A study published online in Nature uses demographic data to reveal a lifespan that human beings cannot exceed, simply by virtue of being human. It’s like running, as an accompanying News and Views article points out. Elite athletes might shave a few milliseconds off the world record for the 100-meter sprint, but they’ll never run the same distance in, say, five seconds, or two. Human beings are simply not made that way. The same is true for longevity. The consequences of myriad factors related to our genetics, metabolism, reproduction and development, all shaped over millions of years of evolution, means that few humans will make it past their 120th birthdays. The name of Jeanne Calment, who died in 1997 at the age of 122, is likely to remain as long in the memory in the Methuselah stakes as that of Usain Bolt on the Olympic track.
Maximum lifespan is a bald measure of years accumulated. It is not the same as life expectancy, which is an actuarial measure of how long one is expected to live from birth, or indeed from any given age. Life expectancy at birth has increased in most countries over the past century, not because people have longer lifespans, but mainly because infectious disease does not kill as many infants as it once did. Factors such as poverty and warfare conspire to decrease life expectancy. Although life expectancy at birth has risen steadily for both men and women in France since 1900, for example, there are dramatic and poignant drops that coincide with the two world wars.
In Britain in the early twentieth century, many children still died from infectious diseases, and men would die shortly after retiring from physically demanding jobs. The National Health Service was the political response. It has become, in some ways, the victim of its own success. People live longer than they did even a few decades ago, and die (eventually) of different (and more expensive) complaints. As any beginning medical student is soon taught, gerontology is far from a dying discipline. So if we owe our increases in life expectancy to better public health, nutrition, sanitation and vaccination, is it not fair to ask whether more-effective treatments for diseases such as cancer, Parkinson’s disease and Alzheimer’s might also yield dividends in maximum lifespan? Will 120th birthday parties become routine, outmatched by a small yet increasing number of sesquicentenarians? The demographic data say no. People are living longer, and the population as a whole is greying, but the rate of increase in the number of centenarians is slowing, and might even have peaked.
Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D), but whether NAFLD plays a causal role in the pathogenesis of T2D is uncertain. One proposed mechanism linking NAFLD to hepatic insulin resistance involves diacylglycerol-mediated (DAG-mediated) activation of protein kinase C-ε (PKCε) and the consequent inhibition of insulin receptor (INSR) kinase activity. However, the molecular mechanism underlying PKCε inhibition of INSR kinase activity is unknown. Here, we used mass spectrometry to identify the phosphorylation site Thr1160 as a PKCε substrate in the functionally critical INSR kinase activation loop. We hypothesized that Thr1160 phosphorylation impairs INSR kinase activity by destabilizing the active configuration of the INSR kinase, and our results confirmed this prediction by demonstrating severely impaired INSR kinase activity in phosphomimetic T1160E mutants. Conversely, the INSR T1160A mutant was not inhibited by PKCε in vitro. Furthermore, mice with a threonine-to-alanine mutation at the homologous residue Thr1150 (InsrT1150A mice) were protected from high fat diet–induced hepatic insulin resistance. InsrT1150A mice also displayed increased insulin signaling, suppression of hepatic glucose production, and increased hepatic glycogen synthesis compared with WT controls during hyperinsulinemic clamp studies. These data reveal a critical pathophysiological role for INSR Thr1160 phosphorylation and provide further mechanistic links between PKCε and INSR in mediating NAFLD-induced hepatic insulin resistance.
Artificial structures of tumour antigens, mimotopes, applied in vaccinations of cancer patients can trigger a long-term immune response. For the vaccine, however, a carrier is required that triggers an immune response itself. Researchers from the Messerli Research Institute at Vetmeduni Vienna thus produced mimotopes for HER2, a tumour antigen of about 30 percent of breast tumours, at virus-like particles of harmless adeno-associated viruses (AAV) without chemical after-treatment and used them directly as a specific vaccine. This vaccine could serve as a prophylaxis for high-risk patients or breast cancer patients that have already received a therapy. Treatment of canine breast tumours likewise seems possible. The results were published in OncoImmunology and Oncology Letters.
Regulatory submissions in the EU and Canada remain on track for 2016
GlaxoSmithKline plc (LSE/NYSE: GSK) today announced that it has submitted a Biologics License Application (BLA) for its candidate shingles vaccine, ShingrixTM, to the United States Food and Drug Administration (FDA), seeking approval for the prevention of herpes zoster (shingles) in people aged 50 years or over.
The regulatory submission for Shingrix is based on a comprehensive phase III clinical trial programme evaluating its efficacy, safety and immunogenicity in more than 37,000 people. This includes the ZOE-50 and ZOE-70 studies published in the New England Journal of Medicine in April 2015 and September 2016, respectively.1,2
Summary Cannabinoid receptor 1 (CB1) is the principal target of Δ9-tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use. CB1 is activated by endocannabinoids and is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. Here, we present the 2.8 Å crystal structure of human CB1 in complex with AM6538, a stabilizing antagonist, synthesized and characterized for this structural study. The structure of the CB1-AM6538 complex reveals key features of the receptor and critical interactions for antagonist binding. In combination with functional studies and molecular modeling, the structure provides insight into the binding mode of naturally occurring CB1 ligands, such as THC, and synthetic cannabinoids. This enhances our understanding of the molecular basis for the physiological functions of CB1 and provides new opportunities for the design of next-generation CB1-targeting pharmaceuticals.
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