Fight Aging! Newsletter, June 24th 2013

June 24th 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that 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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  • Crowdsourced Microfunding of Research at LongeCity
  • New Faces at the SENS Research Foundation
  • The Latest Update on Naked Mole Rat Cancer Immunity
  • A Few Reports From the Global Future 2045 Conference
  • A Review on Exercise and Aging
  • Latest Headlines from Fight Aging!
    • Clinical Trials for Blood Produced from Stem Cells
    • Why Public Research Funding is Comparatively Unproductive
    • A Small Molecule Treatment that Boosts Memory in Mice
    • Building One Function of an Artificial Spleen
    • Calorie Restriction Slows Loss of Neurogenesis
    • Using Centenarians to Improve Genetic Studies of Aging
    • MicroRNA Levels Can Correlate With Individual Variations in Longevity
    • Sonic Hedgehog Therapy Partially Reverses Age-Related Decline in Muscle Regeneration
    • Still in Search of a Practical Use for Sirtuin Activators in Aging
    • Considering GSK-3 in Aging


LongeCity has been around for a while, and is home to an energetic community interested in health and longevity. There is as much talk of supplements, frivolous stuff to my eyes, as there is of serious longevity science aimed at rejuvenation, such as the Strategies for Engineered Negligible Senescence, but over the years the folk there seem to have made that work in a sustainable way. The LongeCity crowd are more biased towards supporting rejuvenation research than any other health-focused community you're likely to find out there.

One of the other distinctions of LongeCity is that they have spent some years raising funds from the community for small research projects. They have been doing that for some time longer than the current crop of science crowdfunding startups have existed, for example. Making this work is a hard nut to crack, both from the point of view of practical administration and from convincing people to donate, but plenty of $20-40,000 sized projects exist in longevity-related life science research that are both useful and feasible to undertake. So the LongeCity administrators have established an ongoing grant scheme under which they solicit applications, raise funds, and monitor the progress of projects such as evaluating the effects of transplanting young microglia cells into old mice to see if such a procedure can slow or reverse neurodegeneration.

This ongoing set of initiatives and the efforts of crowdfunding startups like Microryza are just the opening notes in the near future symphony of community science funding. There will be a great deal more open fundraising and many more people helped to advance their own favored causes by careful funding of specific small research projects. Like medical tourism, this is still at the stage of shaking out an industry with standards, best practices, and approaches that work. Growth is yet to come: the foundation work is still underway.

On this topic I noticed a recent post that looks over the LongeCity crowdfunding activities and projects of past years:

Help Conquer Death with Grants and Research Funding from LongeCity!

LongeCity has been doing advocacy and research for indefinite life extension since 2002. With the Methuselah Foundation and the M-Prize's rise in prominence and public popularity over the past few years, it is sometimes easy to forget the smaller-scale research initiatives implemented by other organizations. Anyone can have a great idea, and there are many low-hanging fruits that can provide immense value and reward to the field of life extension without necessitating large-scale research initiatives, expensive and highly-trained staff or costly laboratory equipment.

In the past LongeCity has raised funding by matching donations made by the community to fund a research project that used lasers to ablate (i.e. remove) cellular lipofuscin. LongeCity raised $8,000 dollars by the community which was then matched by up to $16,000 by SENS Founation. LongeCity's second successfully funded research initiative was mitochondrial uncoupling. LongeCity's 3rd success was their project on Microglia Stem Cells in 2010. This project studied the benefits of transplanting microglia in the aging nervous system. LongeCity's fourth research-funding success was on Cryonics in 2012, specifically uncovering the mechanisms of cryoprotectant toxicity.

These are real projects with real benefits that LongeCity is funding. Even if you're not a research scientist, you can have an impact [by helping to fund a] small-scale research grant from LongeCity.


The SENS Research Foundation advocates, organizes, and funds rejuvenation research based on the Strategies for Engineered Negligible Senescence (SENS) program. The aim is to produce the means to repair and reverse the fundamental known differences between young tissue and old tissue, things like damaged mitochondrial DNA and a build up of various forms of hardy metabolic waste product that impair cellular functions. This isn't so far away as you might thing: some of the presently envisaged approaches are within a couple of years of practical technology demonstrations in laboratory animals, given sufficient funding.

The SENS Research Foundation remains the only easy way to donate funds that will go towards research very likely to produce meaningful extension of healthy life when complete. There is no other group that has yet proceeded as far down the road of building a network within the longevity science community, establishing an organization, and gathering support for a research strategy devoted to effective ways to reverse the course of aging in the old. We'd like to see that change in the future: the SENS Research Foundation budget is growing but still small, and it will take hundreds of millions of dollars over the next decade or two to complete SENS or something like SENS. The SENS Research Foundation must continue to grow, but it will be good to see other SENS-like groups following the same path and working on many of the same problems. Competition makes the world go round, and more funding speeds progress.

Given that the SENS Research Foundation is growing (the annual budget has increased from $1 million to $3 million in the past couple of years) you might not recognize many of the new staff. The Foundation puts out the occasional post to feature members of the research team, coordinators, and affiliated scientists, and here are four noted in recent weeks:

New Staff Spotlight: Ehud Goldin, PhD

Dr. Ehud Goldin has recently joined SENS Research Foundation as head of the Research Center's A2E degradation project. Dr. Goldin [worked] with Fabry disease before joining the NIH's National Human Genome Research Institute as a staff scientist. There, he developed models for high-throughput drug discovery and conducted drug development studies for Gaucher's and Parkinson's diseases.

These numerous experiences have given Dr. Goldin over eighty publications, along with a deep understanding of lysosomal storage diseases. He brings this expertise to the SRF Research Center's own lysosomal storage work: his new project is to enable the lysosomes of retinal pigment epithelial cells to degrade A2E. A successful treatment that follows this strategy could prevent or even cure age-related macular degeneration. Dr. Goldin hopes to bring this project into an animal model, and follow it with more work on the various forms of lipofuscin that build up in lysosomes and drive age-related diseases.

Dr. Gregory Chin: SRF's new Director of Education

One of the best parts of my outreach positions was always working with student researchers. Research mentors will work alongside the SRF interns at the bench, but I am excited to play a role in developing presentation and data interpretation skills via feedback on reports and presentations. Being around education all my life, I couldn't help but love to learn. The variety of research that the SENS Research Foundation supports is astounding. It's going to be fun learning more about these projects through my work with the interns and through the upcoming online seminar series that will highlight the work of some of the top aging-related research labs in the world.

Intern Spotlight: Ali Crampton

Ali returns to the SRF Research Center this summer to work on the problem of damage to mitochondrial genes. Mitochondrial genes are prone to damage from by-products of cellular respiration, which leads to a loss of cell function. Ali's 2013 summer project will be to investigate two possible methods of supplying proteins to the affected mitochondria, in order to restore proper function. This fall, Ali will begin the next chapter of her career as a Biomedical Engineering graduate student at the University of Minnesota.

SENS6 Speaker Highlight: Dr. Eric Lagasse

The work that has come to define Dr. Lagasse's career began with an NIH Director's Transformative R01 Award in 2009. Lagasse had proposed a radical new idea: that transplanted cells from organs like the liver might be able to develop, grow, and function within the lymph nodes of living organisms. The miniature organs produced in this way would have the potential to save the lives of patients waiting for an organ transplant, or even to cure some conditions outright. Within three years, Dr. Lagasse had published his team's success in Nature Biotechnology. The results were striking. Not only could mice be saved from a deadly liver disease with hepatic cells transplanted to the lymph nodes, but diabetic animals could have their blood sugar brought back to normal using pancreatic islet cells. Mice lacking a proper immune system could similarly be saved using cells from the thymus. Dr. Lagasse will discuss this very project during SENS6's ninth session, "Beyond organ transplantation." We're looking forward to learning more about his work, his latest results, and his plans for the future.

As I've said numerous times in the past, helping the SENS Research Foundation to grow, gather more support, and prosper is the best present path to speed the development of methods of human rejuvenation. A strong Foundation will drag the rest of the aging research field along with it as the research proceeds, and competitors and cooperative projects will naturally arise along the way. This is all a vital part of the sea change in aging research that must take place over the years ahead: to move away from useless and expensive tinkering with drug discovery to slightly slow aging, and towards targeted implementations of new technologies that repair specific forms of damage that cause aging.

If this change happens, we have a shot at living far longer than the present human life span: the old will have access to rejuvenation therapies. If this change falters, then the only outcome of enormously expensive research programs two or three decades from now will be drugs that slightly slow down aging, and do next to nothing for people already old. That would be a grand failure indeed. So support the SENS Research Foundation: it's very much in your own self-interest.


Naked mole rats are exceedingly long lived in comparison to similarly sized rodents, and furthermore appear to be immune to cancer. A number of researchers are engaged in uncovering the reasons why the species has these characteristics. On the longevity front, differences in the composition of vulnerable cell membranes is one candidate, making cells more resistant to the more important forms of oxidative damage to protein machinery that accumulate over time. Cancer immunity on the other hand seems to be connected to the p16 gene and cellular reactions to overcrowding:

Like many animals, including humans, the mole rats have a gene called p27 that prevents cellular overcrowding, but the mole rats use another, earlier defense in gene p16. Cancer cells tend to find ways around p27, but mole rats have a double barrier that a cell must overcome before it can grow uncontrollably.

Neighboring species of blind mole rat may also be immune to cancer, but appear to have evolved a different mechanism to achieve the same end.

The modern research community being what it is, I expect that the years ahead hold a lot more work on the cancer angle than on aging and longevity. There is much more money in cancer research, and it is actually possible in the present regulatory environment to take new discoveries straight into development and clinical trials. No such luck for potential ways to treat aging: the FDA doesn't recognize aging as a disease, and therefore there is no path to gaining approval for a way to treat aging. Hence there is little funding for research like that organized by the SENS Research Foundation, aimed at plausible near future paths to human rejuvenation.

In investigating naked mole rat cancer immunity researchers are following the normal script, which is to find any important part of the biological mechanisms of interest - such as by removing genes until they find one that is necessary for the process to work - and then from that starting point move along the chains of protein interactions in an effort to understand how it all fits together. So starting from p16, researchers have moved on to identify a role for hyaluronan. The full paper isn't open access, unfortunately, but the publicity materials give a fair overview:

Biologists Identify the Chemical Behind Cancer Resistance in Naked Mole Rats

[Researchers] discovered that these rodents are protected from cancer because their tissues are very rich with high molecular weight hyaluronan (HMW-HA). The biologists' focus on HMW-HA began after they noticed that a gooey substance in the naked mole rat culture was clogging the vacuum pumps and tubing. They also observed that, unlike the naked mole rat culture, other media containing cells from humans, mice, and guinea pigs were not viscous. [They] identified the substance as HMW-HA, which caused them to test its possible role in the naked mole rat's cancer resistance.

When HMW-HA was removed, the cells became susceptible to tumors, confirming that the chemical did play a role in making naked mole rats cancer-proof. [The] team also identified the gene, named HAS2, responsible for making HMW-HA in the naked mole rat. Surprisingly, the naked mole rat gene was different from HAS2 in all other animals. In addition naked mole rats were very slow at recycling HMW-HA, which contributed to the accumulation of the chemical in the animals' tissues.

[Previously researchers] showed that the p16 gene in naked mole rats stopped the proliferation of cells when too many of them crowd together. In their latest work, the two biologists identified HMW-HA as the chemical that activates the anti-cancer response of the p16 gene.

The next step will be to test the effectiveness of HMW-HA in mice. If that test goes well, [researchers] hope to try the chemical on human cells. "There's indirect evidence that HMW-HA would work in people. It's used in anti-wrinkle injections and to relieve pain from arthritis in knee joints, without any adverse effects. Our hope is that it can also induce an anti-cancer response. We speculate that naked mole rats have evolved a higher concentration of HA in the skin to provide skin elasticity needed for life in underground tunnels. This trait may have then been co-opted to provide cancer resistance and longevity to this species."

A little early to be seeking out and stockpiling hyaluronan, I think - unless you have an aggressive cancer, in which case it doesn't seem like there's all that much to lose given the present safety profile. There are all sorts of reasons why hyaluronan may not have the same effect in anything other than naked mole rats: if the presence of hyaluronan is unusual in this species, then why not the reaction to it as well? So wait for the mouse studies before getting excited.


This year's Global Future 2045 conference took place earlier this week. The focus, as for other aspects of the 2045 Initiative, is on creating artificial bodies and minds and the many technologies needed to support that goal. There is also a fair-sized chunk of social utopianism driving the Initiative's founder, Dmitry Itskov, and that shows in the way he presents his vision for a machine humanity: not just a proposal to eliminate the death and suffering caused by aging and disease, but also to undermine as much as possible of the basis for man's ongoing inhumanity to man.

We shall see how well that plays. Certainly analogous and admired visions have emerged from the past few decades of transhumanist writing, such as the Hedonistic Imperative: technology shackled primarily to the goal of ending pain and suffering, with the defeat of aging and disease merely one necessary line item along the way. But this is more or less the opposite way round from the way in which I usually think of these things: I say focus on building the technologies of rejuvenation and disease control first, second, and last of all, and let society sort itself out. Creating the means to reduce suffering and involuntary death is a worthy goal to focus on regardless of how people choose to behave towards one another.

A couple of press items on the Global Futures 2045 conference have emerged in the past few days, and some of them manage to avoid the eye candy robotics in favor of noting more interesting items. In the first case below, that means getting the essence of Aubrey de Grey's SENS proposals wrong, but such is life.

Dmitry Itskov's Immortal Robots Hit the Big Stage, in Name Only

There's a broader question that's yet to be broached: If we're searching for immortality, do we really need to become robots? Conference attendee Aubrey de Grey, the biologist and longevity scientist known for his colorful interviews and wizard beard, thinks the biological solution to eternal life will be available first as it is "easier" to achieve. Much of de Grey's research revolves around solving the free radical problem, through which rogue molecules accumulate inside and randomly damage our cells, which in turn make us age. As biological robots, our bodies should be able to repair themselves indefinitely, but free radicals prevent cells from doing this after you reach a certain age.

The prospect of his research failing to find a cure for aging before Itskov's timeline plays out doesn't phase Grey one bit. When asked how he would feel about his work becoming obsolete if the goals of the 2045 initiative come to fruition, Grey responded with a smile and "good, the sooner the better."

This is what the world will look like in 2045

"It's not so hard to predict the future, but it's sometimes hard to connect the dots." In the opening of his lecture to the Global Futures 2045 Congress, famed geneticist Dr. George Church neatly summed up what being a futurist is all about, though he was reminding the audience rather than the other speakers assembled at Alice Tully Hall in New York City this past weekend. Gathered there by a young Russian tech tycoon on a mission to do nothing less than achieve immortality through technology, a who's-who of renowned technologists, scientists, futurists, and entrepreneurs painted a sometimes terrifying, sometimes electrifying picture of what the world is going to look like in the decades to come, describing how technology is going to drastically alter economies, biologies, and perhaps even consciousness itself.

'Mind Uploading' & Digital Immortality May Be Reality By 2045, Futurists Say

By 2045, "based on conservative estimates of the amount of computation you need to functionally simulate a human brain, we'll be able to expand the scope of our intelligence a billion-fold," Kurzweil said. Itskov and other so-called "transhumanists" interpret this impending singularity as digital immortality. Specifically, they believe that in a few decades, humans will be able to upload their minds to a computer, transcending the need for a biological body. The idea sounds like sci-fi, and it is - at least for now. The reality, however, is that neural engineering is making significant strides toward modeling the brain and developing technologies to restore or replace some of its biological functions.

I shouldn't have to repeat myself to say that the 2045 timeline seems overly ambitious, and for all the same reasons as Ray Kurzweil's projections seem overly ambitious. For so long as we are still essentially human, it takes a certain minimum amount of time to organize a business, raise funding, process and assimilate new knowledge into the entrepreneurial and scientific zeitgeist, and so on. The technological capabilities discussed at Global Futures 2045 will come to pass, but not for at least another few decades, I think.

That said, nothing wrong with aiming high if you're in the business of working on the problem rather than just talking about it. It's just a pity that working towards machines to replace biology is highly unlikely to be of greater benefit over the next thirty years than working on rejuvenation biotechnology after the SENS model. Progress on the problem of aging in the next thirty years is critical for those of us in middle age today: it determines whether we make it or not, whether we live for as long as our parents, or we live for thousands of years in a golden future of ever-increasing technological capabilities.


Exercise is good for you: there is a big difference in likely long term health between moderate regular exercise and being sedentary. Exercise seems to be roughly on a par with calorie restriction when it comes to improving health and extending average life span, but interestingly it doesn't extend maximum life span in the way that calorie restriction does in animal studies. There is that intriguing disconnect between improved long-term health and maximum observed longevity that someone, one day, will be able to explain: from a naive perspective that considers aging to be accumulated damage, you'd expect it that any improvement in health over the long term would tend to push out maximum life span.

While the difference between no exercise and moderate exercise (the traditionally recommended 30 minutes of aerobic exercise a day that every doctor will tell you about) is well supported by the evidence, it's harder to say that more is better, or that some exercise is better than other exercise. Human data shows us that athletes are longer lived than the rest of us on average, for example, but it's far from clear that they are long-lived because they exercise, versus there being a bias towards athletics as a career for more robust individuals who would have lived longer anyway.

Going by the published research, the 80/20 win for personal health involves taking the 30 minutes a day at this point. A recent paper suggests that it doesn't matter how you rack up the time so long as it's somewhat regular:

Total amount of exercise important, not frequency, research shows

[Researchers] studied 2,324 adults from across Canada to determine whether the frequency of physical activity throughout the week is associated with risk factors for diabetes, heart disease and stroke. "The findings indicate that it does not matter how adults choose to accumulate their 150 weekly minutes of physical activity. For instance, someone who did not perform any physical activity on Monday to Friday but was active for 150 minutes over the weekend would obtain the same health benefits from their activity as someone who accumulated 150 minutes of activity over the week by doing 20-25 minutes of activity on a daily basis."

So in general keep in mind that the outcomes with exercise are much better than those without it. Living a sedentary life is a matter of stabbing yourself in the back thirty years down the line: making your future more expensive, more painful, and shorter. Perhaps the pace of medical science will keep up with you and you'll be rescued by new medical technologies - but why take risks that you don't have to?

Exercise training as a preventive tool for age-related disorders: a brief review

There is structural and functional deterioration of almost all physiological systems during aging, even in the absence of discernible disease, resulting in reduced independence and increased incidence and progression of chronic diseases in older adults.

However, regular participation in physical activity and/or exercise training programs can minimize the physiological alterations that occur during aging and may contribute to improvements in health and well-being. Numerous studies have shown that exercise training programs improve the muscle strength, balance, cardiorespiratory fitness, metabolism, glucose tolerance, daily living activities and psychological health of elderly people, even those in their 80s or 90s. Accordingly, national and international agencies have recommended regular physical activity or exercise participation to promote older adult health and disease prevention.

In this context, avoiding a sedentary life style by performing any type or level of daily exercise is a prudent recommendation to follow as it will reduce the impact of aging on some physiological functions, reduce the risk of developing chronic disease and prevent premature mortality, regardless of age.

Ultimately, of course, you can't treadmill your way out of aging to death. What you can do is make life more likely to be pleasant and longer by a handful of years. The studies that compare those who exercise with those who don't suggest that the value of being active is 5 to 10 years of life expectancy, a bonus above and beyond the health benefits. If you want to live longer than that, and with greater certainty of a long future ahead, then the development of new medical technology is the only viable way forward. The earlier you start helping to make foreseeable technologies of human rejuvenation a reality, the more likely it is that they will exist in time to save you from the frailty, suffering, and death caused by degenerative aging.


Monday, June 17, 2013

Ten years from now blood donation might be a thing of the past in wealthier regions of the world:

Researchers based at the Scottish Centre for Regenerative Medicine (SCRM) in Edinburgh hope to use stem cells to manufacture blood on an industrial scale to help end shortages and prevent infections being passed on in donations. The UK's Medicines and Healthcare products Regulatory Agency (MHRA) has now granted a licence so scientists can make blood from stem cells which can be tested in humans - the first step towards large-scale clinical trials, which will hopefully lead to the routine use of blood created in this way.

As well as the blood research, the licences will also allow scientists in the coming years to create stem-cell products to treat patients who have suffered a stroke and people with Parkinson's disease, diabetes and cancer. But much of the attention has focused on how stem cells could be harnessed to create blood products - seen by many as the "holy grail" of blood research.

A key difference in their work going forward would be the use of stem cells derived from adult tissue - known as induced pluripotent stem cells. "In the first part of the project we used human embryonic stem cell lines and one of the problems with using those lines is you can't choose what the blood group is going to be. Over the last few years there has been a lot of work on induced pluripotent stem cells and with those an adult can donate a small piece of skin or a blood sample and the technology allows for stem-cell lines to be derived from that sample. This makes our life a lot easier in some ways because that means we can identify a person with the specific blood type we want and get them to donate a sample from which we could manufacture the cell lines."

Monday, June 17, 2013

Something like a third of medical research funding comes from government sources. It is the most transparent and easily quantified source, so it is the one most often discussed. The incentives put upon researchers competing for these funds steer them towards largely mundane, low-risk, low-reward work, and greatly favor large institutions over smaller research groups. This is a proven way to edge out the sort of research that tends to occasionally produce meaningful or even spectacular results, in favor of research that is essentially make-work or pointless in comparison to what could be done. It's why you shouldn't expect much from massive public spending on research: the yield of meaningful work is very low.

The private funding world is mostly for-profit research, and that has its own issues that are driven by the enormous imposed costs of regulation and short time horizons. So as a general rule near all of the really interesting and potentially game-changing research programs in aging and the broader life sciences were started by and are still largely funded by philanthropists. Consider the SENS Research Foundation, for example, or the Glenn Laboratories, or the points made by Peter Thiel's radical philanthropy initiative: too much funding is biased towards the incremental and the meaningless, while ignoring the tremendous possibilities of the near future. So progress is far slower than it might be.

Here are a few comments on the public funding environment from a discussion on the Gerontology Research Group list:

One of the main reasons for a lack of serious anti-aging basic science [is] the current and recent funding climate of academia. As a scientist currently in the middle of the funding rat race, I can tell you why not a lot of scientists want to work on aging. The NIH/NIA/NCI want preliminary data. They want it on every single grant application. If you don't have it, they won't fund it, and this is a relatively new phenomenon (and the definition of "preliminary data" has become significantly more burdensome). Effectively, in order to get new work funded, it has to be partially (or in some cases nearly entirely) complete, meaning that you have to have some other funding source and a functional laboratory *before you get the grant*.

This shifts risk from the funding agency to the investigator, such that if you are using your current funding, left over from some already completed grant or tangentially related to a grant in progress on a new project, you want to be sure that the new project will work, because if it doesn't, you're out of funding and have exhausted the most precious resource you have in securing new funding - your old funding! You won't do things that are hard or risky unless you're a very rich lab (which tend to be entrenched in certain fields that aren't hard or risky, because that's how they got to be a rich lab), because hard and risky things can fail, and then your career is over. Aging research is hard and risky.

There's too much focus on low hanging fruits because of the pressure to publish and get grants. My lab is no exception on this, but the fact is that all my high-risk, high-reward grant applications have been rejected (my more conservative grants also often get rejected, but at least sometimes they are funded). Some years ago I asked a well-known biogerontologist why his lab was doing a certain series of experiments that, while getting results and papers, seemed to beat around the bush of understanding aging. His answer was: "Because I've got a mortgage to pay."

Tuesday, June 18, 2013

Researchers involved in one of the very the early portions of drug discovery, in which as many types of molecule are tested as possible, have discovered a way to improve memory in mice:

Memory improved in mice injected with a small, drug-like molecule discovered [by] researchers studying how cells respond to biological stress. The memory-boosting chemical was singled out from among 100,000 chemicals screened at the Small Molecule Discovery Center at UCSF for their potential to perturb a protective biochemical pathway within cells that is activated when cells are unable to keep up with the need to fold proteins into their working forms.

The chemical acts within the cell beyond the biochemical pathway that activates this unfolded protein response, to more broadly impact what's known as the integrated stress response. In this response, several biochemical pathways converge on a single molecular lynchpin, a protein called eIF2 alpha. "Among other things, the inactivation of eIF2 alpha is a brake on memory consolidation." The chemical identified by the UCSF researchers is called ISRIB, which stands for integrated stress response inhibitor. ISRIB counters the effects of eIF2 alpha inactivation inside cells.

In one memory test included in the study, normal mice were able to relocate a submerged platform about three times faster after receiving injections of the potent chemical than mice that received sham injections. The mice that received the chemical also better remembered cues associated with unpleasant stimuli - the sort of fear conditioning that could help a mouse avoid being preyed upon. "It appears that the process of evolution has not optimized memory consolidation; otherwise I don't think we could have improved upon it the way we did in our study with normal, healthy mice."

Evolution has failed to optimize many individually desirable and arguably advantageous aspects of mouse biology, such as life span, for example. That tells us something about the details of the way in which natural selection operates.

Tuesday, June 18, 2013

Researchers are working on technology that is analogous to dialysis machines, but provides one of the functions of the spleen instead of the kidney. This sort of thing is a very early step on the road that eventually leads to machines capable of reproducing every necessary function of the body's major organs:

Taking advantage of recent advances in nanotechnology and microfluidics, researchers have made significant progress toward a device that could be used to rapidly remove pathogens from the blood of patients with sepsis, a potentially life-threatening condition that occurs when an infection is distributed throughout the body via the bloodstream. The new system effectively acts as an artificial spleen, filtering the blood using injectable magnetic nanobeads engineered to stick to microorganisms and toxins. After the beads are injected, blood is removed and run through a device that uses a magnetic-field gradient to extract the nanobead-bound germs. Then the blood is returned to the body.

[Researchers] looked to the human immune system - specifically, at a class of proteins in the blood that attach to potentially harmful microorganisms or toxins and mark them as targets for other immune cells. The group genetically engineered one such protein - known to bind to over 90 different pathogens, including bacteria, fungi, viruses, parasites, and toxins - so that it functions as a coating for magnetic nanobeads, giving them the ability to collect infectious agents in the bloodstream.

Following an injection of the beads, a patient's blood is run through an external device that contains a system of microfluidic channels, the design of which is inspired by the spleen. In the device, which the inventors call a "spleen-on-a-chip," contaminated blood flows through the channels alongside a saline solution. A magnetic-field gradient is then used to pull the nanobeads and their bound pathogens into that solution.

Wednesday, June 19, 2013

Neural plasticity is the ability of the brain to remodel and adapt, and one of the necessary mechanisms supporting this process is neurogenesis, the creation of new neurons. The practice of calorie restriction has been shown to slow the age-related decline in numerous mechanisms in the brain, which is to be expected since it slows near every measurable aspect of aging in the course of producing extended life in laboratory species.

Production of new neurons from stem cells is important for cognitive function, and the reduction of neurogenesis in the aging brain may contribute to the accumulation of age-related cognitive deficits. Restriction of calorie intake and prolonged treatment with rapamycin have been shown to extend the lifespan of animals and delay the onset of the age-related decline in tissue and organ function.

Using a reporter line in which neural stem and progenitor cells are marked by the expression of green fluorescent protein (GFP), we examined the effect of prolonged exposure to calorie restriction (CR) or rapamycin on hippocampal neural stem and progenitor cell proliferation in aging mice. We showed that CR increased the number of dividing cells in the dentate gyrus of female mice. The majority of these cells corresponded to nestin-GFP-expressing neural stem or progenitor cells; however, this increased proliferative activity of stem and progenitor cells did not result in a significant increase in the number of newborn neurons [with markers of precursor cells]. Our results suggest that restricted calorie intake may increase the number of divisions that neural stem and progenitor cells undergo in the aging brain of females.

Wednesday, June 19, 2013

Researchers here propose an interesting use for genetic data obtained from the many centenarians now known to the scientific community from past studies of genetics and longevity:

In the last ten years the scientific community has devoted a consistent effort to identify the genetic basis of the most common age-related diseases, as they represent one of the most important public health and socio-economical burden all over the world and particularly in Western Countries. This challenge was mainly faced up by genome wide association studies (GWASs) based on microarray technology that allows the simultaneous analyses of hundred thousands of single nucleotide polymorphisms (SNPs), within the framework of the "common variant common disease" theory.

So far, more than 1,000 published GWASs reported significant associations of ~4,000 SNPs for more than 200 traits/diseases. GWASs of age-related, chronic human diseases often suffer from a lack of power to detect modest effects, which can to some extent explain why the identified genetic effects comprise only a small fraction of the estimated trait heritability. These limitations can be overcome simply by ever increasing sample size in order to achieve the necessary statistical power to detect variants with small effects, which is not always feasible.

Here we propose an alternative approach of including healthy centenarians as a more homogeneous and extreme control group. As a proof of principle we focused on type 2 diabetes (T2D) and assessed genotypic associations of 31 SNPs associated with T2D, diabetes complications and metabolic diseases and SNPs of genes relevant for telomere stability and age-related diseases. We hypothesized that the frequencies of risk variants are inversely correlated with decreasing health and longevity. We performed association analyses comparing diabetic patients and non-diabetic controls followed by association analyses with extreme phenotypic groups (T2D patients with complications and centenarians). Results drew attention to rs7903146 (TCF7L2 gene) that showed a constant increase in the frequencies of risk genotype (TT) from centenarians to diabetic patients who developed macro-complications and the strongest genotypic association was detected when diabetic patients were compared to centenarians. We conclude that robust and biologically relevant associations can be obtained when extreme phenotypes, even with a small sample size, are compared.

Thursday, June 20, 2013

MicroRNA molecules are a part of the complex machinery of gene expression that builds proteins from the blueprints encoded in DNA. This machinery determines levels of specific proteins in a cell. By doing so it steers cell processes, and is in turn steered by the structures and activities of those proteins. A cell is an enormously intricate feedback loop.

Individual differences in longevity exist for entities living in very similar environments, and these differences have to arise from some collection of mechanisms - such as the differences in gene expression between individuals. Here researchers move from checking global gene expression levels to checking microRNA levels in much the same way: to see if they can find correlations between specific microRNA molecules and individual longevity. No amazing results yet, but these are early days:

In the round worm Caenorhabditis elegans, genetically identical animals exhibit large differences in their lifespan with associated declines in motor skills and pathogen resistance. We have previously shown that aging behavioral phenotypes in individual worms are associated with statistically significant changes in gene expression. We hypothesized that the distinct age dependent gene expression profiles that exist between genetically identical individuals are likely to be mediated through variations in gene regulatory networks. miRNAs represent likely candidates for mediating some of this variation in expression as they are known modulators of gene expression, which have been shown to act to facilitate the robustness of such networks.

We measured the abundance of 69 miRNAs expressed in individual animals at different ages [and] found that miRNA abundance was highly variable between individual worms raised under identical conditions and that expression variability generally increased with age. To identify expression differences associated with either reproductive or somatic tissues, we analyzed wild type and mutants that lacked germlines. miRNAs from the mir-35-41 cluster increased in abundance with age in wild type animals, but were nearly absent from mutants lacking a germline, suggesting their age-related increase originates from the germline. Most miRNAs with age-dependent levels did not have a major effect on lifespan, as corresponding deletion mutants exhibited wild-type lifespans. The major exception to this was mir-71, which increased in abundance with age and was required for normal longevity. Our genetic characterization indicates that mir-71 acts at least partly in parallel to insulin/IGF like signals to influence lifespan.

Thursday, June 20, 2013

There are a good number of genes with quirky names, and sonic hedgehog might not even be the quirkiest. Here researchers increase levels of the protein produced by this gene to roll back some of the loss of muscle regenerative capacity that occurs with aging:

Sonic hedgehog (Shh) is a morphogen regulating muscle development during embryogenesis. We have shown that the Shh pathway is postnatally recapitulated after injury and during regeneration of the adult skeletal muscle and regulates angiogenesis and myogenesis after muscle injury. Here, we demonstrate that in 18-month-old mice, there is a significant impairment of the upregulation of the Shh pathway that physiologically occurs in the young skeletal muscle after injury. Such impairment is even more pronounced in 24-month-old mice.

In old animals, intramuscular therapy with a plasmid encoding the human Shh gene increases the regenerative capacities of the injured muscle, in terms of Myf5-positive cells, regenerating myofibers, and fibrosis. At the molecular level, Shh treatment increases the upregulation of the prototypical growth factors, insulin-like growth factor-1 and vascular endothelial growth factor. These data demonstrate that Shh increases regeneration after injury in the muscle of 24-month-old mice and suggest that the manipulation of the Shh pathway may be useful for the treatment of muscular diseases associated with aging.

Friday, June 21, 2013

Research into sirtuins in relation to longevity has consumed a great deal of money over the past decade, more than enough to fully implement the Strategies for Engineered Negligible Senescence in mice, and yet there is very little to show for it aside from an increased knowledge of one small area of metabolism in a range of species. A drug to slightly slow the pace of aging in humans might yet result in the future, but if it does emerge then it is unlikely to provide greater benefit than, say, the practice of calorie restriction.

This is absolutely characteristic of present mainstream research into interventions in aging: expensive, slow, unlikely to produce results, and the plausible future outcomes if successful will be of limited benefit. Yet so much money has flowed into work on sirtuins that it has inertia now: research and attempts at development will continue until someone finds a way to shoehorn sirtuin activating drugs into a marginal therapy for something. This is a great pity: there are far better ways forward, more productive research plans for therapies to treat aging and age-related disease.

Here is a familiar refrain on sirtuins, nothing that we haven't heard before: a combination of interesting new details on metabolism relating to sirtuins and beating the drum with promises of future treatments under the implicit assumption of further funding for present research.

A gene called SIRT1, previously shown to protect against diseases of aging, plays a key role in controlling circadian rhythms. [Researchers] found that circadian function decays with aging in normal mice, and that boosting their SIRT1 levels in the brain could prevent this decay. Conversely, loss of SIRT1 function impairs circadian control in young mice, mimicking what happens in normal aging. Since the SIRT1 protein itself was found to decline with aging in the normal mice, the findings suggest that drugs that enhance SIRT1 activity in humans could have widespread health benefits. "If we could keep SIRT1 as active as possible as we get older, then we'd be able to retard aging in the central clock in the brain, and health benefits would radiate from that."

[Researchers] created genetically engineered mice that produce different amounts of SIRT1 in the brain. One group of mice had normal SIRT1 levels, another had no SIRT1, and two groups had extra SIRT1 - either twice or 10 times as much as normal. Mice lacking SIRT1 had slightly longer circadian cycles (23.9 hours) than normal mice (23.6 hours), and mice with a 10-fold increase in SIRT1 had shorter cycles (23.1 hours). In mice with normal SIRT1 levels, the researchers confirmed previous findings that when the 12-hour light/dark cycle is interrupted, younger mice readjust their circadian cycles much more easily than older ones. However, they showed for the first time that mice with extra SIRT1 do not suffer the same decline in circadian control as they age.

"I think we should look at every aspect of the machinery of the circadian clock in the brain, and any intervention that can maintain that machinery with aging ought to be good. One entry point would be SIRT1, because we've shown in mice that genetic maintenance of SIRT1 helps maintain circadian function." Some SIRT1 activators are now being tested against diabetes, inflammation and other diseases, but they are not designed to cross the blood-brain barrier and would likely not be able to reach the [suprachiasmatic nucleus that controls circadian cycles]. However, [researchers believe] it could be possible to design SIRT1 activators that can get into the brain.

Friday, June 21, 2013

The two extremes of theorizing on the process of aging might be seen as (a) arguing that aging is damage that causes metabolism to react, alter its processes, and ultimately fail, and (b) arguing that aging is a harmful programmed change in the operation of metabolism, the result of evolved processes that are beneficial in youth continuing past the point at which natural selection operates strongly and progressively becoming ever more damaging to the individual. The views held by researchers tend towards one side of the aisle or the other, largely favoring aging as damage, but it's not a black and white thing: it's perfectly possible to think that some portions of aging are spawned by damage while other portions are programmed, or that the answer is different in different species.

This paper leans towards the programmed side of the house in discussing GSK-3 in the context of the biology of aging. It's a study that only shows accelerated aging, however. This is always less convincing as an argument that a particular gene or protein is related to longevity because researchers can create what appears to be accelerated aging by breaking any number of important biological mechanisms so as to cause more damage and dysfunction in an organism. Very few of those changes can be turned in the opposite direction and shown to extend life, however - and extending life rather than shortening it is the crucial test of relevance:

Very few enzymes exert as broad a regulatory influence on cellular functions as do the two isoforms of GSK-3(α and β). The substrates that are phosphorylated by GSK-3s can be classified into four categories: metabolic enzymes, signaling molecules, structural proteins, and transcription factors, typically involved in regulating cell proliferation and differentiation; cellular metabolism, cell survival and cell cycle regulation. Additionally, GSK-3 has been linked to several chronic diseases, including diabetes and Alzheimer disease. Nevertheless, it was not clear whether GSK-3 might regulate aging.

Our recent work seems to clearly implicate GSK-3, and specifically the α isoform, in aging. Through targeting GSK-3α in the mouse, we found accelerated development of age-related pathologies in multiple organ systems. These included accelerated aging in the bone/skeletal system, leading to severe degenerative joint disease that was accompanied by increased inflammatory cytokines. The gut and liver also showed clear signs of accelerated aging. But the most striking findings were seen in the heart and skeletal muscle (i.e. striated muscle). These organ systems developed profound hypertrophy and dysfunction.

Notably, [we] saw innumerable structurally abnormal organelles, in particular (but not limited to) disrupted mitochondria. The profound nature of this suggested that the [mice] were unable to clear these damaged organelles, possibly implicating dysfunctional autophagy. We confirmed that [knockout] of GSK-3α markedly activated mTOR, and knowing that mTOR suppresses autophagy, we asked if autophagy was dysregulated. We confirmed that it was.

The key remaining question was whether this dysregulation of autophagy was leading to (or at least contributing to) the abnormalities of striated muscle. We employed a second generation inhibitor of mTORC1, everolimus, and found that both cardiac contractile abnormalities and skeletal muscle abnormalities were largely corrected. It remains to be seen whether the numerous other organ systems that we found to be dysfunctional in the absence of GSK-3α will also be corrected by mTORC1 inhibition.

I'd be inclined to read this as simply a confirmation that GSK-3 sits in the same general set of aging-related mechanisms as mTOR, and that autophagy, once again, is shown to be a very important aspect of health and longevity.


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