Metformin is a drug that shows up in discussion here every so often. It is thought to be a calorie restriction mimetic, recapitulating some of the metabolic changes caused by the practice of calorie restriction. Its effects on life span in laboratory animals are up for debate and further accumulation of evidence – the results are on balance more promising than the generally dismal situation for resveratrol, but far less evidently beneficial than rapamycin. Like rapamycin, metformin isn’t something you’d want to take as though it were candy, even if the regulators stood back to make that possible, as the side effects are not pleasant and potentially serious.

I should note as an aside that while ongoing research into the effects of old-school drugs of this nature is certainly interesting, it doesn’t really present a path to significantly enhanced health and longevity. It is a pity that such research continues to receive the lion’s share of funding, given that the best case outcome is an increase in our knowledge of human metabolism, not meaningful longevity therapies. Even if the completely beneficial mechanism of action is split out from the drug’s actions – as seems to be underway for rapamycin – the end results will still only be a very modest slowing of aging. You could do better by exercising, or practicing calorie restriction.

For the billions in funding poured into these drug investigation programs, there should be a better grail at the end of the road – such as that offered by the SENS vision of rejuvenation biotechnology. Targeted repair of the biological damage of aging is a far, far better strategy than gently slowing the pace of damage accumulation through old-style drug discovery programs. This is a biotechnology revolution: time to start acting like it.

Anyway, aside done, let me point you to a recent open access review on metformin: the interesting work that won’t really be in any way relevant to the future of your longevity, but which I’ll wager has raised more funding as an object of study than the entire present extant SENS program and directly related scientific studies:

Metformin, an oral anti-diabetic drug, is being considered increasingly for treatment and prevention of cancer, obesity as well as for the extension of healthy lifespan. Gradually accumulating discrepancies about its effect on cancer and obesity can be explained by the shortage of randomized clinical trials, differences between control groups (reference points), gender- and age-associated effects and pharmacogenetic factors. Studies of the potential antiaging effects of antidiabetic biguanides, such as metformin, are still experimental for obvious reasons and their results are currently ambiguous.

…

The wave of interest, with periodical decays and increasing surges, was associated with the attempts to use antidiabetic biguanides [such as metformin] to control body weight and tumor growth. Another facet of the situation is that almost 45 years ago these drugs were suggested to promote longevity. Over the last years, the expanding bodies of relevant evidence, which mainly related to metformin, started to merge and occupy increasing place in current literature. The objective of the present essay is to attract more attention to accumulating inconsistencies. The first two sections of the essay, which are related to obesity and cancer, are based mostly on clinical data. The third section, which is related to aging or, rather, antiaging, is based predominately on experimental evidence obtained in rodents. Clearly, obesity and cancer have numerous interrelationships with aging, [however], we will separate these aspects for the sake of clarity in discussing the relevant effects of metformin.

See what you think; it makes for an interesting read – and includes a table of results from a number of life span studies that are, indeed, all over the map. It somewhat reinforces the point that unambiguous success in extending healthy life is not going to arrive from this quarter. Think SENS, not drug discovery – what will come from the drug discovery clade is a slow, grinding, and expensive cataloging of the fine details of genetics, metabolism, and aging in mammals.

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In recent years resveratrol has clearly fallen below the dividing line for work that is useful from a longevity perspective – if it could extend life significantly in mice, that would have been demonstrated by now. You might compare with the size of the effects on mouse lifespan for rapamycin to provide an example of a compound that is worth investigating. There is, however, a lot of money sunk into work on resveratrol and the underlying mechanisms of sirtuins, so don’t expect that to halt any time soon. Research and developer institutions are prone to inertia, just like all other fields of human endeavor. In any case, here is some of the latest work on SIRT1: “If resveratrol needs SIRT1 to improve health, then animals lacking the gene should not get any benefits from the chemical. His lab published that experiment in yeast in 2003. But mice lacking SIRT1 die in the womb, or they are born with developmental defects such as blindness. To get around that problem, [researchers] engineered ‘conditional knockout’ mice whereby SIRT1 can be inactivated in adulthood. … It took us two weeks to do the experiment in yeast, and five years in mouse, but finally we’re there … In normal mice, resveratrol combated the effects of a high-fat diet by boosting the efficiency of energy-generating organelles called mitochondria in skeletal muscle tissue. This effect vanished in adult mice without a working version of SIRT1. Yet SIRT1 wasn’t responsible for all the beneficial effects of resveratrol … Resveratrol stabilized the blood glucose levels of both normal and SIRT1-lacking mice on fatty diets. The chemical also improved liver health in mice without SIRT1. [The researchers also contend] that a lot the confusion over how resveratrol works comes down to dosage. At very high doses it binds other proteins besides SIRT1 … For instance, a signalling protein called AMPK is also important to resveratrol’s beneficial effects on metabolism. … low doses of resveratrol boosted AMPK levels in various cells that expressed SIRT1, but not cells without the sirtuin. Much higher doses of resveratrol, however, activated AMPK irrespective of whether the cells expressed SIRT1.”

Link: http://blogs.nature.com/news/2012/05/row-over-resveratrol-rumbles-on.html

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For some years researchers have been investigating the mechanisms of limb and organ regrowth in lower animals like salamanders, with an eye to finding out how easy or hard it would be to recreate those same capabilities in mammals – such as we humans. Do we retain the core mechanisms, lying dormant in our biochemistry, or have they been completely lost? Time and ongoing research will tell.

But these are not the only areas of regrowth wherein researchers might learn something of interest to regenerative medicine. Consider that elk regularly regrow their antlers, for example – not a simple organ by any means. Further down the scale of impressiveness, we might consider the many higher animals that regularly regrow feathers or coats of hair. Is there anything in their biochemistry that might be discovered and adapted to cause humans to regenerate in situations where they normally do not?

If you buy into the argument that salamander biochemistry is worth investigation, then it’s hard to reject similar investigations in other species capable of the lesser forms of regrowth mentioned above. An open access paper is presently doing the rounds on this topic; you can read the summary in the release, or look at the paper itself:

Physiological Regeneration of Skin Appendages and Implications for Regenerative Medicine

The concept of regenerative medicine is relatively new, but animals are well known to remake their hair and feathers regularly by normal regenerative physiological processes. Here, we focus on 1) how extrafollicular environments can regulate hair and feather stem cell activities and 2) how different configurations of stem cells can shape organ forms in different body regions to fulfill changing physiological needs.

Regenerative medicine has great potential. The main challenge is how to elicit and harness the power of regeneration. Currently, the major issues are how to obtain stem cells, how to pattern stem cells into organized tissues and organs, and how to deliver stem cell products to patients. Although human beings have very limited powers of regeneration, many animals have robust regenerative powers, distilled and selected over millions of years of evolution. Here, we review fundamental principles of regenerative biology learned from nature in the hope that they can be applied to help the progress of regenerative medicine.

…

Using the episodic regeneration of skin appendages as a clear readout, we have the opportunity to understand and modulate the behavior of adult stem cells and organ regeneration at a level heretofore unknown. Through this work, we hope to be able to establish or improve the stem cell environment so it can be applied to regenerative medicine.

In conclusion, we think it will be very productive to learn how nature manages the physiological regeneration process. This is a reprogramming process in which the genetic and epigenetic events converge to generate complex functional forms, depending on the physiological need in different parts of the body and at different stages of life. Principles learned from regenerative biology can then be applied toward regenerative medicine.

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An article from the Wellcome Trust: “Researchers have been engineering cartilage in the laboratory for 15 years or more, but as yet the tissues they have created don’t function properly in human joints. [Researchers] are taking a new approach to try to bridge the gap between laboratory-created cartilage and the tissue our bodies make. … Biological texts show that these lab-grown tissues have the appearance, texture, and protein and mineral components of bone and cartilage. But once they are tested in an animal, these tissues simply don’t behave quite like the natural tissues they are supposed to replicate. … Joints are remarkable feats of engineering, but efforts to grow them in the lab have focused mostly on their biology. … Biologists attempting to create cartilage and bone over the past 15 years have typically tested the mechanical properties of their laboratory-grown tissue – for example, whether it is rubbery and resilient enough when pressure is applied. … Just because biological tests indicate a tissue looks like bone and feels like bone, doesn’t actually mean it is bone … This is where an engineering perspective becomes important. To look at how close a match these laboratory-generated tissues really are to native bone and cartilage, [researchers] supplemented the biological analyses with engineering tests, such as bio-Raman microspectroscopy. … You shine a laser on the material, and the way the light scatters gives you an idea of the bonds between its components. Different mineral types form different bonds, so you get a much more precise picture of what is actually present. … If a lab-grown tissue seems from some tests to be the real thing but isn’t really, then it won’t behave like it once it has been implanted in a human body. … [The researchers aim] to use an engineering approach to create a whole osteochondral interface in which bone and cartilage transition seamlessly into each other like they do in the body. … That’s the only way it will effectively transmit loads to the underlying bone. And because bone will heal, it will heal the construct into the joint.”

Link: http://www.wellcome.ac.uk/News/2012/Features/WTVM054966.htm

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Following on from a recent post on the involution of the thymus in adults, the process by which it ceases to generate immune cells and atrophies, here is a another paper that considers some of the possible paths to interventions that maintain the thymus into old age. Given experiments in mice showing that transplant of a young thymus extends life, this seems worthy of further investigation: “The thymus is the primary organ for T-cell differentiation and maturation. Unlike other major organs, the thymus is highly dynamic, capable of undergoing multiple rounds of almost complete atrophy followed by rapid restoration. The process of thymic atrophy, or involution, results in decreased thymopoiesis and emigration of naïve T cells to the periphery. Multiple processes can trigger transient thymic involution, including bacterial and viral infection(s), aging, pregnancy and stress. Intense investigations into the mechanisms that underlie thymic involution have revealed diverse cellular and molecular mediators, with elaborate control mechanisms. This review outlines the disparate pathways through which involution can be mediated, from the transient infection-mediated pathway, tightly controlled by microRNA, to the chronic changes that occur through aging.”

Link: http://www.ncbi.nlm.nih.gov/pubmed/22539280

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Singularity Hub looks at the tissue engineering of teeth: “For years, researchers have investigated stem cells in an effort to grow teeth made for a person’s own cells. Toward this end, [scientists] have developed methods to control adult stem cell growth toward generating dental tissue and ‘real’ replacement teeth. [The] researchers’ approach is to extract stem cells from oral tissue, such as inside a tooth itself, or from bone marrow. After being harvested, the cells are mounted to a polymer scaffold in the shape of the desired tooth. The polymer is the same material used in bioreabsorable sutures, so the scaffold eventually dissolves away. Teeth can be grown separately then inserted into a patient’s mouth or the stem cells can be grown within the mouth reaching a full-sized tooth within a few months. So far, teeth have been regenerated in mice and monkeys, and clinical trials with humans are underway, but whether the technology can generate teeth that are nourished by the blood and have full sensations remains to be seen. Teeth present a unique challenge for researchers because the stem cells must be stimulated to grow the right balance of hard tissue, dentin and enamel, while producing the correct size and shape.”

Link: http://singularityhub.com/2012/05/10/toothless-no-more-researchers-using-stem-cells-to-grow-new-teeth/

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Maria Konovalenko of the Science for Life Extension Foundation here reports on the recent Genetics of Aging and Longevity Conference, held last month in Moscow and attracting researchers in the field from around the world.

It has been a while since I’ve posted my blog updates. The reason was the Genetics of Aging and Longevity conference. I have been involved in preparations of this meeting since December and the last month before the event was especially tough. Anyway, the conference turned out to be pretty good. I was surprised to hear so many good responses and impressions from the attendees and the speakers, so I am proud to say that the meeting was a success. The talks were superb, a lot of new and even unpublished data, a lot of discussions during the breaks and meals. I saw quite many people walking around with burning eyes – from excitement of science, of course) Some of those eyes are in the photos below. I believe this was a ground braking event on life extension topic in Russia, a truly unique gathering of minds. The more meetings like this we have, the more attention they get in the media, the better chances we have to live longer.

The post includes a great many photographs of folk from the aging research community; browse through if you are interested in putting faces to the names you read about in the science press. Konovalenko concludes with this note:

Quite a lot of researchers said that we are on the verge of a breakthrough in the area of life extension. Maybe we have already discovered something fantastic, but haven’t yet realized it’d effective for people. Even if we have a drug that slows aging down, we still need a panel of biomarkers to prove the effect. I do hope we will have both the breakthrough and the markers soon.

I’ll point you to something I said a while back about concrete and conferences:

I’m a fan of the “concrete and conferences” metric for measuring the health of science. Two side effects of increasing research funding in a field are new buildings at universities and research centers (the “concrete” part of the metric) and new gatherings of researchers (the conferences). Both of these symptoms are also fairly easy to track. The more of both, the better, with new buildings indicating more money entering the system than new conferences.

More conferences generally indicates a larger population of researchers with budgets, interest in the field, and progress in their laboratories to talk about.

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An update on the LysoSENS research project from the SENS Foundation, which aims to discover and adapt bacterial enzymes to break down the damaging buildup of unwanted metabolic byproducts in the aging body: “SENS Foundation-funded research shows that expression of a modified microbial enzyme protects human cells against 7-ketocholesterol toxicity, advancing research toward remediation of the foam cell and rejuvenation of the atherosclerotic artery. … Atherosclerotic cardiovascular disease is the principal cause of ischaemic heart disease, cerebrovascular disease, and peripheral vascular disease, making it the root of the leading cause of morbidity and mortality worldwide. Atherosclerosis begins with the entrapment and oxidation of low-density lipoprotein (LDL) cholesterol in the arterial endothelium. As a protective response, the endothelium recruits blood monocytes into the arterial wall, which differentiate and mature into active macrophages and engulf toxic oxidized cholesterol products (oxysterols) such as 7-ketocholesterol (7-KC). Although initially protective, this response ultimately leads to atherosclerotic plaque: oxidized cholesterol products accumulate in the macrophage lysosome, and impair the processing and trafficking of native cholesterol and other materials, leading macrophages to become dysfunctional and immobilized … more and more of these disabled “foam cells” progressively accumulate in the arterial wall, generating the fatty streaks that form the basis of the atherosclerotic lesion. Rejuvenation biotechnology can be brought to bear against this disease of aging through the identification, modification, and therapeutic delivery of novel lysosomal enzymes derived from microbes to the arterial macrophage – enzymes which are capable of degrading oxidized cholesterol products. SENS Foundation-funded researchers have been making steady progress in the identification and characterization of candidate enzymes for several years now, and a new report represents a substantial advance in the research: the rescue of cellular oxysterol toxicity by an introduced microbial lysosomal enzyme.”

Link: http://sens.org/node/2737

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You might recall research published last near on NRG-1 levels in naked mole-rats. Here is an update: “The typical naked mole rat lives 25 to 30 years, during which it shows little decline in activity, bone health, reproductive capacity and cognitive ability. … Naked mole rats have the highest level of a growth factor called NRG-1 in the cerebellum. Its levels are sustained throughout their life, from development through adulthood. … NRG-1 levels were monitored in naked mole rats at different ages ranging from a day to 26 years. The other six rodent species have maximum life spans of three to 19 years. The cerebellum coordinates movements and maintains bodily equilibrium. The research team hypothesized that long-lived species would maintain higher levels of NRG-1 in this region of the brain, with simultaneous healthy activity levels. Among each of the species, the longest-lived members exhibited the highest lifelong levels of NRG-1. The naked mole rat had the most robust and enduring supply. … In both mice and in humans, NRG-1 levels go down with age … The strong correlation between this protective brain factor and maximum life span highlights a new focus for aging research, further supporting earlier findings that it is not the amount of oxidative damage an organism encounters that determines species life span but rather that the protective mechanisms may be more important.”

Link: http://www.mysanantonio.com/life/health/article/The-secret-of-long-life-may-be-in-a-naked-mole-rat-3543091.php

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The choroid plexus is, amongst other things, a filter for cerebrospinal fluid – you might think of this role as analogous to that of the kidney as a filter for blood, though the two organs are very different in structure at every level, and the choroid plexus also produces the fluid it filters. Like all of the systems in the body and brain, the choroid plexus progressively fails in its function with age, and researchers have reason to believe that this failure contributes to conditions such as Alzheimer’s disease:

An organ in the brain called the choroid plexus apparently plays a critical role in preventing the accumulation of a protein associated with Alzheimer’s disease. The researchers found that the choroid plexus acts as a sort of ‘fishnet’ that captures the protein, called beta-amyloid, and prevents it from building up in the cerebrospinal fluid, which surrounds and bathes the brain and spinal cord. Moreover, tissue in the organ is able to soak up large amounts of the protein and may contain enzymes capable of digesting beta-amyloid.

Levels of beta-amyloid in the brain are more dynamic than their slow buildup over the years implies. You might think of the condition – and indeed the increase in amyloid levels in aging in general – as a slowly progressing imbalance of amyloid creation and clearance mechanisms rather than a slow and irrevocable deposition of amyloid. That in turn implies that a working therapy could quickly reverse all but the latest stages of the disease, when neurons are dying in large numbers.

Do rising brain levels of a plaque-forming substance mean patients are making more of it or that they can no longer clear it from their brains as effectively? … Clearance is impaired in Alzheimer’s disease. We compared a group of 12 patients with early Alzheimer’s disease to 12 age-matched and cognitively normal subjects. Both groups produced amyloid-beta (a-beta) at the same average rate, but there’s an average drop of about 30 percent in the clearance rates of the group with Alzheimer’s. … Scientists calculate this week [that] it would take 10 years for this decrease in clearance to cause a build-up of a-beta equal to those seen in the brains of Alzheimer’s patients. The results have important implications for both diagnosis and treatment.

Here is a more recent paper that reviews what is known of the role of the choroid plexus:

Pathological Alteration in the Choroid Plexus of Alzheimer’s Disease: Implication for New Therapy Approaches

In the recent years, much attention has been directed to the roles of the choroid plexus in the central nervous system (CNS) under both normal and pathological conditions. This specialized ventricular structure has recently emerged as a key player in a variety of processes that monitor and maintain the biochemical and cellular homeostasis of the CNS.

The main role of the choroid plexus is to produce cerebrospinal fluid (CSF) and to maintain the extracellular environment of the brain by monitoring the chemical exchange between the CSF and the brain tissue. This involves the surveying of the chemical and immunological status of the extracellular fluid and the removal of toxic substances as well as important roles in the regenerative processes following traumatic events. In addition to CSF, the plexus produces various peptides which can have nourishing and neuroprotective properties.

…

Morphological alterations of choroid plexus in Alzheimer’s disease (AD) have been extensively investigated. These changes include epithelial atrophy, thickening of the basement membrane, and stroma fibrosis. As a result, synthesis, secretory, and transportation functions are significantly altered resulting in decreased cerebrospinal fluid (CSF) turnover. Recent studies discuss the potential impacts of these changes, including the possibility of reduced resistance to stress insults and slow clearance of toxic compounds from CSF with specific reference to the amyloid peptide.

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