University of Missouri School of Medicine researchers have found that reducing daily physical activity for even a few days leads to decreases in the function of the inner lining of blood vessels in the legs of young, healthy subjects, causing vascular dysfunction that can have prolonged effects.

Paul Fadel, associate professor of medical pharmacology and physiology, and John Thyfault, associate professor of nutrition and exercise physiology, also found that the vascular dysfunction induced by five days of inactivity requires more than one day of returning to physical activity and taking at least 10,000 steps a day to improve.

“We know the negative consequences from not engaging in physical activity can be reversed,” said Fadel. “There is much data to indicate that at any stage of a disease, and at any time in your life, you can get active and prolong your life.”

Diabetes and cardiovascular disease risks

“Inactivity is typically going to lead to people being overweight and obese,” said Fadel. “The next step after that is insulin resistance, which leads to Type 2 diabetes and cardiovascular disease.”

According to the Centers for Disease Control and Prevention, more than 29 million Americans are living with diabetes. That number is expected to continue to increase: the CDC estimates one-third of people born after 2000 will have Type 2 diabetes in their lifetimes.

“The best treatment is to become more active, and our research lends proof to that concept,” Fadel said. “If you do not realize how harmful sitting around all day and not doing any activity is to your health, this proves it.”

The researchers studied the early effects on the body’s blood vessels when someone transitions from high daily physical activity — 10,000 or more steps per day — to low daily physical activity, less than 5,000 steps per day. Five thousand steps is the national average, but only half of the daily recommendation from the U.S. Surgeon General.

The research was published in November (2013) in the Journal of Applied Physiology and in September (2014) in Medicine and Science in Sports and Exercise. The research was supported in part by National Institutes of Health grants, an ACSM Foundation Research Grant from the American College of Sports Medicine, and an American Heart Association Pre-Doctoral Fellowship.

Scientists at The Scripps Research Institute (TSRI) have found that a fundamental new mechanism for the known beneficial effects of resveratrol — the grapes and red-wine ingredient once touted as an elixir of youth: it powerfully activates an evolutionarily ancient stress response in human cells.

“This stress response represents a layer of biology that has been largely overlooked, and resveratrol turns out to activate it at much lower concentrations than those used in prior studies,” said senior investigator Paul Schimmel, professor and member of the Skaggs Institute for Chemical Biology at TSRI.

The discovery is reported in Nature.

Resveratrol is a compound produced in grapes, cacao beans, Japanese knotweed and some other plants in response to stresses including infection, drought and ultraviolet radiation.

It has attracted widespread scientific and popular interest over the past decade, as researchers have reported that it extended lifespan and prevented diabetes in obese mice and vastly increased the stamina of ordinary mice running on wheels.

More recently, though, scientists in this field have disagreed about the signaling pathways resveratrol activates to promote health, questioning some of resveratrol’s supposed health benefits.

Stress-response properties discovered

Schimmel’s laboratory is known for its work not on resveratrol, but on an ancient family of enzymes, the tRNA synthetases*. The primary, essential function of these enzymes is to help translate genetic material into the amino-acid building blocks that make proteins.

But as Schimmel and others have shown since the late 1990s, tRNA synthetases have acquired an extensive set of added functions in mammals.

Earlier, Xiang-Lei Yang, a TSRI professor in the Departments of Chemical Physiology and Cell and Molecular Biology and former member of Schimmel’s laboratory, began to find hints that a particular tRNA synthetase called TyrRS, which links the amino acid tyrosine to the genetic material that codes for it, can move to the cell nucleus under stressful conditions — apparently taking on a protective, stress-response role.

Lead author Mathew Sajish, a senior research associate in the Schimmel laboratory, noted that resveratrol appeared to have broadly similar stress-response properties and also resembled TyrRS’s normal binding partner tyrosine. “I began to see TyrRS as a potential target of resveratrol,” he said.

For the new study, Sajish and Schimmel put TyrRS and resveratrol together and showed with tests including X-ray crystallography that resveratrol does indeed mimic tyrosine, well enough to fit tightly into TyrRS’s tyrosine binding pocket. That binding to resveratrol, the team found, takes TyrRS away from its protein translation role and steers it to a function in the cell nucleus.

Tracking the resveratrol-bound TyrRS in the nucleus, the researchers determined that it grabs and activates the protein PARP-1, a major stress response and DNA-repair factor thought to have a significant influence on lifespan. The scientists confirmed the interaction in mice injected with resveratrol. TyrRS’s activation of PARP-1 led, in turn, to the activation of a host of protective genes including the tumor-suppressor gene p53, and most interesting — the longevity genes FOXO3A and SIRT6.

Protective effect activated at 1,000 times lower doses

The first studies of resveratrol in the early 2000s had suggested that it exerts some of its positive effects on health by activating SIRT1, also thought to be a longevity gene. But SIRT1’s role in mediating resveratrol’s reported health-boosting effects has been questioned lately.

The team’s experiments showed, however, that the TyrRS-PARP-1 pathway can be measurably activated by much lower doses of resveratrol — as much as 1,000 times lower — than were used in some of the more celebrated prior studies, including those focused on SIRT1. “Based on these results, it is conceivable that moderate consumption of a couple glasses of red wine (rich in resveratrol) would give a person enough resveratrol to evoke a protective effect via this pathway,” Sajish said. He also suspects that effects of resveratrol that only appear at unrealistically high doses may have confounded some prior findings.

Why would resveratrol, a protein produced in plants, be so potent and specific in activating a major stress response pathway in human cells? Probably because it does much the same in plant cells, and probably again via TyrRS —- a protein so fundamental to life, due to its linkage to an amino acid, that it hasn’t changed much in the hundreds of millions of years since plants and animals went their separate evolutionary ways. “We believe that TyrRS has evolved to act as a top-level switch or activator of a fundamental cell-protecting mechanism that works in virtually all forms of life,” said Sajish.

Natural stress response

Whatever activity resveratrol naturally has in mammals may be an example of hormesis: the mild, health-promoting activation of a natural stress response. “If resveratrol brought significant benefits to mammals, they might have evolved a symbiotic relationship with resveratrol-producing plants,” Sajish said.

“We think this is just the tip of the iceberg,” said Schimmel. “We think there are a lot more amino-acid mimics out there that can have beneficial effects like this in people. And we’re working on that now.”

Schimmel and his laboratory also are searching for molecules that can activate the TyrRS stress response pathway even more potently than resveratrol does.

The National Cancer Institute, the National Foundation for Cancer Research, and aTyr Pharma, Inc. provided funding for the study.

* tRNA (transfer RNA) is an enzyme (a small molecule) in cells that transfers amino acids to organelles called ribosomes, where they are linked into proteins; a synthetase is an enzyme that catalyzes the linking together of two molecules.

http://www.kurzweilai.net/scripps-scientists-discover-how-resveratrol-provides-health-benefits

A systematic review of 37 randomized controlled trials showed promising evidence for the ability of yoga to improve cardiovascular and metabolic health, but found no significant difference in the effectiveness of yoga versus aerobic exercise.

Yoga showed significant improvement in body mass index, systolic blood pressure, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol; and significant changes in body weight, diastolic blood pressure, total cholesterol, triglycerides, and heart rate. ‘

“Despite the growing evidence on the health implications of yoga, the physiological mechanisms behind the observed clinical effects of yoga on cardiovascular risk remain unclear,” the researchers say, adding that “there’s a need for larger randomized controlled studies that meet explicit, high quality methodological standards to ascertain the effects of
yoga” in improving modifiable risk factors of  cardiovascular disease and metabolic syndrome.

Cardiovascular disease (CVD) and metabolic syndrome are major public health problems in the USA and worldwide. Metabolic syndrome is defined as having at least three metabolic risk factors — increased blood pressure, high blood sugar level, excess body fat, and abnormal cholesterol levels — and greatly increases chance of future cardiovascular problems. CVD and metabolic syndrome share many of the same modifiable risk factors, such as physical inactivity, the fourth leading risk factor of global mortality, the researchers note.

The study, by researchers at Erasmus MC, Harvard Medical School, and Harvard School of Public Health, was published (open-access) in the European Journal of Preventive Cardiology.

Abstract of The effectiveness of yoga in modifying risk factors for cardiovascular disease and metabolic syndrome: A systematic review and meta-analysis of randomized controlled trials

Background Yoga, a popular mind-body practice, may produce changes in cardiovascular disease (CVD) and metabolic syndrome risk factors.

Design This was a systematic review and random-effects meta-analysis of randomized controlled trials (RCTs).

Methods Electronic searches of MEDLINE, EMBASE, CINAHL, PsycINFO, and The Cochrane Central Register of Controlled Trials were performed for systematic reviews and RCTs through December 2013. Studies were included if they were English, peer-reviewed, focused on asana-based yoga in adults, and reported relevant outcomes. Two reviewers independently selected articles and assessed quality using Cochrane’s Risk of Bias tool.

Results Out of 1404 records, 37 RCTs were included in the systematic review and 32 in the meta-analysis. Compared to non-exercise controls, yoga showed significant improvement for body mass index (−0.77 kg/m² (95% confidence interval −1.09 to −0.44)), systolic blood pressure (−5.21 mmHg (−8.01 to −2.42)), low-density lipoprotein cholesterol (−12.14 mg/dl (−21.80 to −2.48)), and high-density lipoprotein cholesterol (3.20 mg/dl (1.86 to 4.54)). Significant changes were seen in body weight (−2.32 kg (−4.33 to −0.37)), diastolic blood pressure (−4.98 mmHg (−7.17 to −2.80)), total cholesterol (−18.48 mg/dl (−29.16 to −7.80)), triglycerides (−25.89 mg/dl (−36.19 to −15.60), and heart rate (−5.27 beats/min (−9.55 to −1.00)), but not fasting blood glucose (−5.91 mg/dl (−16.32 to 4.50)) nor glycosylated hemoglobin (−0.06% Hb (−0.24 to 0.11)). No significant difference was found between yoga and exercise. One study found an impact on smoking abstinence.

Conclusions There is promising evidence of yoga on improving cardio-metabolic health. Findings are limited by small trial sample sizes, heterogeneity, and moderate quality of RCTs.

According to a new study published in Science Translational Medicine, researchers have tested a potential anti-aging drug called everolimus (AKA RAD001) — an analog (version) of the drug rapamycin (sirolimus)*.

In previous research, rapamycin extended the life span of mice by 9 to 14%, even when treatment was initiated late in life, and it improved a variety of aging-related conditions in old mice, including tendon stiffening, cardiac dysfunction, cognitive decline, and decreased mobility.

These findings raise the possibility that “mTOR inhibitors”* (like rapamycin and RAD001) may have beneficial effects on aging and aging-related conditions in humans.

Since it would take decades to test the effect of a drug on life span in humans, the researchers at Novartis Institutes for BioMedical Research and affiliates used a proxy: the decline in immune function in seniors’ (age 65 and older) during aging, as assessed by their response to a flu vaccine.

Immune-system aging is a major cause of disease and death, making older people more susceptible to infections — and to have a weaker response to vaccines. In the research, the scientists found that R001 boosted immune systems response to a flu vaccine by 20 percent.

“The immune-enhancing effects of mTOR inhibitors need to be verified with additional studies,” the authors say. Although some scientists are reportedly already self-medicating, “the toxicity of RAD001 at doses used in oncology or organ transplantation results in adverse effects such as stomatitis, diarrhea, nausea, cytopenias, hyperlipidemia, and hyperglycemia.”

*Rapamycin and RAD001 belong to a class of drugs known as “mTOR inhibitors.” Inhibition of the mTOR (Mammaliantarget of rapamycin) pathway extends life span in all species studied to date, the scientists note, and in mice it also delays the onset of age-related diseases and comorbidities (unrelated pathological or disease processes involved at the same time).