Via EurekAlert!: researchers have "explained how rapamycin, a drug that extends mouse lifespan, also causes insulin resistance. The researchers showed in an animal model that they could, in principle, separate the effects, which depend on inhibiting two protein complexes, mTORC1 and mTORC2, respectively. The study suggests that molecules that specifically inhibit mTORC1 may combat age-related diseases without the insulin-resistance side effect. ... The mTOR complexes, for mammalian (or mechanistic) target of rapamycin, are proteins that regulate cell growth, movement, and survival, as well as protein synthesis and transcription. Specifically, there are two mTOR complexes and one mTOR protein. The mTOR protein is the core of both complexes (mTORC1 and mTORC2), which behave differently based on their associated proteins. One or both of the mTOR complexes can be inappropriately activated in certain cancers, and dual-specific inhibitors are being developed as chemotherapeutic agents. Several theories have been put forward by researchers to explain the observations that patients receiving rapamycin are more prone to developing glucose intolerance, which can lead to diabetes. Chronic treatment with rapamycin impairs glucose metabolism and the correct functioning of insulin in mice, despite extending lifespan. The research team demonstrated that rapamycin disrupts mTORC2 in the mice, and that mTORC2 is required for the insulin-mediated suppression of glucose metabolism in the liver. On the other hand, they also demonstrated that decreasing mTORC1 signaling was sufficient to extend lifespan independently from changes in glucose metabolism. They used a mouse strain in which mTORC1 activity was decreased and saw that lifespan was extended by 14 percent, yet the animals had normal glucose metabolism and insulin sensitivity."

Link: http://www.eurekalert.org/pub_releases/2012-03/uops-dol032612.php

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Advanced glycation end-products (AGEs) such as glucosepane are what you might think of as a sort of biological rust. They build up as an undesirable side-product of the chemistry of life and damage important molecular machinery in and around cells by sticking to molecules or sticking molecules together, making it impossible for them to do their jobs. The increase in AGE levels in the body with advancing age isn't a matter of straight accumulation over time - it's more dynamic than that, and the level of AGEs in the diet may play some role - but eventually it becomes enough to cause serious harm. Aging is little more than damage, and AGEs are one form of that damage.

The SENS Foundation is currently sponsoring research into therapies to break down glucosepane, what is probably the most important AGE in humans. I see that the UK-based research group has a few web pages devoted to their work, on one of which is offered some explanation as to why the drug industry isn't all that much help when it comes to building ways to tackle AGEs:

There are two difficulties with creating AGE-breaker drugs. Firstly, AGEs are chemical targets, not genes or proteins. Almost all of pharmaceutical research over the last 40 years has been orientated to finding drugs that interact with proteins, and with the genes that make those proteins. So we cannot call on the trillions of dollars of research and technology development that have created the modern drug industry to help us (very much - we can use some of it). Secondly, AGEs are pretty stable and tough. That is inevitable - they are in essence the physiological equivalent of the black stuff on the bottom of your baking tin - what is left after years of use and the dishwasher. (In the case of humans, 'the dishwasher' is an array of mechanisms that take care of nearly all the waste products of metabolism.) We know how to break them quite easily, but only using a process that would also dissolve every protein in your body. The trick is finding a way to cleave them and leave all the rest of you intact.

Here is a recently posted video from last year's SENS5 conference in which one of the research groups focused on AGEs discusses their work:

Advanced glycation end-products are a class of natural products that form non-enzymatically on exposed protein residues in the human body. AGEs accumulate as a result of normal metabolism and aging, and significant elevations in these molecules have also been observed in the plasma of patients with chronic diseases, such as diabetes, cancer, arthritis, cardiovascular disease, and others. Our laboratory is taking an orthodox approach to studying these materials; we have initiated a synthetic program to prepare AGE- adducts on large scale and in chemically homogenous form. This talk will describe ongoing efforts along these lines, with a particular focus on exploring a class of arginine-derived AGEs. Chemical and biological insight arising from these studies will also be discussed. It is our hope that this small molecule-based strategy will serve to shed new light on the role of AGEs in both healthy and disease physiology.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

There's a range of research to indicate that gut bacteria are important in the relationship between metabolism and aging, though the situation in higher animals is probably far more complex than in nematode worms: "A powerful approach to understanding complex processes such as aging is to use model organisms amenable to genetic manipulation, and to seek relevant phenotypes to measure. Caenorhabditis elegans is particularly suited to studies of aging, since numerous single-gene mutations have been identified that affect its lifespan; it possesses an innate immune system employing evolutionarily conserved signaling pathways affecting longevity. As worms age, bacteria accumulate in the intestinal tract. However, quantitative relationships between worm genotype, lifespan, and intestinal lumen bacterial load have not been examined. We hypothesized that gut immunity is less efficient in older animals, leading to enhanced bacterial accumulation, reducing longevity. To address this question, we evaluated the ability of worms to control bacterial accumulation as a functional marker of intestinal immunity. ... We show that as adult worms age, several C. elegans genotypes show diminished capacity to control intestinal bacterial accumulation. We provide evidence that intestinal bacterial load, regulated by gut immunity, is an important causative factor of lifespan determination; the effects are specified by bacterial strain, worm genotype, and biologic age, all acting in concert. ... In total, these studies focus attention on the worm intestine as a locus that influences longevity in the presence of an accumulating bacterial population. Further studies defining the interplay between bacterial species and host immunity in C. elegans may provide insights into the general mechanisms of aging and age-related diseases."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22452899

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Yet another study showing a correlation between chronic inflammation and abdominal fat: "Obesity-related increases in multiple inflammatory markers may contribute to the persistent subclinical inflammation common with advancing age. ... We used factor analysis to identify inflammatory factor(s) and examine their associations with adiposity in older adults at risk for disability. ... [Inflammatory markers] were measured in 179 participants from the Lifestyle Interventions and Independence for Elders Pilot (Mean ± SD age 77 ± 4 years, 76% white, 70% women). Body mass index, waist circumference, and total fat mass were assessed by anthropometry and dual-energy x-ray absorptiometry. ... Greater total and abdominal adiposity are associated with higher levels of an inflammatory factor related to CRP, IL-1ra, and IL-6 in older adults, which may provide a clinically useful measure of inflammation in this population. ... [The associations were determined] after adjusting for age, gender, race/ethnicity, site, smoking, anti-inflammatory medications, comorbidity index, health-related quality of life, and physical function. These associations remained significant after further adjustment for grip strength, but only waist circumference remained associated with inflammation after adjusting for total lean mass." Waist circumference is a better correlation with the amount of visceral fat packed around the organs in comparison to body mass index.

Link: http://www.ncbi.nlm.nih.gov/pubmed/22451470

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Someone who didn't take note of the eagerness with which people throw money at the shams, fakes, and security blankets of the "anti-aging" marketplace might be forced to conclude that the world's inhabitants are on balance indifferent as to whether they live long or die young, whether they suffer for decades or live healthily some years down the line. There are many common sense health practices that people can undertake to maximize their remaining life expectancy and reduce the risk of age-related disease - and that's even before we start in on supporting research and development of rejuvenation biotechnology - but the majority don't do anywhere near as much as they might, and in consequence they come to suffer for it.

Are we a species whose dominant trait is actually nihilism? One wonders at times.

But the personal future of aging isn't the only thing that most people, judging by their actions, are indifferent to. We might also consider the preventable nature of well known conditions like cancer, to pick one example. Most people know that they should be exercising, they should not let themselves get fat, and they also know how to halve the risk of suffering cancer - but do they adopt the necessary changes in lifestyle? Largely no:

More than half of all cancer is preventable, and society has the knowledge to act on this information today ... What we know [is] that lifestyle choices people make and that society can influence in a number of ways - from tobacco use to diet and exercise - play a significant role in causing cancer. Specifically, the researchers cite data demonstrating that smoking alone is responsible for a third of all cancer cases in the United States. Excess body weight and obesity account for another 20 percent.

This all might be viewed as another facet of the difficulty faced by groups trying to do something about aging and age-related disease - which is to say trying to help people avoid a future that many to most seem to be largely indifferent to, judging by their actions. If a person doesn't care enough about their future trajectory to take basic, simple care of their health today, why would they care enough to donate money to medical research and development? Fortunately, it isn't necessary to persuade everyone - even a few tens of millions of casual supporters, a tiny fraction of the population of the world, could between them generate enough resources to carry the SENS research program to completion, for example. Cancer research is itself an example of what it looks like some decades after that initial group of casual supporter is amassed - once the ball starts rolling and achieves a critical mass, the research programs become accepted as a part of what is.

But we are still left wonder on the rationality of humans, and the degree to which the average person is prepared to let their future self suffer.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

There is plenty of evidence to show that being overweight for any great length of time in life causes harm, either fairly directly by boosting levels of chronic inflammation, or because that fat tissue is associated with a lack of exercise and consequent development of vascular dementia, or for a range of other possible reasons. Here is another study on this topic: "High midlife body mass index (BMI) has been linked to a greater risk of dementia in late life, but few have studied the effect of BMI across midlife on cognitive abilities and cognitive change in a dementia-free sample. ... We investigated the association between BMI, measured twice across midlife (mean age 40 and 61 years, respectively), and cognitive change in four domains across two decades in the Swedish Adoption/Twin Study of Aging. ... Latent growth curve models fitted to data from 657 non-demented participants showed that persons who were overweight/obese in early midlife had significantly lower cognitive performance across domains in late life and significantly steeper decline in perceptual speed, adjusting for cardio-metabolic factors. Both underweight and overweight/obesity in late midlife were associated with lower cognitive abilities in late life. However, the association between underweight and low cognitive abilities did not remain significant when weight decline between early and late midlife was controlled for. ... There is a negative effect on cognitive abilities later in life related to being overweight/obese across midlife. Moreover, weight decline across midlife rather than low weight in late midlife per se was associated with low cognitive abilities." The weight decline association shows up in a range of studies on weight and health; one common conclusion is that it reflects the impact that more serious medical conditions - related to weight or otherwise - can have on people.

Link: http://www.ncbi.nlm.nih.gov/pubmed/22450854

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Advances in biotechnology are greatly reducing the cost of performing broad analyses of metabolism - and so researchers are gathering ever more data on the various breeds of long-lived mice that have been created in recent years: "Significant advances in understanding aging have been achieved through studying model organisms with extended healthy lifespans. Employing (1)H NMR spectroscopy, we characterized the plasma metabolic phenotype (metabotype) of three long-lived murine models: 30% dietary restricted (DR), insulin receptor substrate 1 null (Irs1(-/-)), and Ames dwarf (Prop1(df/df)). A panel of metabolic differences were generated for each model relative to their controls, and subsequently, the three long-lived models were compared to one another. Concentrations of mobile very low density lipoproteins, trimethylamine, and choline were significantly decreased in the plasma of all three models. Metabolites including glucose, choline, glycerophosphocholine, and various lipids were significantly reduced, while acetoacetate, d-3-hydroxybutyrate and trimethylamine-N-oxide levels were increased in DR compared to ad libitum fed controls. Plasma lipids and glycerophosphocholine were also decreased in Irs1(-/-) mice compared to controls, as were methionine and citrate. In contrast, high density lipoproteins and glycerophosphocholine were increased in Ames dwarf mice, as were methionine and citrate. Pairwise comparisons indicated that differences existed between the metabotypes of the different long-lived mice models. Irs1(-/-) mice, for example, had elevated glucose, acetate, acetone, and creatine but lower methionine relative to DR mice and Ames dwarfs. Our study identified several potential candidate biomarkers directionally altered across all three models that may be predictive of longevity but also identified differences in the metabolic signatures. This comparative approach suggests that the metabolic networks underlying lifespan extension may not be exactly the same for each model of longevity and is consistent with multifactorial control of the aging process."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22225495

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Not all tissue structures need to be tailored to the patient - indeed, most of the present tissue engineering industry is in fact directly serving the research and development community rather than clinics. Engineered tissue is used for a broad range of testing, for example, and many life science research programs can progress more effectively with access to tissue structures rather than cells in a petri dish. As costs fall, that becomes an ever more practical alternative, meaning that research becomes more efficient and faster. Behind these falling costs lies a world of automation and infrastructure, leading towards assembly lines that produce pieces of living tissue for use in research and medical development:

Artificial skin for use in transplants or to verify the safety of the active ingredients of drugs, cosmetics and chemicals is a rare commodity. It is currently produced manually on a laboratory scale, and cultivation takes six weeks. The production volume is therefore limited to 2,000 pieces of skin per month, each one only a square centimetre in size. At a lab in Germany's Fraunhofer Institute, automation technology supplier Festo has helped to marry process automation with skin cultivation. The company's automation specialists recently helped the lab change its systems to achieve faster skin cell production

...

The new BioPoLiS organic production laboratory at the Fraunhofer IPA is home to what it says is the only facility in the world for the fully automatic in vitro production of up to 5,000 human skin models a month. The plant reflects the importance of bio-production, a combination of biology and automation technology. ... A particularly noteworthy feature is the continuous process chain. A single production line is used to handle cell extraction, cell proliferation, the cultivation of a three-dimensional tissue structure and cryonic preservation of skin models. Each process step is conducted without interrupting any of the others.

...

The scientists involved in the project are not content merely to produce skin. They say they plan to develop the technology further in the next two years to the point where other types of tissue, such as cartilage, can also be produced automatically.

Tissue is machinery, and we humans have accumulated a great deal of experience in how to build large amounts of homogeneous, quality-controlled machinery in a short period of time. So there is every reason to think that mass production of tissue structures for research and regenerative medicine will result in industrial processes that have much in common with the automated assembly lines that produce appliances or cars. As demand increases, and especially if therapies that use standardized tissues rather than patient-specific tissues become widespread, then we will see a much more of this sort of thing. An industry of large, specialized tissue factories is not an unrealistic expectation for the 2020s, though I would imagine that such a factory will look a lot more like a hospital, clinic, or microchip fabrication plant on the inside than the name might suggest.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm