Fight Aging! Newsletter, May 15th 2017

Autophagy, a catabolic process to maintain intracellular homeostasis, has been recently focus in numerous human disease conditions, such as aging, cancer, development, immunity, longevity, and neurodegeneration. However, sustaining autophagy is essential for cell survival and dysregulation of autophagy is anticipated to speed up neurodegeneration progression; although, the actual molecular mechanism is not yet fully understood. In contrast, emerging evidence suggests that basal autophagy is necessary for removal of misfolded aggregation proteins and damaged cellular organelles through lysosomal mediated degradation. Physiologically, neurodegenerative disorders are related to the accumulation of amyloid β peptide and α-synuclein protein aggregation in Alzheimer disease and Parkinson disease, respectively. Even though autophagy could impact several facets of human biology and disease, however it functions as a clearance for toxic protein in the brain contributes us novel insight into the pathophysiological understanding of neurodegenerative disorder. In particular, several studies demonstrate that natural compounds or small molecule autophagy enhancer stimulates autophagy which is essential in clearance amyloid-β (Aβ) and α-synuclein deposits.

As a therapeutic purpose, it has been indicated that upregulation of autophagy through mTOR complex 1-mediated pathway might be targeted to removal of aggregate protein molecules and decrease cytotoxicity in animal models. However, tauopathies, α-synucleinopathies, and other models has been implicated to treat neurodegenerative disease through this strategy. In particular, mTOR-independent autophagy inducers rapamycin analogs such as rilmenidine and trehalose drugs has been used in these diseases. On the other hand, autophagy inhibitor increases the toxicity of these protein that leads to enhance of the relevant protein during neurodegeneration. It is also mention that rapamycin and its chemically synthesized analogues such as CCI-779 are widely used potential activator of autophagy in yeast and mammalian cells in neurons as well as in vivo in mouse brain. Eventually, widespread preclinical animal model studies are required to induce autophagy in neurodegenerative disease.

Furthermore, statins, a class of lipid-lowering medications, induces autophagy in astrocytes through AMPK-mTOR mediated pathway and it has been suggested that autophagy is essential in insulin-degrading enzyme secretion, thus modulation of autophagy could provide a possible therapeutic approach in Aβ pathology by increasing clearance of extracellular Aβ. Hence, accumulation of Aβ peptide participates to the pathological condition of AD, while inhibiting Aβ production or increasing Aβ removal may be implicated in slowing the improvement of AD. In particular, the promotion of Aβ clearance is currently considered to be an additional therapeutic approach for AD. Thereby, autophagy has been found to be an important role in the clearance of Aβ under physiological conditions, for that reason it is essential to maintain Aβ homeostasis in the healthy brain. Most importantly, our current research is considerable effort directed to identify safe and more effective pharmacological inducers of autophagy in neurodegenerative diseases. Therefore, enhancement of autophagy might represent a sustainable strategy to Aβ clearance.

Even though a variety of autophagy-related proteins participate and control in autophagy pathway, several studies have been performed to explore autophagy regulation through the active ingredients of plants. Although numerous fundamental queries are essential to be further addressed before many novel agents could be useful in a clinical approaches, thus the research of interest in autophagy is developing rapidly and clinically applicable might be anticipated as soon as possible. Furthermore, it is very important to characterize dysfunctional autophagy in diverse stages of genetic and molecular subtypes in neurodegeneration. It is also necessary to study the active clinical translation of downstream autophagy regulation which proposes an exciting new era for the development of therapeutic strategies. Consequently, additional studies are required on physiological roles of modulation of brain autophagy process in neurodegenerative diseases. Finally, we would like to screen new natural compounds that modulate autophagy and identify main targets key molecular mechanisms underlying pathophysiological roles of neurodegeneration with concern for potential therapeutic drugs target.

Researchers have identified a trigger for autoimmune diseases such as lupus, Crohn's disease and multiple sclerosis. The findings help explain why women suffer autoimmune disease more frequently than men, and suggest a therapeutic target to prevent autoimmune disease in humans. "Our findings confirm that Age-associated B Cells (ABCs) drive autoimmune disease. We demonstrated that the transcription factor T-bet inside B cells causes ABCs to develop. When we deleted T-bet inside B cells, mice prone to develop autoimmune disease remained healthy. We believe the same process occurs in humans with autoimmune disease, more often in elderly women."

B cells are important players in autoimmune disease. The research team previously identified a subset of B cells that accumulate in autoimmune patients, autoimmune and elderly female mice. They named the cells Age-associated B cells, or ABCs. Subsequent research showed that the transcription factor T-bet plays a crucial role in the appearance of ABC. Transcription factors bind to DNA inside cells and drive the expression of one or several genes. Researchers believe that T-bet appears inside cells when a combination of receptors on B-cell surfaces - TLR7, Interferon-gamma and the B-cell receptor - are stimulated.

Through breeding and genetic techniques the research team eliminated the ability of autoimmune-prone mice to express T-bet inside their B cells. As a result, ABCs did not appear and the mice remained healthy. Kidney damage appeared in 80 percent of mice with T-bet in the B cells and in only 20 percent of T-bet-deficient mice. Seventy-five percent of mice with T-bet in their B cells died by 12 months, while 90 percent of T-bet-deficient mice survived 12 months. "Our findings for the first time show that ABCs are not only associated with autoimmune disease, but actually drive it."

B cells are known to be involved in different aspects of autoimmune diseases and may contribute in a number of ways including the secretion of autoantibodies, processing and presentation of autoantigen to T cells, and production of inflammatory cytokines. Therefore, B cells are promising targets for treatment of autoimmune diseases. Indeed, this idea has been put into practice and B cell depletion therapy has been tested for multiple autoimmune diseases. It is not yet known why B cell depletion is effective for some but not all diseases and for some but not all patients with a particular malady. One possibility is that the depletion therapies might not affect all B cell subsets equally well and different diseases, or different patients, might have involvements of different B cell subsets.

A novel subset of B cells named age-associated B cells (ABCs) has recently been identified by others and ourselves. Unlike other B cells, ABCs express high levels of CD11c and the transcription factor T-bet. T-bet was subsequently demonstrated to be necessary and sufficient for the appearance of this subset, and triggering of the B cell antigen receptor (BCR), IFN-γ receptor (IFN-γR), and TLR7 on B cells induces high levels of T-bet expression. Our previous data demonstrated that T-bet+ ABCs appear in autoimmune patients and in autoimmune-prone mice. These cells produce high amounts of autoantibodies upon stimulation in vitro, suggesting that they are major precursors of autoantibody-secreting cells.

Moreover, our recent findings indicate that ABCs are very potent antigen-presenting cells and therefore might participate in autoimmune responses by presenting self-antigen to autoreactive T cells. In agreement with our findings, a recent study demonstrated elevated levels of T-bet expression in B cells obtained from peripheral blood mononuclear cells of lupus patients when compared with healthy donors, suggesting that T-bet expression in B cells may be critical for the development of lupus in humans. Others have reported that T-bet-expressing B cells are associated with Crohn's disease activity, and an increased expression of T-bet in B cells was found in a patient with MS and celiac disease, altogether suggesting an important role for T-bet-expressing B cells in human autoimmunity.

Therefore, we hypothesized that ablation of ABCs will prevent or delay the development of lupus-like autoimmunity. We tested this hypothesis by conditionally deleting T-bet from B cells in a mouse model of lupus. Our data demonstrate that this deletion leads to reduced kidney pathology, prolonged survival, and delayed appearance of autoantibodies in these mice. Moreover, our data suggest that T-bet expression in B cells is required for the rapid formation of spontaneous germinal centers that develop without purposeful immunization or infection during such autoimmune responses. The results indicate a critical role for T-bet expression in B cells for the generation of efficient autoimmune responses and the development of lupus-like autoimmunity, and suggest that specific targeting of T-bet+ B cells might be a useful therapy for some autoimmune diseases.

Researchers have provided evidence that adenosine, a biochemical at the heart of human cellular function, plays another crucial role - keeping on hand a steady number of healthy chondrocytes, the cells that make and sustain cartilage. Important to the study's implications, adenosine is derived from adenosine triphosphate (ATP), the molecule that stores the energy needed by the body's cells until they break it up to use it. Scientists have known that both inflammation and aging lead to diminished ATP production (and so lower adenosine levels) in chondrocytes. Until now, they had not linked diminished adenosine levels to osteoarthritis, the commonplace, "wear-and-tear" form of arthritis.

The study found that maintaining high levels of adenosine in rats with damage to the anterior cruciate ligament (ACL), which is known to lead to osteoarthritis in humans, prevented the rats from developing the disease. If the finding proves to be true in humans, adenosine replacement therapy could potentially delay the onset of osteoarthritis and the need for joint replacements. The findings suggest that reductions in the number of cartilage-producing cells, and greater risk for osteoarthritis, may be driven not just by lower adenosine levels but also by lower levels of the protein on the surface of chondrocytes designed to receive and pass on adenosine's signal. Adenosine helps to sustain such cells by fitting into a protein called the A2A adenosine receptor on their surfaces, like a key into a lock.

Researchers observed that mice lacking the A2A adenosine receptor did not walk as easily or as well as mice with the receptor. Radiologic examination of the knees of mice without the receptor confirmed that they had osteoarthritis. The team also found that levels of adenosine A2A receptors went up on rat chondrocytes when osteoarthritis was present, in what the researchers say was a "failed attempt" to compensate for the loss of adenosine from the energy-processing (metabolic) changes underlying the inflammation. Additional tests in tissue samples from osteoarthritic patients who had joint replacements found similarly increased levels of adenosine A2A receptors on chondrocytes.

When researchers treated mouse chondrocytes with a molecule called IL-1beta, which contributes to the development of osteoarthritis, they found that 39 percent less ATP was produced by the inflamed chondrocytes. They also found 80 percent less expression of ANKH, a molecule that exports ATP, in the IL-1beta-treated cells. Finally, they found that lacking the enzyme involved in turning ATP into adenosine caused diminished adenosine levels, which led to osteoarthritis in mice. The lack of the enzyme in humans is also known to lead to the disease. When the team administered adenosine packaged in lipid bubbles into rats' ACL injuries, researchers found that the excess adenosine, as mediated by the adenosine A2A receptor, prevented the development of osteoarthritis in the animals.

Osteoarthritis (OA) is characterized by changes in every structure in the joint, including cartilage destruction, synovial inflammation, osteophyte formation, enthesophytes, and significant bony changes. The central player in OA is the chondrocyte, which responds to excess mechanical loading by releasing inflammatory mediators and proteolytic enzymes causing further cartilage damage. In addition, age-related inflammation contributes to the pathogenesis of OA.

Adenosine is an endogenously produced physiological regulator and its intracellular and extracellular concentration is tightly controlled by oxygen consumption, cellular stress and mitochondrial functionality. Extracellular adenosine derives mainly from hydrolysis of ATP and mediates its effects via activation of G-protein-coupled receptors (A1R, A2AR, A2BR and A3R). Adenosine has long been known to regulate inflammation and immune responses and work from our lab and others have demonstrated the importance of adenosine and its receptors in osteoblast, osteoclast, and bone marrow homeostasis. Prior studies have suggested that adenosine receptors also regulate chondrocyte physiology and pathology in response to inflammatory stimuli although the specific receptor(s) involved are not identified. Removal of endogenous adenosine or blockade of A2AR leads to cartilage degradation in equine tissue. A3R stimulation has been reported to diminish OA development in a chemically induced model of OA, principally due to the anti-inflammatory effects of A3R agonists.

The results presented here provide evidence for a critical homeostatic mechanism in cartilage. Chondrocytes release ATP which is converted to adenosine extracellularly; the adenosine that is present prevents the phenotypic changes in chondrocytes associated with development of OA via engagement of A2AR. Disruption of this mechanism, as a result of inflammation, injury or aging with reduction of intracellular and extracellular ATP and extracellular adenosine, leads to phenotypic changes in chondrocytes with greater expression of matrix metalloproteinases (MMPs) or collagens associated with cartilage hypertrophy. Moreover, these studies demonstrate that replacement of adenosine by intra-articular injection of liposomal preparations of adenosine can restore the homeostatic equilibrium to cartilage following injury by engagement of A2AR. We conclude that adenosine, acting at A2AR, is an important homeostatic regulator of chondrocytes and cartilage and adenosine repletion may represent a novel approach to treating OA.

Thank you for joining us today, Dr. Stambler. First, could you please tell us a little more about the studies of Elie Metchnikoff?

Elie Metchnikoff is the founder of the cellular theory of immunity, who showed for the first time that cells (such as phagocytes) play a vital role in immune defense. Remember that until about mid-19th century, slightly more than 150 years ago, people did not even know that cells existed or that diseases were caused by bacteria. It was just another step forward for Metchnikoff to understand that aging is a part of life that needs to be studied, and that cellular immunity, especially the immunity against one's own organism (that we now call "auto-immunity") also plays a crucial role in the aging processes.

So not only did Metchnikoff coin the term "gerontology" (the scientific study of aging) and established it as a recognized scientific field, but he in fact pioneered many seminal directions of aging research that are continued to the present, such as studying the role of auto-immunity (or inflammation) in aging, the role of intestinal bacteria (what we now often call the "microbiome") and connective tissues (such as collagen) in aging, and others. He studied the aging processes not just because they are academically intriguing (and they are), but with a clear purpose to combat or ameliorate the degenerative "disease-like" aging processes and extend healthy life. Thus we owe Metchnikoff a great debt of gratitude, not just for his concrete scientific contributions to aging research, but also as one of the founding ideologists of the truly scientific pursuit of healthy life extension, one of the essential founders of the modern intellectual and social movement for healthy longevity (or "life-extensionism").

People come to the movement for healthy longevity in different ways. What made you believe that defeating aging and age-related diseases is a worthy cause?

Metchnikoff was born in the Ukraine, then part of the Russian empire. Since the 19th century to the present, the ideas of life extension, even radical life extension, have been rather popular in Russia, in the Soviet and post-Soviet eras - perhaps more so than in the so-called "West". It was generally ideologically acceptable to want to combat destructive natural processes and improve life conditions for all. How those ideological aspirations played out in real life is a different story, and of course not everybody there embraced such aspirations. I too was born and raised in that environment and absorbed this ideology (being born in Moldova, then part of the USSR, and growing up near Moscow, before my immigration to Israel). For me it does not at all appear strange or unusual that people would want to study things that are killing them (such as destructive aging processes) in order to fight them to extend their own healthy life and the life of their loved ones. Rather it is the people who do not actively pursue these goals that appear a bit strange and unusual to me. It is such people who may need to explain themselves, and why they don't want healthy and productive life extension for themselves and others. For me such goals appear natural.

Can you please tell us about your book. "A History of Life-extensionism in the Twentieth Century" remains, I believe, a unique example of historical analysis of our movement.

Of course, there have been other histories of aging and longevity research. But mine is probably one of the more comprehensive ones, including about 1300 bibliographic notes, considering materials in several languages and national contexts (France, Germany, Russia, the UK and US, and more), and not only in the twentieth century (even though this is the focus), but from ancient times to the present. And indeed, it considers this history not just as a timeline of scientific discoveries, but as a life story of the pursuit of longevity as a social and intellectual movement, insofar as science is an inseparable part of society. Most of this research was done in preparation for my PhD thesis, and then further expanded and developed for the book. I would say it took about 7 years for the PhD completion and the additional preparations until the final product was published. It has not been easy at all, in terms of research and dissemination, and just in terms of making the living during the research and dissemination. The topic has not been very popular or "mainstream" in academia, to put it mildly... Yet, as they say, history is written and taught by the winners. I believe, as the importance of aging research and the pursuit of healthy longevity are gaining an ever increasing traction in the public and academia - so will the history of this pursuit become more sought after.

How do you define the main bottlenecks slowing down progress in the development of rejuvenation biotechnologies? What would be the best way to overcome them, in your opinion?

The main bottleneck is perhaps the general deficit in the ability or willingness of many people to invest time, effort, money and thought for the development of healthspan and lifespan extending therapies and technologies. Clearly, the more people become supportive and involved for their development, the more resources are intelligently and productively invested in it - the faster the technologies will arrive and the wider will be their availability. More worrying, in my view, are the people who already admit that the combat of aging and healthy life extension are feasible, but they still do not invest any (or any significant) intellectual or material resources to achieve these goals. I think a major bottleneck is this transition from a theoretical "belief" or "understanding" into practical action and support.

As you have been in the movement for many years, you have accumulated a significant amount of experience in advocacy. What would be your advice for people who want to get involved but don't know where to start?

The main advice for people who want to get involved in longevity research and advocacy is just: "Start getting involved" - pick yourself up and start studying, thinking and working for the cause. This may sound trivial, but this is exactly the problem of transition from theoretical "understanding" and "wishes" to practical action. Many people remain in the theoretical "wishing" stage. These pieces of advice may not seem very specific, and I wish I could state more specifically: Do this regimen, study this text, join this organization, vote to advance this legislation, or support this project - and then your and everybody else's healthy longevity is guaranteed. But I don't think anyone can be that specific, given the current imperfect state of knowledge, and the diversity of situations and approaches. I could just try to encourage more people to become more interested, knowledgeable, communicative and active in the field, according to their personal wishes and possibilities. From our cumulative actions, not necessarily coordinated, we may have a better chance to create the necessary "pro-longevity" gradient toward our common goal.

Until now, all artificial retinal research has used only rigid, hard materials. The new research is the first to successfully use biological, synthetic tissues, developed in a laboratory environment. The study could revolutionise the bionic implant industry and the development of new, less invasive technologies that more closely resemble human body tissues, helping to treat degenerative eye conditions such as retinitis pigmentosa. Just as photography depends on camera pixels reacting to light, vision relies on the retina performing the same function. The retina sits at the back of the human eye, and contains protein cells that convert light into electrical signals that travel through the nervous system, triggering a response from the brain, ultimately building a picture of the scene being viewed.

Researchers developed a new synthetic, double layered retina which closely mimics the natural human retinal process. The retina replica consists of soft water droplets (hydrogels) and biological cell membrane proteins. Designed like a camera, the cells act as pixels, detecting and reacting to light to create a grey scale image. "The synthetic material can generate electrical signals, which stimulate the neurons at the back of our eye just like the original retina." Unlike existing artificial retinal implants, the cell-cultures are created from natural, biodegradable materials and do not contain foreign bodies or living entities. In this way the implant is less invasive than a mechanical device, and is less likely to have an adverse reaction on the body. At present the synthetic retina has only been tested in laboratory conditions, but the researchers are keen to build on the initial work and explore potential uses with living tissues. The next phase of the work will see the team expand the replica's function. Working with a much larger replica, the team will test the material's ability to recognise different colours and potentially even shapes and symbols.

A stroke prevention strategy appears to be having an unexpected, beneficial side effect: a reduction also in the incidence of dementia among older seniors. A new paper shows there's been a decade-long drop in new diagnoses of both stroke and dementia in the most at-risk group ­­- those who are 80 or older. "Some have said we're on the cusp of an epidemic of dementia as the population ages. What this data suggests is that by successfully fighting off the risks of stroke - with a healthy diet, exercise, a tobacco-free life and high blood-pressure medication where needed - we can also curtail the incidence of some dementias."

This is the first study that has looked at the demographics of both stroke and dementia across Ontario since the province pioneered Canada's first stroke prevention strategy in 2000. That strategy includes more health centres able to manage stroke, more community and physician supports, better use of hypertensive mediation and well-promoted lifestyle changes to reduce risks. Five provinces have stroke strategies and five do not. "We have systems in place for stroke prevention and our hypothesis is that any studies looking at stroke prevention should also investigate dementia prevention. It's a good-news story for Ontario and it could be a good-news story elsewhere."

Most strokes are caused by the restriction or constriction of blood flow to the brain. Vascular dementia also develops as blood supply to the brain is reduced. Someone who has had a stroke is twice as likely to develop dementia. Someone who has had a diagnosis of stroke has also likely had several prior "silent" strokes that may have affected a patient's cognitive abilities. Specifically, the study data shows that the incidence of new stroke diagnosis among highest-risk group, people aged 80-plus, dropped by 37.9 per cent in a span of a little more than a decade. During the same timeframe, the incidence of dementia diagnoses in that age group fell by 15.4 per cent. "As clinicians and researchers, we are still trying to get a handle on how to reduce a person's chances of dementia late in life. Some we can't influence - yet - but here is a pretty clear indication that we can take specific definitive steps to reduce our chances of dementia related to vascular disease."

Like any other organ, our brain ages. As a result, cognitive ability also decreases with increasing age. This can be noticed, for instance, in that it becomes more difficult to learn new things or devote attention to several things at the same time. This process is normal, but can also promote dementia. Researchers have long been looking for ways to slow down or even reverse this process and have now achieved this in mice. These animals have a relatively short life expectancy in nature and display pronounced cognitive deficits even at twelve months of age. The researchers administered a small quantity of THC, the active ingredient in the hemp plant (cannabis), to mice aged two, twelve and 18 months over a period of four weeks. Afterwards, they tested learning capacity and memory performance in the animals - including, for instance, orientation skills and the recognition of other mice. Mice who were only given a placebo displayed natural age-dependent learning and memory losses. In contrast, the cognitive functions of the animals treated with cannabis were just as good as the two-month-old control animals. "The treatment completely reversed the loss of performance in the old animals."

This treatment success is the result of years of meticulous research. First of all, the scientists discovered that the brain ages much faster when mice do not possess any functional receptors for THC. These cannabinoid 1 (CB1) receptors are proteins to which the substances dock and thus trigger a signal chain. CB1 is also the reason for the intoxicating effect of THC in cannabis products, which accumulate at the receptor. THC imitates the effect of cannabinoids produced naturally in the body, which fulfill important functions in the brain. "With increasing age, the quantity of the cannabinoids naturally formed in the brain reduces. When the activity of the cannabinoid system declines, we find rapid ageing in the brain."

To discover precisely what effect the THC treatment has in old mice, the researchers examined the brain tissue and gene activity of the treated mice. The findings were surprising: the molecular signature no longer corresponded to that of old animals, but was instead very similar to that of young animals. The number of links between the nerve cells in the brain also increased again, which is an important prerequisite for learning ability. A low dose of the administered THC was chosen so that there was no intoxicating effect in the mice. Cannabis products are already permitted as medications, for instance as pain relief. As a next step, the researchers want to conduct a clinical trial to investigate whether THC also reverses ageing processes in the brain in humans and can increase cognitive ability.

This is what I call a 'meta-objection', because it's not really meant against rejuvenation per se. Rather, this meta-objection is usually raised after a long, drawn-out conversation between a rejuvenation advocate and an opposer. At the end of the debate, when the suspicion that rejuvenation is in fact desirable and may be feasible is starting to creep up into the opponent's mind, they resort to their final, desperate line of defence, the very last stronghold behind which their cognitive ease can still find shelter. If we all thought like that, no one would do anything to make rejuvenation happen, and consequently it would never happen, in anyone's lifetime, ever. We can either risk it and do all that is in our power to make rejuvenation happen sooner rather than later, or we can sit about and wait to become old and sick.

Besides, if rejuvenation is worthy goal per se, should you not help pursue it just because you might not reap the benefits? We hear all the time that we should take good care of the planet for the sake of future generations and be concerned about the kind of world we leave them with. Well, we can try to leave them with a world where ageing has been cured, so that those very future generations we seem to care so deeply about won't have to go through the plague of age-related diseases. If you have children, this should resonate particularly well with you. Old or young, they'll always be your children, and you'll always care for them, right? Without rejuvenation, they too will be condemned to decades of infirmity and suffering, and ultimately to an unnecessary death.

If rejuvenation could be achievable within the opposer's lifetime, they would have a glimmer of hope to hang on. And as they say, isn't it hope that kills us all? If they decided to accept this possibility, it would mean a lot of mental work, of the kind people generally dislike. First, there's the risk of disappointment. What if something went wrong, and rejuvenation didn't come in time for the opposer? They'd have spent a life hoping for something that never came. The thought isn't particularly nice. Second, there's a choice to be made between activism and 'inactivism'. In order for rejuvenation to become real, there's a lot of work to be done, not only in terms of research but also advocacy. Would the opposer be willing to do their part and spread the word, convince others of the worthiness of the cause, and take action to make it happen sooner? That's a lot of work, and there's no guarantee of success. They'd have to endure endless debates with sceptics, which could be quite taxing.

This is not all! Accepting the possibility that rejuvenation may become a thing within their own life, and that they may actually want it for themselves, the opposer is forced to seriously question their previous assumptions on ageing. This idea that ageing is bad for you and not desirable is a new thing, one they're not used to. They're used to accepting ageing, to think of it as a blessing that prevents the (imaginary) risks of eternal boredom, overpopulation, everliving tyrants, and a series of other sensible-sounding, but ultimately groundless excuses we've made up throughout history to cope with the sad truth of the grim descent into frailty, disability, and disease that precedes death. If they challenged their old assumptions on ageing, the opposer would be forced to conclude that ageing is a really bad thing - and what's worse, that really bad thing is coming for them, and their chances to avoid it are tied to a technology that may or may not come into existence depending not only on the progress of science, but also largely on how willing other opposers will be to challenge their own preconceptions on ageing.

This is where our opposer comes to the realisation that he or she would have to deal with all this trouble only if rejuvenation could happen within their own lifetime. If rejuvenation was so far into the future that the opposer was granted to die before they could ever benefit from it, all of these troubles would just disappear. 'Yes,' the opposer would say, 'maybe defeating ageing is feasible and perhaps even desirable, but it's not doable within my lifetime. So, there's no need to concern myself with it.' It's so easy, isn't it? The easiest way of 'solving' a problem is pretending it isn't there to begin with. You can keep repeating to yourself all the lies about why ageing would be a good thing, until - as it's often the case - they start to feel true and make you feel good.

"Although this project was started in an effort to understand how certain kinds of tumors form, we ended up learning why hair turns gray and discovering the identity of the cell that directly gives rise to hair. With this knowledge, we hope in the future to create a topical compound or to safely deliver the necessary gene to hair follicles to correct these cosmetic problems." The researchers found that a protein called KROX20, more commonly associated with nerve development, in this case turns on in skin cells that become the hair shaft. These hair precursor, or progenitor, cells then produce a protein called stem cell factor (SCF) that the researchers showed is essential for hair pigmentation. When they deleted the SCF gene in the hair progenitor cells in mouse models, the animal's hair turned white. When they deleted the KROX20-producing cells, no hair grew and the mice became bald.

The researchers serendipitously uncovered this explanation for balding and hair graying while studying a disorder called Neurofibromatosis Type 1, a rare genetic disease that causes tumors to grow on nerves. Scientists already knew that stem cells contained in a bulge area of hair follicles are involved in making hair and that SCF is important for pigmented cells. What they did not know in detail is what happens after those stem cells move down to the base, or bulb, of hair follicles and which cells in the hair follicles produce SCF - or that cells involved in hair shaft creation make the KROX20 protein. If cells with functioning KROX20 and SCF are present, they move up from the bulb, interact with pigment-producing melanocyte cells, and grow into pigmented hairs. But without SCF, the hair in mouse models was gray, and then turned white with age, according to the study. Without KROX20-producing cells, no hair grew.

The researchers will now try to find out if the KROX20 in cells and the SCF gene stop working properly as people age, leading to the graying and hair thinning seen in older people - as well as in male pattern baldness. The research also could provide answers about why we age in general as hair graying and hair loss are among the first signs of aging.

The rate at which aging leads to physiological decline, late-life disease, and death varies greatly among species of birds, rodents, and primates. Maximum lifespan varies from 2 years to over 100 years among species of mammals. This variation is thought to represent adaptation, across evolutionary timescales, to niches that reward either rapid reproduction or slower, more sustained patterns of development and reproductive investment. This variation in lifespan can be seen not just across the animal kingdom but within individual animal clades. Maximum lifespan among nonhuman primate species varies from 15 to 60 years. Maximum lifespan among rodent species varies from 4 to 32 years, and maximum lifespan among bird species varies from 5 to 70 years. This implies that a long lifespan has evolved multiple times in different clades. What strategies have been employed by these different groups to extend lifespan and whether these strategies are conserved or divergent among animal clades forms an interesting topic for research. Understanding the mechanisms that different species have employed to extend their lifespan has both medical implications for developing treatments to age-associated diseases.

Comparative analysis of cultured cells from species that vary in lifespan provides a powerful tool to identify factors which may regulate the rate of aging. Much circumstantial evidence links cellular resistance to oxidative stress and organismal lifespan. Genetic, dietary, or drug manipulations that extend lifespan in mice, flies, and worms often increase oxidative stress resistance. Cells from longer-lived species are often more resistant to oxidative stress than cells derived from shorter-lived species of the same clade. Increased resistance to oxidative injury seems often to accompany increased longevity, but to be insufficient to increase lifespan on its own, as demonstrated by the failure of a wide range of antioxidant drugs to improve health or lifespan in humans. Despite the paucity of evidence that increased antioxidant pathways can improve lifespan in rodents, there is one report of increased longevity in mice in which catalase overexpression is targeted to mitochondria, hinting that mitochondrial antioxidant defenses might be of particular importance, rather than oxidation elsewhere in the cell.

Thioredoxin (TXN) is a small redox protein which both removes oxidants and free radicals from the cellular environment and reduces protein disulfide bonds once these are formed. Thioredoxin reductase (TXNRD) reduces oxidized TXN thioredoxin while simultaneously catalyzing conversion of NADPH into NADP+. Thus, TXNRD controls the availability of reduced TXN. The TXN/TXNRD pathway also represses apoptosis through inhibition of ASK-1 signaling. In mammals, there are three forms of thioredoxin reductase: cytosolic TXNRD1, mitochondrial TXNRD2, and TXNRD3, whose function is poorly defined. In Drosophila, there are two forms of thioredoxin reductase: cytosolic Trxr-1, an orthologue of TXNRD1, and mitochondrial Trxr-2, an orthologue of TXNRD2.

In this report, we show a correlation between TXNRD enzyme activity and species lifespan using fibroblasts from birds, rodents, and primates. In some clades, we found similar associations with glutathione reductase activity, but did not see a correlation for any of the other redox enzymes evaluated. The increase in TXNRD activity in the longer-lived species is due to enhanced mitochondrial TXNRD2 with no change in cytosolic TXNRD1 or TXNRD3. A similar increase in TXNRD2 is seen in tissues of several models of enhanced longevity in mice, and in an analysis of mRNA levels from multiple tissues of primate species. Lastly, we demonstrate that overexpression of mitochondrial TXNRD2, but not cytosolic TXNRD1, can extend median (but not maximum) lifespan in female flies with a small lifespan extension in male flies in Drosophila melanogaster.

These data demonstrate that augmentation of mitochondrial thioredoxin reductase 2 is a conserved approach utilized by species from a range of animal clades under selection for a long lifespan. Furthermore, we demonstrate directly that augmentation of this enzyme is able to extend organismal lifespan in Drosophila melanogaster. Our approach shows the power of combining comparative biology cross-species approaches with direct interventions in model organisms as a means of discovering regulators of aging and lifespan. In addition, we identify mitochondrial Thioredoxin reductase 2 as a new target, for basic and applied research in aging.

Despite their best efforts, no scientist has ever come close to stopping humans from aging. But new research reveals you may be able to slow one type of aging - the kind that happens inside your cells. As long as you're willing to sweat. "Just because you're 40, doesn't mean you're 40 years old biologically. We all know people that seem younger than their actual age. The more physically active we are, the less biological aging takes place in our bodies." The study finds that people who have consistently high levels of physical activity have significantly longer telomeres than those who have sedentary lifestyles, as well as those who are moderately active.

Telomeres are the protein endcaps of our chromosomes. They're like our biological clock and they're extremely correlated with age; each time a cell replicates, we lose a tiny bit of the endcaps. Therefore, the older we get, the shorter our telomeres. Researchers found that adults with high physical activity levels have telomeres with a biological aging advantage of nine years over those who are sedentary, and a seven-year advantage compared to those who are moderately active. To be highly active, women had to engage in 30 minutes of jogging per day (40 minutes for men), five days a week. "If you want to see a real difference in slowing your biological aging, it appears that a little exercise won't cut it. You have to work out regularly at high levels."

Researchers analyzed data from 5,823 adults who participated in the CDC's National Health and Nutrition Examination Survey, one of the few indexes that includes telomere length values for study subjects. The index also includes data for 62 activities participants might have engaged in over a 30-day window, which the researchers analyzed to calculate levels of physical activity. The study found the shortest telomeres came from sedentary people - they had 140 base pairs of DNA less at the end of their telomeres than highly active folks. Surprisingly, he also found there was no significant difference in telomere length between those with low or moderate physical activity and the sedentary people. Although the exact mechanism for how exercise preserves telomeres is unknown, it may be tied to inflammation and oxidative stress. Previous studies have shown telomere length is closely related to those two factors and it is known that exercise can suppress inflammation and oxidative stress over time.

Lymph flow is necessary for vital functions, such as fluid and macromolecule homeostasis, absorption of lipids and transport of immune cells. All of these functions require proper functioning of the lymphatic vessels - their phasic contractions that propel lymph forward to central veins, proper permeability and interaction with cellular elements of the surrounding tissue microenvironment. Aging affects all of these functions of lymphatic vessels. However, despite findings of the last decades, our understanding of key regulatory mechanisms that support lymphatic vessel functions is still far from complete. The field of lymphatic biology has historically encountered difficulties in the assessment of lymphatic vessel function in vivo and in obtaining lymphatic vessels for studies in vitro. These difficulties have overlapped with an underappreciation of the importance of the lymphatic vascular component of the pathogenesis of various disorders in the past. Therefore, the lymphatic-related components in the pathogenesis of many diseases of the elderly remain to a large degree unknown.

Until the last decade, there were no published reports of systematic studies on aging-associated changes in the lymphatic vasculature. One study, published more than two decades ago, examined aging-associated changes in the structure of human lymphatic vessels. These authors demonstrated that in older humans, the destruction of the elastic elements and atrophy of muscle cells in the thoracic duct wall resulted in the development of "duct sclerosis." Investigations of the human mesenteric lymphatic bed demonstrated that after the age of 65, the number of collecting lymphatic vessels in the human mesentery was significantly reduced, and the number of connections between lymphatic vessels was greatly diminished. In some preparations of collecting lymphatic vessels, aneurism-like formations containing only endothelial cells in their walls were found, primarily in the areas located downstream but close to the lymphatic valves. Due to the profound difficulty of measuring lymph flow in vivo, there are only a few reports demonstrating measurements of reduced lymph flow in aged animals. In particular, it was reported that aging significantly reduced lymph flow from the main mesenteric lymph duct in rats by ~60% when compared between 3-month-old and 22-month-old animals.

Over the last decade, our group has performed a wide spectrum of studies significantly expanding our knowledge on how and by which mechanisms aging alters the structure and function of lymphatic vessels. These recent findings have led to a better understanding of the regulatory mechanisms of interactions between lymphatic vessels and mast cells (MCs) located in perilymphatic tissues, and demonstrated their importance for the control of all lymphatic functions mentioned above. We believe that these new discoveries provide the groundwork for a better understanding of the pathogenesis of many diseases in the elderly that involve a lymphatic component.

Our studies during the last decade have demonstrated that aging alters the structure and contractile function of lymphatic vessels. These changes are complex and predispose aged lymphatic vessels to diminished lymphatic contractility and lymph flow, especially during edemagenic challenges in the event of overlapping acute inflammation in the elderly. In addition, aging creates conditions for the easier spread of pathogens from lymphatic vessels into perilymphatic tissues. Aging induces the basal activation of perilymphatic MCs, which, in turn, restricts the recruitment/activation of several types of immune cells in perilymphatic tissues. Activated MCs trigger NF-κB signaling through the release of histamine. The aging-associated basal activation of MCs limits acute histamine-driven inflammatory NF-κB activation in aged perilymphatic tissues. Therefore, aging-associated dysfunction of MCs critically affects all NF-κB-mediated reactions of aged tissues to acute inflammation. Proper functioning of the mast cell/histamine/NF-κB axis is essential for the regulation of lymphatic vessel transport and barrier functions, as well as for both the interaction and trafficking of immune cells near and within lymphatic collectors. Thus, this axis appears to play important roles in the pathogenesis of the alterations in inflammation and immunity associated with aging.

Immunosenescence is the lifelong reduction in immunological reserve and homeostasis. This process contributes to reduced resistance to infectious diseases, increased propensity to develop cancer, and increased autoimmune disease observed in aged individuals. Furthermore, immunosenescence limits the success of medical interventions such as vaccination and efforts to augment antitumor immunity. Attempts to pinpoint a single "cause" of senescence in general and immunosenescence in particular have met with limited success. However, recent studies support a critical role for IL-7 in the maintenance of a vigorous healthspan and have identified IL-7 and its receptor and associated proteins, "the IL-7 network," as a useful biomarker of successful aging.

IL-7 is a member of the common γ chain family of cytokines. The signaling cascade(s) initiated by these interleukins and their receptors (IL-7R in the case of IL-7) regulates homeostasis of B, T, and natural killer (NK) cells of the immune system. Immunosenescence affects multiple cells within the hematopoietic lineage. The result is a gradual deterioration of immune function with age. Disruption of the IL-7 signaling pathway plays a central role in this process. In the Leiden Longevity Study, survival analysis was carried out for low versus high IL-7R gene expression in 81 nonagenarians versus the combined group of 619 of their middle-aged offspring and controls. Among nonagenarians, high IL-7R gene expression is associated with reduced mortality over 10 years; that is, higher gene expression levels of IL-7R in blood predict better survival in both age groups. Seemingly, high levels of IL-7R are beneficial. It is as if there is a limited total supply of lymphocytes that can be induced by IL-7 over a lifetime. Consuming the lymphocytes in youth and middle age provides better health, with the caveat that it may limit the possibility of living to old age. Fewer/less active lymphocytes during middle age may increase the chance of disease somewhat but result in a large enough pool of lymphocytes in old age to promote viability. Perhaps IL-7R represents a case of antagonistic pleiotropy.

The notion that low IL-7R expression levels are beneficial for reaching healthy old age corresponds with previous observations that patients suffering from autoimmune disease express increased levels of the IL-7 receptor/ligand complex genes and that antagonizing IL-7 or IL-7R may offer possible treatments. However, the results of the Leiden Longevity Study found that gene expression levels of IL-7R decrease with chronological age. On the other hand, the Leiden study also found that higher levels of IL-7R correlate with reduced 10-year mortality and that effect was pronounced in the nonagenarian population in which individuals at the high end of the overall lower IL-7R expression lived longer. To optimize health and lifespan, it may be useful to "thread the needle," lowering IL-7R enough to preserve peripheral T cells and help maintain low mTOR levels, while maintaining enough to maintain immune function. Transient modulation of IL-7R is one potentially effective strategy to reach this goal. Another possible conclusion is "correlation is not causation" and that the genes of IL-7/IL-7R complex are only part of the answer.

The remarkable plasticity of the adaptive immune system over many decades is a testament to several intrinsic features of its design. Despite attacks on its integrity from multiple angles, the size and diversity of the naive lymphocyte repertoire is maintained well into the 9th decade of life. While IL-7 is a necessary contributor to this "lympho-homeostasis" and its action is required for successful aging, wholesale augmentation of IL-7 above "normal" levels may disrupt this delicate balance. Numerous animal and several human studies suggest much promise remains for the utilization of IL-7 as a specific "immune tonic" or adjuvant. To this end, we look forward to the next generation of improved IL-7-based therapeutics.

New research sheds important light on the inner workings of learning and memory. Specifically, scientists show that a plasma membrane protein, called Efr3, regulates brain-derived neurotrophic factor (BDNF) / tropomyosin-related kinase B (TrkB) signaling pathway and affects the generation of new neurons in the hippocampus of adult brains. In turn, this generation of new neurons plays a significant role in learning and memory. "Our study demonstrates that Efr3a is associated with BDNF signaling and adult neurogenesis, which are important for learning and memory. We hope our results will provide new insights into the mechanisms underlying learning and memory."

To draw their conclusions, the researchers crossbred genetically altered mouse strains to delete Efr3a, one of the Efr3 isoforms, specifically in the brain. Brain-specific ablation of Efr3a promoted adult hippocampal neurogenesis by increasing survival and maturation of newborn neurons without affecting their dendritic tree morphology. Also, the BDNF-TrkB signaling pathway was enhanced in the hippocampus of Efr3a-deficient mice, as reflected by increased expression of BDNF-TrkB, and the downstream molecules, including phospho-MAPK (mitogen-activated protein kinase) and phospho-Akt. "This study once again emphasizes the extreme importance of neurogenesis specifically linked to neurotrophic signaling in the hippocampus. We are again reminded of how far we have come from the era in which neurogenesis in the adult mammalian brain was not believed to even occur."