Houston, Texas, USA : Alzheimer’s patients are five to 10 times more likely to suffer unprovoked seizures compared to healthy individuals. Alzheimer’s patients often also have reduced levels of ascorbate, or vitamin C.
Ascorbate is an important antioxidant in the brain, particularly in the synapse, where it protects against oxidative stress. Ascorbate is released into the synapse as glutamate is cleared from the synapse, an exchange important for excitatory neurotransmission.
Fiona Harrison, Ph.D., and colleagues, investigated the role of ascorbate in susceptibility to seizures. Using genetically-modified mice that, like humans, depend on dietary ascorbate, they report that low ascorbate renders mice more susceptible to pharmacologically-induced seizures and alters the expression of several glutamate transporter genes. Even a single, mild seizure impacted memory in a mouse model for Alzheimer’s disease.
The study published in Neurobiology of Aging supports the importance of brain ascorbate levels in protecting against seizures and cognitive decline in Alzheimer’s disease.
Citation : Deborah J. Mi et al. Altered glutamate clearance in ascorbate deficient mice increases seizure susceptibility and contributes to cognitive impairment in APP/PSEN1 mice, Neurobiology of Aging. DOI: 10.1016/j.neurobiolaging.2018.08.002
A second study found that vitamin C regulates stem cell function and it curbs leukemia development.
Scientists discover vitamin C regulates stem cell function, curbs leukemia development
Not much is known about stem cell metabolism, but a new study from the Children’s Medical Center Research Institute at UT Southwestern (CRI) has found that stem cells take up unusually high levels of vitamin C, which then regulates their function and suppresses the development of leukemia.
“We have known for a while that people with lower levels of ascorbate (vitamin C) are at increased cancer risk, but we haven’t fully understood why. Our research provides part of the explanation, at least for the blood-forming system,” said Dr. Sean Morrison, the Director of CRI.
The metabolism of stem cells has historically been difficult to study because a large number of cells are required for metabolic analysis, while stem cells in each tissue of the body are rare. Techniques developed during the study, which was published in Nature, have allowed researchers to routinely measure metabolite levels in rare cell populations such as stem cells.
The techniques led researchers to discover that every type of blood-forming cell in the bone marrow had distinct metabolic signatures – taking up and using nutrients in their own individual way. One of the main metabolic features of stem cells is that they soak up unusually high levels of ascorbate. To determine if ascorbate is important for stem cell function, researchers used mice that lacked gulonolactone oxidase (Gulo) – a key enzyme that most mammals, including mice but not humans, use to synthesize their own ascorbate.
Loss of the enzyme requires Gulo-deficient mice to obtain ascorbate exclusively through their diet like humans do. This gave CRI scientists strict control over ascorbate intake by the mice and allowed them to mimic ascorbate levels seen in approximately 5 percent of healthy humans. At these levels, researchers expected depletion of ascorbate might lead to loss of stem cell function but were surprised to find the opposite was true – stem cells actually gained function. However, this gain came at the cost of increased instances of leukemia.
“Stem cells use ascorbate to regulate the abundance of certain chemical modifications on DNA, which are part of the epigenome,” said Dr. Michalis Agathocleous, lead author of the study, an Assistant Instructor at CRI, and a Royal Commission for the Exhibition of 1851 Research Fellow. “The epigenome is a set of mechanisms inside a cell that regulates which genes turn on and turn off. So when stem cells don’t receive enough vitamin C, the epigenome can become damaged in a way that increases stem cell function but also increases the risk of leukemia.”
This increased risk is partly tied to how ascorbate affects an enzyme known as Tet2, the study showed. Mutations that inactivate Tet2 are an early step in the formation of leukemia. CRI scientists showed that ascorbate depletion can limit Tet2 function in tissues in a way that increases the risk of leukemia.
These findings have implications for older patients with a common precancerous condition known as clonal hematopoiesis. This condition puts patients at a higher risk of developing leukemia and other diseases, but it is not well understood why certain patients with the condition develop leukemia and others do not. The findings in this study might offer an explanation.
“One of the most common mutations in patients with clonal hematopoiesis is a loss of one copy of Tet2. Our results suggest patients with clonal hematopoiesis and a Tet2 mutation should be particularly careful to get 100 percent of their daily vitamin C requirement,” Dr. Morrison said. “Because these patients only have one good copy of Tet2 left, they need to maximize the residual Tet2 tumor-suppressor activity to protect themselves from cancer.”
Researchers in the Hamon Laboratory for Stem Cell and Cancer Biology, in which Dr. Morrison is also appointed, intend to use the techniques developed as part of this study to find other metabolic pathways that control stem cell function and cancer development. They also plan to further explore the role of vitamin C in stem cell function and tissue regeneration.
Citation for second study: Michalis Agathocleous et al. Ascorbate regulates haematopoietic stem cell function and leukaemogenesis, Nature. DOI: 10.1038/nature23876
Vitamin C, also known as L-ascorbic acid, is a water-soluble vitamin that is naturally present in some foods, added to others, and available as a dietary supplement. Humans, unlike most animals, are unable to synthesize vitamin C endogenously, so it is an essential dietary component.
Vitamin C is required for the biosynthesis of collagen, L-carnitine, and certain neurotransmitters; vitamin C is also involved in protein metabolism. Collagen is an essential component of connective tissue, which plays a vital role in wound healing. Vitamin C is also an important physiological antioxidant and has been shown to regenerate other antioxidants within the body, including alpha-tocopherol (vitamin E). Ongoing research is examining whether vitamin C, by limiting the damaging effects of free radicals through its antioxidant activity, might help prevent or delay the development of certain cancers, cardiovascular disease, and other diseases in which oxidative stress plays a causal role. In addition to its biosynthetic and antioxidant functions, vitamin C plays an important role in immune function and improves the absorption of nonheme iron , the form of iron present in plant-based foods. Insufficient vitamin C intake causes scurvy, which is characterized by fatigue or lassitude, widespread connective tissue weakness, and capillary fragility.
The intestinal absorption of vitamin C is regulated by at least one specific dose-dependent, active transporter. Cells accumulate vitamin C via a second specific transport protein. In vitro studies have found that oxidized vitamin C, or dehydroascorbic acid, enters cells via some facilitated glucose transporters and is then reduced internally to ascorbic acid. The physiologic importance of dehydroascorbic acid uptake and its contribution to overall vitamin C economy is unknown.
Oral vitamin C produces tissue and plasma concentrations that the body tightly controls. Approximately 70%–90% of vitamin C is absorbed at moderate intakes of 30–180 mg/day. However, at doses above 1 g/day, absorption falls to less than 50% and absorbed, unmetabolized ascorbic acid is excreted in the urine. Results from pharmacokinetic studies indicate that oral doses of 1.25 g/day ascorbic acid produce mean peak plasma vitamin C concentrations of 135 micromol/L, which are about two times higher than those produced by consuming 200–300 mg/day ascorbic acid from vitamin C-rich foods. Pharmacokinetic modeling predicts that even doses as high as 3 g ascorbic acid taken every 4 hours would produce peak plasma concentrations of only 220 micromol/L.
The total body content of vitamin C ranges from 300 mg (at near scurvy) to about 2 g . High levels of vitamin C (millimolar concentrations) are maintained in cells and tissues, and are highest in leukocytes (white blood cells), eyes, adrenal glands, pituitary gland, and brain. Relatively low levels of vitamin C (micromolar concentrations) are found in extracellular fluids, such as plasma, red blood cells, and saliva.
Vitamin C Deficiency
Acute vitamin C deficiency leads to scurvy. The timeline for the development of scurvy varies, depending on vitamin C body stores, but signs can appear within 1 month of little or no vitamin C intake (below 10 mg/day). Initial symptoms can include fatigue (probably the result of impaired carnitine biosynthesis), malaise, and inflammation of the gums. As vitamin C deficiency progresses, collagen synthesis becomes impaired and connective tissues become weakened, causing petechiae, ecchymoses, purpura, joint pain, poor wound healing, hyperkeratosis, and corkscrew hairs. Additional signs of scurvy include depression as well as swollen, bleeding gums and loosening or loss of teeth due to tissue and capillary fragility. Iron deficiency anemia can also occur due to increased bleeding and decreased nonheme iron absorption secondary to low vitamin C intake. In children, bone disease can be present. Left untreated, scurvy is fatal.
Until the end of the 18th century, many sailors who ventured on long ocean voyages, with little or no vitamin C intake, contracted or died from scurvy. During the mid-1700s, Sir James Lind, a British Navy surgeon, conducted experiments and determined that eating citrus fruits or juices could cure scurvy, although scientists did not prove that ascorbic acid was the active component until 1932.
Today, vitamin C deficiency and scurvy are rare in developed countries. Overt deficiency symptoms occur only if vitamin C intake falls below approximately 10 mg/day for many weeks. Vitamin C deficiency is uncommon in developed countries but can still occur in people with limited food variety.
Groups at Risk of Vitamin C Inadequacy
Vitamin C inadequacy can occur with intakes that fall below the RDA but are above the amount required to prevent overt deficiency (approximately 10 mg/day). The following groups are more likely than others to be at risk of obtaining insufficient amounts of vitamin C.
Smokers and passive “smokers”
Studies consistently show that smokers have lower plasma and leukocyte vitamin C levels than nonsmokers, due in part to increased oxidative stress. For this reason, the IOM concluded that smokers need 35 mg more vitamin C per day than nonsmokers. Exposure to secondhand smoke also decreases vitamin C levels. Although the IOM was unable to establish a specific vitamin C requirement for nonsmokers who are regularly exposed to secondhand smoke, these individuals should ensure that they meet the RDA for vitamin C.
Infants fed evaporated or boiled milk
Most infants in developed countries are fed breastmilk and/or infant formula, both of which supply adequate amounts of vitamin C. For many reasons, feeding infants evaporated or boiled cow’s milk is not recommended. This practice can cause vitamin C deficiency because cow’s milk naturally has very little vitamin C and heat can destroy vitamin C.
Individuals with limited food variety
Although fruits and vegetables are the best sources of vitamin C, many other foods have small amounts of this nutrient. Thus, through a varied diet, most people should be able to meet the vitamin C RDA or at least obtain enough to prevent scurvy. People who have limited food variety—including some elderly, indigent individuals who prepare their own food; people who abuse alcohol or drugs; food faddists; people with mental illness; and, occasionally, children—might not obtain sufficient vitamin C [4,6-9,11].
People with malabsorption and certain chronic diseases
Some medical conditions can reduce the absorption of vitamin C and/or increase the amount needed by the body. People with severe intestinal malabsorption or cachexia and some cancer patients might be at increased risk of vitamin C inadequacy. Low vitamin C concentrations can also occur in patients with end-stage renal disease on chronic hemodialysis.
Vitamin C and Health
Due to its function as an antioxidant and its role in immune function, vitamin C has been promoted as a means to help prevent and/or treat numerous health conditions. There are four other diseases and disorders in which vitamin C might play a role: cancer (including prevention and treatment), cardiovascular disease, age-related macular degeneration (AMD) and cataracts, and the common cold.