurine, the anti-cancer drug 5-Fluorouracil, and Carbidopa, a drug given to people with Parkinson’s disease, are known to increase the reliance on dietary niacin by interfering with the tryptophan-kinurenine-niacin pathway. Finally, other populations at risk for niacin deficiency include dialysis patients, cancer patients (13, 24), individuals suffering from chronic alcoholism (11), and people with HIV (see HIV/AIDS).

Disease Prevention: Cancer

  • Studies of cultured cells (in vitro) provide evidence that NAD content influences mechanisms that maintain genomic stability. Loss of genomic stability, characterized by a high rate of damage to DNA and chromosomes, is a hallmark of cancer (28). The current understanding is that the pool of NAD is decreased during niacin deficiency and that it affects the activity of NAD-consuming enzymes rather than redox and metabolic functions (29). Among NAD-dependent reactions, poly ADP-ribosylations catalyzed by PARP enzymes are critical for the cellular response to DNA injury. After DNA damage, PARPs are activated.
  • The subsequent poly ADP-ribosylations of a number of signaling and structural molecules by PARPs were shown to facilitate DNA repair at DNA strand breaks. Cellular depletion of NAD has been found to decrease levels of the tumor suppressor protein p53, a target for poly ADP-ribosylation, in human breast, skin, and lung cells (27). The expression of p53 was also altered by niacin deficiency in rat bone marrow cells (30). Impairment of DNA repair caused by niacin deficiency could lead to genomic instability and drive tumor development in rat models (31, 32).
  • Both PARPs and sirtuins have been recently involved in the maintenance of heterochromatin, a chromosomal domain associated with genome stability, as well as in transcriptional gene silencing, telomere integrity, and chromosome segregation during cell division (33, 34). Neither the cellular NAD content nor the dietary intake of NAD precursors (niacin and tryptophan) necessary for optimizing protective responses following DNA damage has been determined, but both are likely to be higher than that required for the prevention of pellagra.

Bone marrow

  • Cancer patients often suffer from bone marrow suppression following chemotherapy, given that bone marrow is one of the most proliferative tissues in the body and thus a primary target for chemotherapeutic agents. Niacin deficiency was found to decrease bone marrow NAD and poly-ADP-ribose levels and increase the risk of chemically induced leukemia in rats (35). Conversely, a pharmacologic dose of niacin was able to increase NAD and poly ADP-ribose in bone marrow and decrease the development of leukemia in rats (36).
  • It has been suggested that niacin deficiency often observed in cancer patients could sensitize bone marrow tissue to the suppressive effect of chemotherapy. However, little is known regarding cellular NAD levels and the prevention of DNA damage or cancer in humans. One study in two healthy individuals involved elevating NAD levels in blood lymphocytes by supplementation with 100 mg/day niacin for eight weeks.
  • Compared to non-supplemented individuals, the supplemented individuals had reduced DNA strand breaks in lymphocytes exposed to free radicals in a test tube assay (37). However, niacin supplementation of up to 100 mg/day in 21 healthy smokers failed to provide any evidence of a decrease in cigarette smoke-induced genetic damage in blood lymphocytes compared to placebo (38).
  • More recently, the frequency of chromosome translocation was used to evaluate DNA damage in peripheral blood lymphocytes of 82 pilots chronically exposed to ionizing radiation, a known human carcinogen. In this observational study, the rate of chromosome aberrations was significantly lower in subjects with high (28.4 mg/day) compared to low (20.5 mg/day) dietary niacin intake (39).

Upper digestive tract

  • Generally, relationships between dietary factors and cancer are established first in epidemiological studies and followed up by basic cancer research at the cellular level. In the case of niacin, research on biochemical and cellular aspects of DNA repair has stimulated an interest in the relationship between niacin intake and cancer risk in human populations (40). A large case-control study found increased consumption of niacin, along with antioxidant nutrients, to be associated with decreased incidence of oral (mouth), pharyngeal (throat), and esophageal cancers in northern Italy and Switzerland (41, 42). An increase in daily niacin intake of 6.2 mg was associated with about a 40% decrease in cases of cancers of the mouth and throat, while a 5.2 mg increase in daily niacin intake was associated with a similar decrease in cases of esophageal cancer.

Skin

  • Niacin deficiency can lead to severe sunlight sensitivity in exposed skin. Given the implication of NAD-dependent enzymes in DNA repair, there has been some interest in the effect of niacin on skin health. In vitro and animal experiments have helped gather information, but human data on niacin/NAD status and skin cancer are severely limited. One study reported that niacin supplementation decreased the risk of ultraviolet light (UV)-induced skin cancers in mice, despite the fact that mice convert tryptophan to NAD more efficiently than rats and humans and thus do not get severely deficient (43).
  • Hyper-proliferation and impaired differentiation of skin cells can alter the integrity of the skin barrier and increase the occurrence of pre-malignant and malignant skin conditions. A protective effect of niacin was suggested by topical application of myristyl nicotinate, a niacin derivative, which successfully increased the expression of epidermal differentiation markers in subjects with photodamaged skin (44). The activation of the “niacin receptors,” GPR109A and GPR109B, by pharmacologic doses of niacin could be involved in improving skin barrier function. Conversely, differentiation defects in skin cancer cells were linked to the abnormal cellular localization of defective “niacin receptors” (45).
  • Nicotinamide restriction with subsequent depletion of cellular NAD was shown to increase oxidative stress-induced DNA damage in a precancerous skin cell model, implying a protective role of NAD-dependent pathways in cancer (46). Altered NAD availability also affects sirtuin expression and activity in UV-exposed human skin cells. Along with PARPs, NAD-consuming sirtuins could play an important role in the cellular response to photodamage and skin homeostasis (47).

Type 1 diabetes mellitus

  • Type 1 (insulin-dependent) diabetes mellitus in children is known to result from the autoimmune destruction of insulin-secreting β-cells in the pancreas. Prior to the onset of symptomatic diabetes, specific antibodies, including islet cell antibodies (ICA), can be detected in the blood of high-risk individuals. The ability to detect individuals at high risk for the development of IDDM led to the enrollment of high-risk siblings of children with IDDM into trials designed to prevent its onset. Evidence from in vitro and animal research indicates that high levels of nicotinamide protect β-cells from damage by toxic chemicals, inflammatory white blood cells, and reactive oxygen species. Pharmacologic doses of nicotinamide (up to 3 grams/day) were first used to protect β-cells in patients shortly after the onset of IDDM.
  • An analysis of 10 published trials (5 placebo-controlled) found evidence of improved β-cell function after one year of treatment with nicotinamide, but the analysis failed to find any clinical evidence of improved glycemic (blood glucose) control (48). However, high doses of nicotinamide could decrease insulin sensitivity in high-risk relatives of IDDM patients (49), which might explain the finding of improved β-cell function without concomitant improvement in glycemic control.

http://lpi.oregonstate.edu/mic/vitamins/niacin

https://en.wikipedia.org/wiki/Tryptophan

https://www.technologyreview.com/s/534636/the-anti-aging-pill/

Click to access bogan08.pdf

Cancer diet, ketogenic – high fat

keto diet no carbs and supplements brain cancer

How a young man delayed cancer progression with high fat and less carbs diet, ketogenic diet?

He eats and fasts. He credits his health to whole foods of greens and dietary supplements. Fats are from coconut oil, omega 3, eggs, fish oil and other veggie sources.

Sugar is food for cancer cells. He avoid sugar and carbs rich in sugar and derives his carbs from greens.

Nicotinamide Riboside converting 60yr old to 20yr old cells in mice, an anti-aging miracle (metabolic and brain issues)

Mitochondria, organelles on the right, interact with the cell’s nucleus to ensure a healthy, functioning cell.

cell

Researchers have discovered a cause of aging in mammals that may be reversible.

Aging Process

The essence of this finding is a series of molecular events that enable communication inside cells between the nucleus and mitochondria. As communication breaks down, aging accelerates. By administering a molecule naturally produced by the human body, scientists restored the communication network in older mice. Subsequent tissue samples showed key biological hallmarks that were comparable to those of much younger animals.

“The aging process we discovered is like a married couple—when they are young, they communicate well, but over time, living in close quarters for many years, communication breaks down,” said Harvard Medical School Professor of Genetics David Sinclair, senior author on the study. “And just like with a couple, restoring communication solved the problem.”

This study was a joint project between Harvard Medical School, the National Institute on Aging, and the University of New South Wales, Sydney, Australia, where Sinclair also holds a position.

The findings are published Dec. 19 in Cell.

Communication breakdown between Mitochondria and Nucleus

Mitochondria are often referred to as the cell’s “powerhouse,” generating chemical energy to carry out essential biological functions. These self-contained organelles, which live inside our cells and house their own small genomes, have long been identified as key biological players in aging. As they become increasingly dysfunctional overtime, many age-related conditions such as Alzheimer’s disease and diabetes gradually set in.

Researchers have generally been skeptical of the idea that aging can be reversed, due mainly to the prevailing theory that age-related ills are the result of mutations in mitochondrial DNA—and mutations cannot be reversed.

Sinclair and his group have been studying the fundamental science of aging—which is broadly defined as the gradual decline in function with time—for many years, primarily focusing on a group of genes called sirtuins. Previous studies from his lab showed that one of these genes, SIRT1, was activated by the compound resveratrol, which is found in grapes, red wine and certain nuts.

Sirt1 protein, red, circles the cell's chromosomes, blue. Image by Ana GomesSirt1 protein, red, circles the cell’s chromosomes, blue. Image by Ana Gomes

Ana Gomes, a postdoctoral scientist in the Sinclair lab, had been studying mice in which this SIRT1 gene had been removed. While they accurately predicted that these mice would show signs of aging, including mitochondrial dysfunction, the researchers were surprised to find that most mitochondrial proteins coming from the cell’s nucleus were at normal levels; only those encoded by the mitochondrial genome were reduced.

“This was at odds with what the literature suggested,” said Gomes.

How Nicotinamide Riboside Works = NAD, NR and Sirtuin Enzymes

There’s basically three important pieces of this puzzle. NAD+, Nicotinamine Riboside (NR) and Sirtuin Enzymes, all of which relate to the nucleus, mitochondria, and most importantly, the communication between the two in every cell.

It all begins with the mitochondria. Mitochondria have long been known as the “power houses” of our cells, as they are responsible for energy production in each specific cell; and therefore, throughout our entire body.

The nucleus, on the other hand, is the controller of the cell. The nucleus ensures that everything inside of the cell is going well, that all of the “employees” at “Cell Corporation” are doing their jobs effectively.

The problem, as Sinclair and Cantó, et al. discovered, occurs when communication between these two important organelles breaks down. When that happens, the cells begin to suffer the effects of age, producing less energy and not working as efficiently as possible. This failure manifests itself in aging – both in the skin, and in the skeletal and muscle structure.

That is to say, when the nucleus and mitochondria don’t communicate properly, everything falls apart.

This is where the three puzzle pieces fit in. This communication is promoted by an enzyme called Sirutin 1, or SIRT1. This enzyme is responsible, essentially, for ensuring outside molecules don’t interrupt the traffic between the nucleus and the cell wall.

SIRT1, in turn, is activated by a chemical called NAD+. NAD+ is what’s known as a co-substrate, which is basically an activator – a compound that ensures the activation of a certain molecule. NAD+ is the most important part of this whole equation.

Luckily for us, NAD+ is a naturally occurring molecule in our body. Without it, our cells would die quickly.

Note: Energy (Sun,Exercise,protein and healthy fats-rich food,negated by  toxins and stress and lack of sleep)

The sirtuins are a family of highly conserved NAD(+)-dependent deacetylases that act as cellular sensors to detect energy availability and modulate metabolic processes. Two sirtuins that are central to the control of metabolic processes are mammalian sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3), which are localized to the nucleus and mitochondria, respectively. Both are activated by high NAD(+) levels, a condition caused by low cellular energy status. By deacetylating a variety of proteins that induce catabolic processes while inhibiting anabolic processes, SIRT1 and SIRT3 coordinately increase cellular energy stores and ultimately maintain cellular energy homeostasis. Defects in the pathways controlled by SIRT1 and SIRT3 are known to result in various metabolic disorders. Consequently, activation of sirtuins by genetic or pharmacological means can elicit multiple metabolic benefits that protect mice from diet-induced obesity, type 2 diabetes, and nonalcoholic fatty liver disease.

Sirtuins are comprised of 7 proteins, and each has different target proteins. Sirtuin 1 (SIRT1) plays important roles in maintaining metabolic functions and immune responses, and SIRT3 protects cells from oxidative stress-induced cell death. Both SIRT1 and SIRT3 are regulated by metabolic status and aging. Hence, SIRT1 and SIRT3 have been researched in metabolic diseases, such as type 2 diabetes mellitus (DM), fatty liver, and heart diseases.

Unluckily, NAD+ levels decline as we age, resulting in wrinkles, bone deterioration, and muscle decline.

dysfunctional mitochondriaThis is where Sinclair and Cantó, et al.’s research comes in. They identified a new vitamin that can stoke the production of NAD+ — without the side effects of other NAD+ precursors like Nicotinic Acid, which causes severe flushing.

This NAD+ producer is nicotinamide riboside.

In both studies, the mice who were supplemented with NR showed powerful anti-aging effects, metabolic energy increases and improvements in cell repair and upkeep. This suggests that supplementation with this new vitamin is a possible key to halting the effects of aging.

Even more interesting, Cantó, et al. suggest that NR can also be used to “ameliorate metabolic and age-related disorders”. This can be applied to problems that arise from our metabolism and aging problems, like arthritis and type 2 diabetes.

It is important to note that these two studies have only been used on mice. There is a bit of a gap as far humans go. Specifically, the amount of NR necessary to induce a change is, at the current moment, nebulous.

Get your NR here

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Final anti-aging tips: Avoid medications/drugs if possible, get sunshine, take fresh air,clean water, whole foods, avoid sugar/soda/processed foods and get good sleep. Avoid anxiety and dwelling on problems, be happy and dance.