Volume 19 Issue 5, May 2013

Nature journals' updated editorial policies aim to improve transparency and reproducibility.

The single biggest risk factor for the vast majority of chronic diseases is old age. For many diseases, in fact, a person's birth date is a larger red flag than all other known risk factors combined. But for too long, physicians thought that the aging process was impossible to modify or slow down. Like death and taxes, growing old—and the medical problems that come with it—was considered inevitable. That's starting to change. In this special news focus on aging, Nature Medicine looks at the progress being made in drug interventions for the elderly and the hurdles that remain in the pursuit of a pharmaceutical elixir for healthy aging.

Mandana Arabi leads the Sackler Institute for Nutrition Science, created in 2011 by the New York Academy of Sciences to address the massive global problem of malnutrition. She spoke with Alisa Opar about how the institute hopes to put nutrition research on the scientific map.

Health insurance covers drugs approved by regulatory agencies, but it often doesn't pay for the products known as 'medical foods' needed to keep individuals alive and well. This lack of reimbursement means that many who cannot afford these life-saving diets suffer brain deterioration and disability—or worse. Roxanne Khamsi reports on the battle for medical foods and how it could affect the treatment of diseases as diverse as osteoporosis and Alzheimer's.

Genomic advances, including next-generation sequencing, offer substantial opportunities and challenges for stratified and personalized medicines. However, the lack of standardization in genomic diagnostics translates into a major risk of error introduction. To ensure the integrity of such data—and their application—we suggest the development of 'good genomic practice' standards to guide the field.

L-Carnitine is a common food supplement and naturally occurs in red meat. This nutrient is metabolized into trimethyl metabolites by the gut microbiota and is associated with an elevated risk for cardiovascular disease. A recent study provides new insights into this link by exploring how the gut microbiota generates proatherogenic metabolites from L-carnitine and how the microbiota is altered in response to an omnivorous diet (pages 576–585).

A new study establishes a link between glucagon-like peptide-1 (GLP-1) release from the gut and the cardiac hormone atrial natriuretic peptide, which lowers blood pressure. As GLP-1 receptor agonists are used to control glycemia in patients with type 2 diabetes, this new gut-heart axis suggests a role of these agents in overall cardiovascular homeostasis (pages 567–575).

It has long been unknown how activation of resident macrophages in the brain, or microglia, is regulated during the inflammatory pathogenesis of multiple sclerosis. Work in a mouse model of human multiple sclerosis identifies the E3 ubiquitin ligase Peli1 as a new crucial regulator of microglia activation (pages 595–602).

The RAS-RAF-MEK-ERK signaling kinase pathway has been the focus of intense cancer drug development efforts because of its central role in tumor cell proliferation and survival. Although inhibitors of RAF and MEK provide therapeutic validation, tumor resistance challenges their effectiveness. Targeting scaffolding proteins such as IQGAP1 may be a new approach (pages 626–630).

Although it is now accepted that adult humans possess active brown adipose tissue, it has been questioned whether this is genuine classical brown adipose tissue. Two new studies provide evidence that humans, both as babies and adults, do have classical brown tissue and also indicate that there is heterogeneity in the composition of brown fat depots in humans, as in mice (pages 631–634 and 635–639).

A study now links platelet generation and cholesterol metabolism, providing new understanding of the mechanisms involved in thrombocytosis and atherogenesis. The authors show that the cholesterol transporter ABCG4 is highly expressed in bone marrow megakaryocyte progenitors, and in its absence, these cells have defective cholesterol efflux and increased proliferation, leading to increased megakaryocyte production, thrombocytosis and accelerated atherogenesis in atherosclerosis-prone mice (pages 586–594).

This Review discusses recent developments in understanding the immune processes that occur at the fetomaternal interface to ensure fetal tolerance during pregnancy, including the roles of fetal trophoblasts, epigenetically modified decidual stromal cells and maternal innate and adaptive immune cells. The authors also explain how impairments in the maternal immune adaptation to pregnancy might influence pregnancy complication,s such as spontaneous miscarriage, as well as postnatal health of the child.

Thiazolidinediones (TZDs), which act through the nuclear receptor peroxisome proliferator activated receptor-γ (PPARγ), are a widely prescribed class of drugs for type 2 diabetes; however, their use has been challenged by a number of side effects. Here the authors outline recent advances in our understanding of the modulation of the PPARγ pathway in metabolism and discuss how these insights might be used to explain the adverse side effects of TZD therapy and develop a new generation of safer PPARγ-targeting drugs.

The peptide hormone GLP-1 has both antidiabetic and antihypertensive effects. Daniel Drucker and his colleagues now show that GLP-1 lowers blood pressure through indirect mechanisms involving the heart: GLP-1 acts on its receptor in atrial cardiomyocytes to stimulate secretion of the peptide hormone ANP, which in turn lowers blood pressure through direct effects on the vasculature and kidney.

The long-noted association of red meat with an increased risk of cardiovascular disease may be due to ingestion of a specific compound found in red meat, l-carnitine. The ability of this compound to promote atherosclerosis in mice requires that it be further metabolized by the gut microbiota. In humans, omnivores but not vegans or vegetarians metabolize l-carnitine in this manner, a difference which may be explained by effects of diet on the presence of specific types of bacteria in the gut.

Nan Wang and colleagues uncover a new function for HDL that may contribute to its anti-atherosclerotic effects. In the bone marrow, HDL removes cholesterol from megakaryocyte progenitor cells in a process requiring the cholesterol transporter ABCG4, thereby dampening megakaryocyte and platelet production.

Microglia are activated in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Here Shao-Cong Sun and colleagues demonstrate that the E3 ubiquitin ligase Peli1 is expressed in microglia and is required for their activation and expression of inflammatory cytokines and chemokines after the induction of EAE. Disease severity is reduced in Peli1-deficient mice, partly through the effects of Peli1 on TLR signaling and Traf3 degradation.

Fragile X syndrome is a type of mental retardation caused by mutations in the Fmr1 gene. Now Andres Ozaita and colleagues show that blocking cannabinoid signaling can restore learning in these mice, suggesting a potential therapeutic approach to this disease.

Gerhard Krönke and his colleagues show that PPARβ/δ regulates Wnt signaling in osteoblasts, which in turn determines the proper ratio of OPG to RANKL and thus bone homeostasis. They go on to show that pharmacological activation of this receptor normalizes bone density in a mouse model of osteoporosis.

Analysis of gene-expression profiles led to the identification of three molecularly distinct subtypes of colon cancer. One of these subtypes is new, and its identification is of clinical interest because it tends to have a particularly unfavorable prognosis and is refractory to existing targeted therapies.

Gene-expression profiles from over 1,000 colorectal tumors define six subtypes with specific phenotypical features, responses to therapy and clinical progression.

The MAPK cascade scaffolding protein IQGAP1, although dispensable for normal epithelial homeostasis, is required for RAS- and RAF-driven tumorigenesis in mouse tumor models. Accordingly, peptide-specific disruption of the interaction between IQGAP1 and ERK1/2 can bypass acquired resistance of vemurafenib-treated BRAF-mutant melanomas and extend the life span of tumor-bearing mice.

Brown fat is a thermogenically active organ that burns energy instead of storing it and has been the focus of intense research recently in the hopes of harnessing this activity to combat obesity. Sven Enerbäck and his colleagues now show that human neonates possess a classical form of this type of fat, suggesting hope that its expansion in adults may indeed be an avenue of therapy to treat obesity.

Brown adipose tissue (BAT) burns, rather than stores, energy and has thus been explored as a way to combat obesity. Aaron Cypess and his colleagues isolate neck fat from adult humans and show that BAT exists in this region, define its anatomical localization in the neck relative to white adipose tissue and demonstrate that it is functional.

It has been thought that a switch by the muscle from oxidative phosphorylation to glycolysis is associated with the development of insulin resistance. Jiandie Lin and colleagues now show that transgenic mice that undergo this switch, due to modest overexpression of Baf60c, are actually more glucose tolerant and insulin sensitive compared to wild-type mice when both are placed on a high-fat diet, suggesting the switch is actually an adaptive process.

Building on their earlier work on heart and lung organ engineering, Jeremy Song and his colleagues have now adapted the technology of using decellularized scaffolds to develop bioengineered kidneys for transplantation. When reseeded with endothelial and epithelial cells, and after orthotopic transplantation in rats, the grafts became perfused by the recipient's circulation, produced urine and provided clearance of metabolites.