FIGHT AGING! NEWSLETTER
January 11th 2016
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.
This content is published under the Creative Commons Attribution 3.0 license. You are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!
To subscribe or unsubscribe please visit: https://www.fightaging.org/newsletter/
- There is Widespread Desire for Extended Longevity, Provided it Brings More Healthy, Youthful Years
- The Much Hyped End to Antibiotics is Nowhere in Sight
- The Slow Progression of Mitochondrially Targeted Antioxidants
- A Review of Mechanisms Involved in Slowing Aging via the Practice of Calorie Restriction
- An Outsider Looks in on the Longevity Science Community
- Latest Headlines from Fight Aging!
- Mechanisms of Memory Impairment in Alzheimer's Disease
- More on Janus Kinase Inhibitors as a Possible Treatment for Cellular Senescence
- To What Degree are Old Exercise Studies Flawed?
- Biogerontology Research Foundation Joins Calls to Classify Aging as a Disease
- Theorizing that Immunosenescence Contributes to Stem Cell Activity Decline in Aging
- Attempting the Growth of Human Organs in Animals
- Efficient Conversion of Skin Cells to Functional Islet Cells
- Autophagy Key to Restoring Function in Old Muscle Stem Cells
- Loss of PHD1 Produces Greater Resistance to Stroke Damage
- Blocking Brain Inflammation in Alzheimer's Disease
THERE IS WIDESPREAD DESIRE FOR EXTENDED LONGEVITY, PROVIDED IT BRINGS MORE HEALTHY, YOUTHFUL YEARS
There is a prevailing public disinterest in medical research to extend healthy life. The open access survey linked here is an attempt to understand which of the present widespread beliefs on medicine, aging, and longevity is a more important determinant of this public disinterest. Note that the paper is only available in PDF format at the moment. Also note that this is a project of the Health Extension folk in the Bay Area - so good for them for stepping up, doing the work, and getting it published.
The longevity science community has long known that the public appears indifferent or even hostile to the prospect of treating aging and extending healthy life spans. I and others believe this goes a long way towards explaining why the funding situation for aging research is particularly bad, even for a world in which near all useful medical research is poorly funded and given little attention by people outside the scientific community. There are a number of schools of thought as to why people don't appear to want to live longer, which include the mistaken belief that only wealthy people would benefit from longevity assurance therapies, the mistaken belief that overpopulation and dystopia would result, and the mistaken belief that greater longevity would mean more years of being ill, frail, and decrepit. There is also the role of conformity to the norm to consider, where the norm is what happened to your parents and grandparents, and the open question of why all of these widespread erroneous beliefs persist though year after year of numerous scientists telling the public that they are incorrect.
I'm sure many long-time readers here will not be surprised to find that the survey linked below identified the primary problem as being the fear of frailty, the unfounded assumption that being older as a result of new medical treatments must mean being having more of the characteristics of people who are presently old. Perhaps it is that many people see all medicine as equal, and make no practical distinction between (a) the present patching over of age-related illness without addressing its causes, an approach that allows survivors to struggle on, to age and decline some more and die later rather than die sooner, and (b) a future treatment that reverses and repairs some of the causes of aging and thus postpones or reverses all age-related disease and decline. This is one of the challenges of standing at the point at which the approach to aging and medicine is fundamentally changing: the old common wisdom is not longer correct, and the expectations among researchers for the near future are not yet widely appreciated.
Great desire for extended life and health amongst the American public
Recent advances in aging research and regenerative medicine may soon translate into dramatically increased human lifespans. But does the American public want to live longer? Popular press argues the answer is no, e.g. a recent survey on desired lifespan reported in the New York Times found 60% of respondents voted for the shortest option, an 80 year lifespan, while fewer than 1% opted for an unlimited lifespan. Here, we show that negative attitudes to longer lives are a consequence of erroneously equating extended life with an extended period of frailty. When we stipulated continued health to the original survey question, responses dramatically favored longer life: only 20% wish to die at age 85, while 42% want an unlimited lifespan. Since funding for aging research depends on its perceived value, better science communication is needed to align public policy with public interests.
We surveyed 1000 individuals about how long they wished to live (to age 85, 120, 150, or indefinitely), under 3 scenarios: (1) sustained mental and physical youthfulness, (2) mental youthfulness only, (3) physical youthfulness only. While responses to the two partial youthfulness conditions recapitulated the results of previous surveys - i.e., most responders (65.3%) wished to live to age 85 only - under scenario (1) the pattern of responses was completely different. When guaranteed mental and physical health, 797 of 1000 people wanted to live to 120 or longer, and 53.1% of the 797 desired unlimited life spans. Furthermore, 70.1% of the people who responded 85 to scenario (2) or (3) changed their answer to 120 or longer in scenario (1). Full survey response data are publicly available. We also reproduced our primary finding - that most people wish to live far longer than the average human lifespan so long as they stay healthy - using Google Surveys. In this replication cohort of 1500 respondents, we found that 74.4% wished to live to 120 or longer if health was guaranteed, but only 57.4% wished to live that long if it wasn't. Full survey data and results are publicly available in an interactive browsable format.
The public wants to live long, and live healthy. Human supercentenarians give some of the best evidence for the possibility of increased healthspan and healthy aging, or compression of morbidity. Making healthy aging a reality for the rest of the population will be scientifically challenging. Nevertheless, it is becoming increasingly more necessary: chronic age-related diseases account for 75% of Medicare spending, and these numbers are projected to rise as baby boomers age. The National Institute on Aging currently receives less than 1% of the National Institutes of Health's overall annual budget, or less than 0.05% of annual Medicare spending; this is a misallocation of resources. There is a growing demand for more awareness and more funding for basic aging research, and new initiatives such as the Healthspan Campaign and the trans-NIH Geroscience Interest Group are helping lead the way forward. Investing in scientific research and development that targets aging, the process underlying multiple chronic diseases, can offer uniquely high potential returns.
THE MUCH HYPED END TO ANTIBIOTICS IS NOWHERE IN SIGHT
Antibiotics are the drugs used to control bacterial infections. Here I'll point out a couple of recent articles relating to antibiotics research, as counterpoints to the prevailing view that we're in danger of running out of antibiotics that work at some unspecified future date. That would be an existential threat to our desired future of extended healthy longevity, were it to happen, but fortunately I think it is a mirage, as are so many of these predictions of doom. As a general rule predictions of doom rely upon people doing nothing to prevent said doom, and that is never the case.
We humans have trouble thinking rationally about progress. We live in an age of profound technological change: it is everywhere, fast enough to see sweeping differences from decade to decade, and yet it is human nature to look at the present state of things and predict a future that is just today with a few of the deckchairs shuffled around. You have to think carefully on a topic to step beyond this instinct, to consider how the fundamental aspects of the picture will change, not just the fiddling details. The moment that you stop paying attention, you'll backslide into making assumptions that are, in essence, based on the belief that nothing important is going to change.
This aspect of our nature gives rise to Malthusian visions of an end to present resources, and a dismal future world that falters because of it. In practice this end never comes to pass because people react to the threat of scarcity, far in advance, by creating new resources and more efficient ways to use existing resources. The moment that price increases due to scarcity emerge as a possibility on the horizon, scores of entrepreneurs start on their varied visions for a better replacement resource. So we have progress, and in our age that is self-evidently continual, rapid, driven progress.
Present popular views on the future of antibiotics are essentially Malthusian in nature: a trend in drug-resistant bacterial species is observed, and if continued it leads to a scarcity of effective antibiotics in the future. That trend is then projected all the way down to zero, to no working antibiotics and a world of rampaging bacterial infections. That grim result will never happen, however, just as any number of other predicted grim results failed to emerge over the past few hundred years. In this case, as always, entrepreneurs both inside and outside the scientific community have been at work for years on varied solutions to bacterial resistance to antibiotics. A few are mentioned here:
Antibiotics Are Dead; Long Live Antibiotics!
We've been hearing the tales of doom for quite a few years now: the breathtaking promiscuity of bacteria, which allows them to mix and match their DNA with others' to an extent that puts Genghis Khan to shame, has increasingly allowed them to accumulate genetic resistance to more and more of our antibiotics. But this pessimism rests entirely on one assumption: that we have no realistic prospect of developing new classes of antibiotics any time soon, antibiotics that our major threats have not yet seen and thus not acquired resistance to. And it now seems that that assumption is unwarranted. It is based on history - on the fact that no new antibiotic class with broad efficacy has been identified for decades. But very recently, a novel method was identified for isolating exactly those - and it seems to work really, really well.
Antibiotics are generally synthesised in nature by bacteria (or other microbes) as defences against each other. We have identified antibiotics in the lab, and thus necessarily only those made by bacterial species that we can grow in the lab. Yet almost all bacterial species cannot be grown in the lab using present day practical methods. Knowing these points, researchers built a device that allowed them to isolate and grow bacteria in the soil itself, with molecules freely moving into and out of the device, thereby sidestepping our ignorance of which such molecules actually matter. And then they were able to isolate the compounds that those bacteria were secreting and test them for antibiotic potency. And it worked. They found a completely new antibiotic that has already been shown to have very broad efficacy against several bacterial strains that are resistant to most existing antibiotics.
And as if that were not enough, here's the kicker. This was not some kind of massive high-throughput screen of the kind we so often hear about in biomedical research these days. The researchers tried this approach just once, in essentially their back yard, on a very small scale, and it still worked the first time. What that tells us is that it can work again - and again, and again.
Researchers on the hunt for more-effective therapies that preserve a healthy microbiome are taking a closer look at the many different viruses that attack bacteria. Bacteriophages (literally, "bacteria eaters") punch holes through the microbes' outer covering and inject their own genetic material, hijacking the host's cellular machinery to make viral copies, then burst open the cell with proteins known as lysins, releasing dozens or hundreds of new phages. The cycle continues until there are no bacteria left to slay. Phages are picky eaters that only attack specific types of bacteria, so they're unlikely to harm the normal microbiome or any human cells. And because phages have coevolved with their bacterial victims for millennia, it's unlikely that an arms race will lead to resistance. This simple biology has led to renewed interest in the surprisingly long-standing practice of phage therapy: infecting patients with viruses to kill their bacterial foes.
While most research is still in the preclinical phase, a handful of trials are underway, and a growing number of companies are investing in the treatment strategy. Phage therapy is receiving as much attention now as it did in the pre-antibiotic era, when it flourished in spite of the dearth of clinical tests or regulatory oversight at the time. "Bacteriophage therapy will have its day again. It sort of had one, before antibiotics came along, but it wasn't well understood then."
On that topic, what to do about the many types of viruses that we don't want to engage with? This is a very different area of research in comparison to the matter of controlling bacterial infection, but again there are numerous promising strategies that look capable of fundamentally changing the picture for the treatment of viral infections. One of those you might be familiar with is DRACO, double-stranded RNA activated caspase oligomerizer, a technology that can in principle control near any type of viral infection by destroying infected cells before viruses can multiply effectively.
THE SLOW PROGRESSION OF MITOCHONDRIALLY TARGETED ANTIOXIDANTS
It was going on a decade ago that I first noticed research on antioxidant compounds that target mitochondria in cells. That was the Russian research team of Vladimir Skulachev and their family of plastinquinone compounds, with SkQ as the canonical example. They started off with a demonstration that SkQ modestly extended healthy life span in mice, which is the source of interest in mitochondrially targeted antioxidants in the longevity science community.
Why would we expect antioxidants in mitochondria to extend healthy life to some degree? Mitochondria are the power plants of the cell, generating chemical energy stores that power other cellular processes. In the course of doing this the mitochondria also create reactive oxidizing molecules that can damage molecular machinery. That damage is usually quickly repaired, but some of it can slip through the gaps to linger, multiple, and cause harmful consequences in the long-term. There is no direct relationship between the level of oxidative stress generated in a cell by its mitochondria and the pace of aging: both slight reductions (less damage) and slight increases (the cell reacts with more repair efforts, so less damage overall) have been shown to extend life in short-lived laboratory animals. Some of the most important potential damage caused by oxidizing molecules is inside mitochondria themselves, however, right at the source. This is probably why antioxidants localized mitochondria can modestly alter the progression of aging, but antioxidants everywhere else do not. There are in fact natural antioxidants produced within cells that localize to mitochondria, and researchers have demonstrated some degree of slowed aging in mice through genetic engineering that results in increased production of these mitochondrially targeted antioxidants.
The types of antioxidant you can go out and buy in a store do not localize to mitochondria and do nothing for your health. That is in fact the scientific consensus on supplements in general, derived from numerous large studies. In fact taking a lot of antioxidants is probably mildly harmful, since it interferes with the oxidative signaling that is a necessary part of the chain of mechanisms that produce benefits from exercise. Exercise causes mild cellular stress, and the raised levels of oxidative molecules generated by mitochondrial activity is a signal for cells to wake up and do something about the situation. Suppress that signal with antioxidants and exercise benefits vanish.
Over the past decade Skulachev's researchers have tested plastiquinone compounds in a variety of laboratory species. As is often the case in these matters, early life span figures settled down to a lower 10% gain or less in more careful studies, much less than can be achieved via calorie restriction, to pick one example. However, they also tested for results in the treatment of range of specific medical conditions. They eventually settled on bringing a drug to market for eye conditions shown to benefit from the actions of mitochondrial antioxidants. Unlike the life extension, these results seem much more robust and transformative. Regardless, translating research to the clinic is a slow business at the best of times, thanks to heavy-handed regulation, and at the present time the only way forward within the system is to treat a specific disease rather than the causes of aging itself. This is the case even if you happen to have an approach to hand that works somewhat better than mitochondrially targeted antioxidants.
Vladimir Skulachev isn't the only researcher with a background in mitochondrial antioxidants, and the Russian teams are not the only groups working in this area. The link I have for you today is related to a US group and their mitochondrially targeted molecule SS-31, also known as MTP-131, Bendavia, and Ocuvia. These researchers are also well down the path of commercial development via the startup Stealth Biotherapeutics. Interestingly, as this article notes, SS-31 may not even be an effective antioxidant but instead reduces oxidant levels via other means:
New Mitochondrial Therapy Based on Bioenergetics Advancing in Range of Clinical Trials
In the pipeline at Stealth Biotherapeutics is a new therapy, MTP-131, with the potential to treat individuals with mitochondrial disease and other diseases affected by mitochondrial dysfunction. The systemic version of MTP-131 (also known as Bendavia) is in clinical trials for skeletal muscle and cardio-renal diseases. The topical eye drop version (also known as Ocuvia) is on track to initiate clinical trials into Fuchs' corneal endothelial dystrophy and Leber's hereditary neuropathy in early 2016. "In collaboration with mitochondrial experts, we are looking at the organs with the most mitochondria (e.g., the heart) or that produce the most energy (e.g., muscle tissue and the eye). Mitochondrial function is involved in many different diseases. The key is which disease areas to focus."
"MTP-131 crosses the plasma membrane of cells and localizes specifically to the mitochondria." Probing further into the mechanism of action, the research team discovered that MTP-131 associates with the inner membrane of the mitochondria, where the respiratory complexes that generate ATP are located. "What's unique about that inner membrane? As it turns out, it's the only place where the phospholipid cardiolipin is found." Cardiolipin, a molecule that composes approximately 20% of the inner mitochondrial membrane's phospholipid content, differs from other phospholipid molecules such as phosphatidylcholine because it has two "phospho" head groups and four acyl chains. This unique structure gives cardiolipin a conical shape that forms a curve in the inner membrane of the mitochondria when the molecules are adjacent to each other, and helps hold the respiratory complexes in place. The binding of MTP-131 to cardiolipin may help the respiratory complexes operate more efficiently, in addition to other potential effects.
This mechanism of action sets MTP-131 apart from other investigational mitochondrial disease therapies because it directly affects bioenergetics rather than scavenges reactive oxygen species (ROS). Whereas therapeutics that neutralize ROS can potentially decrease ROS to harmfully low levels (some ROS activity is necessary in cells for signaling purposes), MTP-131 normalizes ROS levels by increasing the efficiency of mitochondria. In one experiment with old and young mice, it was shown that the mitochondria of old mice reached nearly the same level of ATP generation as that of young mice an hour after treatment with MTP-131, rising from approximately two-thirds the level of young mice. MTP-131 appears to have therapeutic effects only in abnormal or stressed mitochondria, potentially reducing the risk for side effects in patients. Additional safety studies in clinical trials are needed to determine any adverse effects of treatments.
A REVIEW OF MECHANISMS INVOLVED IN SLOWING AGING VIA THE PRACTICE OF CALORIE RESTRICTION
Calorie restriction has been rigorously demonstrated to slow aging in mammals for eighty years, but only in the past thirty years has research on this topic picked up. Since calorie restriction has a sizable and very reliable effect in comparison to most other interventions that can modestly slow aging, and requires no advanced technology or expensive treatments, the fact that it does extend life has been the starting point for many researchers interested in the mechanisms of aging. One of the most important tools in the sciences is the comparison of two similar things in order to pinpoint differences that are important, in this case animals of the same species and lineage with varied dietary calorie intake.
The primary goal of the scientific community is to map the changing molecular biochemistry of aging, with doing something about aging a distant second where it is considered at all. The calorie restriction response is at once useful and frustrating because it changes near everything in the operation of metabolism and slows near every measure of aging. Since all aspects of cellular biology are intertwined, this makes it enormously difficult to figure out chains of cause and effect. Understanding calorie restriction is more or less equivalent to fully understanding and mapping a large swathe of cellular biochemistry. This is a task that is expected to run for decades yet at the present pace. There are a lot of details and blank spots left to be filled in, and the closer researchers look, the more there is to find.
It is useful to understand that complex descriptions of what goes on in a calorie restricted individual are still really only sketches. There are lines drawn, and the high level picture is mostly in place in outline at least, but the full details are yet to be cataloged, and there may yet be surprises. If researchers waded through all the work required, and were to develop drugs that accurately mimicked the calorie restriction response - a tall order - the benefits would still be modest. This is not rejuvenation, repair of damage, but only a slowing of the progression of damage in aging. It is something worth doing when it is free, since every healthy year counts in a time of rapid progress, but the price tag for the scientific community to produce drugs that achieve that end seems excessive to me, at least when considering the marginal outcome. At least a billion has been spent on this so far, and there is nothing much to show for it aside from new knowledge of narrow slices of our biology: see the much hyped work on sirtuins for example. We'd be better off supporting SENS-like rejuvenation research, such as senescent cell clearance, as that has already produced more impressive results in the first studies in mice than calorie restriction mimetics ever have.
None of that means that calorie restriction research is uninteresting. Far from it. Take this open access review, for example. Just bear in mind the costs and the benefits of various approaches when reading the literature:
Calorie restriction as an intervention in ageing
Ageing is not a disease and therefore, disease-oriented research and treatment approaches are not adequate. It has thus been proposed that the use of health-oriented and preventive strategies is more beneficial than disease-oriented treatments. Calorie restriction (CR) is, to date, the most successful intervention to delay ageing progression or the development of age-related chronic diseases. CR has been defined as the reduction of energy intake without malnutrition. During the last few years it has been demonstrated that CR extends lifespan, extending the healthspan by delaying the onset of age-related diseases in many of the animal models studied. This effect of CR on longevity was explained in a unified theory of ageing as not a simple and passive effect but an active, highly conserved stress response that increases the organism's chance of surviving adversity. Thus, CR produces a response that modifies key process in cell protection, reparation mechanisms and modulation of metabolism that permits a higher survival against adversity. This has been supported by the 'Hormesis hypothesis of CR' that suggests that the induction of a moderate stress causes adaptive responses of cells and organs, preventing further damage due to a stronger stress
There are no detailed reports about the effect of CR on longevity in humans. The longer life expectancy of humans in comparison with other animals and the low number of persons tested makes it difficult to reach conclusions about the effect of CR on human longevity. It is not yet clear if the reported effects on longevity and healthspan found in humans are due to the decrease in the calorie intake or are the result of a high quality diet. However, it seems clear that a reduction in calorie intake in humans improves healthspan, and delays cardiac ageing, improving cardiovascular function, one of the main causes of death in humans.
Mitochondrial activity and ROS production are modulated by CR
In spite of the enormous number of articles published about the mechanism involved in the effect of CR on longevity, these mechanisms have not been clarified to date, although an important role of the maintenance of a balanced activity in mitochondria is supported by a large body of evidence. Ageing is associated with the impairment of mitochondria, with a significant increase in reactive oxygen species (ROS) generation and a decrease in antioxidant defences, causing accumulation of mitochondrial DNA and oxidative damage. An important factor involved in the accumulation of damaged mitochondria during ageing is the decline of the mitochondrial turnover by inhibition of mitophagy; the specific autophagy process that removes damaged mitochondria. It is clear that the renovation of mitochondrial network plays a key role in healthspan increase after CR.
Importance of membrane lipid composition on the CR effect
The decrease in the oxidative damage in organic structures is one of the main factors contributing to lifespan extension induced by CR. The fatty acid composition of cell membranes is another important factor involved in ageing progression because it influences the lipid peroxidation rate during ageing. Thus, several findings indicate that the increase in lipid peroxidation during ageing. It is still unclear whether lifespan extension induced by CR can also be explained by changes in membrane fatty acid composition conferring higher resistance to peroxidation. We have recently found that lipid composition in the diet can modulate the effect of CR on longevity, for example.
Antioxidant activities in ageing and CR
Oxidative damage is prevented by endogenous antioxidant activities in cells and organs. Although one of the most popular theories to explain the prolongevity effect of CR on different organisms is based on higher protection against the increase in oxidative stress and subsequent cell damage, the role of antioxidants in CR effect is not clear. Many lines of evidence indicate that CR reduces age-associated accumulation of oxidized molecules. However, the lack of lifespan extension in antioxidant enzyme overexpression experiments casts doubt on the importance of antioxidants in the CR effect. Higher levels of antioxidants do not necessarily indicate a higher antioxidant protection and imbalances produced by the overexpression or higher activity of one antioxidant enzyme must be taken into consideration.
Among the hypotheses to explain ageing, several findings indicate that changes in the insulin-IGF-I receptor signalling system are involved in the modulation of ageing. CR reduces plasma levels of IGF-I, insulin and glucose in rodents and also in humans.
Target of Rapamycin (TOR)
TOR protein members are a conserved family of kinases that respond to stress, nutrient and growth factors. TOR stimulates cell growth when food is available. TOR inhibits autophagy and stimulates protein synthesis and cell proliferation. The importance of TOR in longevity induced by CR was also demonstrated in invertebrates. In these organisms, down-regulation of TOR produces an increase in lifespan.
AMP-dependent protein kinase (AMPK)
AMPK is a very sensitive energy sensor in cells and organisms. AMPK is activated in response to an increase in the AMP/ATP ratio, for example, when cells are deprived of glucose, whereas its activity decreases when cells are full of energy, indicated by a lower AMP/ATP ratio. As in the case of other regulators such as sirtuins, its effect on longevity has been observed in several organisms from yeast to mammals. It has been clearly demonstrated that an increase in AMPK activity is associated with a longer lifespan while its inhibition shortens it. However, in mammals, the importance of this kinase is under debate since it has been reported that its activity is not affected by CR or is even reduced. However, other studies indicate an increase in AMPK activity in heart and skeletal muscle. These discrepancies could be due to differences in the amount of time under CR or the degree of CR which can play an important role in nutrient balance.
Some time ago it was demonstrated that the orthologue of mammalian SIRT-1, Sir2, was able to increase lifespan in invertebrates. In mammals, it is clear that CR induces the expression and the activity of sirtuins in many organs and their activities are associated with many of the metabolic effects found in these organisms after CR. Interestingly, sirtuins seem to play a central role in the response to CR. Sirtuins act as nutrient and metabolic sensors by detecting fluctuations in the NAD+/NADH ratio. When nutrients, especially glucose, decrease, NAD+ accumulates and sirtuins are activated. Thus sirtuins have an opposite effect to TOR activation after glucose input. The complexity of sirtuins in mammals has promoted the idea that they can show both pro- and anti-ageing capacities in mice.
Mitochondrial modifications induced by CR
Several studies found that mitochondrial biogenesis is impaired during ageing, especially in high-energy-demanding tissues such as muscle, brain or heart. CR and other interventions such as exercise or nutraceuticals such as resveratrol induce mitochondrial biogenesis in heart and skeletal muscle in humans and other organisms, indicating their role in the maintenance of the mitochondrial activity in these organs during ageing.
During the past few years, a group of molecularly unrelated compounds have emerged as CR mimetics, able to produce, at least partially, similar effects in different organisms. In general, all these compounds have a common denominator, the activation of the above-described molecular pathways involved in the response to CR such as AMPK and sirtuins. All these compounds have shown, at least in part, similar effects to CR on cells, tissues and organs and all of them have produced mitochondrial regulation by increasing turnover and activating oxidative metabolism through activation of the AMPK/SIRT1 axis and inhibition of TOR. It seems clear then that the regulation of mitochondrial metabolism by these nutrient sensors is at the centre of the effect of CR and its mimetics on healthspan and longevity.
CR and inflammation
Inflammation is also an important factor in ageing. Proinflammatory factors such as TNF-α increase systemically during ageing. It has been shown that the increase in oxidative stress during ageing can be involved in the incidence of age-related diseases and the induction of a chronic inflammatory process. It is likely that the maintenance of mitochondria biogenesis by CR can increase the resistance of muscle against inflammation.
Effect of CR on age-associated diseases in humans
Two of the main age-associated diseases in humans are type 2 diabetes and cardiovascular disease (CVD). In both cases, models of CR, dietary interventions or exercise have shown important improvements in the onset and development of these diseases.
The broad effect of CR on healthspan and longevity occurs through multiple mechanisms that involve most of the metabolic pathways in tissues and organs. The major effectors are sirtuin deacetylases, AMPK and PGC-1α. CR improves aerobic metabolism by increasing efficient mitochondrial metabolism, lowering endogenous ROS production at the same time as it increases the amount and activity of endogenous antioxidant enzymes. These molecular and physiological effects have also been found with some nutraceuticals and compounds that act as CR mimetics such as resveratrol, rapamycin or metformin. CR also affects the lipid composition of membranes by lowering oxidative damage. Further, the study of the mechanisms involved in the prevention of chronic inflammation induced by CR, probably through similar mechanisms to those found in mitochondrial regulation, is increasing and offers new opportunities to understand how CR prevents endogenous damage in the organism.
AN OUTSIDER LOOKS IN ON THE LONGEVITY SCIENCE COMMUNITY
So you want to observe complexity. You might start with the obscure, rapidly moving collection of human endeavors that boil and ferment at the boundary of late medical research and early clinical development. Advocacy, fundraising, research, networking, non-profits, for-profits, and academics, a multi-level debate of a thousand opinions, and the foundations of new medicine are all mixed into one heated cauldron. In one sense it has always been this way. Figuring out what was happening in aging research and the quest for longer, healthier lives was a real challenge fifteen years ago, back at the turn of the century, let me tell you. But at least back then you could ground every investigation in the truth that if someone was trying to sell you something, then that something was irrelevant: snake oil and wishful thinking and nothing more. The serious science of aging and longevity was restricted to the laboratories, not yet to the point at which meaningful therapies could be constructed. Even stem cell treatments for narrow aspects of age-related degeneration or late-stage age-related disease had barely started to emerge back then.
Nowadays it remains a sizable task to make sense of the science and the state of development if you are coming in as an outsider. Where to even start? That is one of the reasons I continue to write Fight Aging! - because signposts are needed, and for better and worse this is one of them. If people find it hard to make sense of where things stand, how can we ask them to give us their support and their funds to move forward towards rejuvenation therapies? Education, in the sense of providing resources and making matters comprehensible for those who are interested in learning more, is an important part of advocacy.
There is one fundamental way in which understanding longevity science has become much harder today: you can no longer draw the line between the laboratory and the commercial world to say that only in the lab can you find legitimate, useful efforts to build treatments for the causes of aging. A limited number of actual, real rejuvenation treatments that clear or repair one specific root cause of aging are in development, in clinical trials, in biotech startups. There will be more with each passing year. As a result you have to know a lot more about what is going on, and must be prepared to evaluate basis for the treatments that will be available via medical tourism, long in advance of any regulatory approval, just a few years from now.
The popular press article I've linked below is written by an outsider in the context of a time of great change, when the approach to aging in the research community has undergone a fundamental shift, SENS rejuvenation research and any number of gene therapies that might compensate for aspects of degenerative aging are moving from lab to development, or and many of these treatments will pour directly into the global medical tourism marketplace. These treatments are not all of the same class, however, and their usefulness will vary greatly: repairing the damage that causes aging and age-related disease, such as via SENS treatments, is very different from modestly compensating for the harm that damage causes, such as via most of the plausible near-future gene therapies. However: it isn't a joke to say that if you know the right people, you can go to an overseas clinic and pay a few tens of thousands to undergo a gene therapy today. It probably won't be terribly efficient at obtaining a good percentage of cells affected, but that issue is already pretty much solved back in the labs, and will also be solved in the field in a few years. The avalanche is underway, and loud enough that even normally oblivious sections of the media are pricking up their ears:
Special Series: Is Silicon-Valley Birthing the Next Set of Pro-Lifers
Elizabeth Parrish is 44, the tough-gunning, sharp-talking CEO of life-sciences startup BioViva, and seemingly full of life herself. But she says she suffers from a deadly disease. Hoping to stave off the sickness, Parrish recently journeyed to a clinic in Colombia, where she underwent a course of therapy that the FDA hasn't touched with a 10-foot pole. One treatment would alter her telomeres - the stuff at the end of her DNA. The other would inhibit a protein that stops muscle growth. Her affliction? Aging - and all the nasty diseases that come with it, from Alzheimer's and heart trouble to "basic muscle deterioration." Parrish, though perhaps unorthodox, is not alone in her insistence that aging is an evil we have a right to combat. Rather, she's part of a whole generation of futurists talking eagerly of the right to grow old in a better way. At a time when we're living longer - the average life expectancy in 2013 was nearly 80 years old, according to the CDC - this cohort wants even more. They want to live not a few years longer, but tens, even hundreds, of years longer, and what's more, they believe they - and one day all of us - are entitled to do so.
The burgeoning interest in long life isn't mere academic fodder: It has implications for public policy, law, and the health care system as we know it. The central question around which this explosive new debate will churn: Is aging itself a disease? Or is it, as the dominant thinking goes today, just the unfortunate condition that gives rise to a bunch of other nasty illnesses? If societies decided that old age was not a sad yet inevitable fact of life and that it - like malaria, like cancer - demanded funding and doctors battling it, then your primary care doctor and insurers, palliative care providers and government agencies would all have to adjust to a brand-new gravity. This is a whole new iteration of the term "pro-life."
The aging haters have a reasonable spiel down: It's health, pure and simple. That's the line researcher Aubrey de Grey, one of the most prominent scientists working on anti-aging issues, gives me. We're not talking about a right to never die, in his view, or even a right to live on and on. It's the right to have your health taken care of, your diseases ebbed away. It's just that aging happens to be an "uber-disease" we've not yet started to fight. Rather, if we live longer, well, that'll just be a rather nice side effect of researchers like him solving aging diseases.
Despite controversy over certain methods, some spine-tingling peer-reviewed research has lately appeared from hospitals, universities and privately funded groups like de Grey's Mountain View-based SENS Research Foundation - which just had its first paper in Science this year - or Google's biotech company Calico (which is still stealthy as hell and said they couldn't speak to us yet). Nonetheless, progress so far has come at a pace far slower than the private sector likes, and is laden with all the annoyances of bureaucracy and peer review. The National Institutes of Health organizes itself around diseases, but aging is a "constellation of diseases," like cancer, muscle wasting and dementia. The NIH doesn't really tackle constellations. De Grey spares no words: The National Institute on Aging (NIA) doesn't have much money, and the way it gets distributed is "inherently biased against revolutionary work," he huffs. A spokeswoman for the NIA pointed us to some examples of NIA-supported research in aging biology and in the "burgeoning field" of geroscience (which doesn't treat aging as a disease, but offers a kind of interdisciplinary approach).
And so, as with so many of our grand inventions of the future, the wealthy and the adventurous of the world will enter the fray first, potentially paying exorbitant amounts to be patient zero over and over again. Does that mean the right to a long life won't trickle down to the masses? No, de Grey insists, obviously tired of this question of access. "Once people get over the psychological stranglehold that humanity has" when they talk about death, "there's not going to be any problem at all." People will see the tech and demand it; doctors, insurers and the government will have to cave. It'll get cheaper, as technology does. Anti-aging therapies, de Grey predicts, are "going to be as available as water."
LATEST HEADLINES FROM FIGHT AGING!
MECHANISMS OF MEMORY IMPAIRMENT IN ALZHEIMER'S DISEASE
Monday, January 4, 2016
This is an example of ongoing work on one narrow slice of the exceptionally complex mechanisms of Alzheimer's disease. It is worth considering that while Alzheimer's is the high level call to action, the real work is the business of understanding the fine details of the brain. This is the often the way in medical research: treating cancer was the call to action that funded research leading to our present understanding of cellular biochemistry in regeneration, replication, and development. The hue and cry of AIDS activism was the call to action that funded the development of our present understanding of viruses, much increased these past three decades. So it is for Alzheimer's and the biochemistry of the mind.
A new study has identified activity of brain proteins associated with memory impairments in Alzheimer's disease, and has also found that "repairing" this activity leads to an improvement in memory. "In the study we found that the nerve cells in the mouse models of Alzheimer face a type of metabolic stress. When a cell faces such metabolic stress, it is logical that it will reduce its activity level in order to survive. The problem is that this stress is chronic and leads to impairment of cognitive functioning."
In a previous study, researchers found a connection between abnormal activity of the elF2 protein, which is known to regulate the formation of new proteins needed for the creation of long-term memories, and mice that carried the human gene APOE4, which is known as a key risk factor for sporadic Alzheimer's. In the present study, a group of young mice carrying the human gene APOE4 showed cognitive impairment on the behavioral level - in other words, they showed signs of damage on the level of spatial memory. A molecular examination showed that the protein elF2 had undergone phosphorylation, changing its action and leading to several processes, including elevated expression of the RNA on another protein, ATF4. This elevation delayed the expression of additional genes associated with the consolidation of memory - i.e. the creation of long-term stable memory.
"The abnormal activity in the regulation of the activity of the ATF4 probably causes the cell to 'feel' that is under stress, that is - overactive. A cell that is in stress reduces its activity in order to survive with the goal of restoring it to a normal condition after the stress passes. The problem is that in Alzheimer's the stress is probably chronic, and accordingly there is no return to normal activity." In order to reinforce the connection they found, the researchers performed an additional intervention in which they prevented eIF2 from causing an increase in the RNA of the ATF4. When they examined these mice, they found an improvement in their cognitive capabilities.
MORE ON JANUS KINASE INHIBITORS AS A POSSIBLE TREATMENT FOR CELLULAR SENESCENCE
Tuesday, January 5, 2016
In recent months a number of studies on Janus kinases (JAK) have been published, focusing on their effects on senescent cells, inflammation, and stem cell activity. In animal studies JAK inhibitors seem to reduce the harmful activities of senescent cells, which leads to modest benefits in old individuals, though it is unclear as to the degree to which these treatments are removing senescent cells via programmed cell death versus merely altering their behavior. Reports in the research literature vary on this count, but lean towards modulation. Trying to alter the behavior of senescent cells is in my eyes a poor substitute for a definitive targeted elimination of those cells, but there is value in all sound demonstrations of cellular senescence as an important contribution to degenerative aging, as they increase support for the development of treatments that can measurably impact aging.
Researchers have taken what they hope will be the first step toward preventing and reversing age-related stem cell dysfunction and metabolic disease. "Our work supports the possibility that by using specific drugs that target senescent cells - cells that contribute to frailty and disease associated with age - we could stop human senescent cells from releasing toxic proteins that are contributing to diabetes and breakdowns in stem cells in older individuals."
Researchers found that human senescent fat cells release a protein called activin A that impairs the function of fat tissue stem cells and fat tissue. They discovered an activin A increase in the blood and fat tissue of the aged mice. Treatment with Janus kinase (JAK) inhibitor drugs in aged mice, equivalent to 80-year-old people, decreased the amounts of activin A and partially reversed the fat tissue insulin resistance that contributes to diabetes in old age. In aged mice that are engineered to express a drug-activated gene in their senescent cells (called INK-ATTAC mice) treatment triggering the gene removed senescent cells, decreased activin A and increased the proteins that promote insulin sensitivity and reduce diabetes. This paralleled effects of the JAK inhibitor in normal, naturally aged mice. "The treated animals had improved glucose and insulin tolerance tests, tests that indicate the severity of diabetes. Our work suggests that targeting senescent cells or their products could be a promising avenue for delaying, preventing, alleviating or treating age-related stem cell and tissue dysfunction and metabolic disease."
TO WHAT DEGREE ARE OLD EXERCISE STUDIES FLAWED?
Tuesday, January 5, 2016
The advent of small, cheap accelerometers - such as the one found inside every mobile device these days - has profoundly changed the nature of the data used in scientific studies of the relationship between health and exercise. As in the study I'll point out here, it has been noted that self-reported exercise levels bear only a modest correlation to accelerometer data gathered from those same individuals. There are definitely questions on the interpretation of this data, however. This all starts to suggest that some of the results from older studies are based on artifacts in the data, not reality. For example, that there is a large difference in outcomes between no exercise and some exercise, but little further gain in health and reduced mortality for increased exercise past that point. Is that curve of benefits real, or does it result from the muddiness of self-reported levels of exercise?
Self-reported physical activity questionnaires remain the primary assessment method for large observational studies despite their limitations. Physical activity questionnaires rank participant physical activity levels moderately well, but are less precise assessing the absolute volume of physical activity (e.g. the total amount of time spent in moderate-to-vigorous physical activity (MVPA)) compared to objective measures. Objective measures of physical activity, such as those obtained from accelerometers, may allow for a more precise assessment of physical activity volume.
It is important to understand the relationship between accelerometer-assessment and self-report. Accelerometers, due to their decreasing cost and size, have become increasingly prevalent in both research settings and as commercial products, but are unlikely to fully replace self-report as the primary MVPA assessment method in large observational studies. Self-report questionnaires may be preferred due to fewer logistical challenges as well as to examine specific activities or domains of activity (such as leisure-time, transportation, occupational, and home-based physical activity). Finally, the majority of the existing research examining physical activity and health is based on self-reported physical activity.
Previous studies have shown a low to moderate correlation between self-report questionnaires and uniaxial accelerometer measures, as well as significant differences in absolute volume of MVPA measured. A challenge to describing accelerometer-assessed physical activity is determining the appropriate cutpoint to translate accelerometer measures into physical activity carried out at different intensities. Numerous accelerometer cutpoints for MVPA, all using data collected from the vertical axis, have been proposed based on calibration studies primarily carried out under laboratory settings. Since no 'gold standard' cutpoint for older adults exists, studies have used a variety of cutpoints to describe accelerometer-assessed time in MVPA.
Perhaps the largest challenge in comparing data collected using accelerometers or questionnaires lies in what each method truly measures. Accelerometers measure accelerations in physical motion, and do not directly measure behavior. While accelerometers offer the possibility of greater characterization of physical activity (e.g., identification of short bouts), innovative analytical methods hold promise but are still under development.
According to self-reported physical activity, 67% of women met the US federal physical activity guidelines, engaging in ≥150 minutes per week of MVPA. The percent of women who met the guidelines varied widely depending on the accelerometer MVPA definition (≥760 cpm: 50%, ≥1041 cpm: 33%, ≥1952 cpm: 13%, and ≥2690 cpm: 19%). The main strength of this study is a large sample of more than 10,000 older women, in whom we simultaneously examined assessments from self-report and accelerometer across a range of cutpoints. We show that the choice of accelerometer cutpoint impacts MVPA estimation. Among the cutpoints examined, the triaxial accelerometer MVPA cutpoint compared to self-report yields the most similar median, and lowest interquartile range of MVPA minutes per week. However, use of uniaxial and triaxial cutpoints yielded similar correlations when compared with self-reported physical activity. Although cutpoints may be a simplistic use of the rich accelerometer data, this is the only well-studied metric available today, pending further development of methods.
BIOGERONTOLOGY RESEARCH FOUNDATION JOINS CALLS TO CLASSIFY AGING AS A DISEASE
Wednesday, January 6, 2016
Yet another noted organization in the space is echoing calls from researchers and advocates in recent years for regulatory bodies to classify aging as a disease:
Disease classification is too often dependent on social and cultural context, and separating 'normal' progression from 'healthy' aging lacks coherence and hinders efforts to ameliorate age-related suffering. For example, several currently recognized diseases, such as osteoporosis, isolated systolic hypertension, and senile Alzheimer's disease, were in the past ascribed to normal aging. Recognising aging as a unique, but multisystemic disease would provide a framework to tackle and prevent many chronic conditions; alleviating both financial, social and moral burden.
Researchers have called for a task force to be created to classify ageing as a disease with a granular and actionable set of disease codes in the context of the 11th International Statistical Classification of Diseases and Related Health Problems (ICD-11). Classifying aging as a disease is a highly debated topic, where there is clear disagreement among demographers, gerontologists and biogerontologists on the subject, classification of aging as a disease is likely to unite both scientists and medical practitioners in the effort to prevent the pathological age-related processes and attract more resources to aging research.
In part, the researchers call for creating a task force of scientists to more thoroughly evaluate whether to provide a more granular and actionable classification of aging as a disease in ICD-11. "A more granular classification of ageing as a disease with a set of "non-garbage" ICD disease codes will help put it in the spotlight and help attract resources to accelerate research. Also, like with any disease, acceptance of the disease is the first step to treatment."
THEORIZING THAT IMMUNOSENESCENCE CONTRIBUTES TO STEM CELL ACTIVITY DECLINE IN AGING
Wednesday, January 6, 2016
Immunosenescence is the term given to the aging of the immune system. In old age the immune system falls into a state of chronic inflammation coupled with a lack of effectiveness: it is overactive to the point of damaging tissues, but lacks the capacity to achieve the goals of destroying pathogens and potentially dangerous cells. Researchers here theorize that the progressive deterioration of the immune system is one contributing factor to the characteristic decline in stem cell activity that also accompanies aging, at least where it involves mesenchymal stem cells (MSCs). They propose that this effect is mediated through the interaction of hematopoietic stem cells, responsible for generating immune cells, and mesenchymal stem cells in the bone marrow where they both reside:
Several lines of evidence indicate that the decline in stem cell function during ageing can involve both cell intrinsic and extrinsic mechanisms. The bone and blood formation are intertwined in bone marrow, therefore, haematopoietic cells and bone cells could be extrinsic factors for each other in bone marrow environment. There is growing evidence in animal studies and invertebrate models that the stem cell niche, one of the extrinsic mechanisms, is important for the regulation of cellular ageing in stem cells. We uncovered that there are age-related intrinsic changes in human mesenchymal stem cells. In this study, we assess the paracrine interactions of human bone marrow haematopoietic cells on mesenchymal stem cells.
Our data demonstrate that there are paracrine interactions of haematopoietic cells, via soluble factors, such as TNF-α, PDGF-β or Wnts, etc., on human mesenchymal stem cells; the age-related increase of TNF-α in haematopoietic cells suggests that immunosenescence, via the interactions of haematopoietic cells on mesenchymal stem cells, may be one of the extrinsic mechanisms of skeletal stem cell function decline during human skeletal ageing. TNF-α has a central role in bone pathophysiology and its action in the skeleton results in increased bone resorption by stimulation of osteoclastogenesis and impaired bone formation by suppressing recruitment of osteoblasts from progenitor cells, inhibiting the expression of matrix protein genes, and stimulating expression of genes that amplify osteoclastogenesis.
Our data implied that besides the current approaches to intervene in osteoporosis, such as targeting on osteoclasts to stop bone resorption or osteoblasts to increase bone formation, there may be a new approach that targets the interactions of haematopoietic cells on osteoblast precursors to identify potential intervention for osteoporosis and bone fracture, and to develop therapeutic strategies to prevent or restore skeletal tissue degeneration and loss in the ageing population.
ATTEMPTING THE GROWTH OF HUMAN ORGANS IN ANIMALS
Thursday, January 7, 2016
One approach to organ engineering is to create lineages of chimeric pigs, a species with organs of a similar enough size and shape for transplant into humans, in which the organs of interest are made up of human cells rather than pig cells. This may or may not turn out to be harder than the alternative of taking ordinary pig organs, decellularizing them, stripping them of harmful remaining proteins, and then repopulating the remaining structure with human cells. There is some degree of irrational hysteria surrounding the creation of chimeras, which only makes the real challenges harder to surmount. Still, it seems to me that these are stopgap technologies that will have a short practical life span. They will be overtaken in cost and efficiency by the ability to generate organs from a patient's own cells in a bioreactor:
Braving a funding ban put in place by the NIH, some U.S. research centers are moving ahead with attempts to grow human tissue inside pigs and sheep with the goal of creating hearts, livers, or other organs needed for transplants. Based on interviews with three teams, two in California and one in Minnesota, it is estimated that about 20 pregnancies of pig-human or sheep-human chimeras have been established during the last 12 months in the U.S., though so far no scientific paper describing the work has been published, and none of the animals were brought to term.
The extent of the research was disclosed in part during presentations made to the NIH at the agency's request. One researcher showed unpublished data on more than a dozen pig embryos containing human cells. Another provided photographs of a 62-day-old pig fetus in which the addition of human cells appeared to have reversed a congenital eye defect. The experiments rely on a cutting-edge fusion of technologies, including recent breakthroughs in stem-cell biology and gene-editing techniques. By modifying genes, scientists can now easily change the DNA in pig or sheep embryos so that they are genetically incapable of forming a specific tissue. Then, by adding stem cells from a person, they hope the human cells will take over the job of forming the missing organ, which could then be harvested from the animal for use in a transplant operation.
Other kinds of human-animal chimeras are already widely used in scientific research, including "humanized" mice endowed with a human immune system. Such animals are created by adding bits of liver and thymus from a human fetus to a mouse after it is born. The new line of research goes further because it involves placing human cells into an animal embryo at the very earliest stage, when it is a sphere of just a dozen cells in a laboratory dish. This process, called "embryo complementation," is significant because the human cells can multiply, specialize, and potentially contribute to any part of the animal's body as it develops. In 2010 researchers used the embryo complementation method to show that they could generate mice with a pancreas made entirely of rat cells. "If it works as it does in rodents, we should be able have a pig with a human organ."
EFFICIENT CONVERSION OF SKIN CELLS TO FUNCTIONAL ISLET CELLS
Thursday, January 7, 2016
Researchers here demonstrate the ability to efficiently produce islet cells of the pancreas to order from a skin sample. One of the near term goals for the stem cell research community is to develop reliable, low-cost recipes for turning out patient-matched cells of any desired type. This is a necessary starting point for most of the future of regenerative medicine and tissue engineering: lower cost and higher quality cell sources mean faster development and cheaper clinical treatments. There are more than 200 different types of cell in the body, with that number being somewhat fuzzy around the edges and still subject to change. Thus far it has been clear that different cell types require quite different approaches to growth and culturing, so this is clearly a large project, but progress is ongoing:
Researchers have successfully converted human skin cells into fully-functional pancreatic cells. The new cells produced insulin in response to changes in glucose levels, and, when transplanted into mice, the cells protected the animals from developing type 1 diabetes in a mouse model of the disease. The new study also presents significant advancements in cellular reprogramming technology, which will allow scientists to efficiently scale up pancreatic cell production and manufacture trillions of the target cells in a step-wise, controlled manner. "Our results demonstrate for the first time that human adult skin cells can be used to efficiently and rapidly generate functional pancreatic cells that behave similar to human beta cells."
In the study, the scientists first used pharmaceutical and genetic molecules to reprogram skin cells into endoderm progenitor cells - early developmental cells that have already been designated to mature into one of a number of different types of organs. With this method, the cells don't have to be taken all the way back to a pluripotent stem cell state, meaning the scientists can turn them into pancreatic cells faster. The researchers have used a similar procedure previously to create heart, brain, and liver cells. After another four molecules were added, the endoderm cells divided rapidly, allowing more than a trillion-fold expansion. Critically, the cells did not display any evidence of tumor formation, and they maintained their identity as early organ-specific cells. The scientists then progressed these endoderm cells two more steps, first into pancreatic precursor cells, and then into fully-functional pancreatic beta cells. Most importantly, these cells protected mice from developing diabetes in a model of disease, having the critical ability to produce insulin in response to changes in glucose levels.
AUTOPHAGY KEY TO RESTORING FUNCTION IN OLD MUSCLE STEM CELLS
Thursday, January 7, 2016
A most interesting paper surfaced today, after spending more than a year in the peer review process. The current press coverage is in Spanish only, but we all have access to automated translation these days. The authors of the paper report that the muscle stem cell population known as satellite cells, responsible for regeneration and tissue maintenance, relies upon autophagy to evade the onset of cellular senescence. Unfortunately autophagy fails with age, a decline that is linked to the accumulation of metabolic waste in long-lived cells, but probably has other less direct contributing factors as well. When stem cells fall into senescence, their activity and effectiveness declines. The researchers demonstrated that restoring youthful levels of autophagy in old satellite cell populations can restore them from senescence and return their regenerative capabilities. This has its analogies in earlier work, such as the approach taken to restore function in aged liver tissue back in 2008.
Autophagy is an collection of cellular maintenance processes, focused on clearing out waste and recycling damaged components. Greater autophagy taking place in tissue should mean fewer damaged and disarrayed cells at any given moment in time, which in turn should translate to a longer-lasting organism. The paper linked below is one of the more compelling of recent arguments for putting more effort into treatments based on artificially increased levels of autophagy. This has been a topic in the research community for some time, as many of the methods known to modestly slow aging in laboratory species are associated with increased levels of autophagy. It is a vital component in hormesis, wherein causing a little damage leads to a lasting increase in autophagy and a net gain.
Stem cells spend much of their time in a state of quiescence, only springing into action when called upon. This helps to preserve them for the long term. In older tissues with greater levels of molecular damage, ever more stem cells slip from quiescence into an irreversible senescent state. These senescent cells are no longer capable of generating new cells, and start to secrete all sorts of harmful signal molecules. Cellular senescence is thought to be a response to damage or a toxic environment, so you can probably see how this might be expected to tie into repair processes such as autophagy. There is some debate over the degree to which cellular senescence is irreversible in the normal course of events inside a living organism. When reductions in senescence are observed in a cell population as a result of changing circumstances or a treatment, it may simply be that the relative number of senescent cells falls without any such cell returning to a non-senescent status. Cell populations are dynamic, after all.
Scientists discover how to keep the body young despite age (Spanish)
Muscles have a cleaning system that eliminates waste and preventing degenerate over the years, as scientists have discovered. When this cleaning system stops working properly, the muscles go into senescence. Then, stem cells lose the ability to regenerate tissue and muscle is weakened. It's something that happens gradually from the fifth decade of life and that in elderly people forces them into frailty. But when the cleaning system is restored, as have researchers with drugs, muscle tissue can regenerate again and retrieves the lost vigor. So far the experiments have been performed in mice and in human cells in the laboratory.
The cleaning system, technically called autophagy, removes components of cells that have stopping functioning properly and become toxic. These components range from individual molecules (free radicals or damaged proteins) to whole organelles (such as mitochondria or ribosomes). Since all organs and tissues of the human body depend on autophagy, researchers believe that the same system could be key to slow aging in other organs, and it could be useful to increase their regenerative capacity and rejuvenate. "I think it must be so because every house has to be cleaned, and autophagy is a very fundamental cleaning mechanism in living organisms, but we have not proven that our research is not limited to muscle tissue."
In muscle, autophagy has been shown to maintain the ability of stem cells to regenerate tissue. And when autophagy is no longer efficient and cells begin to accumulate waste, stem cells enter senescence and lose their regenerative capacity. "We were surprised to discover this. When you stop to think about it, it makes sense, because the stem cells need to break free of waste accumulate every day to work properly." But despite intensive research in the last decade on the biology of aging, "this is the first time a relationship between aging and declining autophagy in mammalian tissue is observed. Although senescence due to aging is often seen as an inevitable and irremediable process, we demonstrate that the internal clock of aging stem cells can be manipulated with drugs."
Autophagy maintains stemness by preventing senescence
During ageing, muscle stem-cell regenerative function declines. At advanced geriatric age, this decline is maximal owing to transition from a normal quiescence into an irreversible senescence state. How satellite cells maintain quiescence and avoid senescence until advanced age remains unknown. Here we report that basal autophagy is essential to maintain the stem-cell quiescent state in mice. Failure of autophagy in physiologically aged satellite cells or genetic impairment of autophagy in young cells causes entry into senescence by loss of proteostasis, increased mitochondrial dysfunction and oxidative stress, resulting in a decline in the function and number of satellite cells. Re-establishment of autophagy reverses senescence and restores regenerative functions in geriatric satellite cells. As autophagy also declines in human geriatric satellite cells, our findings reveal autophagy to be a decisive stem-cell-fate regulator, with implications for fostering muscle regeneration in sarcopenia.
LOSS OF PHD1 PRODUCES GREATER RESISTANCE TO STROKE DAMAGE
Friday, January 8, 2016
An interesting study on the mechanisms of cell death in stroke came out today. The damage caused by a stroke is the result of cellular reactions to first loss and then restoration of blood flow and thus oxygen supply. Many of these reactions are, strictly speaking, unnecessary and actually directly harmful. Thus tinkering with the regulating mechanisms of these processes may produce benefits by increasing resistance to cell death due to ischemic injuries like stroke. The specific approach taken by researchers here has uncovered an unusually large effect. They propose their findings as a basis for stroke treatment after the fact, but in this new era of cheap genetic engineering, one has to wonder whether a permanent genetic alteration to human patients prior to old age is feasible in this case:
Scientists have identified the oxygen sensor PHD1, also known as EGLN2, as a potential target for the treatment of brain infarction (ischemic stroke). Of all organs in our body, the brain is unique because it needs the highest levels of oxygen and glucose to function and to survive. The simple reason herefore is that brain cells absolutely rely on oxygen and glucose to generate energy, necessary to function normally. In stroke, reduced blood supply therefore threatens this energy balance, causing neurons to die.
Researchers discovered that brain cells sense and adapt to a shortage of oxygen and nutrients via PHD1. They observed that mice lacking the oxygen sensor PHD1 were protected against stroke induced by an obstruction of a main blood vessel supplying oxygen and glucose to the brain. Not only was their infarct size reduced by more than 70% (which is an unusually large beneficial effect), but mice lacking PHD1 also performed much better in functional tests after stroke.
A critical problem when brain cells are deprived of oxygen is that they generate damaging side-products, "oxygen radicals", which kill brain cells. Most previous stroke treatments are unsucessful, because they are based on the principle to target the consequences rather than the cause of these oxygen radicals. Researchers focused on a completely new concept, i.e. utilizing the endogenous power of brain cells to enhance the neutralization of these toxic side-products. The researchers now discovered that inhibition of the oxygen sensor PHD1 protects brain cells against these toxic side-products by reprogramming the use of sugar in low-oxygen conditions. "By reprogramming glucose utilization, neurons lacking PHD1 have an improved capacity to detoxify damaging oxygen radicals, protecting the brain against stroke. This is a paradigm-shifting concept in the field of stroke protection."
BLOCKING BRAIN INFLAMMATION IN ALZHEIMER'S DISEASE
Friday, January 8, 2016
Researchers have recently shown that suppressing inflammation in brain tissue reduces the symptoms of Alzheimer's disease in a mouse model, and does this without producing any impact on the amyloid build up associated with the condition. A range of past studies have provided evidence for the significant role of inflammation in the brain in the development of Alzheimer's disease. Portions of the specialized subdivision of the immune system in central nervous system tissue are vital to the support of nerve cells, not just involved in attacking pathogens. Consider the populations of microglia and astrocytes, for example, cell types for which the full list of roles remains to be cataloged. Thus dysregulation of the immune system, as is associated with rising levels of chronic inflammation, can have complex effects in the brain that are unlike those elsewhere in the body.
Blocking a receptor in the brain responsible for regulating immune cells could protect against the memory and behaviour changes seen in the progression of Alzheimer's disease. It was originally thought that Alzheimer's disease disturbs the brain's immune response, but this latest study adds to evidence that inflammation in the brain can in fact drive the development of the disease. The findings suggest that by reducing this inflammation, progression of the disease could be halted. The team hope the discovery will lead to an effective new treatment for the disease, for which there is currently no cure.
The researchers used tissue samples from healthy brains and those with Alzheimer's, both of the same age. The researchers counted the numbers of a particular type of immune cell, known as microglia, in the samples and found that these were more numerous in the brains with Alzheimer's disease. In addition, the activity of the molecules regulating the numbers of microglia correlated with the severity of the disease.
The researchers then studied these same immune cells in mice which had been bred to develop features of Alzheimer's. They wanted to find out whether blocking the receptor responsible for regulating microglia, known as CSF1R, could improve cognitive skills. They gave the mice oral doses of an inhibitor that blocks CSF1R and found that it could prevent the rise in microglia numbers seen in untreated mice as the disease progressed. In addition, the inhibitor prevented the loss of communication points between the nerve cells in the brain associated with Alzheimer's, and the treated mice demonstrated fewer memory and behavioural problems compared with the untreated mice.
Importantly, the team found the healthy number of microglia needed to maintain normal immune function in the brain was maintained, suggesting the blocking of CSF1R only reduces excess microglia. What the study did not find is a correlated reduction of the number of amyloid plaques in the brain, a characteristic feature of Alzheimer's disease. This supports previous studies that argue other factors may play more of a role in cognitive decline.