Tag Archives: Aging

Aging and NAD

A conserved NAD+ binding pocket interactions during aging

 

Story from Sciencedaily copied and pasted:

DNA repair is essential for cell vitality, cell survival and cancer prevention, yet cells’ ability to patch up damaged DNA declines with age for reasons not fully understood.

Now, research led by scientists at Harvard Medical School reveals a critical step in a molecular chain of events that allows cells to mend their broken DNA.

The findings, published March 24 in Science, offer a critical insight into how and why the body’s ability to fix DNA dwindles over time and point to a previously unknown role for the signaling molecule NAD as a key regulator of protein-to-protein interactions in DNA repair. NAD, identified a century ago, is already known for its role as a controller of cell-damaging oxidation.

Additionally, experiments conducted in mice show that treatment with the NAD precursor NMN mitigates age-related DNA damage and wards off DNA damage from radiation exposure.

The scientists caution that the effects of many therapeutic substances are often profoundly different in mice and humans owing to critical differences in biology. However, if affirmed in further animal studies and in humans, the findings can help pave the way to therapies that prevent DNA damage associated with aging and with cancer treatments that involve radiation exposure and some types of chemotherapy, which along with killing tumors can cause considerable DNA damage in healthy cells. Human trials with NMN are expected to begin within six months, the researchers said.

“Our results unveil a key mechanism in cellular degeneration and aging but beyond that they point to a therapeutic avenue to halt and reverse age-related and radiation-induced DNA damage,” said senior author David Sinclair, professor in the Department of Genetics at HMS and professor at the University of New South Wales School of Medicine in Sydney, Australia.

A previous study led by Sinclair showed that NMN reversed muscle aging in mice.

A plot with many characters

The investigators started by looking at a cast of proteins and molecules suspected to play a part in the cellular aging process. Some of them were well-known characters, others more enigmatic figures.

The researchers already knew that NAD, which declines steadily with age, boosts the activity of the SIRT1 protein, which delays aging and extends life in yeast, flies and mice. Both SIRT1 and PARP1, a protein known to control DNA repair, consume NAD in their work.

Another protein DBC1, one of the most abundant proteins in humans and found across life forms from bacteria to plants and animals, was a far murkier presence. Because DBC1 was previously shown to inhibit vitality-boosting SIRT1, the researchers suspected DBC1 may also somehow interact with PARP1, given the similar roles PARP1 and SIRT1 play.

“We thought if there is a connection between SIRT1 and DBC1, on one hand, and between SIRT1 and PARP1 on the other, then maybe PARP1 and DBC1 were also engaged in some sort of intracellular game,” said Jun Li, first author on the study and a research fellow in the Department of Genetics at HMS.

They were.

To get a better sense of the chemical relationship among the three proteins, the scientists measured the molecular markers of protein-to-protein interaction inside human kidney cells. DBC1 and PARP1 bound powerfully to each other. However, when NAD levels increased, that bond was disrupted. The more NAD present inside cells, the fewer molecular bonds PARP1 and DBC1 could form. When researchers inhibited NAD, the number of PARP1-DBC1 bonds went up. In other words, when NAD is plentiful, it prevents DBC1 from binding to PARP1 and meddling with its ability to mend damaged DNA.

What this suggests, the researchers said, is that as NAD declines with age, fewer and fewer NAD molecules are around to stop the harmful interaction between DBC1 and PARP1. The result: DNA breaks go unrepaired and, as these breaks accumulate over time, precipitate cell damage, cell mutations, cell death and loss of organ function.

Averting mischief

Next, to understand how exactly NAD prevents DBC1 from binding to PARP1, the team homed in on a region of DBC1 known as NHD, a pocket-like structure found in some 80,000 proteins across life forms and species whose function has eluded scientists. The team’s experiments showed that NHD is an NAD binding site and that in DBC1, NAD blocks this specific region to prevent DBC1 from locking in with PARP1 and interfering with DNA repair.

And, Sinclair added, since NHD is so common across species, the finding suggests that by binding to it, NAD may play a similar role averting harmful protein interactions across many species to control DNA repair and other cell survival processes.

To determine how the proteins interacted beyond the lab dish and in living organisms, the researchers treated young and old mice with the NAD precursor NMN, which makes up half of an NAD molecule. NAD is too large to cross the cell membrane, but NMN can easily slip across it. Once inside the cell, NMN binds to another NMN molecule to form NAD.

As expected, old mice had lower levels of NAD in their livers, lower levels of PARP1 and a greater number of PARP1 with DBC1 stuck to their backs.

However, after receiving NMN with their drinking water for a week, old mice showed marked differences both in NAD levels and PARP1 activity. NAD levels in the livers of old mice shot up to levels similar to those seen in younger mice. The cells of mice treated with NMN also showed increased PARP1 activity and fewer PARP1 and DBC1 molecules binding together. The animals also showed a decline in molecular markers that signal DNA damage.

In a final step, scientists exposed mice to DNA-damaging radiation. Cells of animals pre-treated with NMN showed lower levels of DNA damage. Such mice also didn’t exhibit the typical radiation-induced aberrations in blood counts, such as altered white cell counts and changes in lymphocyte and hemoglobin levels. The protective effect was seen even in mice treated with NMN after radiation exposure.

Taken together, the results shed light on the mechanism behind cellular demise induced by DNA damage. They also suggest that restoring NAD levels by NMN treatment should be explored further as a possible therapy to avert the unwanted side effects of environmental radiation, as well as radiation exposure from cancer treatments.

In December 2016, a collaborative project between the Sinclair Lab and Liberty Biosecurity became a national winner in NASA’s iTech competition for their concept of using NAD-boosting molecules as a potential treatment in cosmic radiation exposure during space missions.

Co-authors on the research included Michael Bonkowski, Basil Hubbard, Alvin Ling, Luis Rajman, Sebastian Moniot, Clemens Steegborn, Dapeng Zhang, L. Aravind, Bo Qin, Zhenkun Lou, and Vera Gorbunova.

The work was funded by the Glenn Foundation for Medical Research, the American Federation for Aging Research, Edward Schulak, grants from the National Institute on Aging and the National Institutes of Health, by the National Library of Medicine/NIH intramural program, the National Cancer Institute, and by Deutsche Forschungsgemeinschaft.

Aging increases cell-to-cell transcriptional variability upon immune stimulation

Scientists have resolved a key question in aging research by showing how mouse immune cells of different ages respond to stimulation. Study demonstrates weaker response of older cells is due to their coordination breaking down, making their response to immune stimulation more variable. Single-cell sequencing technology allows scientists to profile individual cells independently to view cellular activity in high resolution.

Aging is characterized by progressive loss of physiological and cellular functions, but the molecular basis of this decline remains unclear. We explored how aging affects transcriptional dynamics using single-cell RNA sequencing of unstimulated and stimulated naïve and effector memory CD4+ T cells from young and old mice from two divergent species. In young animals, immunological activation drives a conserved transcriptomic switch, resulting in tightly controlled gene expression characterized by a strong upregulation of a core activation program, coupled with a decrease in cell-to-cell variability. Aging perturbed the activation of this core program and increased expression heterogeneity across populations of cells in both species. These discoveries suggest that increased cell-to-cell transcriptional variability will be a hallmark feature of aging across most, if not all, mammalian tissues.

Metabolic Damage and Premature Thymus Aging Caused by Stromal Catalase Deficiency

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown how aging cripples the production of new immune cells, decreasing the immune system’s response to vaccines and putting the elderly at risk of infection. The study goes on to show that antioxidants in the diet slow this damaging process.

The research, published August 6 in the journal Cell Reports, focused on an organ called the thymus, which produces T lymphocytes, critical immune cells that must be continuously replenished to respond to new infections.

“The thymus begins to atrophy rapidly in very early adulthood, simultaneously losing its function,” said TSRI Professor Howard Petrie. “This new study shows for the first time a mechanism for the long-suspected connection between normal immune function and antioxidants.”

Scientists have been hampered in their efforts to develop specific immune therapies for the elderly by a lack of knowledge of the underlying mechanisms of this process.

To explore these mechanisms, Dr. Petrie and his team developed a computational approach for analyzing the activity of genes in two major thymic cell types — stromal cells and lymphoid cells — in mouse tissues, which are similar to human tissues in terms of function and age-related atrophy. The team found that stromal cells were specifically deficient in an antioxidant enzyme called catalase, which resulted in elevated levels of the reactive oxygen by-products of metabolism and, subsequently, accelerated metabolic damage.

To confirm the central role of catalase, the scientists increased levels of this enzyme in genetically altered animal models, resulting in preservation of thymus size for a much longer period. In addition, animals that were given two common dietary antioxidants, including vitamin C, were also protected from the effects of aging on the thymus.

Taken together, the findings provide support for the “free-radical theory” of aging, which proposes that reactive oxygen species such as hydrogen peroxide, produced during normal metabolism, cause cellular damage that contributes to aging and age-related diseases.

While other studies have suggested that sex hormones, particularly androgens such as testosterone, play a major role in the aging process, it fails to answer the key question — why does the thymus atrophy so much more rapidly than other body tissues?

“There’s no question that the thymus is remarkably responsive to androgens,” Dr. Petrie noted, “but our study shows that the fundamental mechanism of aging in the thymus, namely accumulated metabolic damage, is the same as in other body tissues. However, the process is accelerated in the thymus by a deficiency in the essential protective effects of catalase, which is found at higher levels in almost all other body tissues.”

Unrelated but neat:

  1. Meghan E. McGee-Lawrence Karl H. Wenger Sudipta Misra Catherine L. Davis Norman K. Pollock Mohammed Elsalanty Kehong Ding Carlos M. Isales Mark W. Hamrick Joanna R. Erion Marlena Wosiski-Kuhn Phonepasong Arounleut Mark P. Mattson Roy G. Cutler Jack C. Yu Alexis M. Stranahan. Whole-body Vibration Mimics the Metabolic Effects of Exercise in Male Leptin Receptor Deficient Mice. Endocrinology, 2017 DOI: 10.1210/en.2016-1250

    Abstract

    Whole-body vibration has gained attention as a potential exercise mimetic, but direct comparisons with the metabolic effects of exercise are scarce. To determine whether whole-body vibration recapitulates the metabolic and osteogenic effects of physical activity, we exposed male wildtype (Wt) and leptin receptor deficient (db/db) mice to daily treadmill exercise or whole-body vibration for three months. Body weights were analyzed and compared with Wt and db/db mice that remained sedentary. Glucose and insulin tolerance testing revealed comparable attenuation of hyperglycemia and insulin resistance in db/db mice following treadmill exercise or whole-body vibration. Both interventions reduced body weight in db/db mice and normalized muscle fiber diameter. Treadmill exercise and whole-body vibration also attenuated adipocyte hypertrophy in visceral adipose tissue and reduced hepatic lipid content in db/db mice. Although the effects of leptin receptor deficiency on cortical bone structure were not eliminated by either intervention, exercise and whole-body vibration increased circulating levels of osteocalcin in db/db mice. In the context of increased serum osteocalcin, the modest effects of TE and WBV on bone geometry, mineralization, and biomechanics may reflect subtle increases in osteoblast activity in multiple areas of the skeleton. Taken together, these observations indicate that whole-body vibration recapitulates the effects of exercise on metabolism in type 2 diabetes.

A less strenuous form of exercise known as whole-body vibration (WBV) can mimic the muscle and bone health benefits of regular exercise in mice, according to a new study. WBV consists of a person sitting, standing or lying on a machine with a vibrating platform. When the machine vibrates, it transmits energy to the body, and muscles contract and relax multiple times during each second.

A less strenuous form of exercise known as whole-body vibration (WBV) can mimic the muscle and bone health benefits of regular exercise in mice, according to a new study published in the Endocrine Society’s journal Endocrinology.

WBV consists of a person sitting, standing or lying on a machine with a vibrating platform. When the machine vibrates, it transmits energy to the body, and muscles contract and relax multiple times during each second.

Many people find it challenging to exercise regularly and that is contributing to the obesity and diabetes epidemics. These disorders can increase the risk of bone fractures. Physical activity can help to decrease this risk and reduce the negative metabolic effects of each condition.

“Our study is the first to show that whole-body vibration may be just as effective as exercise at combatting some of the negative consequences of obesity and diabetes,” said the study’s first author, Meghan E. McGee-Lawrence, Ph.D., of Augusta University in Augusta, Ga. “While WBV did not fully address the defects in bone mass of the obese mice in our study, it did increase global bone formation, suggesting longer-term treatments could hold promise for preventing bone loss as well.”

To conduct the study, researchers examined two groups of 5-week-old male mice. One group consisted of normal mice, while the other group was genetically unresponsive to the hormone leptin, which promotes feelings of fullness after eating. Mice from each group were assigned to sedentary, WBV or treadmill exercise conditions.

After a week-long period to grow used to the exercise equipment, the groups of mice began a 12-week exercise program. The mice in the WBV group underwent 20 minutes of WBV at a frequency of 32 Hz with 0.5g acceleration each day. Mice in the treadmill group walked for 45 minutes daily at a slight incline. For comparison, the third group did not exercise. Mice were weighed weekly during the study.

The genetically obese and diabetic mice showed similar metabolic benefits from both WBV and exercising on the treadmill. Obese mice gained less weight after exercise or WBV than obese mice in the sedentary group, although they remained heavier than normal mice. Exercise and WBV also enhanced muscle mass and insulin sensitivity in the genetically obese mice. Although there were no significant effects in the young healthy mice, the low-intensity exercise and WBV protocols were designed for successful completion by obese mice. These findings suggest that WBV may be a useful supplemental therapy to combat metabolic dysfunction in individuals with morbid obesity.

Telomeres: You will age faster if you sit around! Telomere length shortens the more sedentary you are – Insane Medicine

  • A great research article in Mayo Clinic Proceedings, marked below, demonstrates the importance of decreasing our sedentary activities. In the study, they determined that telomere length is shortened by sedentary behaviors, measured in the form of leisure-based screen time. Short telomeres is associated with stress, inflammation,  and a variety of cardiometabolic diseases! Short telomeres are an established characteristic of aging. You want to have a successful aging strategy, hence you want to keep your telomeres long! 🙂
  • The measurement of leukocyte telomere length (LTL)  is a method to determine future health, and short LTL is associated with morbidity and mortality independent of age. In the study, 6405 people ages 20-84 were assessed for leisure time screen-based sedentary behavior, namely television, video games and computer use, and a LTL assay was performed on the participants to determine the length of their telomeres over a certain period of time. It was found that for every hour increase in screen based time, the individual had a 7% increased risk of being in the lowest tertile of telomere length. In other words, the more screen based time that was spent, the greater the chance your telomeres were short enough to put you at the bottom of the study group in regards to telomere length.  Hence you have a higher risk of an early illness or death!
  • Physical activity is associated with greater telomere length up to a certain point.
  • The core findings of people with LTL values that were in the bottom group (short telomeres) was that they were more sedentary, engaged in little moderate to vigorous physical activity, had high CRP levels (inflammation marker), had a higher BMI (fatter), and more likely to have diabetes, hypertension, and coronary artery disease.  The chance of a person falling into this category, again increased by 7% for each hour of screen based  leisure time that they spent.
  • Leukocyte telomere shortening is a marker of cellular aging and also is associated with increased morbidity (high blood pressure/diabetes) and mortality. When LTL become critically shortened, the leukocytes secrete pro-inflammatory cytokines and hence increase the CRP ( a marker of inflammation). Thus being sedentary results in inflammation and modulates your metabolic risk in the wrong direction.  In other words, you age faster!!!
  • The key point: Stay active physically and spend less time on Facebook!!
  • Leisure-Time Screen-Based Sedentary Behavior and Leukocyte Telomere Length: Implications for a New Leisure-Time Screen-Based Sedentary Behavior Mechanism –  Paul Loprinzi

Leisure-Time Screen-Based Sedentary Behavior and Leukocyte Telomere Length: Implications for a New Leisure-Time Screen-Based Sedentary Behavior Mechanism

 

Other interesting abstracts:

Bey, L. and Hamilton, M.T. Suppression of skeletal muscle lipoprotein lipase activity during physical inactivity: a molecular reason to maintain daily low-intensity activity. J Physiol. 2003; 551: 673–682

Suppression of skeletal muscle lipoprotein lipase activity during physical inactivity: a molecular reason to maintain daily low-intensity activity  Bottom line of article:  Inactivity caused a local reduction of plasma [3H]triglyceride uptake into muscle and a decrease in high density lipoprotein cholesterol concentration. Treadmill walking raised LPL activity approximately 8-fold (P < 0.01) within 4 h after inactivity The striking sensitivity of muscle LPL to inactivity and low-intensity contractile activity may provide one piece of the puzzle for why inactivity is a risk factor for metabolic diseases and why even non-vigorous activity provides marked protection against disorders involving poor lipid metabolism.

Tremblay, M.S., Colley, R.C., Saunders, T.J., Healy, G.N., and Owen, N. Physiological and health implications of a sedentary lifestyle. Appl Physiol Nutr Metab. 2010; 35: 725–740  Sedentarism, active lifestyle and sport: impact on health and obesity prevention

The benefits of regular physical activity have been known since ancient Greek. But in the last Century the scientific knowledge around this topic has progressed enormously, starting with the early studies of JN Morris and RS Paffenberger, who demonstrated that physical activity at work reduced incidence of cardiovascular disease and mortality. In the Harvard alumni study, the lowest risk was associated with a weekly output of 1000 to 2000 kcal performing vigorous activities. Further studies in all age groups have supported these findings and have added that even moderate levels of physical activity provide considerable benefits to health, including lower prevalence of overweight and obesity at all ages. Metabolic fat oxidation rate is highest at exercise intensities between 45 and 65% of VO2max. This means that people must be active regularly and force physiological mechanisms at certain intensities. All this body of evidence has contributed to current WHO physical activity recommendations of 150 min/week of moderate to vigorous physical activity (MVPA) in adults and elderly, and 60 min/day of MVPA in children and adolescents, with additional strength training, apart from adopting an active lifestyle. In the last 50 years, occupational physical activity has been reduced for about 120 kcal/day, and sedentarism has emerged as an additional risk factor to physical inactivity. Even if less than 60 min of TV time in adults have been related to lower average BMI, there is still a need for research to determine the appropriate dose of exercise in combination with sedentary behaviours and other activities in the context of our modern lifestyle in order to prevent obesity at all ages. As public health measures have failed to stop the obesity epidemic in the last 3 decades, there is clearly a need to change the paradigm. The inclusion of sport scientists, physical education teachers and other professionals in the multidisciplinary team which should be responsible for drawing the road map to prevent the increase of the obesity epidemic effectively is a “must” from our point of view.

 

Physical inactivity as the culprit of metabolic inflexibility: evidence from bed-rest studies

Bergouignan, A., Rudwill, F., Simon, C., and Blanc, S. Physical inactivity as the culprit of metabolic inflexibility: evidence from bed-rest studies. J Appl Physiol (1985). 2011; 111: 1201–1210

PHYSICAL INACTIVITY INDUCES INSULIN RESISTANCE. PHYSICAL INACTIVITY DECREASES FAT OXIDATION. PHYSICAL INACTIVITY AFFECTS LIPID TRAFFICKING BETWEEN ADIPOSE TISSUE AND MUSCLE. PHYSICAL INACTIVITY INDUCES ECTOPIC FAT STORAGE. OVERALL, THE PHYSICAL ACTIVITY LEVEL PREDICTS METABOLIC FLEXIBILITY.

The following sequence of events can be hypothesized to explain the physical inactivity-induced metabolic alterations and thus metabolic inflexibility (Fig. 4). The physical inactivity induced by bed rest leads to insulin resistance in skeletal muscle, requiring a hyperinsulinemic response to properly dispose of glucose in daily postprandial conditions, whereas adipose tissue displays an appropriate response. At the same time, muscle fiber type shifts toward fast-twitch glycolytic fibers, and muscle increases glucose uptake and oxidation through insulin-independent pathways. This in turn inhibits fatty acid oxidation and ultimately uptake. During meal ingestion, hyperlipemia occurs due to a decreased plasma clearance of dietary fat. This increases the flux of dietary lipids to organs and results in ectopic fat storage with consequences on insulin sensitivity. The liver displays susceptibility to hyperinsulinemia and increased lipid synthesis and storage that overcomes rate of oxidations. Hepatic steatosis will likely ensue. With a reduced oxidative capacity, the liver will then contribute to an increased rate of atherogenic lipid products (VLDL) in which the contributions of FFA coming from the diet and neolipogenesis to the total VLDL-triglycerides will increase, feed-forwarding hyperlipemia and ectopic fat storage. Concomitantly, the steatotic liver will become insulin resistant and unable to suppress hepatic glucose production, which leads to increased gluconeogenesis and feed-forward worsening of hyperinsulinemia.Inactivity and metabolic inflexibilityHypothetical metabolic alterations cascade induced by bed rest that can explain how physical inactivity induces metabolic inflexibility. VLDL, very-low-density lipoprotein; NAFLD, nonalcoholic fatty liver disease; DAG, diacylglycerol.

Physical activity predicts metabolic flexibility. For an equivalent food quotient, metabolically flexible subjects will greatly increase carbohydrate oxidation after the consumption of a meal despite a low increase in plasma insulin concentration. A metabolically inflexible individual, i.e., a person who also displays an insulin resistance, will display a low increase in carbohydrate oxidation despite an marked elevation in insulin secretion.

Weischer, M., Bojesen, S.E., Cawthon, R.M., Freiberg, J.J., Tybjӕrg-Hansen, A., and Nordestgaard, B.G. Short telomere length, myocardial infarction, ischemic heart disease, and early death. Arterioscler Thromb Vasc Biol.2012; 32: 822–829

Short Telomere Length, Myocardial Infarction, Ischemic Heart Disease, and Early Death  -> Findings: Short telomere length is associated with only modestly increased risk of myocardial infarction, ischemic heart disease, and early death.

Leucocyte telomere length and risk of cardiovascular disease: systematic review and meta-analysis BMJ 2014;349:g4227 Available observational data show an inverse association between leucocyte telomere length and risk of coronary heart disease independent of conventional vascular risk factors. The association with cerebrovascular disease is less certain.

Chronic inflammation induces telomere dysfunction and accelerates ageing in mice  Our results show that chronic inflammation aggravates telomere dysfunction and cell senescence, decreases regenerative potential in multiple tissues and accelerates ageing of mice. Anti-inflammatory or antioxidant treatment, specifically COX-2 inhibition, rescued telomere dysfunction, cell senescence and tissue regenerative potential, indicating that chronic inflammation may accelerate ageing at least partially in a cell-autonomous manner via COX-2-dependent hyper-production of ROS.

Cawthon, R.M. Telomere measurement by quantitative PCR. Nucleic Acids Res. 2002; 30: e47   Telomere measurement by quantitative PCR

 

 

Insane Medicine – Inflammation and it’s risks.

Inflammation in the body breaks it down over time. Inflammation results from and, in part, causes autoimmune disorders and atherosclerosis with subsequent coronary artery disease and stroke. There are many ways to measure levels of inflammation in the body, but none are sensitive or specific for any particular condition. Likewise, inflammatory markers don’t always point to a specific treatment, but rather the presence of a system that is in trouble and needs thorough evaluation.

  • Inflammatory risk can be determined, in part, by elevations in C-reactive protein (CRP) and fibrinogen, which are both made in the liver as a result of the influence of cytokines such as interleukin-Ib, Interleukin-6 (IL-6), and Tumor necrosis Factor- alpha (TNF). Fibrinogen increases can increase your risk of platelet aggregation (clots) which increase stroke and heart attack risk.
  • There is evidence that DHEA and fish oil can decrease cytokine levels and decrease inflammation. Vitamin K can suppress IL-6 especially and thus decrease inflammatory markers. Nettle leaf extract has been found to suppress TNF-alpha and IL-1b cytokines. Aspirin, green tea, ginko bilboa, garlic, and Vitamin E have been found to decrease platelet aggregation and help blood flow, helping to avoid strokes and heart attacks. Lower fibrinogen levels may decrease the risk of myocardial infarction. Increased vitamin A levels decrease fibrinogen levels. Olive oil and fish have had a similar effect. Niacin (1000 mg a day) and vitamin C (2000 mg a day) will decrease fibrinogen. Bromelain (2000 mg/day) and EPA/DHA from fish oil also have a beneficial impact as well.
  • Elevated homocysteine levels also represent a cardiovascular threat. Elevated homocysteine prevents fibrinogen breakdown by inhibiting tissue plasminogen activator. Ways to diminish homocysteine levels and it’s risk include vitamin B12, vitamin B6, and trimethylglycine (TMG).
  • So elevations of homocysteine will increase your heart attack and stroke risk. Trimethylglycing (TMG) methylates homocysteine and converts it to methionine and s-adenosylmethionine (SAMe). In this process, the body needs folate and vitamin B-12. Homocysteine can also be removed from the body by the transsulfuration pathway using a vitamin B-6 dependent cystathione synthase enzyme. Vitamin B6 is necessary for this, and in some individuals, they lack the ability to produce the active form of vitamin B-6 (pyridoxal-5-phosphate), in which case, pyridoxal-5-phosphate can be supplemented instead to lower homocysteine.
  • So vitamins and supplements that decrease homocysteine to help preserve cardiovascular health include: TMG (500 mg a day), folate (800 mcg a day), vitamin B12 (200 mcg a day), inositol (250 mg a day), zinc (30 mg a day), and vitamin B6 (100 mg a day).
  • C-reactive protein: an inflammatory risk marker that increases under the influence of cytokines IL-6, IL-1B, and TNF-alpha. When elevated, heart attack risk increases by over two-fold .Studies have found that the statin rosuvastatin (Crestor) can decrease CRP levels and the inflammatory risk of heart attacks. Also helpful are aspirin, vitamin E, nettle leaf extract, DHEA, and fish oil.

So here is a basic list of inflammatory markers and cardiovascular risk markers that should be followed:

  1. Fibrinogen
  2. CRP
  3. Homocysteine
  4. Iron
  5. Glucose
  6. Cholesterol (HDL and LDL and triglycerides)
  7. DHEA
  • Obesity is a risk marker for heart attacks and cancer. Why is this? Increased circulating insulin and insulin resistance causes increased fat conversion of glucose and increased fat deposition. The increased insulin causes certain cancer types to grow as well as it serves as a growth factor.
  • The keys to successful strategies for health besides weight loss, include:
  1. Blood pressure control
  2. Glucose control
  3. Decreased LDL cholesterol
  4. Increasing your healthy HDL cholesterol
  5. Decreasing inflammatory markers such as fibrinogen, CRP, homocysteine, and cytokines.

Exercise is important. Be certain to consult your doctor before starting any exercise regimen. Use and exercise every muscle, every day. Exercise increases blood flow and lymph drainage increases. It also builds strength and flexibility, as well as balance and decreased falling risk. You feel less depressed and have more energy.

  • Coenzyme Q10: (Ubiquinone) is beneficial for heart and brain functioning, as well as being a blood pressure lowering supplement. Cells need it for energy production in the mitochondria and deficiency is found in aging and a variety of degenerative disorders. Muscles and the brain have high numbers of mitochondria which need this supplement. Taken orally, CoQ10 is absorbed and incorporated into the mitochondria. As one ages, the body produces only half of what it should of this vital supplement. Dosing is 30-300 mg a day. Of note, statins (anti-cholesterol agent) destroy co Q 10, so it is very helpful to take co Q10 supplements while on any statin. There are studies demonstrating increased energy production in the brain and muscles with Co Q10 supplementation, and it has been noted that there is an antioxidant protective ability as well provided by coQ10. In fact, there is speculation that Parkinson’s disease may result, in part, by reductions of co Q 10 levels in the brain (35% less than normal controls) and that with supplementation, some patients with Parkinson’s disease have had diminished progression of the disorder. As we age, Parkinson’s disease becomes more common, and it may be due to mitochondrial dysfunction and oxygen free radical production due to co-Q10 deficiency which results in the loss of neurons, thereby producing Parkinson’s disease. There is suggestion that dosages of coQ10 up to 1200 mg a day (which has minimal side-effects) seems to diminish the progression of Parkinson’s disease in some patients. This may be a result of the preservation of mitochondrial function.

…more to be added soon!

Insane Medicine – mitochondria and aging – NAD+ and Sirtuins as part of the missing link

Insane Medicine -Aging and mitochondria
Insane Medicine -Aging and mitochondria – aging as a result of mitochondrial and nuclear gene miscommunication. Low levels of NAD in the cell cause HIF -1 to increase, which results in the nucleus and mitochondria to not communicate.
  • The mitochondrion is a cellular organelle that provides the cell with the energy needed to sustain life. It has it’s own genetic material that produces, in part with the nucleus, an oxidative-phosphorylation complex in the cell that produces all our energy. Basically, the mitochondria is a piece of machinery that acts like a battery for the cell.
  • As we age, it has been found that the genes in the mitochondrion mutate and function poorly. This may be the root cause of aging. NAD+ is a molecule used as an energy carrier that regulates the mitochondria, as it decreases in low oxygen states and results in a disruption of the oxidative phosphorylation complex. Increasing the NAD+ levels reverses this rocess.
  • In a functioning normal cell, the nucleus and the mitochondiron communicate with each other and manufacture, using their genes, the oxidative phosphorylation complex, which is the producer of the energy inside the mitochondria. It is the failure of the genes inside the mitochondria that result in the aging process.
  • A gene, called sirtuin 1 is involved in maintaining a clear line of communication between the nucleus and the mitochondrion. HIF-1 is a protein that the cell produces in cancer states and low oxygen states that interferes with this communication process, causing cell aging and death.
  • Aging muscles have been found to have decreased levels of mitochondrial genes.
  • Nuclear levels of NAD+ maintain the mitochondiral homeostasis, with decreased levels disrupting the oxidative-phosphorylation machinery in the cell and thus result in cell aging and death. Raising this NAD+ nuclear level in mice reverses this aging process. Molecules have been developed that can do this.
  • There is a separate system, the PGC-1α/β system, that also regulates energy metabolism in cells and acts as a transcriptional coactivator to regulate gene activity and function. It works separately from the above. PGC-1α regulates mitochondrial biogenesis and interaxcts with nuclear PPAR-gamma, which results in the interaction of numerous transcription proteins that affect cell function. This directly links the external stimuli of the world to the internal cell functioning of mitochondria. For example, PGC-1α may be involved in cholesterol regulation, obesity, and blood pressure.  PGC-1α may  integrate a number of internal cell signals with external signals. For example, endurance exercise increases PGC-1α levels and allows for lactate to be used more efficiently. SIRT-1 may bind and activate PGC-1α.. PGC-1α activates Akt levels in muscle, which is pro-survival in function. Massage therapy can increase PGC-1α, allowing formation of new mitochondria.
  • http://www.cell.com/abstract/S0092-8674%2813%2901521-3
Insane medicine - mitochondria
Mitochondria are the work horse of the cell,producing it’s energy, but also they may be the root cause of aging.
Insane Medicine - Mitochondria are the work horse of the cell,producing it's energy, but also they may be the root cause of aging.
Mitochondria are the work horse of the cell,producing it’s energy, but also they may be the root cause of aging.

http://hms.harvard.edu/news/genetics/new-reversible-cause-aging-12-19-13  <- anti-aging and mechanism regarding this

  • Possible interventions for the process of aging?  Nothing is yet on the market, but some agents may have helpful anti-aging effects: trans-resveratrol is one option.  Red wine, mulberries, grapes, and peanuts have resveratrol. A glass of wine has a milligram of the substance. A higher amount is needed to be effective. About 360 mg may be needed to have an anti-aging effect. It has been noted that in countries where red wine is imbibed, people are thinner and live longer. An option for resveratrol in needed doses can be obtained here:

http://www.longevinex.com/home.php

Calorie restriction has been a way to extend lifespan in animals such as rats. The process of calorie restriction causes the aging machinery to slow down.  Trans-resveratrol simulates calorie restriction without actually eating less. This may be a way to trick the body into a “fasting, yet anti-aging” state.

 

 

Insane Medicine – Resveratrol in wine has multiple benefits – drink in moderation only though!

Insane Medicine - Wine
Red wine can benefit the body and the brain when taken in moderation.
  • Resveratrol is an antioxidant that may benefit the brain as a neuroprotecting agent. It neutralizes the effects of cell-damaging free radicals caused by pollution, stress, metabolism, aging, and other sources.
  • Resveratrol may protect against cardiovascular diseases, diabetes, and neurodegeneration.  It alters inflammation by affecting a class of enzymes called sirtuins that play a role in the aging process.
  • Resveratrol helps eliminate cell-damaging free radicals and enhances the survival mechanisms of cells. It may have anti-cancer properties as well.
  • Women should consume one 4 oz glass of wine per day at most and men can consume up to two 4 oz glasses of wine. Resveratrol is absorbed best by sipping the wine, as it’s absorption is enhanced by contacting the mucus membranes of the mouth.
  • Resveratrol may reduce beta-amyloids in the brain, which are associated with Alzheimer’s disease. It also helps modulate cell communication in the brain as well, which is important for memory. Resveratrol may also protect against oxidative stress and damage from diabetes.

Insane medicine – Telomere length in your chromosomes and your aging are related: diet affects this!

Insane Medicine - Telomeres and aging. Telomeres and their proteins protect chromosomes from degradation and recombination.
Insane Medicine – Telomeres and aging. Telomeres and their proteins protect chromosomes from degradation and recombination.

telomeres and aging Telomere

Telomeres, the ending portion of the chromosome that protect against degradation, have been found to be shortened in humans with poor aging. Premature shortening of telomeres results from oxidative stress in the body and inflammation. This causes premature aging and early death.  So, the longer your telomeres are, the healthier you are overall. However, inflammation triggers T-cell activity that results in telomere shortening. There is an association in humans between shorter telomeres and age-related illness such as cancer and heart disease. Chronic stress and depression can lead to shorter telomeres. Higher omega-3 polyunsaturated fat levels (EPA and DHA)  in the blood is associated with decreased inflammation. The bests test to predict effective diet against telomere attrition ( and hence poor aging) is the n-6:n-3 Polyunsaturated fat (PUFA) ratio. The bottom line is to decrease n-6 PUFAS and increase your intake of n-3 PUFA’s (such as fish) to allow your chromosomes telomeres to lengthen.

Also of note , intake of multivitamins may be associated with longer telomeres as well, especially vitamin C and E intake.  This may result in healthy aging.

Insane Medicine – Inflammation and Aging – Mechanisms of poor aging!!

  • Inflammation affects the body in a number of ways, some we recognize physically and others not so much. For example, a cut on the skin can get red and inflammed. But there is a low grade, chronic inflammation that also occurs that increases as we age.
  • Many factors influence this inflammation, including genetics, lifestyle, and environmental agents. This can cause premature aging and disorders that accompany it, such as diabetes.
  • A study in the Canadian Medical Association Journal did suggest a link between elevated levels of Interleukin-6 (IL-6), a pro-inflammatory cytokine that when elevated, appears to drive other inflammatory marker up, such as CRP (C-reactive protein and fibrinogen).
  • IL-6 elevation appears to play a role in aging, causing people to age poorly when levels are elevated.
  • Successful aging is considered to have occured when an individual has good cardiovascular function ( no heart attacks) , good respiratory and musculoskeletal functioning (no emphysema/arthritis), and good mental well-being. In other words, there is an abscense of disability such as diabetes and severe arthritis or heart failure.
  • High levels of inflammation in the body are linked to cognitive decline (dementia and poor memory)
  • General body inflammation is involved in coronary artery disease, obesity, diabetes, chronic obstructive pulmonary disease (COPD), asthma, allergic conditions, rheumatoid arthritis, inflammatory bowel disease, and Alzheimer’s disease.
  • Inflammation can result in insulin resistance that then promotes obesity. Fat releases pro-inflammatory compounds that then worsens insulin-resistance. This results in a positive feedback cycle, making everything much worse.
  • Inflammatory markers being looked int incude tumopr necrosis factor (TNF), IL-6, C-reactive protein, prostaglandins, and leukotrienes. Elevations of these indicators reflects other conditions in the body, such as worsening arthritis.
  • In the Jupiter study, it was found that people with a nromal LDL (‘bad’) cholesterol would benefit from treatment with a statin to reduce the LDL even further if their CRP was elevated. The CRP elevation reflected an increased risk of heart attacks in these people despite normal or low cholesterol already. The statin (rosuvastatin), decreased the CRP and LDL cholesterol and ppears to decrease the risk of coronary events. Again, the elevated CRP reflects the inflammation in the coronary system, and this inflammation was improved by treatment with the statin.
  • Smoking worsens inflammation in the body and increases the risk of stroke and heart attacks. It promotes inflammation in the coronary arteries.
  • Obesity and high blood pressure also promote inflammation.

It is felt that IL-6 may be the driver of the inflammatory process, especially as increased levels of IL-6 (>2ng/L) increases mortality over three years. High IL-6 levels are associated with poor aging and increased risk of cardivascular events and death.

What to do:

  1. Eat a heart healthy diet including fatty fish, fruits, and vegetables. Include wine, tea, and chocolate, which have anti-inflammatory effects). The Mediterranean diet reduces inflammation.
  2. Avoid saturated fats, trans-fats, and refined sugar, which are pro-inflammatory.
  3. Get aerobic exercise. Being sedentary increases inflammation and pain.
  4. Lose weight  – obesity increases inflammation.
  5. Quit smoking.
  6. Take low dose aspirin if you had a prior heart attack.
  7. Take a statin if your docstor indicates a need. It helps inflammation and cholesterol.
  8. Don’t drink to excess.

Sleep at least 8 hours a day. AVoid stress, anxiety, depression through better coping mechanisms. Social isolation increases chronic inflammation.

http://www.cmaj.ca/content/185/16/E763.full.pdf+html?sid=f29c3195-e7d5-41f0-930f-adcbe22ac120

 

Other inflammatory markers:

Lipoprotein-associated Phospholipase A2) measures inflammation in the arteries –reference range: 81–259 ng/mL – below 200 is consistent with reduced risk of heart attack or stoke.

 

Insane Medicine – Keep your muscle mass maximized at all ages!!!

Insane Medicine - Keep your muscle mass throughout life!
Insane Medicine – Keep your muscle mass throughout life!
  • As we get older, we lose muscle mass. This mass decreases rapidly during times of illness and hospitalizations, which is why grandma may enter the hospital for an infection and never leave her bed again! Her muscles were minimally compensated as were, and after an illness, there is not enough muscle power left for everyday activities, like getting out of bed!!
  • Muscle-strengthening exercises preserve muscle mass but must be combined with adequate dietary protein intake.
  • Sarcopenia (the loss of muscle mass) results in poor muscle strength, increasing the risk of falls and lack of independence.
  • There is an association between protein intake and muscle mass that varies with physical activity. Women need 46 grams of protein a day, men need 56 grams of protein a day. The exact amount is variable depending on a number of factors, but 0.8 grams of protein is needed per 2.2 pounds (one kg). If you are obese, more protein may be helpful.
  • You need High quality protein! Meat, poultry, and fish are complete sources, and the only vegetable source that is complete is soy.
  • Complete protein sources have all the essential amino acids. Grains are not complete because they are low in lysine, while legumes are low in methionine. Grains and legumes are still excellent sources of protein.
  • You need to combine high intakes of beef and pork with vigorous aerobic activity to obtain the highest muscle mass. Exercises that are excellent include swimming, cycling, running, and aerobics classes at least 30 minutes a day. You need to break a sweat!
  • If you don’t use it, you lose it!!
  • Lose unnecessary weight – Losing even ten percent of your body weight gives health benefits that last a decade and decrease diabetes risk by 50%! It also decreases hypertension and sleep apnea. Weight loss decreases the stress on your knees and hips, allowing you to maintain mobility and independence.
  • Try to get 30 minutes of physical activity a day – consider getting a pedometer or fit-bit to monitor your activity and encourage movement.  Low activity is less than 3500 steps a day ( a mile is 2000 steps) Those who walk more, had lower diabetes risk. Also, the more you move, the less pain you have!

Insane Medicine – Alzheimer’s disease new possible treatment: A therapeutic system approach shows success!

Insane Medicine - Plaques in the brain - what a pain
Insane Medicine – Plaques in the brain – what a pain
  • As of yet, no single therapeutic intervention has been found to impact Alzheimer’s disease. Whereas other diseases, such as cancer and HIV treatment have required a multi-modal intervention, why shouldn’t Alzheimer’s?
  • Insane Medicine
    Beta_Amyloid precursor protein (APP) processing. Depending on the processing of APP , if it is cut into sAPPBetta, ABeta, Jcasp, and C31, then programmed cell death and synapse inhibition occurs. This leads to Alzheimers disease. In the other pathway of processing APP, sAPPalpha and alphaCTF form, which mediate synapse formation and a healthy brain.

     

  • Alzheimer’s disease (AD) results, in part, from a failure of synapse formation (called neuronal plasticity), which allows brain cells to connect with each other to preserve memory and basic functions. Instead, in AD, there is an increase in breakdown products on the right side of the diagram above, that cause less neurons to connect.
  • The goal of therapy may be to increase the trophic, anti-AD processing, leading to more neurons connecting and thus preventing Alzheimer’s disease. This requires multiple medicines and processes to intervene. and succeed.
  • A study listed in the link below demonstrated that using these interventions resulted in a reversal of memory loss and even a return to a employment in 10 individuals who followed the regimen. This reversal started in 3-6 months after initiation and remained for the duration of the study over two years.
  • http://www.impactaging.com/index.html  <– The link to the study. Great results!!

The therapeutic system:

  1. Optimize diet, minimize simple sugars to minimize inflammation. Eat Low glycemic, low grain diet. Minimize insulin resistance.
  2. Enhance ketogenesis by fasting 12 hours at night including three hours prior to bedtime. This reduces insulin levels and A-beta.
  3. Reduce stress through meditation or yoga, thereby reducing cortisol levels and stress,
  4. Optimize sleep – obtain 8 hours a night, use melatonin 0.5 mg at night and Tryptophan 500 mg three times a week. Get checked and treated for sleep apnea.
  5. Exercise 30-60 minutes a day for four-six days a week.
  6. Keep you brain active mentally through reading or mental exercises.
  7. Maintain your homocysteine levels to <7 – using methylcobalamin 1mg a day, methyltetrahydrofolate 0.8 mg a day, and pyridoxine-5-phosphate 50 mg a day. Consider taking trimethylglycine.
  8. Maintain serum B-12 above 500 by taking oral B-12 as above
  9. Keep the CRP<1 ( inflammation marker) using an anti-inflammatory diet that includes curcumin, DHA (docosahexanoic acid) 320 mg and EPA (eicosapentanoic acid) 180 mg a day
  10. Optimize fasting insulin <7 and keep the hemoglobin A1c <5.5 by following your diabetic diet precisely.
  11. Optimize your hormone balance, including your free T3 and T4, and estradiol, and testosterone levels. Be certain cortisol and progesterone/pregnenolone levels are in range through lab tests.
  12. GI health maintenance through probiotics use.
  13. Reduce A-beta through the use of cucumin and herbs such as Ashwagandha (500mg a day) and Bacopa Monniera (250 mg a day) and tumeric 400 mg a day.
  14. Cognitive enhancement through the use of Bacopa monniera and magnesium threonate.
  15. Vitamin D3 needs to be between 50-100 ng/ml by appropriate Vitamin D3 intake ( up to 2000 IU/day) and Vitamin K2.
  16. Increase NGF through intake of H. ernaceus or acetyl-L-carnitine.
  17. Provide synaptic structural components through citicoline 500 mg twice a day and DHA (docosohexanoic acid) 320 mg a day.
  18. Optimize antioxidants by intake of mixed tocopherols and tocotrienols, with selenium blueberries, n- acetyl cysteine, ascorbate, and alpha-lipoic acid. For example, use of vitamin C at 1 gram a day, Vitamin E at 400 IU a day, and alpha-lipoic acid a 100 mg a day.
  19. Optimize the zinc and copper ratio: if needed, , zinc picolinate at 50 mg a day may be needed, depending on the zinc levels.
  20. Treat sleep apnes as needed to maximize nighttime oxygenation.
  21. Optimize mitochondrial function through CoQ10 at 200 mg a day, alpha lipoic acid at 100 mg a day, polyquinoline quinone, N-acetyl cysteine, acetyl-L-carnitine, zinc, resverarol, thiamine and Vitamin C intake.
  22. Increase focus through pantothenic acid.
  23. Increase SirT1 function through Resveratrol intake.
  24. Exclude heavy metal toxicity and evaluate fo mercury, lead, cadmium toxicity.
  25. Reduce mMCT effects (medium chain triglycerides – a part of our diet) by taking coconut oil at a teaspoon three times a day or using Axona.

Obviously multiple lab test parameters are needed to determine needs and the interventions are quite rigorous, requiring a strict diet and lots of pills throughout the day, but this multi-modal intervention seems to work!

Lab tests that may be needed include: serum homocysteine, CRP, Vitamin D levels, Hemoglobin A1c, serum copper, serum zinc, ceruplasmin, pregnenolone, testosterone level, albumin:globulin ratio, cholesterol, morning cortisol, free T3 and T4 and TSH levels, DHEA levels, estradiol level, progesterone, insulin.

It is extensive but this seems to hold promise. More later!

www.impactaging.com