Fight Aging!

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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Contents

• Coverage of the Caenorhabditis Intervention Testing Program
• A Brief Tour of the Causes of Immunosenescence in the Adaptive Immune System
• A Method of Rapidly Warming Vitrified Organs with Minimal Damage
• Senescent Cells Make Everything Worse in the Aging Lungs
• Mikhail Batin and the Open Longevity Project
• Latest Headlines from Fight Aging!
  • An Interesting Study on Aggregates in Aged Tissues
  • Calorie Restriction Slows Amyloid Accumulation in Mice
  • Help to Support LongeCity Affiliate Labs
  • Investigating the Mechanisms of Slowed Kidney Fibrosis via Calorie Restriction
  • Protective Effects of Physical Activity
  • Lack of Exercise and Excess Weight Increases Risk of Untreatable Heart Failure
  • An Approach to Reversing Aspects of Aging in the Blood Stem Cell Niche
  • The Impact of Protein Aggregation on Mitochondria
  • Chimeric Antigen Receptor Cancer Immunotherapies Continue to Look Promising
  • Progress in Bioprinting of Vascular Networks

Coverage of the Caenorhabditis Intervention Testing Program
https://www.fightaging.org/archives/2017/02/coverage-of-the-caenorhabditis-intervention-testing-program/

As you may be aware, a faction at the National Institute on Aging has for some years run the Interventions Testing Program (ITP). The objective is to pick out methods shown in the past to extend life span in mice, and rigorously rerun those studies in order to obtain gold standard data that definitively proves or disproves effects on aging. Unfortunately the budget extends no further than a couple of interventions each year, and the focus is on paths that can do no more than modestly slow aging at best. It should really be considered an adjunct effort to the primary goal of mapping metabolism, not an effort to make meaningful inroads into producing treatments for aging as a medical condition.

Motivations to one side, the need for such a gold standard program in aging studies is evident from the fact that so many claims of slowed aging in mice put forward in past decades cannot be reproduced. A common culprit is calorie restriction; in a way it is a pity that calorie restriction has such a large effect on health and aging. It means that many, many studies have been poisoned over the years, the data made useless because the authors failed to control for calorie intake in the animals involved. Even mild inadvertent calorie restriction produces effects that outweigh many others, and have caused researchers to draw entirely incorrect conclusions, misdirecting further research.

Still, to be honest, this doesn't matter much when it comes to the production of therapies at the end of the day. Rejuvenation treatments worth pursuing are highly unlikely to emerge from this part of the field, that concerned with calorie restriction mimetics, marginal slowing of aging via neutraceuticals, and the like. That could all vanish tomorrow and little of value would be lost; rejuvenation will emerge instead from the SENS repair-based approach, an entirely different area of research and development. However, these efforts to modestly slow aging in mice do matter for the researchers who are attempting to map the progression of aging at the detail level, a vast project proceeding hand in hand with efforts to map all of cellular metabolism. Methods of slowing aging are an important tool from that perspective, a way to identify areas of cellular biochemistry for further investigation. Given that this work is very slow and very expensive, false starts and mistaken directions have a large cost.

The problem of inadequate reproducibility is universal in the life science community, not just in mice and not just in aging research, but for today let us consider that in particular it is a challenge when running studies of aging in the nematode worm Caenorhabditis elegans. A great many such studies take place in comparison to the much more expensive undertaking of a mouse study of aging. Most investigations of the biochemistry of aging start in yeast and nematodes precisely because it is so much cheaper and faster than working with even short-lived mammals. The economics make sense, even accounting for the fact that a fair portion of the findings fail to prove relevant to mammals. Wasting time is wasting time, however, and so it also makes sense to create a Caenorhabditis Intervention Testing Program, analogous to the NIA Interventions Testing Program in mice.

In search for the fountain of youth, a lesson in doing good science

The study promised to be a big step toward cracking the code of aging: In 2000, scientists reported that giving roundworms a compound that blunted the effects of oxygen on their cells could boost their lifespans by 44 percent. After publishing their paper, team leader Gordon Lithgow recalls, "We felt our work had moved the field on into seriously thinking about chemical slowing of aging." But soon after, they started getting phone calls from another lab. Researchers led by David Gems couldn't get the same results, no matter what they tried. And in 2003, they published a paper saying so. That dashing of hopes was "exceedingly disappointing."

But the story has a happy ending, one that illustrates the way science works best. The experience jolted Lithgow to join with researchers around the United States to standardize testing of potential anti-aging compounds in roundworms. That project, known as the Caenorhabditis Intervention Testing Program (CITP), has led to its first results published this week: that, in carefully controlled side-by-side testing, most "fountain-of-youth" chemicals gave mixed results at best, but one drug did in fact extend the worms' lifespan. The impetus to form the CITP was the realization that Lithgow wasn't alone. Once, it was antidepressants that researchers said could extend lifespan. Not according to follow-up studies by other labs, though. The same thing happened with compounds known as sirtuins. So what was going on? One possible answer was that "nothing works in Europe," Lithgow told a laughing audience at a Buck Institute conference in August. "The other possible conclusion … is that we don't really know what we're doing here."

So Lithgow's lab catalyzed the beginnings of the CITP, joining forces with others to test 21,000 worms from 22 strains, just to see whether their lifespans - untreated - were consistent. They weren't. The lifespans of roundworms turn out to vary greatly, even within labs. In fact, the largest variation was when the same researchers repeated experiments. Suddenly, it made sense that testing the same compound on what seemed like the same worms would lead to a different result: The worms weren't identical after all. Armed with that information, Lithgow and his colleagues started doing things differently.

Longevity-promoting superstar gets revealed in Caenorhabditis reproducibility project

"The goal of the CITP is to identify pro-longevity chemicals that are effective across diverse genetic distances making them excellent candidates for trials in more complex animals, including mammals," said Gordon Lithgow, PhD, a professor at the Buck Institute for Research on Aging and a senior author of the paper. Lithgow runs the Buck lab that in 2011 showed that Thioflavin T extended lifespan in healthy nematode worms by more than 50 percent and slowed the disease process in worms engineered to mimic aspects of Alzheimer's disease. "Running experiments in three discrete laboratories allowed us to demonstrate the reproducibility of our study with Thioflavin T. But it's important to note that some of our other compounds did not pass this stringent test - getting feedback on the 'fails' also furthers the larger effort."

Researchers characterized the lifespans of 22 Caenorhabditis strains spanning three species. Thioflavin T was found to be the most robust pro-longevity chemical, as it extended the lifespan of all strains tested. In addition, researchers found that six out of the ten pro-longevity chemicals significantly extended lifespan in at least one strain of Caenorhabditis. Three dietary restriction mimetics were mainly effective across strains of C. elegans but showed more variable responses in other species. "Nearly 100,000 worms were individually monitored during this initial project. We hope that the scope and focus of this project will give confidence that our consortium can identify promising compounds for further testing on aging. The genetic differences between the three species of Caenorhabditis utilized by the CITP were vast - they were comparable to the differences between mice and humans. Aging is a variable process. Identifying compounds that promote longevity across all of those species increases the odds that we are hitting pathways common to many animals, including humans. These are the ones that warrant further exploration."

"Reproducibility has been a sticking point in aging research. Compounds that significantly extend lifespan in simple organisms make a big splash in a journal, only to come under question when results can't be duplicated in other labs. I look back at earlier studies and I think many different labs were working in different strains of worms and using different methods. While mouse studies are an essential part of pre-clinical research, they are also expensive to do. Our hope is that the CITP will yield robust and reproducible candidates that will help fuel success in higher organisms, including humans, where these compounds might be candidates for drugs to combat chronic diseases."

A Brief Tour of the Causes of Immunosenescence in the Adaptive Immune System
https://www.fightaging.org/archives/2017/02/a-brief-tour-of-the-causes-of-immunosenescence-in-the-adaptive-immune-system/

The open access paper I'll point out today covers some of the aspects of aging in the immune system, with a particular focus on the role of cytomegalovirus infection, and makes for interesting reading. The immune system is vital to health, not just in defending against pathogens such as bacteria, viruses, and fungi, but also because its agents work to destroy broken and harmful cells, such as those that have become cancerous, remove metabolic waste compounds where they accumulate outside cells, and help to regulate many necessary processes, from wound healing to the formation and destruction of synaptic structures in the brain. When the immune system declines into failure and dysfunction with advancing age, many other parts of our biology are dragged along with it into the downward spiral that ends in major organ failure and death. Finding ways to even partially reverse the progression of immune aging is obviously of great importance for the near future, a necessary part of the first generation of rejuvenation therapies. Fortunately, there are a few comparatively straightforward approaches that might bear fruit in the years ahead, despite the enormous and still incompletely mapped complexity of immune system biochemistry.

The immune system is broadly divided into innate and adaptive components, comprising different types of cell, different behaviors, and different vulnerabilities that lead to accumulated damage and disarray with time. The adaptive immune system is more recent in evolutionary terms, built atop the activities of the innate immune system. It is, as the name suggests, distinguished by being able to adapt to new threats rather than deploying the same set of armaments and strategies against every challenge, as is the case for the innate immune system. The adaptive immune system ultimately fails in large part because adaptation requires a memory of past actions, and over time the cells responsible for maintaining immune memory begin to crowd out the cells capable of taking action. Adults have a slow rate of creation of T cells, the cells of adaptive immunity. These cells are constructed in the bone marrow, but then migrate to the thymus to mature. That organ declines greatly shortly after childhood, and then further with increasing age, reducing its capacity for T cell maturation. This slow rate of replacement effectively puts a cap on the number of T cells present in the body under normal circumstances, and that combined with the lack of any effective limit on the numbers of memory T cells inevitably leads to disaster. Evolutionary processes are good at front-loading for success, producing biological systems that work very well in youth, but that hit architectural limits later in life.

The most effective near-term approach to this problem of misconfigured adaptive immunity is to improve upon and adapt the immune reboot therapies that are presenting being trialed successfully as treatments for severe autoimmune conditions. At the very high level, the age-damaged adaptive immune system is conceptually similar to an immune system fallen into autoimmunity: in both cases the problem is one of misconfiguration, the bad information recorded in immune cells leading to bad behavior. Wiping out these cells and starting over is a very promising approach. In the case of aging this doesn't deal with any of the forms of cellular damage that cause aging, but it should nonetheless do a great deal to restore effectiveness of the immune system in older people. The challenges are numerous: the present chemotherapies for immune ablation would need to be replaced with side-effect-free targeted cell killing technologies, such as that pioneered by Oisin Biotechnologies. Further, replacement of the immune system would likely have to be augmented with cell therapies in older people, as they would not be able to replace those cells rapidly enough on their own for safety. These are, however, very approachable challenges. The technologies largely exist already, and just need to be packaged, trialed, and moved into the clinic. Deploying this class of therapy will answer many of the questions asked in the paper linked below, and more rapidly than other forms of investigation.

Mechanisms Underlying T Cell Immunosenescence: Aging and Cytomegalovirus Infection

The human immune system must fight diverse pathogens and provide sufficient host protection throughout life. Memory T cells, which differentiate from naïve T cells upon primary antigenic stimulation and enable a rapid and robust response to previously encountered pathogens, are key players in adaptive immunity. The generation and maintenance of pathogen-specific memory T cells is crucial for life-long immune protection and effective vaccination. However, profound changes occur in the human immune system over time, known as immunosenescence. These age-related changes contribute to decreased immune protection against infections and diminished responses to vaccination in the elderly. Changes in T cell immunity appear to be have the most impact.

Although T cell numbers remain more or less constant over the human lifespan, pronounced age-associated changes occur in T cell composition (naïve vs. memory T cell subsets). It is well accepted that the functional naïve T cell output decreases after puberty due to thymic involution, resulting in increased homeostatic proliferation of existing naïve T cells and eventually phenotypic conversion of naïve T cells into virtual memory cells. In contrast to the shrinking naïve compartment and its impaired ability to activate and differentiate with age, the proportion of memory T cells increases during early life, remains stable throughout adulthood, but starts to show senescent changes after about 65 years. In humans, circulating memory T cells can be subdivided into two major phenotypically and functionally distinct populations: central memory T cells (TCM), which are largely confined to secondary lymphoid tissues, and effector memory T cells (TEM), which can traffic to multiple peripheral compartments.

One of the most prominent T cell changes to occur with age is the loss of the co-stimulatory molecule CD28 and the progressive accumulation of highly differentiated CD28- TEM cells, mainly in the CD8+ T cell population. These cells are characterized by decreased proliferative capacity, shortened telomeres, a reduced TCR repertoire, and enhanced cytotoxic activity. As CD28 is crucial for complete T cell activation, CD28 loss is associated with increased susceptibility to infections and a weakened immune response to vaccination in older people. It is thought that the memory T cells generated in youth are well preserved and remain strongly protective over decades, while T cell memory responses first derived in old age are severely impaired.

The ability to generate protective immune responses largely depends on the generation and maintenance of a diverse and well-balanced T cell repertoire. Several studies have shown contraction in T cell diversity corresponding to a shrinkage in the naïve T cell compartment in elderly individuals due to thymic involution. However, these studies do not take the dramatic influence of latent persistent infection into account, particularly cytomegalovirus (CMV) infection, which is known to be associated with age-related alterations in the T cell pool and function. Recent evidence suggests that homeostatic proliferation maintains the naïve CD4+ T cell compartment and its diverse repertoire, but not naïve CD8+ T cells, in CMV-negative individuals. A decline in naïve CD4+ T cell subsets occurs in the presence of CMV, but there is no depletion of naïve CD8+ T cells. In principle, thymic involution should have an equal impact on both CD4+ and CD8+ T cells. Therefore, the differences seen between the two subsets suggest that shrinkage of the naïve CD8+ T cell pool is more likely to be due to increased development of virtual memory T cells than the defective regeneration ability of an aged thymus. Moreover, unprimed "innate/memory-like" CD8+ T cells have recently been identified in humans. Taken together, these data imply that thymic involution might be less important for maintaining T cell diversity than previously thought.

Despite intensive studies of T cells providing some insights into immune system aging, they have a number of limitations that need to be taken into consideration in future investigations. First, most of our current knowledge on T cell aging is based on studies of circulating peripheral blood T cells, which only represent 2% of the total T cell pool. Circulating memory T cells predominantly reside in tissues other than the blood. Finally, human memory T cells are generated and maintained in the context of exposure to diverse viral infections throughout life, particularly CMV infection (over 90% of young people in developing countries). It is well-known that CMV plays an important role in human memory T cell function with aging. Therefore, distinguishing CMV seropositive individuals from others is important to provide a more accurate understanding of age-related memory T cell immunity.

Cytomegalovirus (CMV) is an ubiquitous β-herpesvirus that has co-evolved with humans over millions of years. Human CMV (HCMV) is a prevalent human pathogen, infecting 40-100% of world's population. CMV has the capacity to induce both lytic and latent infections to establish lifelong persistence in human hosts following primary infection. Long-term HCMV persistence has a profound impact on the immune system's composition and function, even in healthy HCMV-infected individuals, especially with respect to CD8+ T cells. One hallmark of latent HCMV infection is the progressive and substantial expansion of HCMV-specific memory CD8+ T cells over time, with HCMV-specific memory CD4+ T cells accumulating to a lesser extent. This accumulation of HCMV-specific memory T cells during viral persistence is termed "memory inflation." HCMV-specific memory T cells tend to gradually increase in number with age: in HCMV-infected elderly individuals, the CD8+ T cell response to HCMV antigens occupies nearly 50% of the entire memory CD8+ T cell compartment in peripheral blood, while approximately 30% of total circulating CD4+ T cells can be HCMV responsive.

Human cytomegalovirus (HCMV) persistence is thought to be a driver of immunosenescence in humans. The majority of HCMV-specific inflationary T cells are TEM cells with the typical age-related senescent T cell phenotype. It is widely accepted that late-stage differentiated CD28- T cells are a major characteristic of T cell aging, suggesting that persistent HCMV infection is associated with immunosenescence. This is further supported by the fact that the large population of HCMV-specific CD8+CD28- TEM cells that usually accumulate during HCMV persistence are absent in HCMV-seronegative elderly individuals, even those infected with other persistent herpes viruses. There is increasing evidence to suggest that memory inflation in HCMV infection is associated with impaired T cell immunity in elderly hosts. Despite the CD8+ T cell repertoire being diverse enough to recognize different viral epitopes soon after primary HCMV infection, clonal diversity starts to shrink with age, with a large proportion of the repertoire limited to a few high-avidity clones with a replicative senescent phenotype.

Taken together, HCMV infection in the elderly is implicated in immunosenescence and might have a deleterious impact on host immunity and enhance the aging process. Nevertheless, there remains considerable uncertainty regarding the causative role of CMV in immunosenescence. Although it is well-known that HCMV is a common cause of severe morbidity and mortality in immunocompromised individuals, we cannot exclude the possibility that HCMV might improve the polyfunctionality of CD8+ T cells and consequently benefit the host immune system, at least in young healthy individuals. Moreover, it is still unclear whether HCMV re-activation occurs more frequently in the elderly than in younger individuals. Hence, whether expansion of HCMV-specific CD8+ T cells over time is really deleterious in old age remains unknown.

A Method of Rapidly Warming Vitrified Organs with Minimal Damage
https://www.fightaging.org/archives/2017/03/a-method-of-rapidly-warming-vitrified-organs-with-minimal-damage/

Today I'll point your attention to a most interesting paper on a novel approach to reviving vitrified tissues. Vitrification is a state induced in tissues through the use of cryoprotectant and very low temperatures. All biological molecular activity halts, and the tissue enters a glass-like state of minimal ice crystal formation in which the small-scale structures essential to function are well preserved, or at least to the extent that the process is performed well and cryoprotectant is completely diffused throughout the tissue. Reversing this process without killing cells and essentially destroying the living tissue is another story, however. It cannot be done reliably today, but seems like a very feasible near future goal. Low-temperature storage of cells and other very small amounts of biological materials is well established, and lower animals such as nematode worms can survive vitrification and thawing. Further, researchers have demonstrated vitrification, thawing, and transplant of a mammalian organ that functioned for at least a short time. These are starting points, and a number of research groups are trying to close the various gaps in reliability and technology to enable a robust methodology.

Reversible vitrification of large tissue sections is an important goal for many reasons. Firstly, it would revolutionize the logistics of the organ transplant industry, which is currently expensive and challenging because organs cannot be kept alive for long once available, among other reasons. Secondly it would similarly revolutionize the logistics of the tissue engineering industry that has yet to exist but lies not so far ahead in our future. The ability to create supplies of tissues and organs far ahead of time and store them safely and indefinitely will shape much of the economics of this field. Lastly, and most importantly for the long term, the cryonics industry needs a way to safely warm the people who have been cryopreserved at death, at some future date when rejuvenation therapies, regenerative medicine, and other necessary biotechnologies have advanced to the point at which it is possible to restore or replace an old body and brain, even working from the starting point of a warming individual just past the point of today's clinical death. These individuals took a brave leap into the unknown, and at some point it will become possible to revive them. Even before that time, concrete progress towards reversible vitrification of tissues will greatly increase the legitimacy of cryonics in the eyes of the world. If a kidney can be vitrified, thawed, and used in medicine, its fine structures intact, then why can't a brain and the mind it contains be preserved, or so the line of thought will run.

In the case of the technology demonstrated here, it would most likely be very challenging to apply it to people already preserved, as it involves additions to the cryoprotectant solution. Introducing those additions after the fact would no doubt require technology of the same order of advancement as would be needed to restore aged tissues and manage a safe return to life on thawing. If there is one approach, however, there will be others - and for the people who have yet to be cryopreserved, those who will age to death prior to the advent of comprehensive human rejuvenation therapies, this class of approach is still very relevant. That this can be done at all should also increase any careful assessment of the odds of the whole endeavor of cryonics succeeding for those involved. Time passes and progress is forged, and more rapidly than ever these days.

New technology rewarms large-scale tissues preserved at low temperatures

A research team has discovered a groundbreaking process to successfully rewarm large-scale animal heart valves and blood vessels preserved at very low temperatures. The discovery is a major step forward in saving millions of human lives by increasing the availability of organs and tissues for transplantation through the establishment of tissue and organ banks. "This is the first time that anyone has been able to scale up to a larger biological system and demonstrate successful, fast, and uniform warming hundreds of degrees Celsius per minute of preserved tissue without damaging the tissue."

In the past, researchers were only able to show success at about 1 milliliter of tissue and solution. This study scales up to 50 milliliters, which means there is a strong possibility they could scale up to even larger systems, like organs. Currently, more than 60 percent of the hearts and lungs donated for transplantation must be discarded each year because these tissues cannot be kept on ice for longer than four hours. Long-term preservation methods, like vitrification, that cool biological samples to an ice-free glassy state using very low temperatures between -160 and -196 degrees Celsius have been around for decades. However, the biggest problem has been with the rewarming. Tissues often suffer major damage during the rewarming process making them unusable, especially at larger scales.

In this new study, the researchers addressed this rewarming problem by developing a revolutionary new method using silica-coated iron oxide nanoparticles dispersed throughout a cryoprotectant solution that included the tissue. The iron oxide nanoparticles act as tiny heaters around the tissue when they are activated using noninvasive electromagnetic waves to rapidly and uniformly warm tissue at rates of 100 to 200 degrees Celsius per minute, 10 to 100 times faster than previous methods. After rewarming and testing for viability, the results showed that none of the tissues displayed signs of harm, unlike control samples rewarmed slowly over ice or those using convection warming. The researchers were also able to successfully wash away the iron oxide nanoparticles from the sample following the warming. Although scaling up the system to accommodate entire organs will require further optimization, the authors are optimistic. They plan to start with rodent organs (such as rat and rabbit) and then scale up to pig organs and then, hopefully, human organs.

Improved tissue cryopreservation using inductive heating of magnetic nanoparticles

Vitrification, a kinetic process of liquid solidification into glass, poses many potential benefits for tissue cryopreservation including indefinite storage, banking, and facilitation of tissue matching for transplantation. To date, however, successful rewarming of tissues vitrified in VS55, a cryoprotectant solution, can only be achieved by convective warming of small volumes on the order of 1 ml. Successful rewarming requires both uniform and fast rates to reduce thermal mechanical stress and cracks, and to prevent rewarming phase crystallization. We present a scalable nanowarming technology for 1- to 80-ml samples using radiofrequency-excited mesoporous silica-coated iron oxide nanoparticles in VS55.

Advanced imaging including sweep imaging with Fourier transform and microcomputed tomography was used to verify loading and unloading of VS55 and nanoparticles and successful vitrification of porcine arteries. Nanowarming was then used to demonstrate uniform and rapid rewarming at more than 130°C/min in both physical (1 to 80 ml) and biological systems including human dermal fibroblast cells, porcine arteries and porcine aortic heart valve leaflet tissues (1 to 50 ml). Nanowarming yielded viability that matched control and/or exceeded gold standard convective warming in 1- to 50-ml systems, and improved viability compared to slow-warmed (crystallized) samples. Last, biomechanical testing displayed no significant biomechanical property changes in blood vessel length or elastic modulus after nanowarming compared to untreated fresh control porcine arteries. In aggregate, these results demonstrate new physical and biological evidence that nanowarming can improve the outcome of vitrified cryogenic storage of tissues in larger sample volumes.

Senescent Cells Make Everything Worse in the Aging Lungs
https://www.fightaging.org/archives/2017/03/senescent-cells-make-everything-worse-in-the-aging-lungs/

Here I'll point out a recent open access paper that covers the various ways in which accumulated senescent cells harm the lungs in old age. The count of senescent cells rises with age in all tissues, the consequence of increased cellular damage on the one hand and progressive failure of the immune system to destroy these cells on the other. The presence of these cells is one of the contributing root causes of aging, in fact. They generate a mix of signals known as the senescence-associated secretory phenotype (SASP) that promotes chronic inflammation, destructively remodels the extracellular matrix structures necessary for correct tissue function, and changes the behavior of nearby cells for the worse. When it comes to the lungs, it is already known that senescent cells make people more vulnerable to respiratory infection, and are responsible for loss of elasticity and degraded normal function of structures in the lungs. Further, senescent cells are strongly implicated as a cause of fatal lung diseases such as idiopathic pulmonary fibrosis, due to their harmful effects on tissue structure.

If senescent cells are such a bad deal, why do we have them? The short answer is that evolution tends to produce systems that work well at the outset, during reproductive life span, and then fall over badly later. The antagonistic pleiotropy view of the evolution of aging describes this picture in more detail; in essence there is little evolutionary pressure after the end of reproductive life to select for a biochemistry with improved repair and maintenance. Senescent cells are initially one of the mechanisms that shape a growing embryo, helping to stop growth when growth must end, such as around fingers, or defining the edges of other organs. They also play a short-term role in wound healing. Further, at least initially and in small amounts, cellular senescence can suppress the risk of cancer by halting replication in those cells most at risk of becoming cancerous. Unfortunately, despite the necessary and useful aspects of cellular senescence, the bad behavior of senescent cells in large numbers eventually kills us.

What is to be done about this? The most straightforward approach is to develop targeted cell killing therapies that destroy senescent cells while leaving normal cells alone. Senescent cell clearance has been demonstrated to produce limited rejuvenation in mice, turning back numerous specific aspects of aging and age-related diseases, and a range of approaches to bring this capability to human medicine are currently at various stages of development. Small molecule drugs that trigger apoptosis in senescent cells are the furthest along, and are entering clinical trials this year and next. Beyond that, groups like Oisin Biotechnologies are working on programmable gene therapies and other approaches that should prove more effective than the output of the traditional drug discovery pipeline. This will all cascade into the clinic over the course of the next decade, starting a year or two from now, and given the benefits we should all be putting some funds aside for our own treatment when it becomes available at a reasonable price.

The Impacts of Cellular Senescence in Elderly Pneumonia and in Age-Related Lung Diseases That Increase the Risk of Respiratory Infections

Pneumonia causes significant mortality and morbidity in elderly patients, defined as those aged over 65 years, compared to younger populations. The annual incidence of pneumonia in the elderly populations is 4 times that of younger populations. In addition, the rates of hospitalization for pneumonia increase in elderly patients with each passing year, and with an expected 20% of the world's population reaching elderly status by 2050, the burden of community-acquired pneumonia will be even more significant in the coming years. In the respiratory system, aging might render individuals more susceptible to infection by undergoing various physiological changes, including dilatation of airspaces, increased air trapping, decreased chest wall compliance, reduced respiratory strength, decline in mucociliary clearance, and diminishment of cough reflex. In addition, aging weakens the immune system in conjunction with the presence of comorbid diseases (e.g., diabetes mellitus, chronic heart disease, malignant tumors, and use of immunosuppressive drugs). However, the definitive mechanisms underlying the high morbidity and mortality of pneumonia in elderly populations are not fully understood.

Several lines of evidence indicate that age-associated, nonmicrobial, and chronic low-grade inflammation enhances the susceptibility of pneumonia in the elderly populations. A previous study reported that elevated tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels positively correlated with the incidence of pneumonia in healthy elderly individuals. Other studies demonstrated that aged mice had increased lung inflammation and were found to be highly susceptible to pneumococcal pneumonia.

Cellular senescence, one of the hallmarks of aging, carries out its primary duty as a trigger of tissue repair, regeneration, and remodeling during normal embryonic development and upon tissue damage. To eliminate damaged cells, senescent cells arrest their own proliferation, create an inflammatory microenvironment, recruit phagocytic immune cells for elimination of senescent cells through senescence-associated secretory phenotype (SASP), and promote tissue renewal. These processes are beneficial for organisms in young tissue where the sequence of senescence-clearance-regeneration is transient in manner. However, this beneficial processes can be corrupted in a pathological context and aged tissues, where senescent cells persistently accumulate. The combination of senescent cell accumulation and excessive SASP results in persistent low-grade inflammation in aging tissue, which elevates the susceptibility to pathogen threats. Furthermore, accumulation of senescent cells causes disruption of normal tissue microenvironments and aberrant tissue remodeling through extracellular matrix (ECM) degeneration and tissue fibrosis.

In the respiratory system, emerging evidence indicates that cellular senescence is a key component in the pathogenesis of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), which are known to be age-related diseases and increase the vulnerability to pneumonia. Both of the diseases bear the feature of chronic low-grade inflammation with upregulations of various growth factors and chemokines. Thus, it is speculated that COPD and IPF might enhance the vulnerability to pathogens not only by their structural collapse of lung parenchyma, which makes it easier for pathogens to invade, but also by inducing chronic low-grade inflammation due to SASP. Since both of the lung disorders predominantly affect the elderly and have a lot of involvement in the susceptibility to the pathogens, we contemplate that it is also important to focus on the involvement of cellular senescence in the pathogenesis COPD and IPF for getting to the core of elderly pneumonia.

Mikhail Batin and the Open Longevity Project
https://www.fightaging.org/archives/2017/03/mikhail-batin-and-the-open-longevity-project/

The Life Extension Advocacy Foundation folk recently spoke to Mikhail Batin, long-standing advocate for radical life extension, and noted the latest venture from the Russian community, Open Longevity. In keeping with the spirit of the times, this is focused on setting up the infrastructure to run public human trials of interventions that may slow aging, on actually getting something done. That is admirable; we certainly need more of that in this era of stifling, overbearing regulation of every aspect of medical progress. I hope to see this effort succeed and grow. That said, I can't say as I think their initial choices are worth chasing: calorie restriction mimetics and a polypill approach that mixes existing drugs used to lower cardiovascular disease risk. If there were no other options, then yes, a polypill might be a surprisingly good choice, and calorie restriction is certainly better than nothing. But there are other options, and those options are far, far better. For example, it should be perfectly possible to set up open, responsible trials of some of the senescent cell clearance drug candidates such as navitoclax or piperlongumine, given that their pharmacology is well characterized already. Jailbreaking these compounds from the regulatory establishment would be a worthy exercise, assuming their effects on senescent cells in mice hold up in humans. Alas, each to their own, for better or worse.

As an aside for those readers come more recently to Fight Aging!, I should note that there is a fair-sized Russian-language longevity advocacy movement, on a par with that of the US or Europe. It reflects the strong level of support for the goal of health life extension in that part of the world, given the relative sizes of the overall populations. You might look at the Science for Life Extension Foundation as an organization that occupies an analogous position in the Russian community when compared to the Methuselah Foundation and SENS Research Foundation in the US community. Contact and collaboration between the Russian- and English-language communities has grown considerably over the past decade, which I think has as much to do with advances in automated translation as it does with the research community coming closer to clinical therapies capable of treating the causes of aging. There is certainly much more of a sense of the practical possibilities in the field these days, and that draws in ever more supporters and advocates.

As a sweeping generalization, the Russian end of the longevity science community is more in favor of programmed aging theories, and thus more in favor of tinkering with the operation of metabolism as the best way forward to slow aging or make tissues act in a more youthful fashion. This tends to involve drug discovery aimed at altering cellular behavior, such as via recreating some of the effects of calorie restriction, though some more interesting items have emerged, such as mitochondrially targeted antioxidants. It is somewhat ironic that the English-language research community is much more in favor of theories that describe aging as an accumulation of molecular damage, but the members of that community still near-entirely work on tinkering with metabolism to slow aging via drug discovery, something that their foundation of theory should decry as a marginal effort that does nothing to address the true causes of age and age-related disease. We can hope that this will change as SENS rejuvenation approaches based on damage repair, such as the newly popular efforts to remove senescent cells from aged tissues, continue to produce far more reliable and impressive results than any of the other options - and that organizations such as Open Longevity also pick up that banner to help carry it forward.

LEAF Meets Mikhail Batin

The rejuvenation research community is very diverse. Despite each of us having their favorite projects or directions of activity, the achievement of our common goal - the extended period of health and productivity - is highly dependent on this diversity. We need advocacy organizations to educate the public and fundraise actively, in order to support fundamental research. Once these fundamental studies are done, we need biotechnology startups to play their role in taking these new potential therapies through preclinical testing. Then bigger companies or venture investors need to support these startups with clinical trials in order to get promising interventions approved by regulatory authorities. Each stage is necessary to transform an idea into a treatment. Regardless of what aspect of this process a person or group works within it is always nice to meet like-minded people who are trying to find a way to achieve results sooner.

There are many drugs which are already approved to treat specific diseases, but which are also known to have the potential to address aspects of the aging process. Sadly, most have not yet been tested in healthy middle aged people in clinical trials, so we cannot be sure about their effect on the human lifespan. So, should we just wait for a research organization or pharmaceutical company to do this? Mikhail Batin, the head of Science for Life Extension Foundation, says no. Recently in the US to attend the conference The Biology of Aging: Advances in Therapeutic Approaches to Extend Healthspan, Mikhail also stopped by to visit with LEAF President Keith Comito and discuss life extension activities in Russia and Mikhail's new ambitious project - Open Longevity.

Mikhail believes there are alternative ways to organize pilot clinical trials and obtain crucial data about promising geroprotectors - information that every member of our community would benefit from. The solution is simple and elegant: members of a local community can become participants of a trial themselves, while a specialized patient organization will ensure proper procedures (study protocol development and observation, analysis of the data and preparation of a publication) are followed. This is the main goal of Russian initiative Open Longevity, started few months ago. So far, Open Longevity is planning to test a combination of statins with sartans as a pilot project, the team is open to discussion regarding the experiment design and protocol.

Open Longevity

Our task is to run clinical trials of anti-aging therapies. There are a lot of candidates for anti-aging drugs - geroprotectors. Promising results can be seen in tests on lab animals and in observational human studies. It's time to determine what intervention exactly will be best for each individual. Our plan is to channel the energy of patients to find the best one. We create the infrastructure project linking scientists, physicians and potential subjects.

Open Longevity Project has two parts: First, it's a patients organization initiating clinical trials. Patients will become not only initiators, but also the holders of the obtained data. We want to aim their energy in scientific track and to give everyone a chance to contribute in the fight against aging. Of course, this does not negate the fact that all studies will be conducted strictly under the supervision of professionals. We are talking about a public non-profit organization, and of course there will be other goals for it: fundraising and attracting other resources, lobbying and education. The more members we have, the louder will be our voice.

Second, Open Longevity is an online platform for self health monitoring. Yes, there are a lot of platforms like this. But we're special - we want to turn every patient into the researcher. Do you take medications, supplements or just experiment with your diet? We encourage everyone to pass the required tests before and after your interventions. This will give an understanding of whether it works for you or not. And will generate big data. Isn't it what's been lacking, our little programmers of neural networks?

Latest Headlines from Fight Aging!

An Interesting Study on Aggregates in Aged Tissues
https://www.fightaging.org/archives/2017/02/an-interesting-study-on-aggregates-in-aged-tissues/

The paper here provides an interesting perspective on the formation of solid aggregates of misfolded or damaged proteins with age, one of the distinguishing features of old tissues. There are numerous types of such aggregate, varying by tissue, and a mix of evidence for their contribution to specific aspects of aging or specific age-related diseases. In some cases it is hard to draw a direct line between a form of aggregate and its consequences. In others the chain of cause and effect is comparatively well understood, as is the case for Alzheimer's disease, amyloid-β, and tau, for example. It seems clear that the fastest way to proceed in each case is build a method to remove the aggregate and then observe the outcomes, both for the goal of increased understanding, and the arguably more important goal of removing causes of aging in order to produce rejuvenation therapies.

Deaths from atherosclerotic cardiovascular disease (CVD) comprise 31% of all mortality worldwide. Age and hypertension are the major risk factors for atherosclerotic CVD, and both are associated with increased stiffness of the heart. This rigidity, resulting in diastolic dysfunction, is largely attributed to myofibroblast growth and collagen deposition between cardiomyocytes. Most proteins adopt, either spontaneously or with the help of other proteins, specific folded structures with limited degrees of freedom. Chemically altered or misfolded structures, when they occur, are vulnerable to aggregation with other unstructured proteins. Although protein damage and misfolding are inevitable, multiple proteostasis systems are devoted to the repair or clearance of damaged proteins. The heart, in particular, is subject to continuous mechanical and metabolic stress; as a result, the cardiac proteome may be especially reliant on multi-level quality control to ensure proper folding and integrity of proteins.

Although protein aggregation has been studied extensively in neurodegenerative diseases, aggregates that form during normal cardiac aging or sporadic CVD have not previously been characterized. In this study, we isolated and quantified compact aggregates from the hearts of young-adult and aged mice and identified their protein constituents. To ask whether the hypertensive state itself disrupts proteostasis and thus mimics aging, we compared protein aggregates from hearts of young mice that were either hypertensive or normotensive. We also examined protein aggregation in early- and late-passage cardiac myofibroblasts, to assess whether their proteostasis is impaired during in vitro senescence and thus may contribute to cardiac senescence in vivo.

Detergent-insoluble protein aggregates were isolated from mouse hearts and characterized on 2-dimensional gels. Their levels increased markedly and significantly with aging and after sustained angiotensin II-induced hypertension. Of the aggregate components identified by high-resolution proteomics, half changed in abundance with age (392/787) or with sustained hypertension (459/824), whereas 30% (273/901) changed concordantly in both. One fifth of these proteins were previously associated with age-progressive neurodegenerative or cardiovascular diseases, or both (eg, ApoE, ApoAIV, clusterin, complement C3, and others involved in stress-response and proteostasis pathways). Because fibrosis is a characteristic of both aged and hypertensive hearts, we posited that aging of fibroblasts may contribute to the aggregates observed in cardiac tissue. Indeed, as cardiac myofibroblasts "senesced" (approached their replicative limit) in vitro, they accrued aggregates with many of the same constituent proteins observed in vivo during natural aging or sustained hypertension.

In summary, we have shown for the first time that compact (detergent-insoluble) protein aggregates accumulate during natural aging, chronic hypertension, and in vitro myofibroblast senescence, sharing many common proteins. Thus, aggregates that arise from disparate causes (aging, hypertension, and replicative senescence) may have common underlying mechanisms of accrual.

Calorie Restriction Slows Amyloid Accumulation in Mice
https://www.fightaging.org/archives/2017/02/calorie-restriction-slows-amyloid-accumulation-in-mice/

The practice of calorie restriction is shown to slow the progression of aging and extend healthy life in most species and lineages tested to date, including non-human primates. In humans the degree of life extension is a question mark, as the available data is exceedingly sparse, but the short-term changes are both very beneficial and very similar to those seen in other mammals. Given this, it should be unsurprising to find that calorie restriction slows any one particular aspect of aging, as is the case here for amyloid accumulation in tissues, one of the root causes of age-related disease and dysfunction in normal individuals, but also a prominent feature in a number of genetic diseases. As is frequently true of studies of calorie restriction, the sweeping changes created in the operation of metabolism make it very challenging to determine root causes and chains of cause and effect for the benefits produced, even when those benefits are clear, evident, and robustly reproducible.

Amyloidosis is a group of diseases characterized by extracellular or intracellular deposition of insoluble amyloid fibrils. Fibrils are formed when normally soluble proteins aggregate due to conformational changes caused by various mechanisms. Amyloid fibrils and oligomers of aggregates cause profound dysfunction in both cells and tissues, and these lead to a number of diseases. Apolipoprotein (Apo) A-II is the second most abundant apolipoprotein in serum high-density lipoprotein (HDL) in humans and mice. We found that ApoA-II accumulates to form amyloid fibrils (AApoAII) that deposit extracellularly in various organs with aging. In humans, it is due to a mutation in the normal stop codon in the ApoA-II gene and it has been observed mainly in the kidneys. In aged mice of many strains, it has been observed systemically in several organs. ApoA-II amino acid sequences of humans and mice differ by approximately 40% and they exist in different forms. However, both ApoA-II proteins exist mainly in HDL particles and they may have similar roles.

We have reported that administration of a very small amount of AApoAII fibrils markedly accelerated amyloid deposits in young mice. Intriguingly, our recent studies have suggested that AApoAII amyloidosis was transmissible by a prion-like infectious process through a seeding-nucleation mechanism. These findings have suggested that mouse AApoAII amyloidosis is an extremely useful model for the analysis of systemic amyloidoses and the development of new preventive treatments for amyloidoses. Nutritional control and caloric restriction (CR) may be the most readily available treatment to prevent or slow these amyloidoses. In particular, CR, i.e., a ~60% reduction of intake compared to an ad libitum (AL) diet, has been reported to be the most effective non-genetic treatment to decelerate aging and extend life- and health-span.

The molecular mechanisms by which longevity is promoted by CR intervention are complex. One important metabolic reaction mediated by CR is autophagy. This process supplies organisms with nutrients via the cytoplasmic recycling system. It also maintains damaged organelles and proteins during aging and increases longevity. The underlying mechanisms by which CR treatment mitigates Alzheimer's disease are suggested by a number of observations. First, both circulating insulin and insulin signaling are altered by CR treatment, enhancing the degradation of amyloid-β via enzymatic processes. Second, CR treatment activates sirtuin-1 (SIRT1) signaling and enhances the function of non-amyloidogenic processing enzyme of the amyloid precursor protein. Third, autophagy induced by CR treatment appears to suppress the progression of Alzheimer's disease. In this regard, there are two reports that demonstrated that activated autophagy degraded amyloid fibrils or reduced levels of amyloid-β peptide and amyloid precursor protein.

In AApoAII amyloidosis, we previously reported that chronic CR (60% caloric intake compared with an AL group) decelerated the advancement of senescence in SAMP1 mice and inhibited the spontaneous deposition of AApoAII fibrils with aging. However, the mechanisms reducing amyloidosis were unclear. Here, we hypothesize that CR treatment does indeed play a preventive role against the progression of systemic amyloidosis. Moreover, we demonstrate that CR treatment reduced the progression of amyloidosis in mice with inducible systemic AApoAII amyloidosis. We suggest that suppressing the levels of amyloid precursor proteins in the body might be a good first step in preventing amyloid deposition in almost all amyloidoses. From our data, CR treatment might lessen amyloid deposition by reducing oxidative stress and improving the unfolded protein response. These results suggested that the beneficial effects of CR are indeed complex. It is currently difficult to pinpoint the direct effects of CR that suppress amyloid deposition.

Help to Support LongeCity Affiliate Labs
https://www.fightaging.org/archives/2017/02/help-to-support-longecity-affiliate-labs/

The LongeCity community is presently building a small fund from philanthropic donations in order to help support a selection of affliate laboratories involved in the development of therapies to treat aging as a medical condition. In the past, LongeCity has done a good job of funding small research projects in the field, and this is a worthy continuation of such efforts. Even modest amounts of funding can help to smooth the development and validation of early stage research in the field. If you have a little money to spare, please do consider making a donation.

The LongeCity Affiliate Labs are small, research-focused enterprises or independent academic research groups led by a scientists with strong ties to the LongeCity community and a proven track record of commitment to scientific inquiry directly relevant to the LongeCity mission. These leaders and their colleagues are not just trailblazers in advancing important areas of regenerative and rejuvenation research, but also incredibly helpful when there is a community need for peer review, when providing advice and training to a young scientist, and in providing the expertise and tools to test the novel, controversial, or promising scientific leads sourced from the LongeCity community and beyond.

There is a small support fund that the labs can draw on to flexibly support their research activities. While not a substitute for private investment and public sector grants, the ability to flexibly try out a new idea without needing to assemble lengthy proposals to funding bodies can be an invaluable accelerator to research progress. All Affiliates have an active link to the LongeCity community, so there is a level of accountability and responsiveness beyond anything encountered in traditional research donations. By donating to the Affiliate Labs fund, Members can be assured that every penny goes directly to an expert personally and professionally committed to making a difference in the scientific conquest of death. Current affiliate labs are: Alexandra Stolzing, Loughborough University, UK and Leipzig University, Germany; João Pedro de Magalhães, University of Liverpool, UK; Kelsey Moody, Ichor Therapeutics, USA; Kevin Perrott, Buck Institute, USA; Matthew O'Connor, SENS Research Foundation, USA.

Investigating the Mechanisms of Slowed Kidney Fibrosis via Calorie Restriction
https://www.fightaging.org/archives/2017/02/investigating-the-mechanisms-of-slowed-kidney-fibrosis-via-calorie-restriction/

The practice of calorie restriction produces sweeping changes in the operation of cellular metabolism and acts to modestly slow the progression of aging, extending life in most species and lineages tested to date. The focus in this open access paper is on the ability of calorie restriction to slow the fibrosis that accompanies aging, here in the kidney, though it is significant in other organs as well. Fibrosis is the inappropriate formation of scar-like tissue due to age-related failure in mechanisms of regeneration, a process that degrades organ function and is a major component of conditions such as kidney failure.

Chronic kidney disease (CKD), which is defined by reduced glomerular filtration rate, proteinuria, or structural kidney disease, is a growing problem among the aging population, to the extent that the elderly have an average prevalence of CKD that is three to five times higher than that observed in young and middle-aged populations. Accordingly, CKD predisposes the elderly to a high risk of cardiovascular events and premature death. Morphological and functional changes that accompany kidney aging are thought to contribute the development of CKD in the elderly. For example, processes that characterize kidney aging include glomerulosclerosis, interstitial fibrosis, tubular atrophy, vascular sclerosis, and loss of renal function. The mechanistic basis of kidney aging is cellular senescence, which is characterized by the inability of cells to proliferate despite the presence of ample space, nutrients and growth factors in the medium. Although renal fibrosis has been observed in elderly individuals in the absence of overt CKD, the relationship between cellular senescence and fibrosis during kidney aging is yet to be determined.

Epithelial-mesenchymal transition (EMT) is the process whereby differentiated epithelial cells undergo a phenotypic conversion that gives rise to matrix-producing fibroblasts and myofibroblasts. EMT is increasingly recognized as a key process that contributes to kidney fibrosis and the decline of renal function. Age-related changes in the levels of transforming growth factor-β (TGF-β), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF) result in a complex shift of the microenvironmental milieu that is thought to affect tissue homeostasis under both normal and abnormal conditions, triggering EMT and progressive fibrosis. Given that senescence and EMT play well-documented roles in the etiology and progression of age-associated CKD, the development of therapeutic interventions to retard or reverse these processes is warranted.

Here, we first examined compared age-related metabolic parameters and renal function between the groups of rats. Compared to the young rats, increases in age-related proteinuria, hypercholesterolemia and hypertriglyceridemia were observed in the older rats. We proceeded to demonstrate increased cellular senescence, as indicated by overexpression of P16, P21 and SA-β-gal in the kidneys of the aging rats. Cellular senescence is not only a marker of renal aging but also actively participates in the process. Furthermore, senescent cells secrete inflammatory factors and growth factors, resulting in a complex shift within the cellular microenvironment, which induces EMT. Increased levels of EMT as a function of age were demonstrated in this study. We found that EMT was increased in the older rats, compared with the younger rats, indicating that EMT increases as a function of age. Given that cellular senescence and EMT contribute to the decline in renal function with age, we investigated the effect of interventions on both senescence and age-related EMT in our rat models.

While previous studies have shown that caloric restriction (CR) decreased the abundance of senescent cells, improved telomere maintenance and reduced the levels of oxidative damage markers in the small intestine and liver, and alleviated age-related increase in EMT in the thymus, similar studies in the aging kidney have been lacking. Here we report that short-term CR alleviates cellular senescence and EMT in the aging kidney. However, it should be pointed out that even were our study to substantiate short-term CR as an effective intervention for cell senescence and EMT, the degree of restriction required would limit the utility of this intervention. As an alternative strategy, new research has focused on the development of caloric restriction mimetics (CRMs). The objective of CRM research is to identify compounds that mimic the effects of CR by targeting metabolic and stress response pathways affected by CR without actually restricting caloric intake.

With respect to how short-term CR and CRM treatment might directly impact cellular senescence and EMT, one interesting candidate is the AMPK-mTOR signaling pathway. In the in vivo experiments, we demonstrated that AMPK/mTOR signaling in kidney was downregulated with age, and that this was reversed by short-term CR and CRM treatment. In order to further verify this pathway, we induced EMT and cellular senescence of proximal tubular cells (PTCs) in vitro with high glucose. We found that exposure of PTCs to high glucose for 48 hours resulted in the high glucose-induced EMT and cellular senescence, decreased expression of activated AMPK and decreased AMPK/mTOR signaling. Costimulation of PTCs with high glucose and a CRM, both of which activate AMPK, alleviated high glucose-induced EMT and cellular senescence, and increased AMPK/mTOR signaling. Moreover, mTOR was upregulated, and EMT and senescence were increased in AMPK-silenced cells, but were not alleviated in AMPK-silenced cells that had been treated with a CRM. These results indicated that the CRM inhibited EMT and senescence of PTC via AMPK/mTOR signaling. It is possible that the data presented here could be extrapolated to explain the mechanisms of fibrosis seen in other organs during aging, and to provide strategies to overcome this process.

Protective Effects of Physical Activity
https://www.fightaging.org/archives/2017/03/protective-effects-of-physical-activity/

Regular exercise slows aging more reliably and to a greater degree than any presently available medical technology, something that is more a statement on the poor nature of medicine at present than on the wondrous powers of exercise. The size of the effect is still small in the grand scheme of things; you can't reliably exercise your way to living to 100, and at present the majority of fit older people don't even make it to 90. You will, however, be better off than people who live a sedentary lifestyle. That exercise is better than available medicines at influencing the pace of aging will cease to be true in the near future as the first rejuvenation therapies emerge, but even then there is no reason to use that as excuse to slack on the basics of health maintenance. Exercise is both free and produces benefits, so take advantage.

Some lifestyle factors, such as physical activity (PA), could lower the risk of certain forms of dementia. In this article, our goal is to explore the role of PA in reducing the risks of age-related Alzheimer's disease (AD), vascular dementia (VaD), and mild cognitive impairment (MCI). PA throughout one's life can enhance cognitive function later in life, so it should be encouraged at every age. In contrast, sedentary behaviors, such as viewing television for extended periods over the course of years, can negatively affect cognitive function later in life. Moreover, those who were physically active in midlife have a reduced risk of developing depression in late life. Depression in late life has also been linked to dementia. Ideally, all adults should remain physically active throughout life, starting at a young age, to achieve optimal cognitive health as an older adult.

PA is effective in reducing risk for developing MCI in older adults, but the optimizing of exercise training (i.e., types of PA, intensity, duration), cardiorespiratory fitness, age, level of cognition, medications, and social environments, may all play roles in the outcome. For older adults who have already developed a form of cognitive impairment, whether mild, such as those with MCI, or moderate to severe, as with dementia, PA can improve cognitive function, when compared to those with cognitive impairment who are not physically active. Studies show that six to 12 months of exercise for those with MCI or dementia results in better cognitive scores than sedentary controls.

While the protective effect of PA on the aging brain is supported by numerous studies, the exact mechanisms are less clear. PA can increase blood flow to the brain, both during and shortly after a PA event, in response to increased needs for oxygen and energetic substrate. The increased brain/cerebral blood flow triggers various neurobiological reactions, which provide an increased supply of nutrients. Moreover, cerebral angiogenesis - the development of new blood vessels in the brain - is increased by PA, and the brain's vascular system is plastic, even in old age. The increased vascularization of the brain, as well as the regular increases in blood flow that periods of PA provide, may reduce the risks of MCI and AD, by nourishing more brain cells and helping to remove metabolic waste or AD-inducing amyloid-β.

Hypertension is one of the main risk factors for MCI, AD, and VaD. Hypertension can increase the risk of strokes, as well as small strokes that are often the cause of VaD. Since strokes can complicate AD and aggravate dementia symptoms, it follows that hypertensive individuals could benefit by lowering their blood pressure, regardless of their level of cognitive impairment. Even low-intensity PA for 30 min, three to six times a week for nine months, can significantly lower blood pressure in elderly adults. Because hypertension is a prominent risk factor, lowering blood pressure may be one of the mechanisms by which PA reduces the risk of many age-related neurodegenerative diseases.

Lack of Exercise and Excess Weight Increases Risk of Untreatable Heart Failure
https://www.fightaging.org/archives/2017/03/lack-of-exercise-and-excess-weight-increases-risk-of-untreatable-heart-failure/

If you were in search of yet more reasons to keep up with the health basics, meaning regular exercise, a sensible diet, and avoidance of weight gain, then look no further. Here, researchers note that a sedentary lifestyle and excess weight in the form of visceral fat tissue significantly increase the odds of suffering a class of heart failure that currently lacks any good form of treatment.

Heart failure is a chronic condition in which the heart is unable to supply enough oxygenated blood to meet the demands of the body. Heart failure is approximately equally divided between two subtypes: heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). The ejection fraction refers to the percentage of the blood that exits the heart with each contraction. "Previous studies have consistently found an association between low levels of physical activity, high body mass index (BMI), and overall risk of heart failure, but this study shows that the association is more pronounced for heart failure with preserved ejection fraction, the type of heart failure that is the most challenging to treat."

In heart failure with preserved ejection fraction, the heart stiffens. Instead of being soft, it's rigid and it resists expansion. Cardiologists often explain the difference between the two types of heart failure by saying that in heart failure with preserved ejection fraction, the heart doesn't relax enough, while in heart failure with reduced ejection fraction the heart doesn't squeeze enough. Many treatments have been developed for treating the latter but there are no evidence-based treatments for the former. "The five-year survival rate among heart failure with preserved ejection fraction patients is around 30 to 40 percent. While heart failure with reduced ejection fraction survival has improved significantly over the years, heart failure with preserved ejection fraction prognosis is little changed."

The pooled analysis looked at data from 51,000 participants in three cohort studies, the Women's Health Initiative, the Multiethnic Study of Atherosclerosis (MESA), and the Cardiovascular Health Study. Among the 51,000 participants, there were 3,180 individuals who developed heart failure. Of these, 39 percent were heart failure with preserved ejection fraction, 29 percent were heart failure with reduced ejection fraction, and 32 percent had not been classified when the data was gathered. The incidence of heart failure with preserved ejection fraction was 19 percent lower for individuals who exercised at recommended levels. Similarly, body mass index (BMI) had an inverse relationship with heart failure with preserved ejection fraction. Higher BMI levels were more strongly associated with heart failure with preserved ejection fraction than with heart failure with reduced ejection fraction.

An Approach to Reversing Aspects of Aging in the Blood Stem Cell Niche
https://www.fightaging.org/archives/2017/03/an-approach-to-reversing-aspects-of-aging-in-the-blood-stem-cell-niche/

Stem cell activity declines with age, and for at least some types of stem cell this is as much a matter of signaling and environment changes as is is a matter of accumulated molecular damage to the stem cell lineages themselves. Stem cells reside within a niche of supporting cells, and it is damage and change within that niche that is responsible to some degree for loss of stem cell activity, and thus progressive failure of the tissues maintained by those stem cells. This is a potential target for therapy: researchers here make an attempt to force a more youthful pattern of cell signaling onto the bone marrow niche within which hematopoietic stem cells reside, those responsible for generating blood and immune cells. This fails to address the underlying cellular damage that causes change, but appears to be capable of producing some benefits.

As people get older so do the hematopoietic stem cells (HSCs) that form their blood. In a new study, scientists propose rejuvenating the bone marrow niche where HSCs are created. This could mean younger acting HSCs that form healthier blood cells, boosted immunity in older people, and a better defense mechanism against certain cancers. The researchers conducted a number of experiments to test the formation and vitality of cells in and near the bone marrow microenvironment. One test in aging mice looked at the formation of endosteum stroma cells, which form a thin layer of connective tissue on the inner surface of bones. Another experiment monitored levels of osteopontin and other proteins linked to distinct cells in bone marrow during the aging process. Study authors say they observed reduced production of osteoblasts and other stroma cells in the endosteum of older mice. They also saw decreased osteopontin protein levels in the bone marrow of older animals, which they note was associated with reduced vigor and function of blood-forming HSCs.

Scientists followed up the earlier experiments by transplanting bone marrow cells from older mice (19-21 months) into young mice (8 to 10 weeks). In two other experiments, the authors also transplanted aged HSCs from older mice into younger mice, and they treated aged HSCs with a recombinant form of the osteopontin protein. Transplantation into the younger animals caused cells to act in a younger more vital manner, the authors report. This includes the presence of smaller numbers of HSCs with greater potential for forming different types of blood cells, which included larger populations of B and T cells and smaller production of myeloid cells.

The authors also saw aged HSCs treated with recombinant osteopontin regain their youthful characteristics and capacity to form different blood-cell types. Also observed was diminished signaling of the protein Cdc42, a protein previously shown to cause HSCs to age. Osteopontin levels are not only low in the bone marrow niche, but also in the blood upon aging. As a follow up to the current study, the researchers are investigating the possibility to use osteopontin replacement therapy in mice to counter the influence of an aging niche directly in the animals.

The Impact of Protein Aggregation on Mitochondria
https://www.fightaging.org/archives/2017/03/the-impact-of-protein-aggregation-on-mitochondria/

Aging is characterized by an increased presence in tissues of protein aggregates, solid deposits of misfolded proteins and metabolic waste. This increase is perhaps largely driven by the progressive damage and failure of mechanisms of clearance, such as those associated with the proteasome and lysosome, as well as the activities of the immune system. Here, researchers investigate the impact of aggregates on another vital cellular system, the mitochondria. In many age-related conditions characterized by the presence of aggregates and waste, mitochondrial dysfunction also occurs. Is this an example of independent aspects of aging correlating simply because the condition is age-related, or is there direct causation in this relationship?

Working with yeast and human cells, researchers have discovered an unexpected route for cells to eliminate protein clumps that may sometimes be the molecular equivalent of throwing too much or the wrong trash into the garbage disposal. Proteins in the cell that are damaged or folded incorrectly tend to form clumps or aggregates, which have been thought to dissolve gradually in a cell's cytoplasm or nucleus thanks to an enzyme complex called the proteasome, or in a digestive organelle called the lysosome. But in experiments on yeast, which has many structures similar to those in human cells, scientists unexpectedly found that many of those protein clumps break down in the cell's energy-producing powerhouses, called mitochondria. They also found that too many misfolded proteins can clog up and damage this vital structure.

The team's findings could help explain why protein clumping and mitochondrial deterioration are both hallmarks of neurodegenerative diseases. In a previous study, researchers found protein aggregates, which form abundantly under stressful conditions, such as intense heat, stuck to the outer surface of mitochondria. In this study, they found the aggregates bind to proteins that form the pores mitochondria normally use to import proteins needed to build this organelle. If these pores are damaged by mutations, then aggregates cannot be dissolved, the researchers report. These observations led the team to hypothesize that misfolded proteins in the aggregates are pulled into mitochondria for disposal. Testing this hypothesis was tricky, because most of the misfolded proteins started out in the cytoplasm, and most of those that enter mitochondria quickly get ground up.

As a consequence, the team used a technique in which a fluorescent protein was split into two parts. Then, they put one part inside the mitochondria and linked the other part with a misfolded and clumping protein in the cytoplasm. If the misfolded protein entered the mitochondria, the two parts of the fluorescent protein could come together and light up the mitochondria. This was indeed what happened. To see what might happen in a diseased system, the team then put into yeast cells a protein implicated in the neurodegenerative disease known as amyotrophic lateral sclerosis (ALS). After a heat treatment that caused the ALS protein to misfold, it also wound up in the mitochondria. The researchers then did an experiment in which a lot of proteins in the cytoplasm were made to misfold and found that when too much of these proteins entered mitochondria, they started to break down.

Biological systems are in general quite robust, but there are also some Achilles' heels that may be disease prone, and relying on the mitochondrial system to help with cleanup may be one such example. While young and healthy mitochondria may be fully up to the task, aged mitochondria or those overwhelmed by too much cleanup in troubled cells may suffer damage, which could then impair many of their other vital functions.

Chimeric Antigen Receptor Cancer Immunotherapies Continue to Look Promising
https://www.fightaging.org/archives/2017/03/chimeric-antigen-receptor-cancer-immunotherapies-continue-to-look-promising/

Cancer treatments based on the use of chimeric antigen receptors are one of the more promising of present forms of immunotherapy. In trials they are producing good results in patients with late stage leukemia and lymphoma, who lack any other options, and are comparatively fragile and beaten down by the combination of disease and prior aggressive treatments. They should do even better once deployed earlier, for patients who have not run this gauntlet. In cancer, as in many things, the earlier the intervention the better the prognosis.

Six months after receiving infusions of their own T cells - genetically engineered ex vivo to carry chimeric antigen receptors (CAR) that bind to proteins on the surface of tumor cells - more than one-third of patients with aggressive lymphomas are seemingly disease free, Kite Pharma announced. The results of this six-month follow up in the Phase 2 trial "showed only a slight degradation in response rates and no new safety concerns compared to results previously seen at three months," according to the statement released by the company. "Kite intends to submit a marketing application for the treatment called KTE-C19 to the US Food and Drug Administration by the end of March."

Last year, both Juno Therapeutics and Kite Pharma announced that a small number of patients had died in their respective CAR T-cell therapy trials. Juno's trial was halted, but Kite's carried on. The Kite study enrolled 77 patients with advanced diffuse large B-cell lymphoma (DLBCL) and 24 patients with two other forms of aggressive lymphomas. Combined, 36 percent of those patients - all of which had stopped responding to all previous treatments - showed no detectable cancer at six months following treatment, and 82 percent of patients experienced shrinkage of their cancer by half or more. Most importantly, no additional safety issues beyond the three patient deaths already reported (two of which were believed to be the result of treatment) arose.

With the field facing safety concerns with the new type of treatment, researchers have anxiously awaited the results of ongoing trials by Kite Pharma and Novartis. Novartis is right on Kite's heels in the race to market a CAR-T therapy, with the company expected to file with the FDA for approval of its lead CAR-T therapy, CTL019, for a rare pediatric blood cancer called acute lymphoblastic leukemia.

Progress in Bioprinting of Vascular Networks
https://www.fightaging.org/archives/2017/03/progress-in-bioprinting-of-vascular-networks/

Perhaps the greatest challenge in tissue engineering, and this has been true for a decade now, is creating the necessary networks of blood vessels to support large sections of tissue. The approaches to the problem are no big secret: either print the blood vessels into the tissue structure as it is assembled, or somehow guide cells into doing that job for you. Unfortunately both paths have proven to be far more difficult than anticipated, which is one of the reasons why decellularization of donor organs has received so much attention. In that case, natural vascular network structures already exist and will be recreated much as they were when the decellularized tissue is repopulated with cells cultured from a patient sample. Still, progress towards the goal of fully vascularized engineered tissue continues, either via bioprinting or carefully steered growth, with technology demonstrations such as the one noted here emerging of late:

New research addresses one of the biggest challenges in tissue engineering: creating lifelike tissues and organs with functioning vasculature - networks of blood vessels that can transport blood, nutrients, waste and other biological materials - and do so safely when implanted inside the body. Researchers from other labs have used different 3D printing technologies to create artificial blood vessels. But existing technologies are slow, costly and mainly produce simple structures, such as a single blood vessel - a tube, basically. These blood vessels also are not capable of integrating with the body's own vascular system. "Almost all tissues and organs need blood vessels to survive and work properly. This is a big bottleneck in making organ transplants, which are in high demand but in short supply. 3D bioprinting organs can help bridge this gap, and our lab has taken a big step toward that goal."

The researchers have 3D printed a vasculature network that can safely integrate with the body's own network to circulate blood. These blood vessels branch out into many series of smaller vessels, similar to the blood vessel structures found in the body. The team developed an innovative bioprinting technology, using their own homemade 3D printers, to rapidly produce intricate 3D microstructures that mimic the sophisticated designs and functions of biological tissues. Researchers first create a 3D model of the biological structure on a computer. The computer then transfers 2D snapshots of the model to millions of microscopic-sized mirrors, which are each digitally controlled to project patterns of UV light in the form of these snapshots. The UV patterns are shined onto a solution containing live cells and light-sensitive polymers that solidify upon exposure to UV light. The structure is rapidly printed one layer at a time, in a continuous fashion, creating a 3D solid polymer scaffold encapsulating live cells that will grow and become biological tissue.

"We can directly print detailed microvasculature structures in extremely high resolution. Other 3D printing technologies produce the equivalent of 'pixelated' structures in comparison and usually require sacrificial materials and additional steps to create the vessels." And this entire process takes just a few seconds - a vast improvement over competing bioprinting methods, which normally take hours just to print simple structures. The process also uses materials that are inexpensive and biocompatible. Using their technology, the team printed a structure containing endothelial cells, which are cells that form the inner lining of blood vessels. Researchers cultured several structures in vitro for one day, then grafted the resulting tissues into skin wounds of mice. After two weeks, the researchers examined the implants and found that they had successfully grown into and merged with the host blood vessel network, allowing blood to circulate normally. The implanted blood vessels are not yet capable of other functions, such as transporting nutrients and waste. "We still have a lot of work to do to improve these materials. This is a promising step toward the future of tissue regeneration and repair."