In The News: December 2015

A study published in the journal Hypertension found that those with high blood pressure who regularly take nonsteroidal anti-inflammatory drugs (NSAIDs) have an elevated risk of developing chronic kidney disease.*

While some previous studies have linked NSAIDs to diminished kidney function, the outcome often ignored those who already had hypertension, which itself carries an increased risk for kidney damage.

After examining the data of over 30,000 patients with high blood pressure, researchers at the Institute of Population Health Sciences, National Health Research Institutes in Zhunan, Taiwan, found that those who’d been taking NSAIDs for at least three months were 32% more likely to have chronic kidney disease than those who didn’t take NSAIDs. Those who used NSAIDs more than once a day had a 23% greater risk of developing chronic kidney disease than people who didn’t.

Even taking NSAIDs for less than three months increased the risk of developing chronic kidney disease by 18%.

“Physicians should exercise caution when administering NSAIDs to people with hypertension and closely monitor renal function,” said senior study author Hui-Ju Tsai.

Editor’s Note: Taking NSAIDs may cause the kidneys to retain salt and water, increasing blood pressure and potentially making medications that lower hypertension ineffective.

The World Journal of Gastroenterology reported the results of a case-control study and meta-analysis which both found a lower risk of colorectal adenoma (polyps) in association with higher serum vitamin D levels.*

Researchers conducted a matched case-control study that included 112 Korean men and women with colorectal adenomas and 112 controls who underwent colonoscopy between August 2011 and September 2012. An association between higher vitamin D levels and a reduced risk of adenoma was found in women.

For the meta-analysis, 15 studies involving Western as well as Asian populations that examined serum or plasma vitamin D levels and the risk of colorectal adenoma were selected. The combined studies included 5,454 subjects with colorectal adenomas and 6,656 controls. When highest to lowest categories of vitamin D were compared, a 32% average reduction in the risk of adenoma was uncovered in the highest vitamin D group.

Editor’s Note: While many adenomas remain benign, some are a precursor to colorectal cancer, one of the more common human malignancies.

A recent study published in Oncotarget investigated the effects of metformin and aspirin, alone and in combination, on pancreatic cancer cell lines.* In a xenograft mouse model, the scientists demonstrated that the metformin/aspirin combination inhibited pancreatic tumor growth. For the study, randomized mice with tumors were injected with 200 mg/kg metformin, 60 mg/kg aspirin, or both three times a week for 28 days.

The researchers found that metformin combined with aspirin, at relatively low concentrations, demonstrated a synergistic effect on cell proliferation. Compared to each drug alone, the combination had significantly stronger effects on the inhibition of colony formation and cell migration, as well as the modulation of key molecular targets in AMPK and other signaling pathways. Furthermore the combination led to apoptosis through downregulation of anti-apoptotic proteins and the upregulation of pro-apoptotic proteins.

Editor’s Note: “At the cellular level, metformin stimulates AMPK activation by disrupting mitochondrial respiratory chain complex I and decreasing ATP synthesis,” say study authors. “Recently, aspirin was also shown to inhibit the dephosphorylation of AMPK thus activating AMPK.”

A two-year study supported by the National Institutes of Health found that calorie restriction lowered certain risk factors of age-related diseases.* In the study, published in the Journal of Gerontology, 218 healthy normal-weight and moderately overweight men and women were randomized to a reduced-calorie diet that was 25% below their normal calorie consumption. The calorie restriction group was given a weight-loss target of 15.5% in the first year and weight stability over the second year. Weight loss was expected to be achieved by reducing calorie intake 25% below their regular intake at baseline. The other participants maintained their regular baseline diets over the course of the study.

Although the weight loss by the calorie restriction group was the largest sustained weight loss reported in any clinical trial of nonobese participants, weight loss fell short of the target. The intervention arm only reached 12% caloric restriction instead of the trial’s 25% goal but did maintain calorie restriction over the two-year period.

Calorie restriction significantly reduced several predictors of cardiovascular disease compared to the control group, including decreasing total cholesterol by 6%, increasing HDL levels, and lowering average blood pressure by 4%. Calorie restriction led to a 47% reduction in levels of C-reactive protein and markedly decreased insulin resistance.

Editor’s Note: “It’s important to find out whether these reductions would yield long-term benefits,” said NIH director and paper author Dr. Evan Hadley. “It also would be useful to discover if calorie restriction over longer periods has additional effects on predictors of health in old age, and compare its effects with exercise-induced weight loss.”

An article appearing in Cell Reports describes a role for nutrients in slowing aging of the thymus, a gland responsible for the production of immune cells known as T lymphocytes. The thymus reaches its peak size at adolescence and subsequently begins to atrophy.*

The researchers examined gene activity in the thymus’ stromal (connective tissue) cells and lymphoid cells. They discovered that stromal cells were deficient in the body’s enzyme catalase, making them subject to increased damage from reactive oxygen species.

To help confirm the benefit of this nutrient protection, mice were provided with drinking water enhanced with the nutrients N-acetylcysteine or vitamin C from the time of weaning. In comparison with mice that received plain water, thymus glands from mice that received either nutrient were larger after 10 weeks than those of control animals of the same age.

Editor’s Note: In another experiment, mice that were genetically modified to overexpress mitochondrially targeted catalase had thymus glands that were significantly protected from thymus atrophy at six months of age compared to those of normal control animals.

An article published in Cell Reports reveals a protective effect for supplementation with alpha-lipoic acid on telomere length and vascular health in mice given a high-fat diet.*

“The effects of chronic diseases such as atherosclerosis and diabetes on blood vessels can be traced back to telomere shortening,” noted senior author R. Wayne Alexander, MD, PhD.

Previous research, reported in the journal Circulation, found an inhibitory effect for lipoic acid against high-fat diet-induced atherosclerosis in mouse models of the disease. In the current report, Dr. Alexander and colleagues confirmed that alpha-lipoic acid stimulates peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC1-alpha), which is known to control some aspects of how muscles respond to exercise. “What’s new here is that we show that PGC1-alpha is regulating telomerase, and that has real beneficial effects on cellular stress in a mouse model of atherosclerosis,” first author Shiqin Xiong stated.

Editor’s Note: Telomeres are segments of genetic material that cap and protect the ends of chromosomes. Aging-associated reduction in telomere length is considered a marker and cause of cellular aging. Telomere length is maintained by an enzyme known as telomerase. While telomerase is activated in proliferating cells, including those which are cancerous, Dr. Alexander’s team has not observed an increased incidence of malignancies in animals that received alpha-lipoic acid.

The journal PLOS One published findings derived from NHANES data that reveal a high prevalence of suboptimal alpha-tocopherol (vitamin E) levels among subjects for whom food alone was their only source of the vitamin.*

Michael I. McBurney and associates analyzed information from 7,922 NHANES participants with available measurements of serum alpha-tocopherol. A striking 87% of subjects aged 20 to 30 years and 43% of those aged 51 years and older had vitamin E levels lower than 30 micromoles per liter, which was categorized as inadequate based on Estimated Average Requirement and the individuals with the lowest mortality rates in the Alpha-Tocopherol Beta-Carotene study. Serum alpha-tocopherol levels among subjects whose only source of vitamin E was food were below adequate levels on average, at 24.9 micromoles per liter. In comparison, those whose vitamin E was derived from both food and supplements had an average level of 33.7 micromoles per liter.

Editor’s Note: “We propose that for many Americans, especially those relying exclusively upon food sources, that serum alpha-tocopherol concentrations may not be adequate,” Dr. McBurney and colleagues write.

An article published on August 16, 2015, in the Journal of the American Geriatrics Society reports a successful outcome for home delivery of a vitamin D supplement to older individuals in Forsyth County, North Carolina.*

The study included 68 homebound Meals-on-Wheels participants. Subjects received a supplement providing 100,000 IU vitamin D or a placebo delivered with their meal once per month for five months. Serum 25-hydroxyvitamin D levels were assessed at the beginning and end of the study.

While 57% of subjects had serum vitamin D levels of less than 20 ng/mL prior to treatment, just one of 34 participants who received vitamin D3 had levels that were this low after five months, in comparison to 18 of the 34 participants randomized to the placebo group. After adjustment for several factors, a lower rate of falls was found among those randomized to vitamin D3 in comparison with the placebo group.

Editor’s Note: Improved vitamin D status could aid in the prevention of falls that can be a complication of muscle weakness, osteoporosis, or impaired balance and/or vision that may occur in older men and women.

Findings from studies presented at a Satellite Symposium on Coffee and Cardiovascular Disease Mortality held during the European Association for Cardiovascular Prevention And Rehabilitation’s 2015 Congress add evidence to an association between drinking coffee and a reduced risk of cardiovascular disease and related mortality.*

Most notable were the results of a meta-analysis published in the American Journal of Epidemiology which concluded that, compared to not drinking coffee, consuming three cups per day was associated with up to a 21% reduction in the risk of dying from cardiovascular disease among 997,464 subjects. For all-cause mortality, the greatest protective effect was found in association with four cups daily. Another meta-analysis published in 2014, which appeared in Circulation, suggests that an optimal amount for protection against cardiovascular disease is three cups per day.

Coffee drinking has also been associated with protection against diabetes, a disease that significantly increases cardiovascular disease risk.

Editor’s Note: Protective mechanisms for coffee against the risk of cardiovascular mortality remain uncertain; however, the beverage’s antioxidant and anti-inflammatory effects are likely to play a role.

Exciting advances in breast cancer prevention were made in 2015, with the focus on the diabetes drug metformin.^1-4 A clinical trial demonstrated that metformin can reduce proliferation of some types of breast cancer cells by over 60%, compared with placebo.¹

There are three key pieces of evidence that explain why an antidiabetic drug would be an effective cancer preventive agent.

1. Insulin resistance increases risk for breast cancer and worsens prognosis. Metformin reduces insulin resistance.^5-7
2. Obese people are at higher risk for different types of cancers including breast cancer.⁸ Metformin fights obesity.^9-11
3. High levels of insulin promote tumor formation.¹² Metformin counteracts insulin resistance.^5,10

And large-scale studies have shown substantial reduction in cancer rates and deaths (especially for breast cancer) among diabetics using metformin. ¹³

One exciting finding is that metformin activates a “master signaling molecule” called AMPK.¹ AMPK is involved and plays an important role in systemic energy balance, insulin signaling, and the metabolism of glucose and fats.¹⁴

Another of metformin’s mechanisms is its unique ability to change cancer cells’ metabolism. Studies show that this effect promotes killing of cancer stem cells in breast, prostate, colon, and brain cancers by producing an energy crisis in these rapidly dividing cells.

Metformin has been shown to induce cell death by energy starvation in breast cancer stem cells. This effect made the otherwise treatment-resistant stem cells highly vulnerable to standard chemotherapy.⁴ Chemotherapy works by inducing DNA damage in stem cells, and metformin blocks the normal DNA repair mechanisms by reducing available energy levels.⁴

While promising, these studies require validation from a controlled human trial. Such a study was recently conducted among a group of 200 women scheduled for surgery to remove invasive breast cancer lesions. Subjects were assigned to receive a placebo or metformin at 1,700 mg daily for four weeks preceding their surgery. At surgery, biopsies were taken to determine the effects of metformin. The researchers used a known marker of cancer cell proliferation, a protein called Ki-67, to detect evidence of cell replication, which would be evidence of cancerous progression. ¹⁵

The study found that proliferation of cells in the precancerous lesions called ductal carcinoma in situ (DCIS) among metformin recipients was reduced compared with that in placebo patients in the group of women with several known markers of aggressive breast cancer including the cancer growth factor human epidermal growth factor receptor 2 (HER2), a marker of aggressive cancer seen in 20-30% of breast cancer victims).¹⁶ and the estrogen receptor molecule expressed on the precancerous cells.¹

Women with DCIS and HER2 had a 40% reduction in cell proliferation, while those who had both HER2 and estrogen receptor markers had over 60% reduction in proliferation.¹

These most recent findings add to the evidence base that favors use of metformin in cancer-prevention efforts. The metformin story is a classic example of how closely related all of our bodies’ metabolic systems are to one another, and how simple preventive approaches trump complex “designer drugs” aimed at fixing problems after they arise.