FIGHT AGING! NEWSLETTER
March 23rd 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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- A Long Interview with Aubrey de Grey on London Real
- Continued Interest in Drugs that Might Slightly Slow Aging
- At Some Point the "Anti-Aging" Industry Will Stop Producing Junk and Nonsense, and Will Actually Sell Meaningful Treatments
- Tissue Engineering of Lung and Gut Sections
- What Can Other Primates Teach Us About Aging and Neurodegeneration?
- Latest Headlines from Fight Aging!
- A Look at Peter Thiel's Biotechnology Investments
- Failing Autophagy and Immune System Aging
- Data on Brain Aging and Early Signs of Alzheimer's Disease
- TOM40 and Neurodegeneration
- Targeting Nitric Oxide Metabolism in Calorie Restriction Mimetics
- Dying of Old Age Doesn't Feel So Great
- MicroRNAs Promote Heart Regeneration
- Considering the Path to Curing Blindness
- A Novel Approach in Engineering T Cells to Attack Cancer
- More SIRT7 Improves Aged Stem Cell Regenerative Capacity
A LONG INTERVIEW WITH AUBREY DE GREY ON LONDON REAL
Scientist and advocate Aubrey de Grey is the co-founder of the SENS Research Foundation, one of the most important organizations in aging research today, given its goal of turning the focus of the scientific community towards the implementation of rejuvenation biotechnology. Too much of the aging research establishment has either no interest in treating aging as a medical condition, or they are only interested in expensive and uncertain ways to slightly slow the progression of aging. If we want meaningful progress towards an end to aging in our lifetimes, with the option of continued health and vigor in our extra years of life, then this must change.
The SENS Research Foundation is supported entirely by philanthropic donations, such as those that you and I can provide. Its staff fund and coordinate research, conferences, and advocacy with the aim of pushing forward critical technologies needed to treat the causes of degenerative aging. In most cases work on repair of the cellular and molecular damage that leads to frailty and disease lags far behind other, far less effective approaches that cannot possibly product actual rejuvenation if implemented. This present state of affairs is exactly why we need both more organizations like the SENS Research Foundation and more funding for these and similar efforts to reshape the aging research community.
My attention was drawn today to a longer interview with de Grey recently published online by London Real. At almost ninety minutes long, it covers a lot of ground.
Video: Aubrey de Grey - How To Live Forever
Aubrey de Grey is a true frontiersman, daring to push out against what seems the most natural and unstoppable forces of nature - ageing. He's not just another voice though, he's a scientist and identifies ageing as a disease, one that can be cured with the right medicine. His work calls for serious scientific exploration of what causes tissue to age and to then find solutions to those components - what he calls the roadmap to defeat biological ageing. In fact, he believes that the first humans who will live to be 1,000 years old are already alive today!
Here is a quote to consider from the opening minutes: "We've got to get people more comfortable with undergoing medical treatments while they are still healthy." As rejuvenation therapies are deployed there will be a change in the provision of medicine from treatments to preventative medicine, and eventually near all medicine will be preventative in nature. I'm on the fence as to whether this will in fact be a hurdle for adoption. People are willing today to pay at least lip service to prevention in the form of supplements and exercise. Equally I'm receptive to the argument that clinics are broadly seen as the place you go when you're sick, not the place you go to ensure that you don't get sick. Yet won't longevity assurance treatments be as irregular in life as vaccinations, once every few decades, once a mature technology? People keep up with vaccinations for the most part.
CONTINUED INTEREST IN DRUGS THAT MIGHT SLIGHTLY SLOW AGING
Research institutions are willing to pour comparatively large sums into the pursuit of existing already developed and approved drugs that might, possibly, have some marginal, tiny effect on the course of degenerative aging. This is one manifestation of a large and harmful issue that plagues medical research as a whole, which is that there is very little interest in pursuing radical new improvements to the state of therapies. Rather the larger investments nowadays often go towards mining the existing catalog of approved drugs in search of different uses and slight gains that might have been overlooked in the past. Other groups delve into supplements to evade the FDA, with the similar goal of slight gains and overlooked substances. These are no paths to rapid progress or a future of greatly improved medicine.
Why is this the present state of affairs? I blame regulation. It is so enormously costly to obtain approval for any new drug, let alone a new technology that doesn't quite fall into any of the existing categories that regulators understand, that developers and researchers are steered at every step of the way towards reuse of existing drugs and other technologies. This is what you get when government influence over a field of human endeavor has risen to the point at which all that is not explicitly permitted is forbidden. Progress is greatly slowed and stifled.
Of course everyone puts on the best face for this. Look at these new and bold things we are doing, they say. They are neither new nor bold, however. Nor are they the road to greatly extended healthy lives or the defeat of aging, and those claims should be laughed out of the room when made. No existing drug such as those mentioned below can do more than slightly slow the accumulation of damage that causes aging. They don't repair that damage, they thus won't add significant numbers of years to life, and they are unlikely to even do as much good as calorie restriction or regular moderate exercise. In the case of the various drug candidates noted in the articles linked below, the evidence isn't even all that robust when it comes to extending healthy life in animal studies. This is marginal activity that will most likely do very little for the bottom line of healthy years lived. It is the business as usual of the research establishment of the yesterday, and something that must be disrupted and driven out by new and better approaches to the treatment of aging.
This is all made doubly frustrating by the fact that now, as a result of more than a decade of hard work and advocacy for aging research, many more researchers are willing to speak openly about treating aging as a medical condition. Yet they focus on strategic options for research and development that haven't much of a hope of producing meaningful gains in healthy life span. We are in the midst of a revolution in the capabilities of medical biotechnology: this is not a time to cling to past incrementalism, but rather a time to embrace new approaches and new strategies that could achieve rejuvenation and radical life extension.
Scientists' New Goal: Growing Old Without Disease
Some of the top researchers on aging in the country are trying to get an unusual clinical trial up and running. They want to test a pill that could prevent or delay some of the most debilitating diseases of old age, including Alzheimer's and cardiovascular disease. The focus of the project isn't to prolong life, although that could occur, but to make the last years or decades of people's lives more fulfilling by postponing the onset of many chronic diseases until closer to death.
Researchers expect to enroll more than 1,000 elderly participants in the randomized, controlled clinical trial to be conducted at multiple research centers and take five to seven years. The trial aims to test the drug metformin, a common medication often used to treat Type 2 diabetes, and see if it can delay or prevent other chronic diseases. (The project is being called Targeting/Taming Aging With Metformin, or TAME.) Metformin isn't necessarily more promising than other drugs that have shown signs of extending life and reducing age-related chronic diseases. But metformin has been widely and safely used for more than 60 years, has very few side effects and is inexpensive.
The scientists say that if TAME is a well-designed, large-scale study, the Food and Drug Administration might be persuaded to consider aging as an indication, or preventable condition, a move that could spur drug makers to target factors that contribute to aging. Fighting each major disease of old age separately isn't winnable. "We lower the risk of heart disease, somebody lives long enough to get cancer. If we reduce the risk of cancer, somebody lives long enough to get Alzheimer's disease." "We are suggesting that the time has arrived to attack them all by going after the biological process of aging."
An FDA spokeswoman, said the agency's perspective has long been that "aging" isn't a disease. "We clearly have approved drugs that treat consequences of aging," she said. Although the FDA currently is inclined to treat diseases prevalent in older people as separate medical conditions, "if someone in the drug-development industry found something that treated all of these, we might revisit our thinking."
Beyond Resveratrol: The Anti-Aging NAD Fad
NAD is a linchpin of energy metabolism, among other roles, and its diminishing level with age has been implicated in mitochondrial deterioration. Supplements containing nicotinamide riboside, or NR, a precursor to NAD that's found in trace amounts in milk, might be able to boost NAD levels. In support of that idea, half a dozen Nobel laureates and other prominent scientists are working with two small companies offering NR supplements.
The NAD story took off toward the end of 2013 with a high-profile paper by Harvard's David Sinclair and colleagues. Sinclair, recall, achieved fame in the mid-2000s for research on yeast and mice that suggested the red wine ingredient resveratrol mimics anti-aging effects of calorie restriction. This time his lab made headlines by reporting that the mitochondria in muscles of elderly mice were restored to a youthful state after just a week of injections with NMN (nicotinamide mononucleotide), a molecule that naturally occurs in cells and, like NR, boosts levels of NAD.
NMN isn't available as a consumer product. But Sinclair's report sparked excitement about NR, which was already on the market as a supplement called Niagen. In early February, Elysium Health, a startup cofounded by Sinclair's former mentor, MIT biologist Lenny Guarente, jumped into the NAD game by unveiling another supplement with NR.
This intersection of the supplement marketplace and scientific research is a sideshow and has little to do with any serious efforts that might produce treatments for the causes of aging. It will no doubt be successful in parting fools and their money, however. This sort of thing usually is, even absent a bevy of scientists willing to put their reputations on the line. Remember than nothing of any practical use came of resveratrol and sirtuin research, though it certainly generated a lot of data and new understanding of that small slice of human metabolism. Similarly nothing of practical use will emerge here. Don't fall for the hype, and don't spend time and effort advocating for or supporting efforts that cannot possibly produce meaningful gains in human life span.
AT SOME POINT THE "ANTI-AGING" INDUSTRY WILL STOP PRODUCING JUNK AND NONSENSE, AND WILL ACTUALLY SELL MEANINGFUL TREATMENTS
It is perfectly possible to build a tremendously successful business while failing to deliver on any of the initial motivating goals and ideals. The modern "anti-aging" industry is a perfect example of this point, written thousands of times over in the careers of salespeople and founders. It began in earnest in the 1970s, a point in time when advocates for longevity science were a lot more optimistic, radically overoptimistic in fact, about what could be achieved in the near future. They built a supply pipeline for what they believed would come, but in the end, when the real thing never turned up, filled that pipeline with whatever junk happened to be available and would sell. Most of the original founders strongly believed in the declared goals of providing services that would extend healthy human life spans. Then they sold out. This is what happens when you build the supply chain in advance of the product.
Some of these folk are still very much believers, such as the principals at the Life Extension Foundation, an organization emblematic of the US supplement industry for the past four decades. They have over the years turned a portion of their profits towards real, meaningful research in cryonics and biotechnology, including SENS rejuvenation projects, far more money than I can claim to have helped raise. Nonetheless, the overwhelming majority of their activities lie in selling pills that have no real meaningful effect while loudly proclaiming the merits of those supplements - and the LEF is, I think, the best of that industry when it comes to the balance of ideals, meaningful action, and garbage. To my eyes when it comes to advocacy and obtaining support for rejuvenation research even enlightened "anti-aging" industry organizations like the LEF are probably doing more harm than good.
Yet this pipeline exists, and shows no signs of slowing down. At some point real therapies that address scientifically supported causes of aging will show up in the medical tourism pipeline, or as reapplications of existing widely available drugs, or something else that can be put out there by the existing infrastructure. These first treatments will no doubt be marginal, not very good at all in the grand scheme of things, but they will actually treat aging, and actually do some good. Think of the recent publication showing that a combination of existing drugs clears some portion of senescent cells in mice, for example. An organization outside the US could be selling that treatment today, and it is in effect a really terrible first pass at a SENS-like therapy that trims back one contributing cause of degenerative aging. But a really terrible first pass at a SENS-like therapy is already a league ahead of marginal scientific projects such as testing metformin in clinical trials and a whole different world from overhyped junk like resveratrol. It is step one on a road that actually goes somewhere.
The model for the way this will all unfold has already happened, and very recently too. If you want insight into the next fifteen years of treating aging outside the formalized mainstream of clinical trials, then look at the past fifteen years of applied stem cell research. A big melange of opportunists, entrepreneurs, rapid scientific progress, legitimate clinics, crooks, and the "anti-aging" market, all rolled into one and smeared out across half the world outside the US. At some point in the indefinite future I'm sure I'll be one of those folk out there buying treatments ahead of their availability in the US, sometime after the point at which the science, cost, and expected results make some kind of sense when balanced against the known gains of exercise and calorie restriction. We're not there yet, not by a good decade or more - probably more, frankly. But there will be a time when the "anti-aging" market stops being a bad joke and finally delivers on its original goal, set forty years back, after the good and the real chases out the bad and the fake.
Everyone makes their own calculations on these matters, of course, though I believe most of them are somewhat too eager to jump into the water now rather than supporting work on a pool that actually meets the minimal standards of usefulness. Being more skeptical than you feel you should be and more of a late adopter than you would like to be has many benefits.
Tomorrow's Anti-Aging Therapy, Available Today
For people who have a few hundred thousand dollars to spend and are willing to take on the risks of an "early adopter" and travel to South America, options are now becoming available that were inconceivable just a few years ago. This is a new vision for combining research with treatment, for treating diseases that have no proven therapies, and for aging itself.
You only have to read Time Magazine to notice that this is the year anti-aging medicine is coming of age. Promising life extension technologies are being debuted, with potential for preventing many diseases at once, adding decades to the human life span, and restoring youthful function to an aging body. These include telomerase therapies, stem cell therapies, epigenetic reprogramming, removal of senescent cells, plasma transfer, and hormonal therapies inspired by gene expression changes between young and old.
Inevitably, this has brought a surge in the number of companies eager to jump the gun and offer treatments to consumers based on early lab research, before the technology has proved safe and effective in humans. In an age of wildcat capitalism, we are well-advised to approach all claims with a skeptical eye, and assume that hucksterism is rampant. Anyone who considers signing on with a new company that is offering a promising but unproven anti-aging technology had best start with a foundation of second opinions and broad considerations of risk and rewards.
But I stop short of saying, "stay away". The field is too important, with too much at stake for us individually and as a human community, to sit on the sidelines, to wait for the research to be sorted out. Political control of medical research has protected us imperfectly, and has held back life-saving treatments, sometimes for decades. The system serves pharmaceutical profits more effectively than the public of medical consumers. Too often, the treatments that are approved are not those that offer the best risk/reward ratio, but those that are patentable and owned by someone who can afford to invest hundreds of millions of dollars in scientific advocacy.
The standard path to regulatory approval respects individual human life, and is "conservative" in the Hippocratic sense of "first do no harm". But it is far from the most effective way to move science forward, and probably is not the most efficient way to save the most lives, even in the short run. Many libertarians, anti-aging enthusiasts and ordinary citizens who find themselves with a condition for which there is currently no effective medical treatment want the freedom to participate in experimental medicine, and experimental medicine certainly wants to try to help them and to learn from successes and failures.
For people who see their options for an active and creative life being closed by age-related disabilities, for people who are willing to take personal risks to help move the science forward, for people who are bold and adventure-seeking, the choice to try experimental anti-aging technologies can be a rational decision.
TISSUE ENGINEERING OF LUNG AND GUT SECTIONS
The first practical outcome of tissue engineering research is not therapies, but rather improved tools for further scientific work in this and other fields. At present the structured tissue sections created in the laboratory are largely too small or too dissimilar from natural organs for use in treatments, but these engineered tissues can nonetheless be very useful in drug testing, investigation of disease mechanisms, and many other aspects of medical research. Real tissue is a vast improvement over cells in a dish and animal models, and real tissue grown from patient cells is a tremendous step forward for work on genetic disorders. In the economic development of the field, the ability for companies to form and make money by providing these tools is a vital stepping stone on the way to improving the underlying technologies. That will lead in time to building whole organs to order, one step at a time.
Scientists grow 'mini-lungs' to aid the study of cystic fibrosis
Scientists have successfully created 'mini-lungs' using stem cells derived from skin cells of patients with cystic fibrosis, and have shown that these can be used to test potential new drugs for this debilitating lung disease. The research is one of a number of studies that have used stem cells - the body's master cells - to grow 'organoids', 3D clusters of cells that mimic the behaviour and function of specific organs within the body. Researchers used skin cells from patients with the most common form of cystic fibrosis caused by a mutation in the CFTR gene referred to as the delta-F508 mutation. Approximately three in four cystic fibrosis patients in the UK have this particular mutation. They then reprogrammed the skin cells to an induced pluripotent state, the state at which the cells can develop into any type of cell within the body.
Using these induced pluripotent stem cells, or iPS cells, the researchers were able to recreate embryonic lung development in the lab by activating a process known as gastrulation, in which the cells form distinct layers including the endoderm and then the foregut, from which the lung 'grows', and then pushed these cells further to develop into distal airway tissue. The distal airway is the part of the lung responsible for gas exchange and is often implicated in disease, such as cystic fibrosis, some forms of lung cancer and emphysema. "In a sense, what we've created are 'mini-lungs'. While they only represent the distal part of lung tissue, they are grown from human cells and so can be more reliable than using traditional animal models, such as mice. We can use them to learn more about key aspects of serious diseases - in our case, cystic fibrosis. We're confident this process could be scaled up to enable us to screen tens of thousands of compounds and develop mini-lungs with other diseases such as lung cancer and idiopathic pulmonary fibrosis. This is far more practical, should provide more reliable data and is also more ethical than using large numbers of mice for such research."
Researchers seek to make mini-guts that mimic life
"We are already making human mini-guts in the laboratory. We make them, we can freeze them." However, they are not a perfect model, and she hopes this project will result in better ones. Not only will they have the stretch and pull of living guts, but will also include the immune cells found underneath the epithelium of the gut and the mesenchymal and nerve cells that enhance the environment and function of the gut.
There are two major projects. Project one uses human intestinal enteroids (cells taken from the gastrointestinal tract) to analyze how those cell react to human rotavirus and vaccine replication as well as enteroaggreative E. coli, defining how the epithelial cell responses lead to pathology or disease. Project two will combine tissue engineering, biomaterial design and mechanobiology to develop specially tailored platforms for the human intestinal enteroids that can be stimulated mechanically, promoting cell and tissue polarity and differentiation of intestinal tissue to facilitate infection with the rotaviruses and E. coli. "Infectious disease labs that study enteric disease need better models that faithfully simulate the physiology of the intestine. This organ contains multiple types of cells that are arranged in complex patterns, and these tissues are constantly on the move. They contract and expand all the time."
WHAT CAN OTHER PRIMATES TEACH US ABOUT AGING AND NEURODEGENERATION?
It has been said that the only thing worse than using animals in medical research is to refrain from the use of animals in medical research. It is both terrible and necessary. Throughout the modern history of medical science animal studies have been needed in order to make progress, not just in human medicine, but also veterinary medicine. Many people are opposed to animal studies, and to the degree that this is motivated by compassion - and leads to sensible forms of advocacy - this is to their credit. Unfortunately all too few of these individuals follow the logic though to its end and thus devote near all of their efforts to oppose the animal farming, hunting, and fishing industries. These activities cause harms to animals that tower over those of research. All the animal studies carried out in a year are a rounding error against a few hours of the meat industry.
That aside, animal studies will one day soon be a thing of the past. Some will be replaced by the use of engineered tissue sections, but eventually all will give way to experiments that run on simulation platforms, coupled with a much more modest use of engineered tissues to validate those simulations. Even the early steps on this road will be more effective and far cheaper than maintaining animal colonies and lineages for use in research. The only reason that this transition hasn't yet occurred is that only now has tissue engineering arrived at the point of mass production of functional tissue sections that mimic the real thing closely enough to be useful. I would hope that the farming of animals one day goes the same way, and that we as a species continue on a somewhat upward slope of culture and enlightenment that leaves this and other presently acceptable forms of institutional violence behind us. That is no doubt a much longer and harder road than merely transforming life science research.
Primate studies are already in decline. They are far more expensive than studies in shorter-lived species and far more difficult to arrange in the present climate. Any new study similar to the decades-long calorie restriction studies in rhesus macaques now coming to their final years is unlikely to take place given today's culture and pace of technological progress. Thus I think that these researchers are arguing for the last days of a paradigm that is firmly in its sunset period:
Lessons from the analysis of nonhuman primates for understanding human aging and neurodegenerative diseases
Why do we need animal models? The simplest answer to this question is to increase our general knowledge, to experimentally test theories. Animal model usefulness is manifold, from the study of physiological processes to the identification of disease-causing mechanisms. They are necessary tools for solving the most serious challenges facing medical research. In aging and neurodegenerative disease studies, rodents occupy a place of choice. However, the most challenging questions about longevity, the complexity and functioning of brain networks or social intelligence can almost only be investigated in nonhuman primates (NHPs). Beside the fact that their brain structure is much closer to that of humans, they develop highly complex cognitive strategies and they are visually-oriented like humans. For these reasons, they deserve consideration, although their management and care are more complicated and the related costs much higher.
NHPs have significantly contributed to understanding of aging and neurodegenerative diseases. Aging NHPs show striking similarities with elderly humans. Most of our understanding on the biological changes observed during aging comes from studies in rodents because they present clear advantages (short life span, fully characterized genetic aspects, easy genetic manipulation...). However, rodents and humans diverged much earlier than humans and NHPs, and this is likely to have led to fundamental differences in their aging processes. In one pioneering work, for example, researchers compared the transcriptome of the cerebral cortex in aging mice, rhesus macaques and humans, providing a broad view of the evolution of aging mammalian brain. They found that only a small subset of age-related gene expression changes are conserved from mouse to human brain, whereas such changes are highly conserved in rhesus macaques and humans.
Due to their genetic proximity to humans and their highly developed social skills, NHPs are extremely valuable as experimental animal models. However, as the number of available animals is restricted for ethical reasons and also because of the high cost and large space required for breeding colonies, NHPs should only be used when no other suitable method is available to fill the gap of our knowledge. In any case, rodent (or other small animal models) and primate experimental models need to be used in parallel in order to obtain robust and complementary information. Alongside other models, nonhuman primates should have a unique place in the overall aging and neurodegenerative research strategy.
LATEST HEADLINES FROM FIGHT AGING!
A LOOK AT PETER THIEL'S BIOTECHNOLOGY INVESTMENTS
Monday, March 16, 2015
Investor and philanthropist Peter Thiel has given millions to support the rejuvenation biotechnology research programs funded by the SENS Research Foundation and Methuselah Foundation before it. He was one of the first wealthy individuals to step forward and do this publicly and vocally, well ahead of the coming crowd, and continues to support this work.
I point out this article largely as a reminder that the biotechnology revolution has only just started its acceleration, and Thiel's activities in this space are now illustrative of the approach taken by many other funding institutions. Biotechnology today is greatly improved in comparison to just ten years ago, the tools ten times better, the cost of DNA sequencing and many other fundamental techniques plummeting. But this is just the warm up to the main event, in which the next two decades of life science research and its application will look a lot like the enormous growth and transition of the software industry between 1980 to 2000: a shift to openness, the breaking down of barriers between professional and amateur development as cost of participation falls, and a vast increase in output and experimentation:
What's less well known about Thiel is his affinity for biotechnology. By now he has invested in more than 25 startups, one of which has already turned into a $1 billion success story. That puts Thiel, 47, at the vanguard of prominent tech investors putting their money into biology. Google drew attention when it started Calico, a life-extension company, in 2013, and this year the accelerator Y Combinator said 10 of the 116 startups it accepted were biotechnology companies. Thiel, like Google, is motivated partly by the hope of defeating aging, an area of medicine that he says is "structurally underexplored." "The way people deal with aging is a combination of acceptance and denial," he says. "They accept there is nothing they can do about it, and deny it's going to happen to them."
The wider change is that biology is getting cheaper and easier to do. That means biotech companies are acting more like software startups. These days, you can order DNA online, crowdfund a genetic engineering project, or outsource experiments. Austen Heinz, CEO of Cambrian Genomics, a company that sells built-to-order DNA strands, says you can imagine what will happen if biotech becomes as easy as software to try and to test. An "explosion of biotech companies is coming," he says.
In 2011, the Thiel Foundation created Breakout Labs, an internal organization that gives small companies, often of just two or three people, investments of a few hundred thousand to "de-risk" scientific ideas and prepare them to raise more cash. Breakout has become the foundation's largest effort. It has so far put millions into roughly two dozen hard science companies, nearly all them biotechnology firms. Lindy Fishburne, Breakout's executive director, says Thiel's hope is to "jailbreak" good technologies trapped in universities or other institutions and get them into the economy.
FAILING AUTOPHAGY AND IMMUNE SYSTEM AGING
Monday, March 16, 2015
Autophagy is one of the housekeeping processes responsible for recycling damaged mechanisms and structures in cells before they can cause further harm. A type of organelle called the lysosome performs the recycling, but lysosomal activity is impacted over the course of aging by an accumulation of metabolic byproducts that cannot be broken down, such as the constituents of lipofusin most notably found in retinal cells. As a consequence of being laden with this waste, lysosomes bloat and become dysfunctional, especially in long-lived cells.
The immune system also declines and changes with aging, becoming less effective in its primary tasks of defending the body and eliminating potentially harmful cells, while at the same time also generating ever higher levels of chronic inflammation. Some of this is due to various forms of cellular and molecular damage known to contribute to degenerative aging, while some of it is structural, inherent in having what is a more or less fixed-sized system that tries to devote resources to remembering every pathogen it encounters. It works well at the outset but eventually runs out of space.
These researchers are investigating links between immune system function and declining autophagy, adding another voice to those already suggesting that ways to enhance natural levels of autophagy would be of general benefit in the treatment of aging and age-related disease:
Macrophages provide a bridge linking innate and adaptive immunity. An increased frequency of macrophages and other myeloid cells paired with excessive cytokine production is commonly seen in the aging immune system, known as 'inflammaging'. It is presently unclear how healthy macrophages are maintained throughout life and what connects inflammation with myeloid dysfunction during aging.
Autophagy, an intracellular degradation mechanism, has known links with aging and lifespan extension. Here, we show for the first time that autophagy regulates the acquisition of major aging features in macrophages. In the absence of the essential autophagy gene Atg7, macrophage populations are increased and key functions such as phagocytosis and nitrite burst are reduced, while the inflammatory cytokine response is significantly increased - a phenotype also observed in aged macrophages. Furthermore, reduced autophagy decreases surface antigen expression and skews macrophage metabolism toward glycolysis.
We show that macrophages from aged mice exhibit significantly reduced autophagic flux compared to young mice. These data demonstrate that autophagy plays a critical role in the maintenance of macrophage homeostasis and function, regulating inflammation and metabolism and thereby preventing immunosenescence. Thus, autophagy modulation may prevent excess inflammation and preserve macrophage function during aging, improving immune responses and reducing the morbidity and mortality associated with inflamm-aging.
DATA ON BRAIN AGING AND EARLY SIGNS OF ALZHEIMER'S DISEASE
Tuesday, March 17, 2015
The brain is impacted by the processes of degenerative aging for decades before the damage rises to noticeable levels. When the technologies exist to repair this damage, treatments should ideally begin in the middle of life, not wait until there are obvious signs of degeneration. Prevention beforehand is better than restoration after the fact, for all that most of us are, at best, going to forced along the restoration route given the prospective timelines for the development of repair therapies:
Typical cognitive aging may be defined as age-associated changes in cognitive performance in individuals free of dementia. To assess brain imaging findings associated with typical aging, the full adult age spectrum should be included. Researchers compared age, sex and APOE ɛ4 effects on memory, brain structure (as measured by adjusted hippocampal volume, HVa) and amyloid [brain plaques associated with Alzheimer disease] positron emission tomography (PET) in 1,246 cognitively normal individuals between the ages of 30 and 95.
Overall memory worsened from age 30 through the 90s. HVa worsened gradually from age 30 to the mid-60s and more steeply after that with advancing age. Median amyloid accumulation seen on PET scans was low until age 70 but increased after that. Memory was worse in men than women overall, especially after 40. The HVa was lower in men than women overall, especially after 60. For both males and females, memory performance and HVa were not different by APOE ɛ4 carrier status at any age. From age 70 onward, APOE ɛ4 carriers had greater median amyloid accumulation seen on PET scans than noncarriers.The ages at which 10 percent of the population was "amyloid PET positive" were 57 years for APOE ɛ4 carriers and 64 years for noncarriers. Amyloid PET positive indicates individuals are accumulating amyloid in their brain as seen on PET scans and, while they may be asymptomatic, they are at risk for Alzheimer disease.
"Our findings are consistent with a model of late-onset AD [Alzheimer disease] in which β-amyloidosis arises later in life on a background of preexisting structural and cognitive decline that is associated with aging and not with β-amyloid deposits."
TOM40 AND NEURODEGENERATION
Tuesday, March 17, 2015
Mitochondria, the power plants of the cell, are important in aging. They are the descendants of symbiotic bacteria and contain their own DNA, separate from that in the cell nucleus. This mitochondrial DNA is just a remnant, however, as over the course of evolutionary time most of its genes have moved to the nucleus. A complex set of mechanisms exists to transport proteins produced in the nucleus back into mitochondria where they are needed, one part of which is the TIM/TOM complex. This paper focuses on one of the proteins involved, TOM40, or TOMM40, and in particular its relationship with mutations known to play a role in one or more neurodegenerative conditions:
Mitochondrial dysfunction is an important factor in the pathogenesis of age-related diseases, including neurodegenerative diseases like Alzheimer's and Parkinson's spectrum disorders. A polymorphism in Translocase of the Outer Mitochondrial Membrane - 40 kD (TOMM40) is associated with risk and age of onset of late-onset Alzheimer's, and is the only nuclear- encoded gene identified in genetic studies to date that presumably contributes to Alzheimer's-related mitochondria dysfunction.
In this review, we describe the TOM40-mediated mitochondrial protein import mechanism, and discuss the evidence linking TOM40 with Alzheimer's (AD) and Parkinson's (PD) diseases. All but 36 of the more than ~1,500 mitochondrial proteins are encoded by the nucleus and are synthesized on cytoplasmic ribosomes, and most of these are imported into mitochondria through the TOM complex, of which TOM40 is the central pore, mediating communication between the cytoplasm and the mitochondrial interior. Amyloid precursor protein enters and obstructs the TOM40 pore, inhibiting import of OXPHOS-related proteins and disrupting the mitochondrial redox balance. Other pathogenic proteins, such as amyloid-β and alpha-synuclein, readily pass through the pore and cause toxic effects by directly inhibiting mitochondrial enzymes. Healthy mitochondria normally import and degrade the PD-related protein Pink1, but Pink1 exits mitochondria if the membrane potential collapses and initiates Parkin-mediated mitophagy. Under normal circumstances, this process helps clear dysfunctional mitochondria and contributes to cellular health, but PINK1 mutations associated with PD exit mitochondria with intact membrane potentials, disrupting mitochondrial dynamics, leading to pathology.
Thus, TOM40 plays a central role in the mitochondrial dysfunction that underlies age-related neurodegenerative diseases. Mitochondria underlie many cellular processes and it is not surprising functional and structural mitochondrial defects contribute to the pathogenesis of age-related diseases, including neurodegenerative diseases.
TARGETING NITRIC OXIDE METABOLISM IN CALORIE RESTRICTION MIMETICS
Wednesday, March 18, 2015
Calorie restriction mimetic treatments are those that recreate at least some part of the calorie restriction response. Calorie restriction with optimal nutrition alters near every measure of metabolism and slows near every measure of degenerative aging, producing improved short term metrics of health and extending longevity in those species where that has been evaluated. Thus there is a wide range of possible targets for calorie restriction mimetics, but this comes hand in hand with the continued challenge of identifying primary versus secondary mechanisms, and important versus unimportant mechanisms. One area gaining more attention of late involves the varied roles of nitric oxide in metabolism; having more of it in circulation seems like a good thing:
Calorie restriction is known to extend lifespan among organisms by a debating mechanism underlying nitric oxide-driven mitochondrial biogenesis. We report here that nitric oxide generators including artemisinin, sodium nitroprusside, and L-arginine mimics calorie restriction and resembles hydrogen peroxide to initiate the nitric oxide signaling cascades and elicit the global antioxidative responses in mice. The large quantities of antioxidant enzymes are correlated with the low levels of reactive oxygen species, which allow the down-regulation of tumor suppressors and accessory DNA repair partners, eventually leading to the compromise of telomere shortening. Accompanying with the up-regulation of signal transducers and respiratory chain signatures, mitochondrial biogenesis occurs with the elevation of adenosine triphosphate levels upon exposure of mouse skeletal muscles to the mimetics of calorie restriction.
In conclusion, calorie restriction-triggered nitric oxide provides antioxidative protection and alleviates telomere attrition via mitochondrial biogenesis, thereby maintaining chromosomal stability and integrity, which are the hallmarks of longevity.
DYING OF OLD AGE DOESN'T FEEL SO GREAT
Wednesday, March 18, 2015
There are a surprisingly large number of studies on personality traits and psychological states as they relate to health status in aging. I can't help but feel that all those funds should perhaps have gone towards generating more practical outcomes in the sciences, but it is what it is. The association that consistently emerges from these studies is that positive traits and emotional states correlate with greater survival, health, and longevity. Optimism, conscientiousness, satisfaction, and so forth, all show up more often in healthier old people. I'm sure you can all theorize as to exactly why this is the case: on the one hand people predisposed to these traits will probably take better care of themselves over the long term, but - far more importantly - dying of old age, being sick and frail and in pain, just isn't a good place to find yourself. The worse your health, the worse you feel.
People spend a lifetime striving to forget what lies ahead, thinking it inevitable. That was a good strategy when aging was in fact inevitable, but now, in an age in which we could be developing therapies to defeat degenerative aging, most of the public still keep their heads in the sand, unwilling to even think about the topic, let alone provide the support and funding needed for rapid progress in medicine. The habits of the past are sabotaging prospects for the future.
High morale is defined as future-oriented optimism. Previous research suggests that a high morale independently predicts increased survival among old people, though very old people have not been specifically studied. Here we investigate whether high morale is associated with increased survival among very old people.
The Umeå 85+/GErontological Regional DAtabase-study (GERDA) recruited participants aged 85 years and older in northern Sweden and western Finland during 2000-02 and 2005-07, of whom 646 were included in this study. Demographic, functional- and health-related data were collected in this population-based study through structured interviews and assessments carried out during home visits and from reviews of medical records. The 17-item Philadelphia Geriatric Center Morale Scale (PGCMS) was used to assess morale.
The 5-year survival rate was 31.9% for participants with low morale, 39.4% for moderate and 55.6% for those with high morale. The relative risk (RR) of mortality was higher among participants with low morale (RR = 1.86) and moderate morale (RR = 1.59) compared with participants with high morale. Similar results were found after adjustment for age and gender. In a model adjusted for several demographic, health- and function-related confounders, including age and gender, mortality was higher among participants with low morale (RR = 1.36) than those with high morale. There was a similar but non-significant pattern towards increased mortality in participants with moderate morale (RR = 1.21). We conclude that high morale is independently associated with increased survival among very old people.
MICRORNAS PROMOTE HEART REGENERATION
Thursday, March 19, 2015
Researchers have discovered a novel approach to spur greater regeneration in heart tissue:
The heart tissue of mammals has limited capacity to regenerate after an injury such as a heart attack, in part due to the inability to reactivate a cardiac muscle cell and proliferation program. Recent studies have indicated a low level of cardiac muscle cell (cardiomyocyte) proliferation in adult mammals, but it is insufficient to repair damaged hearts. Researchers have now shown that a subset of RNA molecules, called microRNAs, is important for cardiomyocyte cell proliferation during development and is sufficient to induce proliferation in cardiomyocytes in the adult heart. MicroRNAs, which do not generate proteins, repress gene expression by binding messenger RNAs, which do generate proteins, and promote their degradation.
The loss of the microRNA cluster miR302-367 in mice led to decreased cardiomyocyte cell proliferation during development. In contrast, increased expression of the microRNA cluster in adult hearts led to a reactivation of proliferation in the normally non-reproducing adult cardiomyocytes. This reactivation occurred, in part, through repression of a pathway called Hippo that governs cell proliferation and organ size. "The Hippo pathway normally represses cell proliferation when it is turned on. The cluster miR302-367 targets three of the major kinase components in the Hippo pathway, reducing pathway activity, which allows cardiomyocytes to re-enter the cell cycle and begin to regrow heart muscle. This is a case of repressing a repressor."
In adult mice, re-expression of the microRNA cluster reactivated the cell cycle in cardiomyocytes, resulting in reduced scar formation after an experimental myocardial infarction injury was induced in the mice. There was also an increase in the number of heart muscle cells in these same mice. However, long-term expression of more than several months of the microRNA cluster caused heart muscle cells to de-differentiate and become less functional. The investigators surmised that cardiomyocytes likely need to de-differentiate to divide, but they may lose their ability to contract over time. "We overcame this limitation by injecting synthetic microRNAs with a short half-life called mimics into the mice." Mimic treatment for seven days after cardiac infarction led to the desired increase in cardiomyocyte proliferation and regrowth of new heart muscle, which resulted in decreased fibrosis and improved heart function after injury.
CONSIDERING THE PATH TO CURING BLINDNESS
Thursday, March 19, 2015
The most prevalent causes of blindness are degenerative and associated with aging, the result of loss of cells and structure in the retina. There are numerous other causes, including optic nerve damage that can result from trauma, but these are fortunately less common. At the high level there are two main approaches that will lead to reliable future restoration of vision. The first is some form of cell therapy, inducing regeneration that would not normally take place in order to repair the damage such that the functional components of sight are restored. The second is to bypass dysfunctional tissues and replace them with machinery. At present regenerative medicine is much further ahead, while state of the art retinal prostheses consist of electrode grids that provide only a poor substitute for vision, not the real thing. Both will improve considerably in the years ahead.
Losing eyesight is a common problem, be it due to the process of aging or the development of a specific condition. A range of conditions exists where those who develop them are faced with a gradual loss of vision until their impairment is so severe that they are effectively blind. Retinal degeneration disorders have no cure. These diseases break down the retina, the layer of tissue found at the back of the eye containing cells that detect light entering the organ.
Embryonic stem cells could be used to build new retinal pigmented epithelial cells - cells that nourish retinal visual cells and absorb light - that could be transplanted into a patient. Doing this could slow or prevent the loss of the visual cells, and while deriving new visual cells from embryonic stem cells could lead to even more pronounced results, researchers have found it more difficult to successfully derive these cells and transplant them into the retina. Mouse studies have previously shown that this technique can work and that transplanted cells can integrate fully with the retina, restoring vision to the animals. Researchers have managed to derive rod cells from embryonic stem cells and are currently working on deriving cone cells and transplanting them into animals. If these trials prove successful, the next step could be human trials.
"In patients who have already lost their sight, our therapeutic goal is to restore vision. This has been successfully accomplished via the Argus II retinal prosthesis in patients with advanced retinitis pigmentosa." The 15th man in the US to receive the life-changing device is now able to make out the outlines of objects and people thanks to his new retinal prosthesis. He is now able to navigate through crowded environments - such as shopping centers - without the use of a cane. A camera connected to a pair of glasses transmits visual information to a small chip attached to the back of the eye via a small computer worn in a belt pack. The chip can send light signals directly to the optic nerve, bypassing the damaged retina and providing the patient with visual information in the form of flashes of light. While this form of vision could be considered basic compared with what normal-sighted people are used to, it is a marked improvement for many without sight. As he used his retinal prosthesis for the first time, the patient described the artificial vision as "crude, but significant."
A NOVEL APPROACH IN ENGINEERING T CELLS TO ATTACK CANCER
Friday, March 20, 2015
A broad range of methods are under development to engineer T cells that can selectively attack cancer cells. If aggressive enough and selective enough, the immune system should in theory be able to tame and destroy most cancers, but the devil is in the details as is always the case in these matters. The use of chimeric antigen receptors in altered T cells is one noteworthy approach, and here researchers report on their efforts to mine the biochemistry of another species for similarly useful additions to human T cells:
T cells are the linchpin in the attack of the immune system. On their surface they have anchor molecules (receptors) with which they recognize foreign structures, the antigens of bacteria or viruses, and thus can target and destroy invaders. Cancer researchers and immunologists are attempting to mobilize this property of the T cells in the fight against cancer. The objective is to develop T cells that specifically recognize and attack only cancer cells but spare other body cells.
Researchers have now developed human T cell receptors (TCRs) that have no tolerance toward human cancer antigens and specifically recognize the antigen MAGE-A1, which is present on various human tumor cells. First, the researchers transferred the genetic information for human TCRs into mice, thus creating an entire arsenal of human TCRs. When the humanized mouse T cells come into contact with human cancer cells, they perceive the tumor antigens as foreign - like viral or bacterial antigens. Thus, the T cells can specifically target, attack and destroy the tumor cells. The researchers subsequently isolated the human T-cell receptors of these mice, which are specifically targeted toward the tumor antigen MAGE-A1. Then they transferred the T-cell receptors into human T cells, thereby training them to recognize the cancer cells as foreign.
Some people possess T cells which naturally recognize MAGE-A1 on tumor cells, but only in the Petri dish. In studies using an animal model, only the human TCRs derived from mice were shown to be effective against the tumor. The TCRs from human T cells ignored the tumor completely. "The fact that our TCRs from the mouse are better is a strong indication that the T cells of a human are tolerant toward MAGE-A1." Using the T-cell receptors they developed, the researchers are planning an initial clinical trial with patients with MAGE-A1 positive multiple myeloma, a malignant disease of the bone marrow.
MORE SIRT7 IMPROVES AGED STEM CELL REGENERATIVE CAPACITY
Friday, March 20, 2015
There is relatively little study of sirtuin 7 (SIRT7) in comparison to the better known and greatly overhyped sirtuin 1 (SIRT1). All members of the sirtuin family have broad influence over a range of fundamental cellular processes, and thus cataloging their roles in metabolism is an enormous undertaking, still in the early stages despite the mountains of data and years of work to date. Still, inroads are being made, but it remains to be seen whether they are any more likely to result in practical applications than the past decade of work on SIRT1.
Mitochondria host a multitude of proteins that need to be folded properly to function correctly. When the folding goes awry, the mitochondrial unfolded-protein response, or UPRmt, kicks in to boost the production of specific proteins to fix or remove the misfolded protein. Researchers stumbled upon the importance of UPRmt in blood stem cell aging while studying a class of proteins known as sirtuins, which are increasingly recognized as stress-resistance regulators. The researchers noticed that levels of one particular sirtuin, SIRT7, increase as a way to help cells cope with stress from misfolded proteins in the mitochondria. Notably, SIRT7 levels decline with age. There has been little research on the UPRmt pathway, but studies in roundworms suggest that its activity increases when there is a burst of mitochondrial growth.
Adult stem cells are normally in a quiescent, standby mode with little mitochondrial activity. They are activated only when needed to replenish tissue, at which time mitochondrial activity increases and stem cells proliferate and differentiate. When protein-folding problems occur, however, this fast growth could lead to more harm. "We isolated blood stem cells from aged mice and found that when we increased the levels of SIRT7, we were able to reduce mitochondrial protein-folding stress. We then transplanted the blood stem cells back into mice, and SIRT7 improved the blood stem cells' regenerative capacity."
The new study found that blood stem cells deficient in SIRT7 proliferate more. This faster growth is due to increased protein production and increased activity of the mitochondria, and slowing things down appears to be a critical step in giving cells time to recover from stress, the researchers found. "When there's a mitochondrial protein-folding problem, there is a traffic jam in the mitochondria. If you prevent more proteins from being created and added to the mitochondria, you are helping to reduce the jam." Until this study, it was unclear which stress signals regulate the transition of stem cells to and from the quiescent mode, and how that related to tissue regeneration during aging. "Identifying the role of this mitochondrial pathway in blood stem cells gives us a new target for controlling the aging process."