High Intensity Exercise And Age

There is the popular misconception that high intensity exercise is for the young, and the aging should just shuffle around a little bit and call it a day.

This paper from several years ago says otherwise.  This doesn't mean an elderly person needs to be doing a "Heavy Duty Mike Mentzer" bodybuilding workout, but there needs to be sufficient stimulus for the exercise to be effective.  Thus, the authors talk about the benefits of "low volume, high-intensity aerobic and/or resistance training" to achieve a variety of health benefits.

Of course, at any age, consult your physician before starting any exercise program, but we see a clear indication that high volume, low intensity does not need to be the way to go for the aging.  High intensity can do a better job.

PTSD And Gene expression: The MicroRNA Connectiom

Here is a fascinating article suggesting that post-traumatic stress disorder is associated with varying levels of certain microRNAs, which can affect gene expression.  Abstract:

Posttraumatic stress disorder (PTSD) affects many returning combat veterans, but underlying biological mechanisms remain unclear. In order to compare circulating micro RNA (miRNA) of combat veterans with and without PTSD, peripheral blood from 24 subjects was collected following deployment, and isolated miRNA was sequenced. PTSD was associated with 8 differentially expressed miRNA. Pathway analysis shows that PTSD is related to the axon guidance and Wnt signaling pathways, which work together to support neuronal development through regulation of growth cones. PTSD is associated with miRNAs that regulate biological functions including neuronal activities, suggesting that they play a role in PTSD symptomatology.

This altered gene expression may be linked to the mechanism of the disorder, both underscoring the seriousness of it and possibly pointing in the direction of therapy.  This article was from several years ago; we will be looking for any updates.

Artificial Sweeteners And Type 2 Diabetes Study

Here is an article on artificial sweeteners and type 2 diabetes risk.  Abstract:

BACKGROUND:

The influence of artificial sweeteners on metabolic diseases is controversial. Artificially sweetened beverages have been associated with an increased risk of type 2 diabetes (T2D) but biases and reverse causation have been suspected to have influenced the observed association. In addition, it has been suggested that investigation into the relationship between the frequency and duration of the consumption of packet or tablet artificial sweeteners and T2D risk is necessary.

METHODS:

We used data from 61,440 women in the prospective E3N-European Prospective Investigation into Cancer and Nutrition study, conducted between 1993 and 2011. We estimated hazards ratios (HRs) and 95% CIs of T2D risk associated with both the frequency and the duration of use of artificial sweeteners consumed in packets or tablets.

RESULTS:

Compared to "never or rare" consumers of artificial sweeteners, those using them "always or almost always" had an increased risk of T2D (HR = 1.83 [95% CI 1.66-2.02] in the multivariate model [MM], HR = 1.33 [95% CI 1.20-1.47] when further adjusted for body mass index, BMI). Women consuming artificial sweeteners in packets or tablets for more than 10 years also had an increased risk of T2D compared to never or rare users (HR = 2.10 [95% CI 1.83-2.40] in the MM and HR = 1.15 [95% CI 1.00-1.33] when adjusted for BMI, respectively).

CONCLUSIONS:

Our data suggest that both a higher frequency and a longer consumption of artificial sweeteners in packets or tablets was associated with T2D risk, independently of major T2D risk factors, but partially mediated by adiposity. A precautionary principle should be applied to the promotion of these products that are still largely recommended as healthy sugar substitutes.

A reasonable strategy may be to not use such artificial sweeteners and cut down on sugar in your diet as well. Avoid diabetes, and your health will thank you for it.

Dangers Of Shift And Night Work

Here is an article outlining the dangers of shift/nigh work to human health.

Shift/night work disrupts normal circadian (internal timing) rhythms, affecting sleep and promoting disorders “including cancer, diabetes, cardiovascular risks, obesity, mood disorders and age-related macular degeneration. “  Melatonin secretion may be involved.  The paper suggests “melatonin, bright light, or psychotropic drugs, have been proposed as a means to combat circadian clock disruption and improve adaptation to shift and night work.”

If you can at all avoid shift/night work do so; if you cannot because of work requirements then discuss with your physician strategies to adjust and hopefully reduce the risk of serious heath disorders consequent to disruption of normal life rhythms.

An Optimal Diet?

An article on whether there is an optimal diet for weight management and metabolic health can be found here.

The bottom line is that while different types of diets may stress optimizing different health outcomes (low fat diets helping with LDL; low carb diets helping more with triglycerides and HDL), the main point is to adhere to a healthy diet.  Both low fat and low carb can work; people have different preferences, but if you are overweight, sticking to a diet that results in weight loss will improve many metrics of health and fitness.

Genome Editing In The (Mouse) Brain

Here is a paper from several years ago discussing a fascinating and very promising finding.  We'll need to take a look at any subsequent developments in this field as they have occurred or will occur. Abstract:

We demonstrate editing of post-mitotic neurons in the adult mouse brain following injection of Cas9 ribonucleoprotein (RNP) complexes in the hippocampus, striatum and cortex. Engineered variants of Cas9 with multiple SV40 nuclear localization sequences enabled a tenfold increase in the efficiency of neuronal editing in vivo. These advances indicate the potential of genome editing in the brain to correct or inactivate the underlying genetic causes of neurological diseases.

The ability o directly alter gene sequences in the adult brain can yield a vast array of therapeutic options for certain genetic neurological diseases.  An additional thing that will become necessary for certain of those diseases is the ability to therapeutically intervene, on  brain-wide level, at the protein level as well (e.g., misfolded protein disorders).

Fat Tissue miRNAs

Here is an article from several years ago that should raise some eyebrows, and we'll have to keep track of further developments in this field.  Abstract:

Adipose tissue is a major site of energy storage and has a role in the regulation of metabolism through the release of adipokines. Here we show that mice with an adipose-tissue-specific knockout of the microRNA (miRNA)-processing enzyme Dicer (ADicerKO), as well as humans with lipodystrophy, exhibit a substantial decrease in levels of circulating exosomal miRNAs. Transplantation of both white and brown adipose tissue-brown especially-into ADicerKO mice restores the level of numerous circulating miRNAs that are associated with an improvement in glucose tolerance and a reduction in hepatic Fgf21 mRNA and circulating FGF21. This gene regulation can be mimicked by the administration of normal, but not ADicerKO, serum exosomes. Expression of a human-specific miRNA in the brown adipose tissue of one mouse in vivo can also regulate its 3' UTR reporter in the liver of another mouse through serum exosomal transfer. Thus, adipose tissue constitutes an important source of circulating exosomal miRNAs, which can regulate gene expression in distant tissues and thereby serve as a previously undescribed form of adipokine.

So we have known for a long time that fat (adipose) tissue can release macromolecular factors (adipokines) that can affect metabolism of other tissues.  These adipokines may mediate some  of the negative health effects of obesity including an increased risk for cancer. MicroRNAs (miRNAs) are small RNA molecules that affect gene expression by binding to target mRNA and are this crucially important to both normal function and to disease.  Initially, it was thought that the miRNAs operated within the cell producing them, but later it was learned that miRNAs can be released by one cell to affect others (exosomal miRNAs).  This paper shows that fat tissue is an important source of such circulating miRNAs, demonstrating another mechanism by which fat tissue can affect metabolism of other parts of the body, contributing to human disease.

The harmful effects of overweight/obesity keep on growing.

Maternal Smoke Exposure And Cell Signaling

It is know that maternal smoke exposure can possibly cause problems to the fetus.  Here is a mouse study demonstrating that offspring of smoke-exposed pregnant female mice were underweight with deceased lung volume, and that there were alterations in important cell signaling pathways that may have caused the negative effects on the fetal mice  Abstract:

The present study tested the hypothesis that maternal smoke exposure results in fetal lung growth retardation due to dysregulation in various signaling pathways, including the Wnt (wingless-related integration site)/β-catenin pathway. Pregnant female C57BL/6J mice were exposed to cigarette smoke (100-150 mg/m3) or room air, and offspring were humanely killed on 12.5, 14.5, 16.5, and 18.5 d post coitum (dpc). We assessed lung stereology with Cavalieri estimation; apoptosis with proliferating cell nuclear antigen, TUNEL, and caspase assays; and gene expression with quantitative PCR (qPCR) and RNA sequencing on lung epithelium and mesenchyme retrieved by laser capture microdissection. Results demonstrated a significant decrease in body weight and lung volume of smoke-exposed embryos. At 16.5 dpc, the reduction in lung volume was due to loss of lung mesenchymal tissue correlating with a decrease in cell proliferation (n = 10; air: 61.65% vs. smoke: 44.21%, P < 0.05). RNA sequence analysis demonstrated an alteration in the Wnt pathway, and qPCR confirmed an increased expression of secreted frizzled-related protein 1 (sFRP-1) [n = 12; relative quantification (RQ) 1 vs. 2.33, P < 0.05] and down-regulation of Cyclin D1 (n = 7; RQ 1 vs. 0.61, P < 0.05) in mesenchymal tissue. Furthermore, genome expression studies revealed a smoke-induced up-regulation of Rho-GTPase-dependent actin cytoskeletal signaling that can lead to loss of tissue integrity.-Unachukwu, U., Trischler, J., Goldklang, M., Xiao, R., D'Armiento, J. Maternal smoke exposure decreases mesenchymal proliferation and modulates Rho-GTPase-dependent actin cytoskeletal signaling in fetal lungs.

The importance of pregnant women avoiding maternal smoke exposure is underlined with this study.

Wnt Signaling And TB

Here is an interesting paper from several years ago discussing a potential link between a signaling pathway more commonly associated with (colorectal) cancer and the immune response to tuberculosis. Abstract:

Mycobacterium tuberculosis (M. tuberculosis), an intracellular pathogenic Gram-positive bacterium, is the cause of tuberculosis (TB), a major worldwide human infectious disease. The innate immune system is the first host defense against M. tuberculosis. The recognition of this pathogen is mediated by several classes of pattern recognition receptors expressed on the host innate immune cells, including Toll-like receptors, Nod-like receptors, and C-type lectin receptors like Dectin-1, the Mannose receptor, and DC-SIGN. M. tuberculosis interaction with any of these receptors activates multiple signaling pathways among which the protein kinase C, the MAPK, and the NFκB pathways have been widely studied. These pathways have been implicated in macrophage invasion, M. tuberculosis survival, and impaired immune response, thus promoting a successful infection and disease. Interestingly, the Wnt signaling pathway, classically regarded as a pathway involved in the control of cell proliferation, migration, and differentiation in embryonic development, has recently been involved in immunoregulatory mechanisms in infectious and inflammatory diseases, such as TB, sepsis, psoriasis, rheumatoid arthritis, and atherosclerosis. In this review, we present the current knowledge supporting a role for the Wnt signaling pathway during macrophage infection by M. tuberculosis and the regulation of the immune response against M. tuberculosis. Understanding the cross talk between different signaling pathways activated by M. tuberculosis will impact on the search for new therapeutic targets to fuel the rational design of drugs aimed to restore the immunological response against M. tuberculosis.

Once again, the importance of basic science research is seen.  First, the Wnt pathway was studied as a model of cell signaling, including in the fruit fly model.  Then, the absolute importance of this pathway in cancer, particularly colorectal cancer, was determined.  Next, Wnt signaling was identified as important in many other disorders, including neurodegenerative, and now has important implications in infectious disease.

Gene Editing For Muscular Dystrophy

Here is a paper from several years ago discussing promising results with gene therapy in a mouse model of muscular dystrophy.  Abstract:

Gene replacement therapies utilizing adeno-associated viral (AAV) vectors hold great promise for treating Duchenne muscular dystrophy (DMD). A related approach uses AAV vectors to edit specific regions of the DMD gene using CRISPR/Cas9. Here we develop multiple approaches for editing the mutation in dystrophic mdx4cv mice using single and dual AAV vector delivery of a muscle-specific Cas9 cassette together with single-guide RNA cassettes and, in one approach, a dystrophin homology region to fully correct the mutation. Muscle-restricted Cas9 expression enables direct editing of the mutation, multi-exon deletion or complete gene correction via homologous recombination in myogenic cells. Treated muscles express dystrophin in up to 70% of the myogenic area and increased force generation following intramuscular delivery. Furthermore, systemic administration of the vectors results in widespread expression of dystrophin in both skeletal and cardiac muscles. Our results demonstrate that AAV-mediated muscle-specific gene editing has significant potential for therapy of neuromuscular disorders.

That's very promising.  What's going on more recently? Future posts here will explore the progress in this and other similar projects using gene therapy tested in mouse models. This is why basic science research is so important, as the methods utilized are ultimately derived from such research.