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Fight Aging! Newsletter, January 5th 2014

FIGHT AGING! NEWSLETTER
January 5th 2015

Herein find a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress on the road to bringing aging under medical control, the prevention of age-related disease, and present understanding of what works and what doesn't when it comes to extending healthy life. Expect to see summaries of recent advances in medicine, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

This content is published under the Creative Commons Attribution 3.0 license. You are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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CONTENTS

  • A Three Part Interview with a Tissue Engineer
  • The Latest from Telomerase Gene Therapy Research
  • Looking Back at 2014
  • Updates on a Crowdfunded Mouse Life Span Study
  • An Example of Ongoing Investigations of the Biochemical Details of Arterial Stiffening
  • Latest Headlines from Fight Aging!
    • Investigating the Details of Mitochondrial Dysfunction in the Aging Mouse Heart
    • Cortical Neurodynamics and Age-Related Memory Function
    • More Correlation of Dementia with Many Tiny Strokes
    • Following Up on a Trial of an Immune System Reset to Treat Multiple Sclerosis
    • A Scaffolding Approach to Anterior Cruciate Ligament Repair
    • Last Day of the Year, and a Little Room is Left in the Last SENS Matching Fund of 2014: Donate!
    • A Potential Approach to Sabotage Telomerase in Cancer Cells
    • Klotho in Vascular Health and Disease
    • Recent Investigation of Naked Mole Rat Cancer Immunity
    • An Example of Short Term Detrimental Effects Due to Inactivity

A THREE PART INTERVIEW WITH A TISSUE ENGINEER
https://www.fightaging.org/archives/2014/12/a-three-part-interview-with-a-tissue-engineer.php

For much of this year the Bristlecone, the Methuselah Foundation's blog, has published a series of interviews with researchers of note in the field of tissue engineering. They have been quite education, often covering some of the important infrastructural aspects of the research and development process that gain little attention elsewhere. The Foundation has a strong interest in advancing this arm of medicine, and does so through strategic early stage investments, such as in bioprinter startup Organovo, as well as through initiatives such as the New Organ research prize series. This month the Bristlecone published a lengthy three part interview with David Williams of the Tissue Engineering and Regenerative Medicine International Society (TERMIS). Some interesting opinions can be found therein, and you should certainly read the whole thing as there is much more there than is quoted below:

Biomaterials and Clinical Translation

I published a short paper recently called "The Biomaterials Conundrum in Tissue Engineering," and to put it simply, I think we've mostly gotten it wrong. I'm not being too critical, because it was probably inevitable, but the early attempts at tissue engineering involved material scaffolds, and that's where biomaterials come in. The scaffold is the form in which you're going to develop an engineered organ, and the originators felt that they needed to get FDA approval for them. Therefore, they needed to use an FDA approved material, and although this was understandable, I think it was misguided.

The sole criteria for FDA approval for biomaterials used in implantable devices was that the material did no harm. It had to be known to be safe. You're never going to get a scaffold or template material to function properly if all it does is play safe. You need the material to actually stimulate cells through mechanical forces or growth factor delivery, and standard synthetic polymers were never going to do this reliably and routinely. Because of this, I think we need totally different types of materials that try to replicate or represent the micro-environment of the cell. I've been shouting this from the rooftops for a long time now. It can't be an engineered fabricated structure that looks nothing like the cell micro-environment, or we'll never be able to make the cell regenerate the tissues that we want.

We do have a number of pretty good hydrogels that do this, especially biologically-based hydrogels. That's why decellularized extracellular matrix (ECM) is getting so popular. I don't think we're there yet by any means, but there are some interesting approaches around. But the key is that we have to have a different mindset regarding how we develop our biomaterials, and the regulators have to have a different mindset regarding how they regulate them. We can't use the standard tests for safety that the FDA is saying that we still have to use, and that's a big issue at the moment. For the most part, the regulators still want to play it too safe.

Core Principles and Challenges

Bear in mind that what we're trying to do is to take a group of cells and persuade them to do something they don't want to do. That is, to express new extracellular matrix that can then be organized into the structure and function of an organ. I think many of the different scientific principles are in place. We've made big progress already, and to me, the key issue is in putting everything together such that we can develop the structures that function as organs do. We know how to do the little bits, but we still have to explore the complex functioning of the whole.

[Vascularization] is still one of the most important issues. There has been a fair bit of progress made in vascularization, especially in using some small molecules and certain growth factors to encourage newer vascularization. So there are encouraging signs in this area, but it does remain one of the bigger challenges. Take muscle tissue engineering, for example. It's already possible to regenerate small amounts of muscle, but the integration of that into a functional muscle regenerative project is much, much harder. We need to address the integration issues more than anything, and we need to start doing it for the areas where our current therapies are weakest. We had to start somewhere, and so skin, cartilage, and bone were good starting points. In most all of these areas, we've now had some degree of clinical success in alternative treatment modalities. Where we don't have good therapies at the moment is in areas like degenerative disease, especially neurodegeneration and musculo-skeletal regeneration, and I'd like to see more effort being addressed in those areas.

The International Front

It's pretty clear that the United States, and a few countries in Europe, and one or two elsewhere, are at the forefront of developments in these medical technologies in regenerative medicine. But they can't do everything. We have to recognize that there are very good academic, clinical, and commercial entities all around the world. And I think it is appropriate that we interact with them in order to get the best of everything.

Also, when you look at issues of commercialization and clinical translation, we know that here in the U.S., there are - sometimes understandably - many limitations and barriers to how far and how fast we can go. And there are opportunities in other parts of the world where there are different formats and different styles. Part of my rationale is to try to get the best of all possible commercial, clinical, and academic opportunities in different parts of the world.

THE LATEST FROM TELOMERASE GENE THERAPY RESEARCH
https://www.fightaging.org/archives/2014/12/the-latest-from-telomerase-gene-therapy-research.php

Telomeres are caps of repeated DNA sequences at the end of chromosomes. A little telomere length is lost every time a cell divides and its DNA is replicated, and this is one portion of the limiting mechanism that causes the somatic cells that make up the overwhelming majority of tissues to divide only a set number of times and then destroy themselves. Stem cells on the other hand make use of the enzyme telomerase to add repeated DNA sections to the ends of their telomeres as needed. They must maintain lengthy telomeres as it is their job is to continually spin off new long-telomere somatic cells to keep tissues running smoothly. This is a considerable simplification of the actual situation, but it is good enough for this discussion. The important point here is that if you measure average telomere length in a given tissue, and immune cells from blood are the most commonly used for this purpose at the moment, what you are in fact measuring is a some combination of present cell replication rates, cell replenishment rates, and telomerase activity.

There is a statistically significant correlation between average telomere lengths in immune cells and age and illness across a population. This isn't so useful for any given individual looking at a number and trying to figure out whether or not it means anything for future health, but it is true that the older and more ill a person is, the more likely it is for average telomere length in immune cells to be comparatively short. Is this meaningful to efforts to extend life? That is a question worth asking twice, given that telomere length measures look very much like a secondary marker resulting from the characteristic decline of stem cell activity and tissue maintenance with advancing age, and we really want to aim at primary causes rather then secondary and later mechanisms.

Nonetheless, a fair number of researchers are interested in trying to lengthen telomeres as a potential way to treat illness or lengthen life, and in recent years one research group has used gene therapy to raise levels of telomerase in mice. This turns out to extend mouse life span, with the caveats that (a) short-lived mammals like mice actually have quite different telomere dynamics from long-lived mammals such as we humans, so it is far from clear as to what the same thing would do in people, and (b) it is by no means certain what exactly is going on under the hood here. Is telomerase keeping somatic cells alive for longer, it is increasing stem cell activity, is it perhaps interacting with mitochondria in some way to reduce their contribution to aging, or is some other as yet undiscovered mechanism is at work?

Researchers will come to a conclusion at some point, as there seems to be slow but steady progress towards further investigations of telomerase gene therapy in mice. The same group that pioneered this approach is now heading down the traditional path of attempts to apply this treatment as a late stage intervention for age-related disease and dysfunction. They do this because it is still the only practical way to bring treatments to the clinic these days: approaches are inevitably sidelined into marginal applications intended to be applied after the damage is done. It is a ridiculous situation, and one that causes immense damage to the pace of progress by diverting researchers away from producing methods of prevention.

CNIO researchers treat heart attacks with new gene therapy based on telomerase enzyme

The enzyme telomerase repairs cell damage produced by ageing, and has been used successfully in therapies to lengthen the life of mice. Now it has been observed that it could also be used to cure illnesses related to the ageing process. Researchers at the Spanish National Cancer Research Centre (CNIO) have for the first time treated myocardial infarction with telomerase by designing a very innovative strategy: a gene therapy that reactivates the telomerase gene only in the heart of adult mice, thus increasing survival rates in those animals by 17% following a heart attack.

"We have discovered that following a myocardial infarction, hearts that express telomerase show less heart dilatation, better ventricular function and smaller scars from the heart attack; these cardiac events are associated with an increased survival of 17% compared to control animals." Furthermore, everything points to cardiomyocytes - the cells responsible for heart beating - being regenerated in those hearts with telomerase, a long searched-for goal in post-heart-attack therapy. The regeneration of heart muscle would counter the formation of scars as a consequence of the heart attack, a tough tissue that hinders cardiac function and increases the likelihood of heart failure.

Telomerase expression confers cardioprotection in the adult mouse heart after acute myocardial infarction

Coronary heart disease is one of the main causes of death in the developed world, and treatment success remains modest, with high mortality rates within 1 year after myocardial infarction (MI). Thus, new therapeutic targets and effective treatments are necessary. Short telomeres are risk factors for age-associated diseases, including heart disease. Here we address the potential of telomerase (​Tert) activation in prevention of heart failure after MI in adult mice. We use adeno-associated viruses for cardiac-specific ​Tert expression. We find that upon MI, hearts expressing ​Tert show attenuated cardiac dilation, improved ventricular function and smaller infarct scars concomitant with increased mouse survival by 17% compared with controls. Our work suggests telomerase activation could be a therapeutic strategy to prevent heart failure after MI.

LOOKING BACK AT 2014
https://www.fightaging.org/archives/2014/12/looking-back-at-2014.php

Another year passes us by, and change is always in the air. As was the case in 2013 more people are working on fundraising, and this is a comparatively recent development. It is taking place at both ends of the funding spectrum: we held a successful grassroots fundraiser for early stage rejuvenation research coordinated by the SENS Research Foundation, while Google Ventures is working to pour hundreds of millions of dollars into much more mainstream Big Pharma approaches to aging research. This has also been a year of continued efforts and growth in crowdfunding as it applies to science. Microryza garnered more attention and changed their name to become Experiment, while the Buck Institute has been working on an interesting approach called LabCures. In general I am optimistic that we will see movement beyond a simple cut and paste of Kickstarter towards models more likely to work in research fundraising for modestly sized projects at a large scale.

There have been other funding developments relevant to longevity science around the world also, such as the greater prominence of the UMA Foundation, and a growing confidence in the research community when it comes to talking about treating aging and seeking funding for the same. From the point of view of developing advocacy and conversation this is a whole different world in comparison to just a few years back. Even the large and exceedingly conservative Wellcome Trust research foundation has things to say about longevity and medicine, which hopefully portends more of an investment in the space in the years ahead.

Research prizes of relevance have also emerged as another way for people to attempt to guide significant funding into the scientific projects most useful to a given field - though there are far too few of them given their effectiveness. The New Organ liver prize gained contending teams this year, and the Palo Alto Longevity Prize launched just a few months ago.

In hindsight some years hence it is likely that the Google investment in longevity science, for all that I see it achieving little of immediate practical relevance to human longevity because of its focus on pharmaceutical development, is the sort of landmark that people point to when noting that "this is where things changed." It is hard to pick out the exact point of a pivotal shift in a field of science and technology, because in truth these things are always slow and hard-fought incremental changes at the time, but we are in the midst of one now. Aging research is changing from a field of look-but-don't-touch to a field of clinical intervention, developing the means to slow, repair, or otherwise alter the aging process rather than merely cataloging what is taking place when we decline with age.

Thus I think that the long period of persuading the research community to talk about, support, and work on treatments for the causes of aging is nearly over. Now the efforts move to persuading people to fund the work, persuading researchers to work on projects that are likely to produce actual results in the near future rather than just data, and persuading the public to support the idea of curing all age-related disease - something that a surprisingly large majority oppose at this time.

So the market is up, investing is hot, and Google's California Life Company is far from the only longevity-related venture that received significant funding this year. Reinforcing the view of the mainstream that genetics is an important part of any attempt to intervene in aging to enhance healthy longevity, Human Longevity, Inc. raised tens of millions this year also. Sadly, again, I really think this is one of those initiatives that can improve medicine and the state of knowledge considerably without having much of a hope of moving the needle on practical treatments to extend life. Another similar venture closer to our community that launched this year was In Silico Medicine.

This tendency for the mainstream to pursue courses that are natural extensions of the research imperative to map all genetics and metabolism, but which are very unlikely to produce rejuvenation treatments that can help the old, is exactly why we need more grassroots advocacy and fundraising to draw attention to SENS and similar repair-based strategies. The deciphering and manipulation of metabolism will be slow, exceedingly expensive, and no-one has a concrete plan at this point as to how to produce meaningful results. The most likely outcome for the next two decades is a few drugs that might slightly slow aging - adding perhaps five years to human life span if someone can recapture almost all of the natural calorie restriction response. If that is all that happens, it will be a grand missed opportunity. The whole point of SENS as a research strategy is that we don't have to strive to understand the whole of aging and manipulate highly complex metabolic states in this way: researchers can instead try to repair the known fundamental differences between old and young tissues. These differences are well-described and well-known to a point sufficient for detailed plans for repair therapies to exist. The development of these therapies will thus cost a fraction of the exploration of metabolism needed for the slowing aging approach, and since repair will induce rejuvenation the expected outcome is far better: adding decades to healthy life spans, not merely a few years.

But much of the research community remains to be convinced. There is an enormous inertia in the Big Pharma, drug discovery, work backwards from the end state of aging approach that has consumed billions over the past decade in search of age-slowing drugs with nothing to show for it but data and an increased appreciation for the complexity of our biology. If that funding had gone to SENS, there are good odds we'd have the answer today as to whether many of its repair modes can create rejuvenation in old mice. Thus much advocacy lies ahead: we still have to make this happen if we want a good shot at living to see human rejuvenation.

Speaking of advocacy, this past year the SENS Research Foundation launched a new conference series, Rejuvenation Biotechnology, that is intended to build the relationships between science and industry needed for faster commercial hand-off and support of the sort of repair biotechnologies that the Foundation works on. By all accounts the first conference went pretty well. The second in the series is coming in 2015, so stay tuned. Other interesting conference series going strong include the Genetics of Aging and Longevity Conference organized by groups within the active Russian gerontology community. Of course there is a near endless parade of conferences devoted to individual fields that are relevant to longevity science: those for the large and still growing fields of tissue engineering and regenerative medicine alone would be quite a long list.

On a sad note, this past year saw the death of several vocal and productive members of the advocacy community. As our community grows, the consequences of aging become ever more apparent. The one closest to my network was Stephen Coles of the Gerontology Research Group, whom you might recall as one of the researchers involved in uncovering the predominant cause of death in supercentenarians, but he was by no means the only one. This should be a continued and painful reminder for all of us as to why we do this: why persuade the world, why raise funds, why keep working on the science. It is perhaps unfortunate that it is only human to feel little to nothing for the hundreds of people who will die due to aging while you read this post, and to only be affected by the comparatively few deaths among those people you happen to have exchanged emails with here and there.

But on to the science, which does not suffer as we do, and it is, I think, why most of you peruse this modest website, after all. This year has seen something of great interest every month, usually several advances if you are particularly enmeshed in the field. There are scores of very interesting items buried in the posts here from the past year, and I couldn't possibly mention them all. I'd say that the theme of the year was stem cell research and tissue engineering, but that is the theme for every year. This is the age of cell control with all that implies, and the advances in regrowth and regeneration are going to continue apace for decades yet: every few weeks a research group somewhere in the world is discovering a new way to make cells perform desired tasks, or coming that little bit closer to building an organ from scratch.

If there was a theme unique to the year, than it is probably that genetics has reached the sort of critical mass that stem cell research did a decade ago. Unlike stem cell research this is of less direct relevance to the path to human rejuvenation, however, although all improvements in the tools of biotechnology are welcome. The variations in human genetics that influence variations in natural longevity are fascinating, but we all age for the same root causes. Any repair technology that successfully treats aging will be exactly the same for everyone: the subtle genetic variants in our responses to the cellular and molecular damage that cause aging simply don't matter if we can repair that damage.

Another important theme in the past year of research has been the continued investigations of differences in factors between old and young blood, first identified in parabiosis experiments in which old and young mice have their circulatory systems linked. Results are, as usual, mixed. Researchers are showing benefits from manipulation of levels of GDF-11, but also finding that replicating the effects of parabiosis via blood transfusion isn't straightforward and doesn't seem to have the same outcome. There are human transfusion trials underway, but based on the results in mice I'm not expecting much to result from that effort.

For research directly relevant to rejuvenation after the SENS model, you might look at the 2014 annual report from the SENS Research Foundation, which is a glossy overview of advances made in the last twelve months. One of the items the Foundation leadership is particularly pleased with is progress in the comparatively high-profile work on catabody methodologies to treat senile systemic amyloidosis, the condition thought to kill the very oldest people who survive everything else that old age throws at them. The Foundation staff are doing a lot to change the nature of aging research, and not just through the scientific projects that they sponsor. It is also a matter of changing minds, persuading more people to move from the less effective old Big Pharma model of medical research via drug discovery to work on new and more exciting technologies that can lead to rejuvenation.

To wind up this post, I'll note that I have been slacking when it comes writing my own short essays from scratch rather than commenting at length in reaction to events and publications. So the following is a short list this year, but I hope that you find some of them interesting if you missed them the first time around:

  • The 2010s in Biotechnology Reflect the 1960s in Computing
  • It Comes Time for the Next Wave of Advocacy and Initiatives in Longevity Science
  • The Decade to Come in Which Treatments for Aging Exist, But Are Largely Illegal
  • What is Robust Mouse Rejuvenation, and Why Should We Care?
  • The Strategic Future of the SENS Research Foundation
  • Reaching the Larger Audience
  • A Brief Letter to the Long Retired
  • Why Do We Advocate for Rejuvenation Research?

UPDATES ON A CROWDFUNDED MOUSE LIFE SPAN STUDY
https://www.fightaging.org/archives/2015/01/updates-on-a-crowdfunded-mouse-life-span-study.php

For all that I think it isn't an efficient path forward, one likely to produce meaningful results in moving the needle on human life spans, there is considerable interest in testing combinations of existing drugs and various dietary compounds in mice to see if healthy life is extended. I expect that as public interest grows in the prospects for aging research to move from being an investigative to an interventional field, wherein researchers are actively trying to treat aging, we'll only see more of this. There is certainly a sizable portion of the research community who think that the the best path ahead is in fact the pharmaceutical path of drug discovery in search of ways to slightly slow the aging process. To their eyes slightly slowing the aging process is all that is plausible, and adding five healthy years to life by 2035 would be a grand success. Google's Calico initiative looks set to take that path, for example, which I is why I'm not all that hopeful it will produce meaningful results in terms of healthy years gained and ways to help the old suffer less.

There is a considerable overlap between researchers aiming to gently slow aging via drug discovery and researchers whose primary motivation is still investigation, not intervention: to produce a complete catalog of metabolism and how it changes with age, and it's someone else's problem to actually use that data. So we have, for example, the Interventions Testing Program at the NIA. This program was long fought for by researchers tired of the lack of rigor in most mouse life span studies, and the people involved are essentially engaged in replacing a lot of carelessly optimistic past results with the realistic view that very little other than calorie restriction and exercise actually does reliably extend life in mice if you go about the studies carefully. This is good science, but it isn't the road to extended human life spans: it instead has much more to do with understanding the process of aging at a very detailed level. That task is vast and will take a very long time even in this age of computing and biotechnology.

To my eyes the right way to go is the repair approach: build the biotechnologies needed to repair the forms of cellular and molecular damage produced as a side-effect of the normal operation of metabolism, and which clearly distinguish old tissues from young tissues. If you want rejuvenation of the old, a path to adding decades to healthy life, and to eliminate all age-related disease, then repair is the way to go. Fix the damage, don't just tinker with the engines of life in ways that might possibly slow down damage accumulation just a little. This strategic direction can allow researchers to largely bypass the great complexity of the progression of aging and focus instead on fixing things that are already well known and well cataloged. But I say this a lot, and will continue to do so until more than just a small fraction of the research community agree with me.

Back to mice and life span studies: in this day and age institutional research is far from the only way to get things done. Early stage research is becoming quite cheap as the tools of biotechnology improve, and the global economy allows quality scientific work to be performed in locations that are lot less expensive than the US or Western Europe. We have crowdfunding, the internet, and a supportive community, which means that any group of ambitious researchers can raise a few tens of thousands of dollars and set an established lab in the Ukraine to running a set of mouse life span studies. So that happened back in 2013, and has been ongoing since then despite the present geopolitical issues in that part of the world. It is perhaps worth noting that this is the same group that found no effect on longevity from transfusions of young blood plasma into old mice. The studies mentioned below used pre-aged mice, starting at old age as a way to try to discover effects more rapidly, an approach that is fairly widespread.

I am a little mouse and I want to live longer: updates

Dear contributors, we wish you a happy New Year! We are sorry to be taken by a very-expected but very time-consuming c60 lifespan study to digest the data in a way to make the long report we had announced. So, for the New Year and in order for you not to wait longer, please find at least the main results so far:

1) 23 months old C57BL6 mice received a mixture of 6 therapies that had already been reported to extend the lifespan of mice: Aspirin; Everolimus (mTOR inhibitor, similar action as rapamycin); Metoprolol (beta blocker); Metformin (anti-diabetic drug); Simvastatin (lowers LDL cholesterol); Ramipril (ACE inhibitor).

The drugs were given in the food, at doses that had been reported to extend lifespan ... when taken individually. Some people are given that combination of medicines so we hoped that the drug interaction would not be too damaging, and we had wondered if some lifespan synergy within some of these drugs could lead to an overall high lifespan (eg if the different drugs improve different functions). But we observed a lifespan reduction in males and in females.

2) In the food of some remaining females we mixed low doses of 4 medications against cardiovascular conditions: Simvastatin; Thiazide (lowers blood pressure); Losartan potassium (angiotensin receptor blocker, lowers blood pressure); Amlodipine (calcium channel blocker, lowers blood pressure).

The question was: taken at a low-to-medium dose, could these drugs that many aged persons take have some overall preventive effect? We transposed to mice an ongoing polypill clinical trial in the UK, using a basic human-mouse conversion scale. Again, a decrease in lifespan was observed.

3) Adaptations of the first combination of drugs actually extended lifespan!

We started at age 18 months instead of 23 months, reduced the dose (as a function of weight) and gave a) the 6 compounds b) 'only' aspirin+metformin+everolimus. The results are to be analysed in greater details as we haven't analyzed the latest data yet. Also, whatever the refined analysis, we would already like to indicate that it would be good to reproduce the experiment in some other conditions, eg hybrid mice; in particular as the mortality rates of these mice was higher than the first series (but in a consistent way that supports the life extending effect).

4) Ongoing C60 experiments

After many difficulties in setting the experiment (cross-border transportation in current geopolitical times, checking absorption in mice/ detecting C60/correct source of C60, administration tried in food and replaced by gavage, training for gavage and various measures) we have transposed the popular lifespan test with c60 fullerenes reported in rats by Baati et al. to mice (CBA strain, common in the lab) and with more animals (N=17 per group). There are three groups (gavage of water, of olive oil, of C60 dissolved in olive oil), there are ... a lot of health measures and a lot of gavage (at the beginnings of the experiment as administrations are first very frequent and then gradually less frequent). Given that the experiment starts with mid-aged animals, the results are expected for the beginning of 2016.

The original C60 results from a few years back were greeted with some skepticism in the research community, given the very large size of the effect claimed and the small number of animals tested. There was, I think, also a certain annoyance: now that someone had made what was on the face of it an unlikely claim of significant life span extension via administration of C60, then some other group was going to have to waste their time in disproving it. We'll see how that all turns out, I suppose. This is science as it works in practice.

At some point the broad structural classes of research illustrated by the Interventions Testing Program and this crowdfunded mouse study will meet in the middle, and the process of funding and organizing scientific programs will be a far more complicated, dynamic, and public affair than is presently the case. I think this will be for the better. All that we have we owe to science, and a majority of the public thinks all too little of the work that will determine whether they live in good health or suffer and die a few decades from now. The more they can see what is going on the better for all of us in the end, I think.

AN EXAMPLE OF ONGOING INVESTIGATIONS OF THE BIOCHEMICAL DETAILS OF ARTERIAL STIFFENING
https://www.fightaging.org/archives/2015/01/an-example-of-ongoing-investigations-of-the-biochemical-details-of-arterial-stiffening.php

The functions of many important tissues in the body depend on physical properties such as elasticity or ability to bear load. These properties derive from the particular structure of the extracellular matrix formed by a tissue, an arrangement of proteins constructed as a mesh to surround and support the cells it holds. The structural properties of the extracellular matrix are increasingly degraded over the course of aging, however, such as by the formation of advanced glycation end-products (AGEs) that can link together proteins of the extracellular matrix in ways that alter the physical properties of the tissue. In the case of blood vessels, rising levels of these cross-links lead to a progressive loss of elasticity, and that in turn causes a whole range of issues in the cardiovascular system that start at hypertension and culminate in catastrophic structural failure of the heart or important blood vessels.

Biochemistry is as a rule always more complicated than we'd like it to be, and so there are many areas of open investigation when it comes to the chemistry of stiffening blood vessels. Metabolic waste products come in many varieties, and it isn't always the case that any given class is actually doing what it is thought to do. Small consensus positions are quietly overturned on a daily basis at the edges of the field, given the falling costs of performing the necessary work, and the foundations of tomorrow are being built beneath the notice of even most researchers.

One of the more important lines of research at the moment, for all that is has little funding and is paid little attention, is to create the means for more research groups to work on glucosepane in human tissues. This appears to be the most prevalent type of AGE forming cross-links in our species - and here it is worth noting that a part of the complexity of this issue is that the chemistry of extracellular matrix cross-linking is very different in various different mammalian species. Lessons learned in mice are only relevant in a very general sense. You'll see few papers on glucosepane despite its importance in our biochemistry, as good tools for working with the class of compounds that glucosepane belongs to in the context of cells and tissues really don't exist yet. For a variety of not-so-good reasons no major research establishment has yet turned its eyes to building them, and so it has fallen on forward-thinking philanthropy to bridge the gap.

As I said, however, there are a lot of different waste products: it is a large space to explore. Those researchers not working on glucosepane are putting in time on other chemicals thought to be relevant to the issue of blood vessel stiffening, but they often draw a blank or find that presence of waste in cells doesn't necessarily correspond to a significant impact on the function of the extracellular matrix, as is the case here. That may not always be the case, of course, and there are certainly good reasons to think that stiffening isn't just AGEs. Science is as much a process of opening doors to empty rooms as it is of finding the one that hides the goal.

Elastin aging and lipid oxidation products in human aorta

In normal arteries, the proteins of the extracellular matrix (ECM) (collagen, elastin, fibrillin, glycoproteins and proteoglycans) produced by smooth muscle cells (SMC) ensure the stability, resilience, and compliance of arteries. Collagen and elastin, two major scaffolding ECM proteins provide structural integrity and elasticity to the vessels, allowing them to stretch while retaining their ability to return to their original shape when the pressure is over. Vascular aging is most of the time associated with structural and functional modifications of the arteries, even in healthy elderly, and particularly by an increase in arterial wall thickening in the intima and the media, mainly resulting from the accumulation and structural modification of ECM components and a disorganization of SMC.

Arterial stiffness is characterized by structural and functional alterations of the intrinsic elastic properties of the arteries and an increased resistance to vessel deformation, resulting from a decrease in artery elasticity (compliance) and an increase in pulse wave velocity (pwv), generating an increased systolic pressure, with deleterious consequences on the heart, generating cardiac hypertrophy and increased ventricular oxygen consumption. Arterial stiffening is a hallmark of vascular aging, and a major risk factor for the development of cardiovascular diseases, that can be exacerbated by diabetes, hypertension or atherosclerosis. It is a direct cause of ventricular hypertrophy, renal dysfunction and stroke, independently of the other causes of vascular aging. It is an independent risk factor for cardiovascular diseases, which may predispose to atherosclerosis, and vice-versa.

Among the factors known to accumulate with aging, advanced lipid peroxidation end products (ALEs) are a hallmark of oxidative stress-associated diseases such as atherosclerosis. Aldehydes generated from the peroxidation of polyunsaturated fatty acids (PUFA) form adducts on cellular proteins, leading to a progressive protein dysfunction with consequences in the pathophysiology of vascular aging.

The contribution of these aldehydes to ECM modification is not known. This study was carried out to investigate whether aldehyde-adducts are detected in the intima and media in human aorta, whether their level is increased in vascular aging, and whether elastin fibers are a target of aldehyde-adduct formation. Immunohistological and confocal immunofluorescence studies indicate that [these] adducts accumulate in an age-related manner in the intima, media and adventitia layers of human aortas, and are mainly expressed in smooth muscle cells. In contrast, even if the structure of elastin fiber is strongly altered in the aged vessels, our results show that elastin is not or very poorly modified by [these adducts].

LATEST HEADLINES FROM FIGHT AGING!

INVESTIGATING THE DETAILS OF MITOCHONDRIAL DYSFUNCTION IN THE AGING MOUSE HEART
Monday, December 29, 2014
https://www.fightaging.org/archives/2014/12/investigating-the-details-of-mitochondrial-dysfunction-in-the-aging-mouse-heart.php

This is a look at a specific form of mitochondrial dysfunction in aging heart tissue, with a focus on the sarcoplasmic reticulum structure inside cells responsible for, among other things, storing and pumping calcium ions. Calcium has many roles; calcium ions (Ca2+) are important in signaling for muscle contractions for example. Here it seems that the problem lies in the interaction between two cellular organelles, and is more subtle than just damage to one or other:

Mitochondrial alterations are critically involved in increased vulnerability to disease during aging. We investigated the contribution of mitochondria-sarcoplasmic reticulum (SR) communication in cardiomyocyte functional alterations during aging. Heart function [was] preserved in hearts from old mice (20 months) with respect to young mice (5 - 6 months). Mitochondrial membrane potential and resting O2 consumption were similar in mitochondria from young and old hearts. However, maximal ADP-stimulated O2 consumption was specifically reduced in interfibrillar mitochondria from aged hearts.

Second generation proteomics disclosed an increased mitochondrial protein oxidation in advanced age. Because energy production and oxidative status are regulated by mitochondrial Ca2+, we investigated the effect of age on mitochondrial Ca2+ uptake. Although no age-dependent differences were found in Ca2+ uptake kinetics in isolated mitochondria, mitochondrial Ca2+ uptake secondary to SR Ca2+ release was significantly reduced in cardiomyocytes from old hearts, and this effect was associated with decreased NAD(P)H regeneration and increased mitochondrial reactive oxygen species (ROS) upon increased contractile activity.

[We] identified the defective communication between mitochondrial voltage-dependent anion channel and SR ryanodine receptor (RyR) in cardiomyocytes from aged hearts associated with altered Ca2+ handling. Age-dependent alterations in SR Ca2+ transfer to mitochondria and in Ca2+ handling could be reproduced in cardiomyoctes from young hearts after interorganelle disruption with colchicine, at concentrations that had no effect in aged cardiomyocytes or isolated mitochondria. Thus, defective SR-mitochondria communication underlies inefficient interorganelle Ca2+ exchange that contributes to energy demand/supply mismatch and oxidative stress in the aged heart.

CORTICAL NEURODYNAMICS AND AGE-RELATED MEMORY FUNCTION
Monday, December 29, 2014
https://www.fightaging.org/archives/2014/12/cortical-neurodynamics-and-age-related-memory-function.php

Below find referenced an interesting view of age-related changes in brain function and memory. As is true throughout the aging body and brain, the higher level changes produced in these intricate systems are far more complex than the few forms of cellular and tissue damage thought to cause aging. Simple damage and a complex system inevitably leads to complex outcomes, but that doesn't necessarily mean it is as hard to fix the damage as it is to understand the system. Consider rust in an ornate, many-legged, load-bearing iron structure as an analogy. Rust is easily dealt with, but it would be hard to try to model or predict exactly the ways in which the structure will weaken and fail over time.

The relatively random spiking times of individual neurons provide a source of noise in the brain. We show how this noise interacting with altered depth in the basins of attraction of networks involved in short-term memory, attention, and episodic memory provide an approach to understanding some of the cognitive changes in normal aging. The effects of the neurobiological changes in aging that are considered include reduced synaptic modification and maintenance during learning produced in part through reduced acetylcholine in normal aging, reduced dopamine which reduces NMDA-receptor mediated effects, reduced noradrenaline which increases cAMP and thus shunts excitatory synaptic inputs, and the effects of a reduction in acetylcholine in increasing spike frequency adaptation.

Using integrate-and-fire simulations of an attractor network implementing memory recall and short-term memory, it is shown that all these changes associated with aging reduce the firing rates of the excitatory neurons, which in turn reduce the depth of the basins of attraction, resulting in a much decreased probability in maintaining in short-term memory what has been recalled from the attractor network. This stochastic dynamics approach opens up new ways to understand and potentially treat the effects of normal aging on memory and cognitive functions.

MORE CORRELATION OF DEMENTIA WITH MANY TINY STROKES
Tuesday, December 30, 2014
https://www.fightaging.org/archives/2014/12/more-correlation-of-dementia-with-many-tiny-strokes.php

Studies of many aged brains shows that the progression of various types of dementia correlates with a history of many small, unnoticed strokes. These leave behind small infarcts, areas of tissue death in the brain caused by a local blockage of small blood vessels. The brains of people suffering neurodegeneration tend to have more of these infarcts. Is this causative, however? Some of the past evidence is fairly compelling with regard to causation, but this remains an open question: since aging is a global phenomenon many of its aspects should be expected to correlate with one another regardless of any direct linkage.

Here is another recent paper demonstrating the correlation, in which the researchers show off the capabilities of an evolution of magnetic resonance imaging (MRI) technology that is more capable of picking out these small areas of structural damage than has been the case in the past:

Until recently cortical microinfarcts (CMIs) were considered as the invisible lesions in clinical-radiological correlation studies that rely on conventional structural magnetic resonance imaging. The present study investigates the presence of CMIs on 7.0-T magnetic resonance imaging (MRI) in post-mortem brains with different neurodegenerative and cerebrovascular diseases. One hundred-seventy five post-mortem brains, composed of 37 with pure Alzheimer's disease (AD), 12 with AD associated to cerebral amyloid angiopathy (AD-CAA), 38 with frontotemporal lobar degeneration, 12 with amyotrophic lateral sclerosis, 16 with Lewy body disease (LBD), 21 with progressive supranuclear palsy, 18 with vascular dementia (VaD) and 21 controls were examined. According to their size several types of CMIs were detected on 3 coronal sections of a cerebral hemisphere with 7.0-T MRI and compared to the mean CMI load observed on histological examination of one standard separate coronal section of a cerebral hemisphere at the level of the mamillary body.

Overall CMIs were significantly prevalent in those brains with neurodegenerative and cerebrovascular diseases associated to CAA compared to those without CAA. VaD, AD-CAA and LBD brains had significantly more CMIs compared to the controls. While all types of CMIs were increased in VaD and AD-CAA brains, a predominance of the smallest ones was observed in the LBD brains. The present study shows that 7.0-T MRI allows the detection of several types of MICs and their contribution to the cognitive decline in different neurodegenerative and cerebrovascular diseases.

FOLLOWING UP ON A TRIAL OF AN IMMUNE SYSTEM RESET TO TREAT MULTIPLE SCLEROSIS
Tuesday, December 30, 2014
https://www.fightaging.org/archives/2014/12/following-up-on-a-trial-of-an-immune-system-reset-to-treat-multiple-sclerosis.php

Some autoimmune diseases can be successfully treated by suppressing or destroying the existing immune system and then transplanting new stem cell populations responsible for generating immune cells. This can result in an effective resetting of the immune system, or at least removal of those parts of it that have become misconfigured to attack the patient's own tissues. It is, however, a pretty drastic process and certainly not one to be undertaken lightly: the sort of chemotherapy required is not a walk in the part for the patient. For autoimmune conditions where even partially effective alternative treatments exist, as is the case for rheumatoid arthritis, for example, researchers have all but abandoned work on the destroy-and-rebuild approach despite some early promising results. Nonetheless, it has been shown to produce results in terms of halting the progression of multiple sclerosis (MS), one of the more serious forms of autoimmunity in which the myelin sheathing of nerves is attacked:

Multiple sclerosis (MS) is a degenerative disease and most patients who receive disease-modifying therapies experience recurrence of the disease process. Three years after a small number of patients with MS were treated with high-dose immunosuppressive therapy (HDIT) and then transplanted with their own hematopoietic stem cells, most of the patients sustained remission of active relapsing-remitting MS (RRMS) and had improvements in neurological function.

Study results indicate that of the 24 patients who received HDIT/HCT, the overall rate of event-free survival was 78.4 percent at three years, which was defined as survival without death or disease from a loss of neurologic function, clinical relapse or new lesions observed on imaging. Progression-free survival and clinical relapse-free survival were 90.9 percent and 86.3 percent, respectively, at three years. The authors note that adverse events were consistent with the expected toxic effect of HDIT/HCT and that no acute treatment-related neurologic adverse events were seen. Improvements in neurologic disability, quality-of-life and functional scores also were noted.

"In the present study, HDIT/HCT induced remission of MS disease activity up to three years in most participants. It may therefore represent a potential therapeutic option for patients with MS in whom conventional immunotherapy fails, as well as for other severe immune-mediated diseases of the central nervous system. Most early toxic effects were hematologic and gastrointestinal and were expected and reversible. Longer follow-up is needed to determine the durability of the response."

A SCAFFOLDING APPROACH TO ANTERIOR CRUCIATE LIGAMENT REPAIR
Wednesday, December 31, 2014
https://www.fightaging.org/archives/2014/12/a-scaffolding-approach-to-anterior-cruciate-ligament-repair.php

The use of scaffolding in regenerative medicine is becoming more sophisticated, with researchers developing a wider range of approaches that offer a variety of different structural characteristics. This allows for attempts to repair load bearing or supporting tissues such as ligaments and tendons:

Not only is the anterior cruciate ligament (ACL) inelastic and prone to popping, it is incapable of healing itself, causing surgeons to rely on autografts for reconstruction. Most common is the bone-patellar tendon-bone (BPTB) graft, in which the surgeon removes part of the patellar tendon to replace the damaged ACL. "BPTB autografts have a high incidence of knee pain and discomfort that does not go away. By saving the patient's patellar tendon and using an off-the-shelf product, one may have a better chance of preserving the natural biomechanics of the knee."

[Researchers] are working to engineer such a product by combining three components: polyester fibers that are braided to increase strength and toughness, an inherently antioxidant and porous biomaterial, and calcium nanocrystals, a mineral naturally found in human teeth and bones. During ACL reconstruction surgeries, tunnels are drilled into the femur and tibia bones to hold the new ligament in a fixed position. [The researchers] created a bone-like material by combining antioxidant biomaterials with the calcium nanocrystals and then embedded braided polyester fibers into it. The artificial ligament's bone-like ends healed to the native bone in the drilled tunnels, anchoring the ligament into place.

By studying an animal model, the team noticed that the animal's natural bone and tissue cells migrated into the pores of the artificial ligament, populating it throughout and integrating with the bone tunnels. "The engineered ligament is biocompatible and can stabilize the knee, allowing the animal to function. Most importantly, we may have found a way to integrate an artificial ligament with native bone."

LAST DAY OF THE YEAR, AND A LITTLE ROOM IS LEFT IN THE LAST SENS MATCHING FUND OF 2014: DONATE!
Wednesday, December 31, 2014
https://www.fightaging.org/archives/2014/12/last-day-of-the-year-and-a-little-room-is-left-in-the-last-sens-matching-fund-of-2014-donate.php

Our 2014 fundraiser to benefit the work of the SENS Research Foundation on rejuvenation biotechnology came to a successful completion two weeks ago. At the time I noted that a new matching fund was put in place by a generous supporter, and all donations for the remainder of the year are matched. It is now the last day of the year and just a few thousand remain in order to meet this goal. So donate!

We are excited to note that a new challenge grant has been received from Ronny Hatteland, AutoStore - Software Developer. For every dollar we receive from now until the end of the year (December 15 - 31st), the first thousands will be matched by Ronny's generous gift. Ronny tells us that "The work of the SENS Research Foundation gives us all a chance to secure ourselves a healthy future and an extended lifetime to continue to embrace all that life has to offer us. I am very pleased to support SENS Research Foundation and I encourage all of you to join me."

A POTENTIAL APPROACH TO SABOTAGE TELOMERASE IN CANCER CELLS
Thursday, January 1, 2015
https://www.fightaging.org/archives/2015/01/a-potential-approach-to-sabotage-telomerase-in-cancer-cells.php

Advocates for cancer research often bemoan the enormous complexity of cancer, the vast range of differences between types of cancer and even between cancers of the same type in different individuals. A cancer is cellular evolution on fast forward, rampant growth and mutational damage, which has made it a thousand moving targets for the research community. However there is a commonality to all cancer, and that is the need for cancer cells to maintain lengthy telomeres through the use of telomerase or less well understood alternative lengthening of telomeres (ALT) methods. Without this abuse of telomere lengthening mechanisms cancerous cells would not be able to continuous replicate to a degree that makes their presence life-threatening. A little of the length of telomeres are dropped every time a cell divides, and when they become too short the cell permanently ceases replication and usually activates its own programmed cell death process. This insight is the basis for the SENS approach to cancer, which is to aim at suppressing all mechanisms by which the body can lengthen telomeres.

What other approaches might be taken to attack this potential single point of failure in all cancers? These researchers are attempting to corrupt the process of telomere lengthening via telomerase in cancer cells so as to generate telomere sections that a cell considers to be damaged. This then results in much the same outcome as for very short telomeres, which is to say no more replication for the affected cells:

[Researchers] have targeted telomeres with a small molecule called 6-thio-2'-deoxyguanosine (6-thiodG) that takes advantage of the cell's 'biological clock' to kill cancer cells and shrink tumor growth. 6-thiodG acts by targeting a unique mechanism that is thought to regulate how long cells can stay alive, a type of aging clock. This biological clock is defined by DNA structures known as telomeres, which cap the ends of the cell's chromosomes to protect them from damage, and which become shorter every time the cell divides. Once telomeres have shortened to a critical length, the cell can no longer divide and dies though a process known as apoptosis.

6-thiodG is preferentially used as a substrate by telomerase and disrupts the normal way cells maintain telomere length. Because 6-thiodG is not normally used in telomeres, the presence of the compound acts as an 'alarm' signal that is recognized by the cell as damage. As a result, the cell stops dividing and dies. Telomerase is an almost universal oncology target, yet there are few telomerase-directed therapies in human clinical trials, researchers noted. "Using telomerase to incorporate toxic products into telomeres is remarkably encouraging at this point." Importantly, unlike many other telomerase-inhibiting compounds, the researchers did not observe serious side effects in the blood, liver and kidneys of the mice that were treated with 6-thiodG. "We observed broad efficacy against a range of cancer cell lines with very low concentrations of 6-thiodG, as well as tumor burden shrinkage in mice."

KLOTHO IN VASCULAR HEALTH AND DISEASE
Thursday, January 1, 2015
https://www.fightaging.org/archives/2015/01/klotho-in-vascular-health-and-disease.php

Klotho is a longevity-associated gene that has been under investigation for some years. Increasing its expression lengthens life in mice, while reducing it has the opposite effect. Here is an open access review on the topic with a focus on mechanisms relating to cardiovascular disease (CVD):

Klotho, a gene originally identified in 1997 codifying for a novel anti-aging protein, has been implicated in a multitude of biological processes, most of them related to human longevity. Mice lacking the Klotho gene develop a phenotype similar to premature human aging, which includes endothelial dysfunction, vascular calcification, progressive atherosclerosis and shortened lifespan. A reduction in Klotho levels is observed in chronic kidney disease (CKD) patients, similar to other premature vascular aging diseases, such as hypertension or diabetes mellitus. Even normal aging is associated with a reduction in serum and urine concentration of Klotho.

More recently, the involvement of Klotho in vascular protection through different mechanisms has been demonstrated. These mechanisms include inhibition of oxidative stress, modulation of inflammation or attenuation of vascular calcification. Therefore, Klotho has been suggested as a master regulator of CVD. The disruption in the homeostasis of this factor seems to be a key element in the development of CVD. The reduction of circulating levels of Klotho is associated with the presence and severity of coronary artery disease (CAD) and is also an independent marker of some forms of vascular dysfunction such as arterial stiffness. Likewise, various genetic studies have shown the association between gene variants of human Klotho gene with CAD or stroke.

RECENT INVESTIGATION OF NAKED MOLE RAT CANCER IMMUNITY
Friday, January 2, 2015
https://www.fightaging.org/archives/2015/01/recent-investigation-of-naked-mole-rat-cancer-immunity.php

In addition to being very long lived for their size and showing few signs of degenerative aging over their life span, naked mole-rats are essentially immune to cancer. Arguably there is more research interest in this latter point than in the life span question. So far scientists have focused on contact inhibition of cellular replication, which seems to be much more aggressive in naked mole-rat cells: when cells begin to crowd, as in a potential cancer, their ability to divide is rapidly shut down. This better contact inhibition is probably partially due to a different form of the protein hyaluronan, involved in the processes by which the p16 gene acts as a cancer suppressor.

Here researchers find another new angle to add to these discoveries. Naked mole rats generate a novel protein from the same area of the genome as p16, one not produced in other mammals, and it seems to be a better tumor suppressor than the other proteins produced from that region. Since it can be produced via genetic engineering in the cells of other mammals, the logical next step might be to create a lineage of mice that have it and see what happens:

The naked mole rat (Heterocephalus glaber) is a long-lived and tumor-resistant rodent. Tumor resistance in the naked mole rat is mediated by the extracellular matrix component hyaluronan of very high molecular weight (HMW-HA). HMW-HA triggers hypersensitivity of naked mole rat cells to contact inhibition, which is associated with induction of the INK4 (inhibitors of cyclin dependent kinase 4) locus leading to cell-cycle arrest. The INK4a/b locus is among the most frequently mutated in human cancer. This locus encodes three distinct tumor suppressors: p15INK4b, p16INK4a, and ARF (alternate reading frame).

p16INK4a and ARF share common second and third exons with alternative reading frames. Here, we show that, in the naked mole rat, the INK4a/b locus encodes an additional product that consists of p15INK4b exon 1 joined to p16INK4a exons 2 and 3. We have named this isoform pALTINK4a/b (for alternative splicing). We show that pALTINK4a/b is present in both cultured cells and naked mole rat tissues but is absent in human and mouse cells. Additionally, we demonstrate that pALTINK4a/b expression is induced during early contact inhibition and upon a variety of stresses. When overexpressed in naked mole rat or human cells, pALTINK4a/b has stronger ability to induce cell-cycle arrest than either p15INK4b or p16INK4a. We hypothesize that the presence of the fourth product, pALTINK4a/b of the INK4a/b locus in the naked mole rat, contributes to the increased resistance to tumorigenesis of this species.

AN EXAMPLE OF SHORT TERM DETRIMENTAL EFFECTS DUE TO INACTIVITY
Friday, January 2, 2015
https://www.fightaging.org/archives/2015/01/an-example-of-short-term-detrimental-effects-due-to-inactivity.php

Over the long term leading a sedentary lifestyle is about as harmful to health and longevity as smoking. Thus there should also be short term changes that can be observed and measured, as is shown to the be the case here:

Researchers found that reducing daily physical activity for even a few days leads to decreases in the function of the inner lining of blood vessels in the legs of young, healthy subjects causing vascular dysfunction that can have prolonged effects. The vascular dysfunction induced by five days of inactivity requires more than one day of returning to physical activity and taking at least 10,000 steps a day to improve. "We know the negative consequences from not engaging in physical activity can be reversed. There is much data to indicate that at any stage of a disease, and at any time in your life, you can get active and prolong your life."

The researchers studied the early effects on the body's blood vessels when someone transitions from high daily physical activity - 10,000 or more steps per day - to low daily physical activity, less than 5,000 steps per day. Counting steps and daily physical activity is different than defined exercise, such as working out at the gym. While there are significant benefits to defined exercise, [this] research is based on what amounts to 30 minutes of moderate activity per day. "The impairment we saw in just five days was quite striking. It shows just how susceptible the vascular system is to physical inactivity."

The researchers studied inactivity and glycemic control as well as how inactivity affects blood flow and vascular function through the body. A decrease in blood vessel function has been shown in previous studies to be linked to early cardiovascular death and hypertension. Now, this research shows that even an acute period of inactivity of five days changes the measure that is already known to be important for long-term cardiovascular health. Also, although blood flow responses to glucose ingestion were not affected by five days of inactivity, impairments in glycemic control and insulin sensitivity are also a consequence of reduced daily physical activity.

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