FIGHT AGING! NEWSLETTER
August 31st 2015
Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, 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.
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- Reporting on Rejuvenation Biotechnology 2015: Thymus Regeneration and Thoughts on Research Strategy
- The DRACO Fundraiser Site: killingsickness
- An Audio Interview with Aubrey de Grey and Brian Kennedy
- More Life, Less Severe Illness, but More Years of Illness
- A Few Recent Papers on Alzheimer's Disease
- Latest Headlines from Fight Aging!
- Generating Oligodendrocytes to Spur Remyelination
- Radiation Hormesis Studied in Flies
- A Look at Blastema Mechanisms in Zebrafish Regeneration
- Studies Show that Elite Athletes Live Longer
- Proposing a Mechanism to Explain the Association Between Type 2 Diabetes and Alzheimer's Disease
- GDF-11 and Myostatin Correlate with Heart Disease Outcomes
- Fatty Acids Correlate with Longevity in Bird Species
- Towards Cell Therapy as a Replacement for Liver Transplant
- Theorizing on Gene Network Stability and Aging
- A Recent Interview with Aubrey de Grey of the SENS Research Foundation
REPORTING ON REJUVENATION BIOTECHNOLOGY 2015: THYMUS REGENERATION AND THOUGHTS ON RESEARCH STRATEGY
To go along with a few posts from last week, here is a longer report from this year's Rejuvenation Biotechnology conference, hosted by the SENS Research Foundation. There are some interesting tidbits in the section on thymus regeneration, which is an approach to immune system rejuvenation that promises to be very helpful, even if not capable of solving all of the problems of the aging immune system in and of itself. A sizable component of the frailty of aging arises because the immune system becomes dysregulated and incompetent, its complement of cells capable of destroying pathogens reduced to very low levels, replaced by other types of immune cell that do little to help in this situation. Regeneration of the thymus is one of a number of possible ways to introduce much larger numbers of fresh new immune cells into an old body, thereby patching this problem to at least an initial degree:
Report from Rejuvenation Biotech 2015
Georg Hollander presented a cogent and enlightening exegesis of the thymus, from basic function to ongoing projects. The thymus is a small gland under the breastbone that is responsible for a crucial function of the immune system: training white blood cells (T-cells) to distinguish between self and other, so they can consistently attack the latter and spare the former. In adulthood, the thymus atrophies ("thymic involution"), and in old age there is almost no thymus left, with the disastrous result that T-cells not only fail to protect our bodies from invaders, but treat our bodies as the enemy, leading to autoimmunity. The training is performed by web-like epithelial cells, shaped like crumpled blankets, each epithelial cell in contact with up to 60 developing T-cells. Epithelial cells must express every single protein in the genome, and there is a transcription factor called AIRE that binds to DNA, promoting "promiscuous expression." Curiously, AIRE works best for genes that are normally turned off by methylation or acetylation. 15% of genes are expressed only in the presence of AIRE. There are microRNAs that are also necessary for promiscuous expression of all genes.
Hollander has been working on the hypothesis that each epithelial cell succeeds in programming only a random subset of the genome, so if you have fewer epithelial cells late in life, the cells collectively will not express every single gene in the body; there will be holes in the set of all genes represented in the thymus, and as a result there will be autoimmunity. He said we need a minimum 200-300 epithelial cells for a fully-functioning thymus that protects the body against itself.
At Wake Forest Inst, John Jackson is working on growing epithelial cells in a petri dish, then forming them on a scaffold, integrating blood vessels (vascularization) and structural (stromal) cells. His intern Blake Johnson made remarkable progress in a single summer toward creating a functional mouse thymus. Mice (like other small animals) have much larger thymi in relation to body size; and (like humans), they lose most of their thymic volume over their short lifetimes, with the result that their immune systems are disabled and they are vulnerable especially to cancer.
FOXN1 may be a key to reactivating the tired thymus. Greg Fahy of 21st Century Medicine is conducting a tiny clinical trial in the coming year, using growth hormone and other blood factors to regrow the thymus in people 50-65 yo. (Enrollment is closed; they are not seeking test subjects.)
The author here is more or less on the other side of what I consider to be a very important divide in how best to approach longevity research. I'd separate the research world between those who want to alter the operation of metabolism to make the damage of aging accrue more slowly, which is roughly the current mainstream, and those who want to leave metabolism working exactly as it is but periodically repair the damage. I favor the latter approach, the author the former.
To me attempts to rebuild a new state for the operation of cellular metabolism, while ensuring it to be safe and effective, looks both very hard and very expensive. We can look back at the the vast sums of money and years of work poured into efforts to make some headway, and with very little to show for it other than a massive increase in the size of databases and the scope of what is yet to be understood. Metabolism is fantastically complicated. It is still the case that researchers cannot definitively explain how the most reliable intervention to slow aging actually works: a full accounting of how calorie restriction improves health and extends life still lies somewhere in the future. Billions have been spent on attempts to understand and replicate these effects, and yet even if successful a calorie restriction mimetic drug far better than all of the possible candidates touted today will still have only modest effects on human life span.
The repair approach on the other hand is unbounded in its potential benefits. Repair well enough and aging can be reversed or indefinitely postponed: your only limit is the effectiveness of the technology. This is still the disruptive minority interest in the field, but I predict that change lies ahead as research programs following this path produce much larger and more reliable benefits to health and longevity than are achieved through the traditional drug discovery process when applied to aging. We have seen the first steps on this path of late in the form of senescent cell clearance and progress towards clinical implementation of allotopic expression to work around mitochondrial DNA damage.
Obviously there are no clear cut lines in life, and grey areas abound in a field this complex. The author's terminology is useful, I think, though I differ on which path is the better one. It seems to me that some significant forms of damage in the aging body cannot be repaired by the biochemistry we have, no matter what signals we issue to change cell behavior, such as some forms of cross-link that degrade tissue structure and elasticity:
Very broadly, there are two approaches to anti-aging medicine, which might be called "bioengineering" and "endocrinology". The question is, how much of the change that takes place with age can the body reverse with its internal resources, given the appropriate chemical signals (that's endocrinology)? And how much remains that must be rebuilt or replaced with prosthetics (bioengineering)? From the beginning, SENS has emphasized the bioengineering approach - its middle name is "engineering". I am more optimistic about what the body might be able to do on its own, if only we can master its biochemical language.
Significant advances have been made in bioengineering in the 15 year history of SENS. A prosthetic limb no longer needs to be a peg leg, but can be designed to respond to neural signals. Prosthetic eyes and ears have come down from the clouds into the realm of the feasible. The first organs grown cell-by-cell on scaffolds in the lab have been re-implanted successfully in human patients.
But even more stunning and promising breakthroughs have appeared in the realm of chemical signaling. In 2000, before the Bush Ban, all stem cell research depended on embryonic stem cells harvested from foetal tissue; but turning muscle or skin cells back into stem cells has turned out to be surprisingly easy (though the process is still being refined). "Epigenetics" was an abstract noun in 2000, and it is now the fastest-growing area of biological science. Epigenetic signaling may be the organizing principle of whole-body aging. Signal proteins have been identified that turn on whole systems of genes that retard aging. Better yet, pathways that promote inflammation (e.g. TGF-β, NFkB) can be blocked, while some blood factors turn on regenerative pathways, with the promise of rejuvenation.
THE DRACO FUNDRAISER SITE: KILLINGSICKNESS
This is a year of much grassroots fundraising for longevity science, it seems, with more new projects launched and more new faces joining the community of supporters. All of these developments are collectively, hopefully, yet another sign that faster growth and more publicity are yet to come: the tipping point for public acceptance of efforts to treat aging as a medical condition is somewhere near, just around the corner. Ten years from now, people will conveniently forget that they were ever opposed to the development of therapies for aging. How silly that would be, like opposing cancer research or heart disease treatments, like self-sabotage. Who would think such a thing?
Here at Fight Aging! we're preparing to launch our 2015 SENS rejuvenation research fundraiser on October 1st, which coincidentally is also Longevity Day and the International Day of Older Persons. The crowdfunding site Lifespan.io launched recently, and their first project is a part of the SENS research programs aimed at bypassing mitochondrial DNA damage so as to remove that contributing cause of degenerative aging. Drop by and give them a few dollars: it's just the starting point for that team of crowdfunding developers, and I expect to see interesting things from them in the years ahead.
Similarly, a fundraising effort is presently coming together with the aim of raising philanthropic donations for development of the anti-virus technology DRACO. This is an approach that can be applied to near any virus in mammals, as it targets cells in which viruses are replicating rather than the viral particles themselves. DRACO has been featured at SENS conferences in the past, and is an excellent example of a technology that is too radically different from the present status quo to have an easy time in fundraising, even when backed by studies that would be more than enough to raise money were the results produced by the output of the standard drug discovery process.
Hence the work of a small group of volunteers putting together initiatives like killingsickness, and aiming at starting a crowdfunding campaign starting on October 1st this year. It's a busy time.
As you already know, DRACOs research and development may lead to a cure for virtually all viruses. More importantly, DRACOs may end suffering and save millions of lives! Unfortunately, this has received only limited funding to date and so DRACOs research and development will only happen with your help! We will launch an IndieGoGo campaign October 1, 2015 and we hope you will donate. We do know you have a lot questions first, and we want to answer them! To that point, please comment with your key questions and we will develop and post an FAQ's here and on the IndieGoGo campaign page.
The DRACO approach and results have been called "visionary" by the White House and named one of the best inventions of the year by Time magazine. However, research on DRACO has entered the well-known "Valley of Death," in which a lack of funding prevents DRACO and many other promising new drugs from being developed further and advancing toward human medical trials. With your help, we would like to raise enough funding to help DRACO successfully pass through the Valley of Death and advance toward human trials.
In cell culture, DRACO is reported to have broad-spectrum efficacy against many infectious viruses, including Marburg marburgvirus and Zaire ebolavirus, dengue flavivirus, Amapari and Tacaribe arenavirus, Guama bunyavirus, H1N1 influenza and rhinovirus. Although DRACOs have not yet been tested against other viruses, their broad-spectrum activity may mean that they might also be effective against HIV, HSV (cold sores and genital herpes), herpes zoster virus (chickenpox/shingles), HTLV, Ebola, MERS, SARS, avian influenza (bird flu), and other major viruses. DRACOs might be effective against viruses that are currently untreatable, or that can currently only be controlled but not cured by existing drugs. Because of their broad-spectrum activity, DRACOs might be useful in treating viruses that have become resistant to existing antiviral drugs, or even in promptly treating outbreaks of newly emerged viruses (like MERS).
Looking beyond the consideration of this one technology, and this effort to bypass the issues afflicting funding of early stage research, I see this and other similar efforts as representative of an ongoing and important change in the research ecosystem. The falling cost of communication, still on its way down towards the vicinity of zero, is fundamentally changing all aspects of human interaction and collaboration. The need for organizations to act as middlemen in funding the least costly, most risky, and earliest stage research is evaporating: the people with the interest and incentive to fund this work can collaborate among themselves, talk to the researchers directly, and set up their own fundraising efforts.
All of this produces a much greater incentive to educate ourselves about research and medicine, so as to better pick the winners, and to be able to make a difference to our own futures. It is the same incentive as drives us to understand diet and exercise. That incentive will play out over the next decade or two to produce a funding landscape, a dynamic interaction between laboratory staff, researchers, and the public, that is very different from what we see today - at least in the areas that really matter to the pace of progress, which is to say the innovation that occurs in early stage research that is very hard to fund adequately through traditional channels.
AN AUDIO INTERVIEW WITH AUBREY DE GREY AND BRIAN KENNEDY
Here I'll point out a twenty minute podcast interview with Aubrey de Grey of the SENS Research Foundation and Brian Kennedy of the Buck Institute for Research on Aging. This was recorded at the recent Rejuvenation Biotechnology 2015 conference, hosted by the SENS Research Foundation in the Bay Area, where both institutions are based. The SENS Research Foundation remains perhaps the world's only organization focused wholly on developing the fundamental biotechnologies needed for near future rejuvenation therapies capable of actually reversing the course of aging. A little of the work taking place at the Buck Institute is funded in part by the SENS Research Foundation, such as the research programs in the Campisi Lab aiming at the end goal of senescent cell clearance therapies, but for the most part the Buck Institute funds much more modest and mainstream goals in aging research, meaning attempts to slightly slow the aging process through traditional approaches of investigating cellular metabolism and drug discovery.
Brian Kennedy and Aubrey de Grey on their Converging Approaches to Aging Research
Last week we attended the 2015 Rejuvenation Biotechnology Conference where we heard about the latest developments in aging research. We were fortunate enough to sit down with two of the major figures in the field of aging research, Aubrey de Grey, CSO of the SENS Research Foundation and Brian Kennedy, CEO of the Buck Institute for Research on Aging. Brian and Aubrey gone about their work in different ways but say that their approaches are now converging as the momentum behind aging research increases. How do the two see the field since Calico and Human Longevity emerged? What developments in the past year stand out to them? Join us for an exclusive interview with two of the aging field's visionary leaders.
I put in a fair attempt to extract coherent text from the audio via software, but it wasn't on the cards today, or at least not via the standard recourse of feeding it to CMU Sphinx. If anyone else has better luck, let me know. In the meanwhile, here is a transcription of the middle of the interview, which might be of more interest to those of you who have followed the evolution of SENS since the early days.
Moderator: Let's try to hone in on the difference between you two and your view of aging, and what should be done. I mean, you know each other, so maybe you could just speak up.
AdG: Ok, well, so the big thing, the big innovation that I introduced fifteen years ago was the idea that we might actually find it easier in the long run to postpone substantially the ill-health of old age in human beings by not slowing down the rate at which the body creates damage to itself as a side-effect of normal metabolic processes, but rather by periodically repairing that damage after it has been created - but of course before it gets to a level that is so bad for us that we start going downhill.
Moderator: Ok, so one focused on repair...
Aubrey: That's right, that was the idea I brought forward. And the basis for that idea came, in large part, from areas of biology that had never previously been associated with the biology of aging. So that meant of course that the people who were working in the biology of aging were completely unfamiliar with those areas. It took a long time for me to actually make that case, and only because I had to bring together a lot of scientists who had never talked to one another before, and generally get people to pay attention to areas of biology that they had previously thought were not relevant to their work.
Brian: I think there has been some convergence on our end from the point of view that we've been following the genetics of aging, and have identified a lot of genes that impact the aging process. It seems clear that while some of them may prevent the onset of damage, a lot of them can actually induce repair mechanisms to clean up the damage that exists. So I think that at least superficially there was a significant difference in what we were saying ten years ago - and in reality there was some difference too - but there has been a lot of convergence on both sides so that I doubt that our messages are all that much different now.
Aubrey: Right, I think that a lot of the differences were more perceived and not so real, and I think the mutual education that has gone on in the meantime has clarified that, and besides there isn't all that much difference in terms of the emphasis that goes on. But I think it is also very important to note that one thing where convergence has been extremely strong is not so much on the science, but on the communication of the science. I think that now that everybody in the field is comfortable with saying that aging is really actually quite bad for you and we ought to try and do something about it...
Moderator: And that it's modifiable.
Aubrey: Yes, and that we can do something about it, that's right. Now we all really speaking from the same hymn sheet, even that actual sort of words we're using here are converging. Brian gave an example today, in that he's talking of longevity as a side-effect of good health, and that's exactly the same thing that I've been saying.
Moderator: There is a big difference in the accents. Now how did you two meet?
Brian: It was certainly at the aging meetings, and we met at one of them.
Aubrey: The biogerontology community is actually pretty small, even now, and it was smaller ten years, twenty years ago.
Moderator: So you met ten years ago?
Aubrey de Grey: At least fifteen, I would say.
Brian: Yes, probably right.
Moderator: So was that like, wow somebody else gets it, or?
Brian: I think that there was a period where we had to get comfortable with each other. Speaking my side from the field as a whole, I think that Aubrey's message was... there was a lot of insight, and also it was also more aggressive than we were used to, so at the time we had to figure out how to deal with each other.
Moderator: Did that make you kind of bolster up, get some more courage?
Brian: It created different responses in different people in the field, but what I think is that we need multiple voices - there's no reason that the field should be speaking with only one voice. When you have different ideas and you have some people that are more grounded in saying "this is what the data has already shown" and other people that are more visionary I think it is good.
Aubrey: All that is certainly true, I agree with all of that. I think one thing that made it difficult for me to find common ground, common rhetorical ground especially, with the community back then, was something that I have been calling longevity sticker shock. Specifically that if I'm right about the science, that actually the most promising approach to postponing the ill health of old age consists of periodic preventative repair, repairing damage rather than slowing down the creation of damage, then what that implies for longevity is rather dramatically different. Slowing down the accumulation of damage, you'll get a modest increase in longevity, and that increase will be less if you start later. But if you are repairing damage every so often then you are buying time much more effectively. I pointed out way back in 2003 or 2004 that this led to a concept I call longevity escape velocity, that via really very imperfect but improving treatments one might be able to stay indefinitely ahead of the process of aging by keeping damage below pathogenic levels. This of course implies that the longevity consequences would be very dramatic. I, perhaps slightly naively, pointed this out and said, look, it's perfectly reasonable to think that there are people alive today who will live to a thousand, because that's how long you would live if you just didn't have an increased risk of death per year as we do today. And a lot people ran away very rapidly, shall we say.
Brian: Yes, it was the number. I think that at the time, that message appealed to a very small segment of the population, of which there were prominent people who were good to appeal to, but the public didn't understand enough to get to the point of your message, I think.
Aubrey: That's right, yes.
Moderator: And that's changed?
Brian: I think, well, I still don't go around talking about escape velocity. I think it is an interesting concept, but I represent a very large institute conducting NIH-funded research, and what I saying is that I don't know what is possible in the future, but I know what is possible in the short term. If we can start extending healthspan using strategies that we are developing today, the benefits of that are huge. The long-term consequences we just don't know; it could be that you're right, but I want to get those first incremental steps so that we can really get everyone excited about the approach.
Aubrey: You touched on a really important point at the beginning of that answer, which was the funding sources. When I started talking in those terms, I started getting the attention of people who wouldn't dream of funding someone like Brian because Brian's too...he's not aiming high enough, in their view. People like Peter Thiel, for example, they just want to live forever and that's that. So when I come along and I explain longevity escape velocity, they'll say "that sounds like what I want to deal with," whereas conversely, as Brian points out, if he starts talking like that in grant applications to the NIH, it isn't going to be good for his chances.
Moderator: What response have both of you had to the entrance of Calico, the Google company, and Human Longevity, Craig Venter's new company?
Aubrey: It's a complicated question. I'll talk about Human Longevity first. In my opinion they are not really working on what we're working on. They are working on personalized medicine, trying to optimize therapies that essentially already exist using analysis of large amounts of genetic data.
Moderator: So a similar company to other companies that are out there, with a fancier name?
Aubrey: I would say that definitely their hearts are in the right place, but they are a regular, perfectly normal company. They want to make profits fairly soon. Calico have set themselves up as a completely unusual company with the goal of doing something very long-term, however long it takes, they want to actually fix aging. They said so - Larry Page was perfectly clear about that. The question is how are they going about it, and that's getting really interesting. The first thing that they've done, which I feel is an absolutely spectacularly good move, is to bifurcate their work into a relatively short-term track and a long-term track. The short term track involves drug discovery for age-related diseases, doing deals with big companies like Abbvie, and so on. That's all very wonderful and all very lucrative in the relatively short term, and has more or less nothing to do with the mission for which Calico was set up - but it is a fabulous way to insulate the stuff that they do that is to do with why Calico was set up from shareholder pressure. It gets a little more complicated though. So then on the long term side, the stuff being led by David Botstein and Cynthia Kenyon, the question is how are they going about their mission. Of course an awful lot of this unknown because they are a secretive company, but from the perspective of whom they are hiring, and what kinds of work those people have done in the past, one can certainly say that they are not just focusing on one approach. They are interested in diversity. My only real concern is that they may be emphasizing a curiosity-driven long term exploratory approach to an unnecessary degree. I'm all for finding out more and more about aging, but I'm also all for using what we've already found out to the best of our ability to try stuff and see what we can do. I should emphasize that this is only my impression from a very limited amount of information available, but my impression is that it is perhaps turning into an excessively curiosity-driven, excessively basic science, inadequately translational outfit. And that's kind of what I feared when Botstein came along in the first place, because he's on record as saying he doesn't have a translational bone in his body. Now Brian could obviously say a lot more if he wants to, as he's done a deal with Calico.
Brian: Let me start by saying that I think its great that these big companies are getting into the game. Almost no matter what happens that is going to help the field get more people, more private sector people involved, maybe get Big Pharma involved, and so I think it is a good thing. I can't say too much about Calico because we have a relationship with them, but I will say that I think it is an interesting challenge when all of a sudden a lot of money is on the table, and very good people are hired to say "go solve this problem," and they haven't been thinking about that problem until a month ago. So I think what we're going to see with Calico is that they're going to continue to evolve as they go forward, and I think it will be very interesting to see the kinds of stuff they choose to do, and it may be very different two years or three years from now.
Moderator: You were saying in the panel we were just at that you thought it was a game-changer.
Brian: I think it adds great momentum, and I think it will be equally important to really get Big Pharma to get into this game too. It is easy to say you've got a ton of money, but what is a ton of money? If you're going to start doing real clinical trials, phase III clinical trials, it takes more than a ton of money; Big Pharma has to come in. Getting Abbvie involved is a good step, but it would also be good if everyone else starts saying this is the place to be.
MORE LIFE, LESS SEVERE ILLNESS, BUT MORE YEARS OF ILLNESS
Global trends in life expectancy, at birth, at 30, and at 60, continue onward and upward at a fairly slow but steady pace: approximately two years every decade for life expectancy at birth and a year every decade for remaining life expectancy at 60. The research linked below crunches the numbers for the much of the world from 1990 to 2013, an extension of similar past studies to include more recent data. The authors show that lives are longer and age-related illness less severe, but the period of time spent in disability or illness has grown.
We are machines. Very complex machines, but nonetheless collections of matter subject to the same physical and statistical laws regarding component failure and damage as a car or an electronic device. Aging is damage, and a substantial portion of the trend in life extension is caused by an incidental, unintentional slowing of the pace at which that damage accrues. This slowing results from diverse causes, including control of infectious disease and reduction of the life-long burden imposed by infection, increased wealth and consequently greater access to medical care of all types, and an improved capacity to treat age-related medical conditions as they emerge. None of this is aimed at aging per se, and the historical trend in rising life expectancy has been slow precisely because there has been neither the ability nor the attempt to meaningfully intervene in the aging process.
What happens when you slow down the pace at which damage accumulates in a machine? You extend all the phases of its life span, both fully functional and in decline. At a given age its average level of dysfunction is lower than it would otherwise have been and it lasts longer as a result - but that also means it is spending more time with at least some dsyfunction before finally failing. The story should be little different for us, which is why I've long been fairly skeptical of the concept of compression of morbidity, wherein some factions of the research community suggest it should be possible to engineer a long period of good health followed by a rapid decline. In their defense, there are species, such as naked mole rats and salmon, that have exactly this shape to their lives, so it is clearly possible in principle. But in humans, with the way we work, intervention in aging means slowing down or repairing the damage, and slowing it down has this outcome of a longer period of a slower decline.
The future of health and longevity will look nothing like the past, however. The trend will not continue: it will leap to the upside in a much faster gain in longevity. This is because are now entering a transitional period in which researchers aim at the deliberate treatment of the mechanisms of aging, the underlying cause of age-related disease, rather than continuing expensive and ultimately futile efforts to patch over disease symptoms and proximate mechanisms. This is a night and day change in the entire approach to medicine, and upsets many regulatory frameworks and established business models, which means it has taken time and a lot of effort to get to the point at which enough people are on board to make it happen. We are close to the tipping point these days, but the vast majority of the money and the research community remains stuck in the past, working on strategies in medicine for age-related conditions that are now outmoded. Change is painfully slow in heavily regulated fields like medicine, and I expect that this transitional period will continue well past the point at which the first partial rejuvenation treatments are proven in the clinic, such as senescent cell clearance.
If we want to see the trends change, and the slowly lengthening period of slowly lessening disability be replaced by sudden leaps in life expectancy, accompanied by outright cures for many age-related conditions, then we have to make repair of the damage of aging a priority. Not merely slowing down the pace at which that damage accumulates as a side-effect of the operation of normal metabolism, but creating targeted biotechnologies capable of deliberate repair of the points of failure. More than enough is known today in order to do this, it is just a matter of finding the money and the will to proceed.
Life expectancy climbs worldwide but people spend more years living with illness and disability
Global life expectancy has risen by more than six years since 1990 as healthy life expectancy grows; ischemic heart disease, lower respiratory infections, and stroke cause the most health loss around the world. People around the world are living longer, even in some of the poorest countries, but a complex mix of fatal and nonfatal ailments causes a tremendous amount of health loss, according to a new analysis of all major diseases and injuries in 188 countries. Global life expectancy at birth for both sexes rose by 6.2 years (from 65.3 in 1990 to 71.5 in 2013), while healthy life expectancy, or HALE, at birth rose by 5.4 years (from 56.9 in 1990 to 62.3 in 2013).
The study's researchers use DALYs, or disability-adjusted life years, to compare the health of different populations and health conditions across time. One DALY equals one lost year of healthy life and is measured by the sum of years of life lost to early death and years lived with disability. The leading global causes of health loss, as measured by DALYs, in 2013 were ischemic heart disease, lower respiratory infections, stroke, low back and neck pain, and road injuries. For communicable, maternal, neonatal, and nutritional disorders, global DALY numbers and age-standardized rates declined between 1990 and 2013. While the number of DALYs for non-communicable diseases have increased during this period, age-standardized rates have declined. The number of DALYs due to communicable, maternal, neonatal, and nutritional disorders has declined steadily, from 1.19 billion in 1990 to 769.3 million in 2013, while DALYs from non-communicable diseases have increased steadily, rising from 1.08 billion to 1.43 billion over the same period.
Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: quantifying the epidemiological transition
The Global Burden of Disease Study 2013 (GBD 2013) aims to bring together all available epidemiological data using a coherent measurement framework, standardised estimation methods, and transparent data sources to enable comparisons of health loss over time and across causes, age-sex groups, and countries. The GBD can be used to generate summary measures such as disability-adjusted life-years (DALYs) and healthy life expectancy (HALE) that make possible comparative assessments of broad epidemiological patterns across countries and time. We used the published GBD 2013 data for age-specific mortality, years of life lost due to premature mortality (YLLs), and years lived with disability (YLDs) to calculate DALYs and HALE for 1990, 1995, 2000, 2005, 2010, and 2013 for 188 countries.
Sociodemographic status explained more than 50% of the variance between countries and over time for diarrhoea, lower respiratory infections, and other common infectious diseases; maternal disorders; neonatal disorders; nutritional deficiencies; other communicable, maternal, neonatal, and nutritional diseases; musculoskeletal disorders; and other non-communicable diseases. However, sociodemographic status explained less than 10% of the variance in DALY rates for cardiovascular diseases; chronic respiratory diseases; cirrhosis; diabetes, urogenital, blood, and endocrine diseases; unintentional injuries; and self-harm and interpersonal violence. Predictably, increased sociodemographic status was associated with a shift in burden from YLLs to YLDs, driven by declines in YLLs and increases in YLDs from musculoskeletal disorders, neurological disorders, and mental and substance use disorders. In most country-specific estimates, the increase in life expectancy was greater than that in HALE. Leading causes of DALYs are highly variable across countries.
A FEW RECENT PAPERS ON ALZHEIMER'S DISEASE
Here you'll find links to a selection of recent papers on Alzheimer's disease with no particular central thesis: merely a sampling of representative research results. Alzheimer's research is as much investigation of cellular metabolism and the biochemistry of the brain as it is research into the disease itself. Scientists strive to understand everything that might put the mechanisms of disease development into context. Our neural biochemistry is enormously complex, and thus so is any form of dysfunction in the many interacting systems of the brain. Since there is still so much blank space still left on the comprehensive map of human biochemistry, there are many competing theories to explain the development and pathology of Alzheimer's disease (AD), in part or in whole. Theories proliferate in times of uncertainty, and since therapies emerging from the dominant branch of theories based on amyloid accumulation are still in search of meaningful results, there is plenty of room for heresy, hypothesis, and debate.
It is perhaps ironic that aging has such simple and well-cataloged roots, a few forms of cell and tissue damage that occur as a result of the normal operation of metabolism, and yet the research community spends all of its time working backwards from enormously complicated end states of diseases, where a great deal of time and money are required to make even modest advances in understanding. This makes more sense if one assumes that the goal is less one of treatment and more one of understanding human biochemistry: Alzheimer's disease is the narrow end of the wedge to obtain funding to develop that understanding. That may be part of the problem, that the incentives and the goals for much of the research establishment are not necessarily aligned with rapid progress towards effective treatments. The output of traditional investigation followed by drug discovery is almost entirely marginal treatments that tinker with some aspect of cellular behavior in the late-stage disease process, a far cry from the most effective approach of tackling root causes.
Yet at the same time Alzheimer's research is actually one of the few fields where it is possible to say that at least some within the community work on ways to attack fundamental forms of damage, in the form of amyloid clearance. With enough money and enough different competing research groups, someone somewhere will be close to doing the right thing. Clearance of amyloid is a capability that will be needed for rejuvenation therapies, since the presence of amyloid is a distinguishing difference between old tissues and young tissues. A robust way to clear amyloid in Alzheimer's should require little work to adapt to other forms of amyloid in the body, at which point we might start to see a greater understanding developed as to exactly how and why these deposits contribute to degenerative aging. The fastest way to enlightenment and practical results is often to remove the potential cause of a problem, rather than to keep analyzing the system as it is.
The papers below are illustrative of these points, being representative of several types of output generated by the Alzheimer's research community. Theories abound, as do suggested forms of compensatory treatment, and books can be written to provide an overview of even just aspects of Alzheimer's development in the full context of how the brain works. It is a very complicated business, and some of the approaches to treating Alzheimer's patients are now more than a decade old, still gathering data in search of any benefit.
Nerve Growth Factor Gene Therapy - Activation of Neuronal Responses in Alzheimer Disease
In 2001, we initiated a clinical trial of nerve growth factor (NGF) gene therapy in AD, the first effort at gene delivery in an adult neurodegenerative disorder. This program aimed to determine whether a nervous system growth factor prevents or reduces cholinergic neuronal degeneration in patients with AD. We present postmortem findings in 10 patients with survival times ranging from 1 to 10 years after treatment.
Among 10 patients, degenerating neurons in the AD brain responded to NGF. All patients exhibited a trophic response to NGF in the form of axonal sprouting toward the NGF source. Comparing treated and nontreated sides of the brain in 3 patients who underwent unilateral gene transfer, cholinergic neuronal hypertrophy occurred on the NGF-treated side. Activation of cellular signaling and functional markers was present in 2 patients who underwent adeno-associated viral vectors-mediated NGF gene transfer. Neurons exhibiting tau pathology and neurons free of tau expressed NGF, indicating that degenerating cells can be infected with therapeutic genes, with resultant activation of cell signaling. No adverse pathological effects related to NGF were observed.
These findings indicate that neurons of the degenerating brain retain the ability to respond to growth factors with axonal sprouting, cell hypertrophy, and activation of functional markers. Sprouting induced by NGF persists for 10 years after gene transfer. Growth factor therapy appears safe over extended periods and merits continued testing as a means of treating neurodegenerative disorders.
Aberrant Lipid Metabolism in the Forebrain Niche Suppresses Adult Neural Stem Cell Proliferation in an Animal Model of Alzheimer's Disease
Lipid metabolism is fundamental for brain development and function, but its roles in normal and pathological neural stem cell (NSC) regulation remain largely unexplored. Here, we uncover a fatty acid-mediated mechanism suppressing endogenous NSC activity in Alzheimer's disease (AD). We found that postmortem AD brains and triple-transgenic Alzheimer's disease (3xTg-AD) mice accumulate neutral lipids within ependymal cells, the main support cell of the forebrain NSC niche. Mass spectrometry and microarray analyses identified these lipids as oleic acid-enriched triglycerides that originate from niche-derived rather than peripheral lipid metabolism defects.
In wild-type mice, locally increasing oleic acid was sufficient to recapitulate the AD-associated ependymal triglyceride phenotype and inhibit NSC proliferation. Moreover, inhibiting the rate-limiting enzyme of oleic acid synthesis rescued proliferative defects in both adult neurogenic niches of 3xTg-AD mice. These studies support a pathogenic mechanism whereby AD-induced perturbation of niche fatty acid metabolism suppresses the homeostatic and regenerative functions of NSCs.
Vascular dysfunction in the pathogenesis of Alzheimer's disease - A review of endothelium-mediated mechanisms and ensuing vicious circles
Despite considerable research effort, the pathogenesis of late-onset AD remains unclear. Substantial evidence suggests that the neurodegenerative process is initiated by chronic cerebral hypoperfusion (CCH) caused by aging and cardiovascular conditions. CCH causes reduced oxygen, glucose and other nutrient supply to the brain, with direct damage not only to parenchymal cells, but also to the blood-brain barrier (BBB), a key mediator of cerebral homeostasis. BBB dysfunction mediates the indirect neurotoxic effects of CCH by promoting oxidative stress, inflammation, paracellular permeability, and dysregulation of nitric oxide, a key regulator of regional blood flow. As such, BBB dysfunction mediates a vicious circle in which cerebral perfusion is reduced further and the neurodegenerative process is accelerated. Endothelial interaction with pericytes and astrocytes could also play a role in the process. Reciprocal interactions between vascular dysfunction and neurodegeneration could further contribute to the development of the disease.
The Role of Oxidative Damage in the Pathogenesis and Progression of Alzheimer's Disease and Vascular Dementia
Oxidative stress (OS) has been demonstrated to be involved in the pathogenesis of the two major types of dementia: Alzheimer's disease (AD) and vascular dementia (VaD). Evidence of OS and OS-related damage in AD is largely reported in the literature. Moreover, OS is not only linked to VaD, but also to all its risk factors. Several researches have been conducted in order to investigate whether antioxidant therapy exerts a role in the prevention and treatment of AD and VaD. Another research field is that pertaining to the heat shock proteins (Hsps), that has provided promising findings. However, the role of OS antioxidant defence system and more generally stress responses is very complex. Hence, research on this topic should be improved in order to reach further knowledge and discover new therapeutic strategies to face a disorder with such a high burden which is dementia.
Relationships Between Mitochondria and Neuroinflammation: Implications for Alzheimer's Disease
Mitochondrial dysfunction and neuroinflammation occur in Alzheimer's disease (AD). The causes of these pathologic lesions remain uncertain, but links between these phenomena are increasingly recognized. In this review, we discuss data that indicate mitochondria or mitochondrial components may contribute to neuroinflammation. While, mitochondrial dysfunction could cause neuroinflammation, neuroinflammation could also cause mitochondrial dysfunction. However, based on the systemic nature of AD mitochondrial dysfunction as well as data from experiments we discuss, the former possibility is perhaps more likely. If correct, then manipulation of mitochondria, either directly or through manipulations of bioenergetic pathways, could prove effective in reducing metabolic dysfunction and neuroinflammation in AD patients. We also review some potential approaches through which such manipulations may be achieved.
LATEST HEADLINES FROM FIGHT AGING!
GENERATING OLIGODENDROCYTES TO SPUR REMYELINATION
Monday, August 24, 2015
Researchers here investigate a way to generate more oligodendrocytes in the brain, the cells responsible for creating the myelin sheathing essential to correct function of the nervous system. The presence of more of these cells improves the pace of myelin generation, which may form the basis for therapies to treat the medical conditions that involve accelerated loss of myelin. It is also the case that some loss of myelin maintenance will occur for all of us in old age due to growing cellular dysfunction and damage. This likely contributes to cognitive decline and other manifestations of old age, so it is worth keeping any eye on the development of potential treatments in this area.
Scientists found that deleting from the adult brain a protein necessary for early development actually fosters the growth of cells that generate myelin, the important protective coating neurons need to function. The research on lab animals provides new insight into how critical brain cells are generated. The finding may lead to improved treatments for brain injury, demyelinating diseases, certain developmental diseases and brain tumors. Researchers studied Nuclear Factor I X (NFIX), a transcription factor - a protein that turns genes on and off. NFIX is required for normal development of the early brain and it's known that losing NFIX before birth results in a number of rare human diseases, characterized by severe developmental and physiological defects. However, the new study shows that the loss of NFIX is necessary at a certain point in order for some brain cells to develop normally.
Oligodendrocytes surround neurons, which transmit electrical signals in the brain, protecting them from damage and speeding the transmission of those signals. The research shows that as neural stem cells differentiate into oligodendrocytes, the expression of NFIX decreases, apparently an essential step in the normal formation of the myelin-making cells. "In terms of a treatment, this could lead to the development of a small molecule that could be used to shut off NFIX activity in MS patients, thus promoting the growth of more oligodendrocytes." This study and previous ones have found that loss of NFIX could also increase the growth of adult neural stem cells, which, in turn, generate new neurons in adult animals. "This could also help us find ways to stimulate new neuron production in diseases where neurons die, such as in Alzheimer's and Parkinson's diseases and in spinal cord injury." The researchers' next step is to learn which genes are regulated by NFIX, and the best way to promote this increase in both oligodendrocytes and neural stem cells.
RADIATION HORMESIS STUDIED IN FLIES
Monday, August 24, 2015
Hormesis is the process whereby a little damage leads to a lasting increase in the activities of cellular repair mechanisms, with the outcome of a net gain in systems integrity and function. Hormesis is involved in a majority of the interventions shown to modestly slow aging in at least some short-lived species, such as low level radiation treatment. Here researchers add to the data on radiation hormesis and life span in flies, showing life extension of 3% to 7% that varied by gender but, perhaps surprisingly, not by dose:
Although there are many common mechanisms of response of organism and cell to irradiation and other stresses (thermal, oxidative, etc.), their principal difference is a significant role of DNA damage on the biological effects of ionizing radiation. However, these differences are attributed mostly to high dose rates. In the case of low dose radiation, direct effects of irradiation such as clustered DNA damage and DNA double strand breaks are minimal, whereas indirect DNA damages caused by the induction of reactive oxygen species become the primary result. In high doses, adverse effects accumulate in the tissues in a deterministic manner that depends linearly on the dose, but in low doses the effects are stochastic, non-linear on the dose, and depend mainly on the efficiency of the stress response's protective mechanisms.
Therefore, low doses of radiation can be regarded as moderate stress, which is known to induce hormesis. Indeed, in our previous work, and in the work of other authors it has been revealed, that relatively low dose exposure (20-75 cGy) of fruit flies on immature preimaginal stages in some cases has long-term effects that lead to an increased life span and resistance to other stresses, such as hyperthermia. It is known that preimaginal stages of Drosophila have comparable radiosensitivity to mammals. At the same time, adult individuals, due to the postmitotic state of most tissues, are about 100 times more radioresistant. Other researchers have revealed that irradiation of Drosophila individuals in the imago stage in doses from 0.1 to 400 Gy causes a statistically significant effect on lifespan and gene expression only if the dose is higher than 100 Gy. At the same time, in our recent work on comparing the effects of irradiation in the adult Drosophila male and female at the 20 cGy dose rate, we observed some differentially expressed genes.
Although some changes in life extensity in males were identified (the effect of hormesis after the exposure to 5, 10 and 40 cGy) as well as in females (the effect of hormesis after the exposure to 5 and 40 cGy), they were not caused by the organism "physiological" changes. This means that the observed changes in life expectancy are not related to the changes of organism physiological functions after the exposure to low doses of ionizing radiation. The identified changes in gene expression are not dose-dependent, there is not any proportionality between dose and its impact on expression. These results reflect nonlinear effects of low dose radiation and sex-specific radio-resistance of the postmitotic cell state of Drosophila melanogaster imago.
A LOOK AT BLASTEMA MECHANISMS IN ZEBRAFISH REGENERATION
Tuesday, August 25, 2015
In species capable of regrowing limbs and organs, such as salamanders and zebrafish, tissues form a blastema at the site of regeneration. This mass of cells recapitulates much of the behavior of embryonic development, including the complex signal interactions that steer the construction of replacement tissue. How exactly are the correct structures produced? Researchers hope that understanding the underlying processes will enable the inducement of similar cellular activity to heal injuries and age-damaged tissues in our species. That better understanding may also have other applications, such as in ongoing efforts to find a robust way to build complex blood vessel networks to support engineered tissue, which at the moment is one of the limiting factors preventing the creation of entire organs from a patient's own cells:
When parts of the zebrafish tailfin are injured by predators, or are experimentally amputated, the lost tissue is replaced within three weeks. Zebrafish fins consist of a skin that is stabilized by a skeleton of bony fin rays; similar to an umbrella that is supported by metallic stretchers. Fin rays are formed by bone-producing cells, the osteoblasts. In order to rebuild an amputated fin, a large number of new osteoblasts have to be formed by cell divisions from existing osteoblasts.
Retinoic acid is required to regulate the addition of bone material in growing fish. During regeneration, mature osteoblasts have to revert to an immature osteoblast precursor, which enables the switch from bone synthesis to cell division. The switch requires retinoic acid levels to drop below a critical concentration. However, upon amputation the tissue beneath the wound initiates a massive bout of retinoic acid synthesis that is required to mobilize cell division in the fin stump. How do mature osteoblasts circumvent this dilemma? The answer: osteoblasts that participate in regeneration transiently produce Cyp26b1, an enzyme that destroys and inactivates retinoic acid. Protected by this process, osteoblasts are able to rewind their developmental clocks, thus turning into precursor cells that contribute to a pool of undifferentiated cells, the blastema. Cells in the blastema pass through a number of cell divisions to provide the building blocks for the regenerated fin.
However, these cell divisions are supported by high concentrations of retinoic acid, which poses the next predicament: The reversion to become a mature osteoblast is inhibited by high levels of retinoic acid. Connective tissue in those areas of the blastema from which new mature osteoblasts eventually emerge produces the retinoic acid killer Cyp26b1. This lowers the local concentration of retinoic acid, so that osteoblast precursors are again able to mature and produce new fin rays. Other parts of the blastema, which replenish the supply of cells needed for regeneration to occur, continue to produce retinoic acid. "This is an elegant mechanism that ensures a gradient of cells experiencing high and low levels of retinoic acid. This allows two processes to run in parallel during regeneration: Proliferation for the production of all cells that replace the lost structure and redifferentiation of osteoblasts where the skeleton re-emerges."
How is the exact shape of the fin skeleton regenerated? In order to form new fin rays, newly formed osteoblasts have to align at the correct positions. Osteoblasts are ultimately guided to target regions by a signaling protein called Sonic Hedgehog. This is produced locally in the epidermis, a skin-like layer that covers the fin and the blastema. However, signal production only occurs in locally restricted cells that are free of retinoic acid. Such epidermal cells produce Cyp26a1, an enzyme that is functionally similar to Cyp26b1. Lastly, it emerged that osteoblasts themselves exert a piloting function for other cell types, particularly mesenchymal cells and blood vessels that also have to be directed to appropriate destinations during the rebuilding process. "The re-emergence of the skeletal pattern relies on a navigation system with interacting parts. Initially, retinoic acid is inactivated where new rays are to form. This allows the local production of a signal that pilots immature osteoblasts to areas where existing fin rays are to be extended. Interestingly, over the course of regeneration other cell types in the blastema are informed by osteoblast precursors to respect the boundaries between emerging fin rays."
STUDIES SHOW THAT ELITE ATHLETES LIVE LONGER
Tuesday, August 25, 2015
Here I'll point out a review of dozens of studies shows that the balance of evidence points to greater longevity in successful professional athletes. This is one part of a still open question on exercise and long-term health: is it actually better to exercise much more than the recommended moderate levels? There is conflicting evidence from various different types of epidemiological study. The data on professional athletes unfortunately does not show causation, so it may well be that they live longer because more robust individuals tend become professional athletes. In that case had they chosen a different life path, and kept up with regular moderate exercise, they would have had much the same higher than average life expectancy.
Understanding of an athlete's lifespan is limited with a much more sophisticated knowledge of their competitive careers and little knowledge of post-career outcomes. In this review, we consider the relationship between participation at elite levels of sport and mortality risk relative to other athletes and age- and sex-matched controls from the general population. Our objective was to identify, collate, and disseminate a comprehensive list of risk factors associated with longevity and trends and causes of mortality among elite athletes.
Fifty-four peer-reviewed publications and three articles from online sources met the criteria for inclusion. An overwhelming majority of studies included in this review reported favorable lifespan longevities for athletes compared to their age- and sex-matched controls from the general population. In fact, only two studies reported lower lifespan longevities in athletes relative to the controls. Although our overall understanding of modifiable and non-modifiable factors that contribute to mortality risk in elite athletes remains limited, in part due to methodological and data source inconsistencies, some trends emerged from our investigation. In particular, our review supports previous conclusions that aerobic and mixed-sport athletes have superior longevity outcomes relative to more anaerobic sport athletes. In addition, playing position and weight, as well as education and race, appeared to be consistent indicators of mortality risk, whereas other mechanisms such as handedness, precocity, and names and initials appeared to be less consistent and/or examined.
As a variety of confounders may impact longevity, the reasons for the differences in lifespans between elite athletes and the general population are likely to be multifactorial. There are several possible explanations of increased survival in the elite athlete cohort; namely, participation in higher volumes of exercise training leading to higher physical fitness levels, the likelihood that elite athletes are comprised of the healthiest and fittest individuals, and the maintenance of active and healthy lifestyles later in life. The extents to which these confounders contribute to mortality risk are still largely unknown however, as survival statistics may undermine the interplay of complex socioeconomic factors. For example, medical care accessibility made available by higher income may improve the life expectancy of athletes when compared to other groups. Further, plenty of corroborating evidence suggests health-care services alone do not result in improved health outcomes, but a variety of social factors such as education and employment produce these widespread biases in health. As a result, the historical investigations of elite athletes and longevity outcomes need to be cautiously interpreted and discussed in the contexts of a variety of possible influential factors of mortality.
PROPOSING A MECHANISM TO EXPLAIN THE ASSOCIATION BETWEEN TYPE 2 DIABETES AND ALZHEIMER'S DISEASE
Wednesday, August 26, 2015
Type 2 diabetes patients have a considerably greater risk of suffering Alzheimer's disease, as well as many other age-related conditions. It is commonly theorized that this is because the underlying risk factors are the same, which is to say that a sedentary lifestyle and excess fat tissue leading to metabolic syndrome contributes to the development of both conditions. Researchers here propose that type 2 diabetes results in increased generation of the amyloid-β involved in Alzheimer's, because it also has an associated amyloid, and because various different types of amyloid can spur a faster pace of creation of one another once they start accumulating. At this point the evidence is still fairly tenuous, however:
Several proteins have been identified as amyloid forming in humans, and independent of protein origin, the fibrils are morphologically similar. Therefore, there is a potential for structures with amyloid seeding ability to induce both homologous and heterologous fibril growth; thus, molecular interaction can constitute a link between different amyloid forms. Intravenous injection with preformed fibrils from islet amyloid polypeptide (IAPP), proIAPP, or amyloid-beta (Aβ) into human IAPP transgenic mice triggered IAPP amyloid formation in pancreas in 5 of 7 mice in each group, demonstrating that IAPP amyloid could be enhanced through homologous and heterologous seeding with higher efficiency for the former mechanism.
Proximity ligation assay was used for colocalization studies of IAPP and Aβ in islet amyloid in type 2 diabetic patients and Aβ deposits in brains of patients with Alzheimer disease. Aβ reactivity was not detected in islet amyloid although islet β cells express AβPP and convertases necessary for Aβ production. By contrast, IAPP and proIAPP were detected in cerebral and vascular Aβ deposits, and presence of proximity ligation signal at both locations showed that the peptides were less than 40nm apart. It is not clear whether IAPP present in brain originates from pancreas or is locally produced. Heterologous seeding between IAPP and Aβ shown here may represent a molecular link between type 2 diabetes and Alzheimer disease.
GDF-11 AND MYOSTATIN CORRELATE WITH HEART DISEASE OUTCOMES
Wednesday, August 26, 2015
Here researchers study natural variations in GDF-11 and myostatin levels, finding correlations with health outcomes in heart disease patients. This is one of a number of lines of research emerging from the search for cell signals that differ between old and young tissues, and that might be altered to induce old cell populations to behave more like young cell populations despite the damage they have suffered. In recent years researchers have demonstrated the use of GDF-11 to spur greater levels tissue maintenance in aged mice, for example:
Individuals previously diagnosed with heart disease may be less likely to experience heart failure, heart attacks, or stroke, or to die from these events, if they have higher blood levels of two very closely related proteins. One of these proteins, known as GDF11, has attracted great interest since 2013, when researchers showed that it could rejuvenate old mice. Based on these findings, scientists have speculated that drugs that increase GDF11 levels might reverse physiological manifestations of aging that lead to heart failure in people.
The study population included 1,899 men and women with heart disease who ranged in age from 40 to 85 (average 69 years). Because they already had been diagnosed with stable ischemic heart disease, in which blood supply to the heart is reduced due to coronary artery disease, the participants were at elevated risk for stroke, heart attack, hospitalization for heart failure, and death. Hundreds of the participants experienced one or more of these outcomes during the course of the study, in which they were monitored for nearly nine years.
Researchers used a lab test to measure combined blood levels of GDF11 and a very similar protein called myostatin - the test could not distinguish between the two, because they are quite similar both structurally and functionally. The scientists determined that research subjects who had relatively high blood levels of these two proteins at the beginning of the study - in the top 25 percent of all participants - were less than half as likely to die from any cause, in comparison to participants whose blood levels ranked them in the bottom 25 percent. Those in the highest 25 percent also experienced fewer adverse health events associated with heart disease. "We also found that combined levels of GDF11 and myostatin in humans decline with advancing age, but that the rate of this decline varies among individuals."
In mouse studies published in 2013 researchers found that four weeks of GDF11 treatment in old mice that restored the youthful level of this protein reversed potentially harmful thickening of heart muscle. In humans this thickening of heart muscle, known as ventricular hypertrophy, is associated with aging and contributes to heart failure and death. In the new study, the researchers used standard clinical imaging tests to measure ventricular hypertrophy and found that participants with lower levels of the GDF11 and myostatin proteins were more prone to having thickened heart muscle. "This association with less ventricular hypertrophy and death suggests the possibility that GDF11 might act similarly in humans as in mice. Restoring GDF11 or myostatin to their higher, youthful levels might potentially serve as a so-called 'fountain-of-youth' treatment, but far more work remains to be done,"
FATTY ACIDS CORRELATE WITH LONGEVITY IN BIRD SPECIES
Thursday, August 27, 2015
Birds, like bats, have high metabolic rates due to the demands of flight but are also long-lived in comparison to similarly sized members of other species. This has a lot to do with mitochondria and membrane fatty acid composition, as shown by the evidence in the paper linked below. The membrane pacemaker theory of aging tells us that the genetically determined ratios of specific fatty acids in cell membranes determine resistance to oxidative damage, as well as other important properties in the operation of metabolism that are particularly relevant to mitochondrial function and the ways in which mitochondria become damaged in aging. From a practical point of view, this is one of the things that should steer our attention towards mitochondrial DNA damage as an important contribution to aging, and cause us to prioritize research on methods of repair of that damage.
The evolution of lifespan is a central question in evolutionary biology, begging the question why there is so large variation among taxa. Specifically, a central quest is to unravel proximate causes of ageing. Here we show that the degree of unsaturation of liver fatty acids predicts maximum lifespan in 107 bird species. In these birds, the degree of fatty acid unsaturation is positively related to maximum lifespan across species. This is due to a positive effect of monounsaturated fatty acid content, while polyunsaturated fatty acid content negatively correlates with maximum lifespan. Furthermore, fatty acid chain length unsuspectedly increases with maximum lifespan independently of degree of unsaturation. These findings tune theories on the proximate causes of ageing while providing evidence that the evolution of lifespan in birds occurs in association with fatty acid profiles. This finding suggests that studies of proximate and ultimate questions may facilitate our understanding of these central evolutionary questions.
TOWARDS CELL THERAPY AS A REPLACEMENT FOR LIVER TRANSPLANT
Thursday, August 27, 2015
The liver is the most regenerative of mammalian organs, so liver transplantation is the natural first candidate for replacement by some form of cell therapy, delivering cells that will regrow lost and damaged tissue. The details are important in these types of treatment, as seemingly small differences in the methodology of creating and transplanting cells leads to a wide variation in outcomes. A great deal of effort is devoted to finding exactly the right methodology for each tissue type in order to coax cells into carrying out regeneration, and here researchers demonstrate progress for liver tissue in rats:
Liver transplantation is currently the only established treatment for patients with end stage liver failure. However, this treatment is limited by the shortage of donors and the conditional integrity and suitability of the available organs. Transplanting donor hepatocytes (liver cells) into the liver as an alternative to liver transplantation also has drawbacks as the rate of survival of primary hepatocytes is limited and often severe complications can result from the transplantation procedure.
In an effort to find potential therapeutic alternatives to whole liver transplantation and improve the outcomes of hepatocyte transplantation, this study tested the therapeutic efficacy and feasibility of transplanting multi-layered sheets of hepatocytes and fibroblasts (connective tissue cells) into the subcutaneous cavity of laboratory rats modeled with end stage liver failure. The results of the study demonstrated that the cells in the multi-layered hepatocyte sheets survived better than cells transplanted by traditional methods and that the cells proliferated, maintaining liver function in the test animals for at least two months.
The researchers called the fibroblasts "feeder cells" that helped preserve the "high viability and functionality" of the hepatocytes in both in vitro and in vivo studies. The researchers also noted that in other methods of hepatocyte transplantation such as intrasplenic (through the spleen) or intraportal, only a small number of hepatocytes can be transplanted at one time, and many die. By contrast, the transplanted cell sheets showed "dramatically higher albumin expression levels" in vivo one month after transplantation into the subcutaneous cavity.
"Hypoxia is a major cause of poor hepatocyte survival. Therefore, immediately after transplantation, all transplanted cells are supplied with oxygen only from surface diffusion because of the lack of capillary vessels when other methods of transplantation are used." However, in the current study it was observed that merely one week after transplantation, the hepatocyte sheets were permeated with multiple capillary vessels. That the hepatocytes were close to blood vessels confirmed that vascularization is crucial for their survival and function.
THEORIZING ON GENE NETWORK STABILITY AND AGING
Friday, August 28, 2015
Researchers here model the relationship between genetic regulation and aging with an eye towards trying to fit the outcomes in both negligibly senescent and "normally aging" species. It is known that advancing age brings with it epigenetic dysregulation, meaning significant changes in the levels of various proteins produced from their genetic blueprints, and therefore significant changes in cell behavior. Researchers differ on what this means and how close it is to the root causes of aging. In the theories in which aging is an accumulation of damage, then epigenetic changes are far downstream in the chain of cause and consequence; they are a reaction to rising levels of cell and tissue damage.
Several animal species are considered to exhibit what is called negligible senescence, i.e. they do not show signs of functional decline or any increase of mortality with age. Recent studies in naked mole rat and long-lived sea urchins showed that these species do not alter their gene-expression profiles with age as much as other organisms do. This is consistent with exceptional endurance of naked mole rat tissues to various genotoxic stresses. We conjectured, therefore, that the lifelong transcriptional stability of an organism may be a key determinant of longevity.
We analyzed the stability of a simple genetic-network model and found that under most common circumstances, such a gene network is inherently unstable. Over a time it undergoes an exponential accumulation of gene-regulation deviations leading to death. However, should the repair systems be sufficiently effective, the gene network can stabilize so that gene damage remains constrained along with mortality of the organism. We investigate the relationship between stress-resistance and aging and suggest that the unstable regime may provide a mathematical basis for the Gompertz "law" of aging in many species. At the same time, this model accounts for the apparently age-independent mortality observed in some exceptionally long-lived animals.
A RECENT INTERVIEW WITH AUBREY DE GREY OF THE SENS RESEARCH FOUNDATION
Friday, August 28, 2015
Aubrey de Grey is the co-founder of the SENS Research Foundation, a non-profit organization focused on speeding up development of the biotechnologies needed for human rejuvenation. The underlying model behind the research programs funded is that aging is caused by forms of cell and tissue damage that are currently well defined and understood. Periodic repair of that damage will allow for effective treatment of age-related disease and ultimately indefinite extension of healthy life spans. The only thing separating us from rejuvenation therapies is the matter of building the necessary treatments, a process of a few decades all told were it adequately funded - which is, sadly, still not the case, and one of the reasons why advocacy and grassroots fundraising is so important.
THE INSIGHT: That leads me into the next question: Google has created the California Life Company (Calico), the hedge-fund billionaire Joon Yun has launched the Palo Alto Longevity Prize, so there seems to be a lot of movement in this area. What I'm really fascinated by is - a lot of people are investing a lot of time and money into this area of defeating ageing - if you do implement this 7-stage plan and you see breakthroughs in this area, what's to say that something else, some other large obstacle, doesn't come up? Are you relatively sure that if this 7-stage plan is implemented it will create an open passageway for a longer life?
AUBREY DE GREY: That's a great question. I'm going to give a slightly complicated answer to it - really a two-part answer: the point about the approach that we're taking now is that it's based on this classification of the types of damage that occur in the body and eventually contribute to ill health of old age - classification into seven major categories - and that classification is important because within each category we have a generic approach, a generic therapeutic strategy that should be able to work against every example within that category. So, then your question really divides into two questions. The first question is: are we going to identify new types of damage that fit into the existing classification? The second part of your question is: are we going to find new types of damage that don't fit into the classification - type number 8, and so on?
The answer to the first question is: absolutely, we're going to find more of those; we've been seeing more of those turn-up over the years - throughout the time that I've been working in this area. But, the fact that they fit into the classification means that they're not a problem. It means that, yes, we're going to have to carry on developing additional therapies to address these additional types of damage, but that's kind of okay, because the difficulty of developing those additional therapies will be very slight as a result of the fact that they will be minor variations of the therapies that we already developed to address the examples of that category, that we already knew about.
So, now we move onto the second part of the question, of are we going to identify damage-type number 8, and so on - ones that don't fit into the classification. That's a very important question, but the evidence is looking very good that it's not going to happen. First of all, we can just look and say, "Has it happened anytime recently?" and the answer is absolutely not. SENS has been around for 15 years and, in fact, all of the types of damage that SENS discusses have been well studied and known about for more than 30 years. That's a very long time for nothing to be discovered that breaks the classification.
THE INSIGHT: Have you at any point in your career had an anxious response from governments about your work, like it being a national security threat?
AUBREY DE GREY: No, the government don't behave in that way, because everyone in the government is caught in this trap that I talk about so often, where they're desperate to continue to pretend that any talk of radical life extension is just science-fiction; they don't want to think about it. The reason they don't want to think about it is the reason why the general public don't want to think about it and the reason why quite a lot of scientists don't want to think about it: namely, they don't want to get their hopes up. They really don't want to reengage a psychological battle that they have already lost, that they have already submitted to. They have already made their peace with ageing and the inevitability of declining health, old-age and eventual death; getting into a mode of thinking where maybe science will come along and prevent that from happening or maybe it wont, that's a mindset that disturbs a lot of people; that's a mindset a lot of people would prefer not to even engage in, if the alternative is to continue to believe that the whole thing is science-fiction. It's fatalistic but it's calming.
THE INSIGHT: I'm interested in the psychology of people, I guess you can put them into two camps: one doesn't have an inherent understanding of what you're doing or saying, and the other camp willingly resign themselves to living a relatively short life. You've talked to a whole wealth of people and come across many counter-opinions, have any of them had any merit to you, have any of them made you take a step back and question your approach?
AUBREY DE GREY: Really, no. It's quite depressing. At first, really, I was my own only affective critic for the feasibility - certainly never a case or example of an opinion that amounted to a good argument against the desirability of any of this work; that was always 100% clear to me, that it would be crazy to consider this to be a bad idea. It was just a question of how to go about it. All of the stupid things that people say, like, "Where would we put all the people?" or, "How would we pay the pensions?" or, "Is it only for the rich?" or, "Wont dictators live forever?" and so on, all of these things... it's just painful. Especially since most of these things have been perfectly well answered by other people well before I even came along. So, it's extraordinarily frustrating that people are so wedded to the process of putting this out of their minds, by however embarrassing their means; coming up with the most pathetic arguments, immediately switching their brains off before realising their arguments might indeed be pathetic.
THE INSIGHT: I'd be fascinated to know what your dialogue has been like with pharmaceutical companies and why they have not been more forthcoming?
AUBREY DE GREY: So, there's a somewhat different scenario, because that problem of believing that the whole thing is never going to happen is still true, but there are various other aspects that influence the attitude of... well, beyond big-pharma, the medical industry in general. One thing is, they want to make money; they're worried about quarterly balance sheets, they want to make money now; they don't want to make money 20 years from now. They also don't know that the particular approaches that we're taking are the ones that are going to work; they want to buy up ideas that have already gone through and have been through clinical trials, and then run with them and capitalise on them. They know perfectly well that when things are at the pre-clinical stage - especially when they're only in a conceptual stage and haven't even been tested in mice - that the hit-rate is really low, even when the concept is correct, such that the concept has to be retried multiple times before one comes up with an actual substantiation of the concept that works.