Fight Aging! Newsletter, December 25th 2017

The beneficial longevity effect of a simple reduction in calorie intake was first established in rodent studies more than 80 years ago. In the last few decades as genetic techniques have advanced, scientists have made considerable progress in identifying cellular and systemic processes that likely contribute to the increase in disease vulnerability that is associated with aging. Traditionally, these insights have come from studies of short-lived laboratory animals, but the recent confirmation of the relevance of the CR paradigm to primates has placed renewed emphasis on studies that delve into the mechanisms of delayed aging by CR. "Remarkably, caloric restriction has been shown to be effective in delaying aging in multiple species and the results in humans look equally promising. Indeed for many studies, CR is used as the gold-standard for enhanced longevity against which new drugs and anti-aging strategies are measured."

The principle of geroscience is that aging itself is a worthy target for intervention: if aging can be offset then age-related vulnerability to diseases and disorders such as cancer, heart disease, frailty, and neurodegeneration, would be postponed and attenuated. If we could understand how CR exerts its effects to prolong health and delay mortality we will surely be able to identify key regulatory nodes involved in countering the causative factors in aging that lead to morbidity and mortality.

Within the last 10 years, the long suspected but previously unconfirmed demonstration that primate aging is indeed malleable came from studies of CR in rhesus monkeys. Over the course of that ~30-year study longitudinal biometric, physical activity, and metabolic data, were captured and used to evaluate the monkey model as a means to investigate frailty. The group showed clear differences between control-fed and CR monkeys. Further, the CALERIE study is the first human clinical trial of CR. Conducted across three sites in the United States, this pioneering work showed not only that CR could be tolerated in humans but it also produced beneficial effects on numerous clinical disease risk indices.

The search for agents that can exert the beneficial effects of CR without the requirement for a reduction in calorie intake has undergone considerable expansion over the last decade. Among these aptly named "CR mimetics" are resveratrol and metformin both of which have been shown to produce beneficial effects in rodents. Recent studies point to potential new applications for these CR mimetics as a means to counter skeletal muscle aging. Furthermore, they demonstrates the power for mechanistic discovery in the application of CR mimetics to uncover the biology of discrete factors within tissues that contribute to the aging phenotype.

Biological aging refers to the gradual and progressive decline in the integrity of the body's systems occurring with advancing chronological age. Rather than any specific disease process, this decline in system integrity is thought to reflect biological changes having their origins in aging itself. Whereas chronological age increases at the same rate for everyone, biological age can increase faster for some and slower for others. To the extent that geroprotective therapies modify basic biological processes of aging, their effects should be reflected in a slowed rate of decline in system integrity - slowed biological aging. Recently, several methods have been proposed to quantify biological aging using algorithms that combine information from multiple biomarkers.

Caloric restriction is among the oldest and most effective geroprotective interventions in worms, flies, and mice. Growing evidence suggests caloric restriction also benefits life span and healthspan in primates and humans. A unique resource to study effects of caloric restriction in humans is the 2-year randomized controlled trial of caloric restriction in young, non-obese healthy humans, Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy (CALERIE).

We analyzed CALERIE Biobank data to test whether recently proposed methods to quantify biological aging would prove sensitive to geroprotective effects of caloric restriction over the relatively short, 2-year span of the human trial. Tests using two different methods to quantify biological aging (Klemera-Doubal method Biological Age and homeostatic dysregulation) produced a consistent result: participants in the caloric-restriction arm of the trial experienced slowed biological aging as compared to participants in the ad libitum arm. Sensitivity analysis showed that slowed biological aging in the caloric restriction arm of the trial was not accounted for by weight loss during the intervention phase.

The main contribution of this study is to provide initial evidence that methods to quantify biological aging are sensitive enough to detect effects of geroprotective therapy delivered to middle-aged adults in a small randomized trial. This evidence argues for using methods to quantify biological aging as outcomes in trials of geroprotective therapies.

A new study shows that inflammatory mechanisms caused by the brain's immune system drive the progression of Alzheimer's disease. In recent years, studies revealed that deposits of amyloid-β, known as "plaques", trigger inflammatory mechanisms by the brain's innate immune system. However, the precise processes that lead to neurodegeneration and progression of pathology have thus far not been fully understood. Previous work had established that the molecular complex NLRP3, which is an innate immune sensor, is activated in brains of Alzheimer's patients and contributes to the pathogenesis of Alzheimer's in a mouse model. NLRP3 is a so-called inflammasome that triggers production of highly pro-inflammatory cytokines. Furthermore, upon activation, NLRP3 forms large signaling complexes with the adapter protein ASC, which are called "ASC specks" that can be released from cells.

In the current study, it was demonstrated that ASC specks are also released from activated immune cells in the brain, the microglia. Moreover, the findings provide a direct molecular link to classical hallmarks of neurodegeneration. "We found that ASC specks bind to amyloid-β in the extracellular space and promote aggregation of amyloid-β, thus directly linking innate immune activation with the progression of pathology." This view is supported by a series of experiments in mouse models of Alzheimer's disease. In these, the researchers investigated the effects of ASC specks and its component, the ACS protein, on the spreading of amyloid-β deposits in the brain. "Additionally, analysis of human brain material indicates at several levels that inflammation and amyloid-β pathology may interact in a similar fashion in humans. Together our findings suggest that brain inflammation is not just a bystander phenomenon, but a strong contributor to disease progression. Therefore, targeting this immune response will be a novel treatment modality for Alzheimer's."

The spreading of pathology within and between brain areas is a hallmark of neurodegenerative disorders. In patients with Alzheimer's disease, deposition of amyloid-β is accompanied by activation of the innate immune system and involves inflammasome-dependent formation of ASC specks in microglia. ASC specks released by microglia bind rapidly to amyloid-β and increase the formation of amyloid-β oligomers and aggregates, acting as an inflammation-driven cross-seed for amyloid-β pathology.

Here we show that intrahippocampal injection of ASC specks resulted in spreading of amyloid-β pathology in transgenic double-mutant APPSwePSEN1dE9 mice. By contrast, homogenates from brains of APPSwePSEN1dE9 mice failed to induce seeding and spreading of amyloid-β pathology in ASC-deficient APPSwePSEN1dE9 mice. Moreover, co-application of an anti-ASC antibody blocked the increase in amyloid-β pathology in APPSwePSEN1dE9 mice. These findings support the concept that inflammasome activation is connected to seeding and spreading of amyloid-β pathology in patients with Alzheimer's disease.

Mitochondrial dysfunction is linked to various aspects of aging including impaired oxidative phosphorylation (OXPHOS) activity, increased oxidative damage, decline in mitochondrial quality control, reduced activity of metabolic enzymes, as well as changes in mitochondrial morphology, dynamics, and biogenesis. Mitochondrial dysfunction is also implicated in numerous age-related pathologies including neurodegenerative and cardiovascular disorders, diabetes, obesity, and cancer.

The role of mitochondria in aging was first proposed more than 40 years ago in the free radical theory of aging, suggesting that accumulation of cellular damage with increasing age results from reactive oxygen species (ROS) and mitochondria are one of the most important sources and targets of ROS that could function as an 'aging clock'. Since then, a growing body of evidence has shown that mitochondrial dysfunction contributes to aging in multiple model organisms and that several factors cause increased mitochondrial dysfunction with chronological age including accumulation of somatic mtDNA mutations, enhanced oxidative damage, decreased abundance and quality of mitochondria, as well as dysregulation of mitochondrial dynamics.

Mitochondria are unique as they harbor their own genome (mtDNA). Point mutations and deletions are the two most frequent types of mutations that arise in mtDNA genome with age mainly due to spontaneous errors during mtDNA replication or damage repair. A wealth of supportive evidence demonstrates that mitochondrial dysfunction occurs with age due to accumulation of mtDNA mutations; however, the causative role of mtDNA mutations in aging remains controversial. Various mtDNA point mutations have been shown to significantly increase with age in the human brain, heart, skeletal muscles and liver tissues. Increased frequency of mtDNA deletions/insertions have also been reported with increasing age in both animal models and humans. The strongest evidence to date that favors a causative role of mtDNA mutations in aging comes from the study of mtDNA mutator mice that exhibit significant accumulation of mtDNA mutations as well as a premature or accelerated aging phenotype.

Mitochondria are highly dynamic structures as they continuously undergo fission and fusion processes that shape their morphology and regulate mitochondrial size, number and function. Mitochondrial dynamics is essential for mitochondrial viability and response to changes in cellular bioenergetic status. Mitochondrial fission is vital for mitotic segregation of mitochondria to daughter cells, distribution of mitochondria to subcellular locations, and mitophagy. Unopposed fission leads to mitochondrial fragmentation, loss of OXPHOS function, mtDNA depletion and ROS production, which are associated with metabolic dysfunction or disease. Mitochondrial fusion is essential for maintaining mitochondrial membrane potential, ATP production, and maximal respiratory capacity. Unopposed fusion generates a network of hyperfused mitochondria associated with increased ATP production, reduced ROS generation and which exhibit an ability to counteract metabolic insults, protect against autophagy as well as apoptosis.

In the past decade, several studies have shown that mitochondrial dynamics plays a crucial role in the regulation of mitochondrial function and metabolism. Studies suggest that dysregulation of mitochondrial dynamics could contribute to aging and age-related pathologies. However, there are several outstanding questions that yet remain to be addressed regarding the link between mitochondrial dynamics and aging. For example, which factors cause altered expression of mitochondrial fission and fusion proteins during aging, and are these factors genetic or affected by environmental stimuli? Is altered mitochondrial dynamics a major cause of mitochondrial dysfunction in aged cells or tissues? Can proteins involved in mitochondrial dynamics serve as promising candidates for promoting healthy aging and/or alleviating various age-related pathologies? Future experimental studies that are designed to address these questions would help to better understand the role of mitochondrial dynamics in aging and age-related pathologies.

Changes in the components of large arteries due to advancing age have been described in humans and animals. Age-associated blood vessel remodeling includes such features as dilation of the lumina, intimal and medial thickening, changes in the extracellular matrix (ECM), and augmented stiffness. In addition to these structural changes, other mechanisms contribute to the overall consequences of aging to the arterial wall, including such phenomena as inflammation, endothelial dysfunction, and oxidative stress. Fibroblasts and smooth muscle cells (SMC) contribute to aging in the vasculature, in part by increasing ECM; macrophages contribute by increasing inflammatory factors that have a wide range of possible consequences. These pathobiological events adversely affect the vessel wall and all of its components, potentially contributing to arterial aging.

It has been shown that the aged human arterial wall exhibits a more proinflammatory signature, with increased expression and activity of matrix metalloproteinases (MMPs) and chemokines. Atop these considerations is the effect of co-morbid conditions in aging, which may augment production of inflammatory mediators and exacerbate the impact of arterial aging, examples of which include diabetes mellitus (types 1 or 2 or the rarer forms of diabetes); chronic renal disease; and chronic immune/inflammatory disorders.

Advanced glycation endproducts (AGEs) are a diverse group of macromolecules and at least 20 different specific AGEs have been described to date. Among the major groups of AGEs are carboxymethyl lysine (CML), carboxyethyl lysine (CEL), pentosidine, glucosepane, methylglyoxal lysine dimer, glyoxal lysine dimer, and glycolic acid lysine amide. AGEs form throughout life via the process of non-enzymatic glycation of proteins and lipids, and this process is accelerated during hyperglycemia, oxidative stress, aging, advanced renal disease, and inflammation. Humans and animals are also exposed to exogenous sources of AGEs ingested through food-derived AGEs and tobacco products. It has been shown that restriction in dietary AGE intake may increase the lifespan in animals.

AGEs accumulate in aging tissues and on vulnerable plasma proteins. Higher levels of circulating AGEs have been linked to chronic diseases in aging subjects. The accumulation of AGEs is increased and accelerated in hypertensive subjects and is also associated with diabetes. In fact, aged subjects, even though healthy, may have higher AGE accumulation compared to younger subjects with diabetes and its complications, thus underscoring that AGE production and accumulation accompanies the normal aging process. Therefore, multiple factors such as the rate of accumulation of AGE ligand, the absolute concentration of the ligand, and individual susceptibility to AGE formation may be important in determining an individual's AGE burden.

Numerous studies have confirmed the correlation between AGE accumulation and increased artery stiffness. Arterial stiffness is associated with greater risk for aging-associated cardio- and cerebrovascular diseases and mortality. AGE accumulation causes upregulation of inflammation and destruction of collagen and elastin, along with other proteins of the ECM. It is noteworthy that despite testing of multiple classes of anti-AGE agents, none have obtained, at least to date, approval for anti-AGE indications. Although there are many possible reasons for this, we propose that one reason is that solely targeting AGEs fails to capture the pathobiological effects of distinct RAGE ligands. Therefore, it is not surprising that attempts are underway to directly target RAGE as a therapeutic strategy.

RAGE is expressed on a number of important cell types implicated in arterial aging and vascular pathology. Once AGEs are formed, albeit by diverse intrinsic and environmentally-triggered mechanisms, their interaction with RAGE on endothelial cells, SMCs, and immune cells such as macrophages, results in upregulation of inflammatory and oxidative stress-provoking factors, thereby providing a mechanism to link AGE-RAGE to arterial aging and its consequences.

Approaches to limit RAGE ligand AGEs have been accompanied by efforts to block RAGE itself and these have been tested in vitro and in vivo; in addition, human clinical trial testing is also underway. In vitro, pre-treatment of AGE-stimulated endothelial cells with anti-RAGE antibodies or anti-oxidants blocked cellular perturbation. Another RAGE blocking agent currently in Phase III clinical trials in Alzheimer's disease is the small molecule Azeliragon, which inhibits the receptor for advanced glycation endproducts and prevents RAGE ligands from interacting with RAGE. Certainly, more research is required to understand the entire scope of RAGE signaling and the extent to which blocking AGEs/RAGE interaction may intercept the full pathobiology of RAGE activation.

In the second half of the 19th century, doctors believed that old age occurred when the body ran out of "vital energy" - which was no mere metaphor. The stuff was thought to be tangible, literally present in the body and its fluids. Everyone had a finite reservoir of vital energy that gradually became depleted over a lifetime. When you began to run low on vitality, you were old; death followed when the tank was empty.

For the era's doctors, the concept conveniently solved the mystery of why illness seemed far more curable in the young than the old. Physicians supposed that the loss of vitality created a "predisposing debility," as one historian has put it, making the older body vulnerable to a host of secondary maladies. The theory also fit with American religious thought as influenced by the Second Great Awakening, which peaked in the 1830s. The amount of vitality you were endowed with at birth was simply your lot. Whether you used it well or squandered it, however, was your personal responsibility.

In continental Europe in the 1850s and 1860s, vitality theory began to wane as French and German pathologists realized that the lesions, fibrous tissue and calcium deposits they discovered in older people's cadavers could provide an explanation for some of the complaints of old age. But in the United States and Britain, many of those aware of these continental findings simply doubled down on their existing beliefs: Any wasting observed in cadavers was simply due to the loss of vital energy.

Perhaps the best evidence for that point of view was the moment in a patient's life when vitality began to appreciably decline, which English-speaking physicians named the "climacteric period," or "climacteric disease." In women, the climacteric period was believed to begin between ages 45 and 55 and was associated with menopause; in men, it took place between 50 and 75 and was indicated by such signs as wrinkles, white hair, and complaints of feebleness.

Eventually, insights from the medical field of pathology discredited vital-energy theory, but only after it molded the development of a long-lasting set of social, cultural and economic institutions. The first dedicated old-age homes, the rise of public and private pensions, the normalization of retirement both as something bad your boss could do to you and also a new stage of life - these all marinated in vital-energy theory for decades before emerging fully baked into the 20th century, complete with implications for what it meant to be an "older person."

The story of Faust has become a metaphor for a promise or tradeoff that at first seems appealing, but with time is revealed to be a bad bargain. The story of human aging and the modern rise in longevity has remarkable correlates to the story of Faust, but with some interesting twists. Here's the connection. The first longevity revolution that began in the middle of the nineteenth century occurred primarily because of gains made against infant and child mortality resulting from advances in basic public health. This was followed by reductions in death rates from cardiovascular disease late in the twentieth century. A quantum leap in life expectancy of 30 years ensued at lightning speed. Nothing in history has ever come close to the magnitude of this benefit to humanity. While there is no disputing the value of life and health extension from the first longevity revolution, rarely does something so desirable come without a Faustian-like price.

Along with 30 years of additional life and the opportunity to see almost all our children live long enough to have families of their own, humanity also witnessed a subsequent dramatic escalation in the prevalence of age-related chronic, fatal and disabling diseases and their attendant costs and heartache. That is, we now live long enough to experience the aging of our bodies. In retrospect, it was worth every part of the bargain. But Mephistopheles isn't done with us. Like a street magician that lets you win the first game, and then sucks you into a bigger con with larger stakes, or a drug dealer that gets you hooked with free samples, the next much costlier offer is before us now. We've had our taste of longevity, but now we want more - much more at any cost, and Mephistopheles knows this.

With life itself as the most precious commodity there is, it's easy to see the next con. The first is the rise of what has become known as the antiaging industry - a multibillion enterprise designed to convince us that the secret to the fountain of youth is already within our grasp. Pay dearly for their elixirs now and wait for the promise of a longer life to appear decades later. What do you think the chances are that your investment will pay off? The catch is that the alleged benefits don't appear, if at all, until after the longevity salesmen has left the scene and pocketed your cash. What's different today from the cons of the past is the rise of the scientific study of aging and genuine opportunity offered for healthy life extension. The modern practitioners of anti-aging medicine try and sell the public what appear to be genuine scientific interventions based on real science, before they're proven to be safe and efficacious: "whenever science makes a discovery, the devil grabs it while the angels are debating the best way to use it."

The second response to an insatiable desire for more life is also predictable, but the danger could be an even worse Faustian bargain than that posed by the antiaging industry. The method used to manufacture the first longevity revolution is known as the "infectious disease model" - that is, as soon as a disease appears, attack it with everything in the medical arsenal. Beat the disease down, and once you succeed, push the patient out the door until they face their next challenge; then beat that one down. The formula is simple - repeat until failure. This model was perfect for infectious diseases and effective at first for chronic degenerative diseases, and no doubt there is still progress to be made, but evidence has emerged that this approach is likely to run out of steam. The application of an infectious disease model to chronic fatal and disabling diseases associated with aging is Mephistopheles latest "bargain." The irony behind this new bargain (otherwise known as the current medical model of disease) is that the medical community advocating for disease eradication doesn't even recognize the health consequences of success.

The bargain today is crystal clear - we're being offered incrementally smaller amounts of survival time at a very high cost, and the prospect that most of the additional months and years of life will be riddled with frailty and disability. Keep in mind that the human body has no designer; it was not constructed for long-term use; and our Achilles heels are already visible - neurological conditions such as Alzheimer's disease and related conditions are associated with non-replicating neurons; and muscles and joints have a difficult time navigating the ravages of biological time. The Faustian bargain before us now is, in exchange for small doses of additional life, humanity will experience a suite of fatal and disabling conditions expressed at later ages that rob us of what we hold most precious - our mental and physical functioning.

What's the solution? Don't sign the contract! A clue about what we should do instead was presented to us decades ago. In the mid-1950s, it was suggested that attacking aging itself rather than the diseases associated with it offered the greatest hope in warding off the infirmities of old age. In 2006, my colleagues and I extended this line of reasoning by coining the phrase "the Longevity Dividend" to describe the economic and health benefits that would accrue to individuals and societies if we extend healthy life by slowing the biological processes of aging. This idea was distinctive because we proposed to extend healthy life by shifting our emphasis from disease management to delayed aging. Recent advances in biogerontology suggested that it is plausible to delay aging in people. For example, "senolytics" may offer a unique opportunity to forestall the ravages of aging through the systematic elimination of cells that are still alive, but which no longer function normally.

The Longevity Dividend is an approach to public health based on a broader strategy of fostering health for all generations by developing a new horizontal model to health promotion and disease prevention. Unlike the current vertical approach to disease that targets individual disorders as they arise, the Longevity Dividend model seeks to prevent or delay the root causes of disease and disability by attacking the one main risk factor for them all-biological aging. Evidence in models ranging from invertebrates to mammals suggests that all living things have biochemical mechanisms influencing how quickly they age, and these mechanisms are adjustable.

Slowing down the processes of aging - even by a moderate amount - will yield dramatic improvements in health for current and future generations. Advances in the scientific knowledge of aging may thus create new opportunities that allow us, and generations to follow, to live healthier and longer lives than our predecessors. By embracing a new model for health promotion and disease prevention in the twenty-first century, we can give the gift of extended health and economic wellbeing to current and all future generations. What is the cost of this new more effective model of primary prevention that will save the world trillions in health care costs? A fraction of the basic research cost required to create sixth generation fighter jets; or the salary from just one quarterback in the National Football League.

During deep sleep, older people have less coordination between two brain waves that are important to saving new memories. The finding appears to answer a long-standing question about how aging can affect memory even in people who do not have Alzheimer's or some other brain disease. "This is the first paper that actually found a cellular mechanism that might be affected during aging and therefore be responsible for a lack of memory consolidation during sleep." To confirm the finding, though, researchers will have to show that it's possible to cause memory problems in a young brain by disrupting these rhythms.

The study was the result of an effort to understand how the sleeping brain turns short-term memories into memories that can last a lifetime. A team of scientists had 20 young adults learn 120 pairs of words, then put electrodes on their head and had them sleep. The electrodes let researchers monitor the electrical waves produced by the brain during deep sleep. They focused on the interaction between slow waves, which occur every second or so, and faster waves called sleep spindles, which occur more than 12 times a second.

The next morning the volunteers took a test to see how many word pairs they could still remember. And it turned out their performance was determined by how well their slow waves and spindles had synchronized during deep sleep. "When those two brain waves were perfectly coinciding, that's when you seem to get this fantastic transfer of memory within the brain from short term vulnerable storage sites to these more permanent, safe, long-term storage sites." Next, the team repeated the experiment with 32 people in their 60s and 70s. Their brain waves were less synchronized during deep sleep. They also remembered fewer word pairs the next morning. "If you're 50 milliseconds too early, 50 milliseconds too late, then the storing mechanism actually doesn't work."

The team also found a likely reason for the lack of coordination associated with aging: atrophy of an area of the brain involved in producing deep sleep, the medial frontal cortex. People with more atrophy had less rhythm in the brain. That's discouraging because atrophy in this area of the brain is a normal consequence of aging, and can be much worse in people with Alzheimer's. But the study also suggests that it's possible to improve an impaired memory by re-synchronizing brain rhythms during sleep. One way to do this would be by applying electrical or magnetic pulses through the scalp.

Hippocampal overexpression of FK506-binding protein 12.6/1b (FKBP1b), a negative regulator of ryanodine receptor Ca2+ release, reverses aging-induced memory impairment and neuronal Ca2+ dysregulation. Here, we test the hypothesis that FKBP1b also can protect downstream transcriptional networks from aging-induced dysregulation. We gave hippocampal microinjections of FKBP1b-expressing viral vector to male rats at either 13-months-of-age (long-term) or 19-months-of-age (short-term) and tested memory performance in the Morris water maze at 21-months-of-age. Aged rats treated short- or long-term with FKBP1b substantially outperformed age-matched vector controls and performed similarly to each other and young controls.

Transcriptional profiling in the same animals identified 2342 genes whose hippocampal expression was up-/down-regulated in aged controls vs. young controls (the aging effect). Of these aging-dependent genes, 876 (37%) also showed altered expression in aged FKBP1b-treated rats compared to aged controls, with FKBP1b restoring expression of essentially all such genes (872/876, 99.5%) in the direction opposite the aging effect and closer to levels in young controls. This inverse relationship between the aging and FKBP1b effects suggests that the aging effects arise from FKBP1b deficiency.

Functional category analysis revealed that genes downregulated with aging and restored by FKBP1b associated predominantly with diverse brain structure categories, including cytoskeleton, membrane channels, and extracellular region. Conversely, genes upregulated with aging but not restored by FKBP1b associated primarily with glial-neuroinflammatory, ribosomal and lysosomal categories. Immunohistochemistry confirmed aging-induced rarefaction, and FKBP1b-mediated restoration, of neuronal microtubular structure. Thus, a previously-unrecognized genomic network modulating diverse brain structural processes is dysregulated by aging and restored by FKBP1b overexpression.

Basic researchers have produced skin, veins, trachea and urethras -the relatively easy structural tissues and organs those in the field call "sheets and tubes" - but the processes are painstaking and expensive. A decade ago researchers pioneered the development of 3D printers capable of printing customized organ scaffolds made of keratin, collagen, or biodegradable polymers, then ones that could print skin cells directly onto a patient; and then ones that could print cells and the vessel passages that keep them alive directly onto scaffolds that could then be implanted in the body. Growing these tissues or organs can take anywhere from days to weeks depending on their size and complexity.

But getting these groundbreaking innovations off the lab bench and into commercial production has proved a daunting task. The engineering challenges are enormous, and most basic scientists have no experience in creating mass assembly systems, much less ones whose production can earn Food and Drug Administration approval for use in living people. Dozens of private companies have been at work trying to develop products for clinical use, but progress has been painfully slow. "We were making an esophagus, but the manufacturing processes were really the views of a scientist thinking about how manufacturing should be done. The industry is still basically making things largely by hand, one by one, with people handling the equipment that feeds the tissue making decisions in real time... There's very little process control."

Dean Kamen likens the problem to that of a grandmother who can make the world's greatest chicken soup. "OK, Grandma. How are you going to run a canning operation?" he asks. "She wants to go to scale, what does she do? She hires 10,000 other grandmas! They have a bigger kitchen They all stir by hand in bowls. And then the FDA comes in there and says 'How do you know your production is consistent?'!" If she were making soup, Grandma could outsource production to Campbell's Soup, but tissue engineering researchers can't. "They could win the Nobel prize for figuring out how to grow more cool stuff in a petri dish than anyone I know, but they're not going to figure out how to make 400,000 of the things. But interestingly, he can't go to Campbell's because there is no Campbell's!"

A chance meeting with another famous entrepreneur, Martine Rothblatt, set Kamen on a path that would lead him to try to create, from scratch, the manufacturing equipment, procedures and the know-how to move regenerative medicine from a science experiment to mass production. Then, out of the blue, one of Kamen's colleagues saw a request for proposal from the Department of Defense to establish a state-of-the-art institute tasked with creating an advanced innovation ecosystem for the manufacture of human tissues and organs to help wounded soldiers and civilian patients alike. "We looked at this and we saw that the equipment they were going to need to help soldiers were pretty much the same things we would need to build for Martine. So we figured, let's scale this thing up and build all the tools and processes for all the tissues and organs."

One year later, a three-story, 65,000-foot former mill building next to Kamen's headquarters houses the Advanced Regenerative Manufacturing Institute, where over 100 engineers, researchers and programmers are already at work building machines and devices and testing the processes that will allow its dozens of member firms to perfect and mass produce their respective products, from skin to, one day, hearts. Kamen has persuaded venture capital firms to help fund the startups that have joined the coalition and recruited a veteran FDA official to consult with the agency on regulatory approval. "I think in the next five years we are going to have some awesome results and some nice functional tissues to really start helping people on a bigger scale."

Studies among long-term cancer survivors indicate numerous possible clinical complications resulting in considerable morbidity and mortality, related to chemotherapy, radiation therapy, or both. A wealth of observational data on the development of late complications in cancer survivors are available, but information documenting the pathological basis for development of these effects is sparse. To understand the biology of late effects better and provide a foundation for the development of interventions, it is important to characterise late effects at the cellular level. Cancer survivors, in general, appear to develop age-related diseases and phenotypes sooner than members of the general population. This is likely because damage to normal tissues from cancer therapies diminishes physiological reserve, accelerates processes typically associated with ageing, or both.

The roles of telomeres, senescent cells, epigenetic modifications, and microRNA have been described in terms of their contributions to the pathobiology of accelerated ageing. However, published data linking clinical phenotypes seen in cancer survivors with processes of accelerated ageing at the cellular level is lacking. On a microscopic level, ageing is a consequence of gradual, lifelong accumulation of molecular and cellular damage and loss of physiological integrity. Hallmarks of ageing include genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, loss of proteostasis, chronic low-grade inflammation, and cellular senescence. We have demonstrated with clinical data that cancer survivors develop the health-related manifestations of ageing more quickly than their peers. While ageing prematurely is a better alternative to dying prematurely, a better understanding of what drives this process presents an opportunity for improvement.

As many cancer treatments appear to induce an accelerated ageing-like state, interventions that target fundamental ageing processes may have a role in cancer survivors. Since many cancer therapies induce cellular senescence, among the most promising agents are senolytics, drugs that selectively eliminate senescent cells and SASP inhibitors, which blunt local and systemic effects of the SASP. These agents alleviate frailty, restore progenitor function, reduce insulin resistance, rescue cardiac and vascular dysfunction, decrease adverse effects of radiotherapy and reduce osteoporosis in a variety of animal models of ageing and disease. Senolytics are effective when administered intermittently, potentially reducing toxicity, and resistance to these drugs is unlikely to develop as, unlike cancer cells or microbes, senescent cells do not divide.

Researchers have identified a critical switch that controls T-cell function and dysfunction and have discovered a pathway to target it. T-cells, which are a type of white blood cells that protect the body from infection, play a central role not only in infections, but also autoimmune diseases and transplant rejection. Understanding how T-cells work is of critical importance for treating these diseases. Researchers are doing this by systematically deleting different molecules in T-cells to check which ones are required for the T-cells to function.

What they have found is that one of the most critical molecules controlling gene expression in T-cells is the transcription factor IRF4, which is usually only found in the immune system and not expressed in other cells. IRF4 is what needs to be targeted to solve the problem of transplant rejection or to develop an autoimmunity cure. "If we delete IRF4 in T-cells they become dysfunctional. In doing so, you can solve the issue of autoimmunity and have a potential solution for organ transplant rejection. You need them functional, however, to control infection. If we can find an IRF4 inhibitor, then those issues would be solved. That's big."

The way they will be able to do this is by only targeting active T-cells that have already been exposed to antigens, leaving the so-called naïve T-cells - those that have never seen antigens and produce no or little IRF4 - alone. These naïve T-cells produce IRF4 only when needed to fight infections. It's the activated T-cells armed with IRF4 that are responsible for organ transplant rejection and autoimmunity. These are the ones that are a potential target, thereby leaving other T cells in the immune system still armed against infection.

Their initial results were promising. By inhibiting IRF4 expression for 30 days - the usual timeframe required for transplant patients to remain infection free - the T-cells became irreversibly dysfunctional. In practice, this could mean prolonging a patient's ability to tolerate a transplanted organ. "How to therapeutically inhibit IRF4 is the Nobel-prize winning question. If we can find a way to inhibit IRF4 as desired in activated T-cells, then I think most autoimmune diseases and transplant rejection will be solved."

An FDA-approved drug to treat high blood pressure, hydralazine, extended life span about 25 percent in two strains of C. elegans, one a wild type and the other bred to generate high levels of a neurotoxic protein called tau that in humans is associated with Alzheimer's disease. "This is the first report of hydralazine treatment activating the NRF2/SKN-1 signaling pathway. We found the drug extends the life span of worms as well as or better than other potential anti-aging compounds such as curcumin and metformin. The treatment also appeared to maintain their health as measured by tests of flexibility and wiggling speed."

The NRF2 pathway protects human cells from oxidative stress. The body's ability to protect itself against damaging oxygen free radicals diminishes with age. One of the hallmarks of aging and neurodegenerative diseases such as Alzheimer's and Parkinson's is oxidative stress, which is believed to result cumulatively from inflammatory and infectious illnesses throughout life. SKN-1, a C. elegans transcription factor, corresponds to NRF2 in humans. Both play a pivotal role in their respective species' responses to oxidative stress and life span.

The researchers performed in vivo (in a living creature) and in vitro (in a lab dish) studies on the worms. Compared with untreated controls, roundworms treated with the drug showed about a 25 percent increase in life span (from 15-18 days to about 20-23 days), the team reported. The results of a series of biochemical experiments indicated that the hydralazine-linked life span extension was dependent on the worms' SKN-1 pathway via a mechanism that appeared to mimic caloric restriction. "Based on these results, we suggest that hydralazine may be a good candidate for clinical trials for the treatment of age-related disorders in humans as it may also offer general health benefits to the aging population."

A shorter life may be the price an organism pays for coping with the natural assaults of daily living, according to researchers. The scientists used fruit flies to examine the relationship between lifespan and signaling proteins that defend the body against environmental stressors, such as bacterial infections and cold temperatures. Since flies and mammals share some of the same molecular pathways, the work may demonstrate how the environment affects longevity in humans.

The research identified Methuselah-like receptor-10 (Mthl10), a protein that moderates how flies respond to inflammation. The finding provides evidence for one theory of aging, which suggests longevity depends on a delicate balance between proinflammatory proteins, thought to promote aging, and anti-inflammatory proteins, believed to prolong life. These inflammatory factors are influenced by what an organism experiences in its every day environment.

Mthl10 appears on the surface of insect cells and acts as the binding partner to a signaling molecule known as growth-blocking peptide (GBP). Once Mthl10 and GBP connect, they initiate the production of proinflammatory proteins, which, in turn, shortens the fly's life. However, removing the Mthl10 gene makes the flies unable to produce Mthl10 protein and prevents the binding of GBP to cells. As a result, the flies experienced low levels of inflammation and longer lifespans. "Fruit flies without Mthl10 live up to 25 percent longer. But, they exhibit higher death rates when exposed to environmental stressors."

When the project started in 2013, scientists did not know what cell-surface protein was working with GBP to promote inflammation. So they began testing 1700 compounds that could individually suppress the production of every known cell-surface protein in the fruit fly. They looked for the protein that prevented GBP from binding and activating inflammation. They found several candidates, but all were eliminated during further testing, except Mthl10. The study proposes that the human counterpart to GBP is a protein called defensin BD2, but the nature of its binding partner is currently unknown.

It's not uncommon, especially for outsiders of a given field, to use an inappropriate word to indicate a more complex concept than the word itself conveys - maybe because they think that the two are close enough or possibly because they just don't see the difference. For this reason, it's likely that each field has its own unspeakably profane word; in the field of rejuvenation, that word is the dreaded I-word: immortality.

Whether or not immortality is possible is an intriguing question, but it is decidedly off-topic in the field of rejuvenation, because rejuvenation is not immortality. If a universal antiviral drug existed, able to wipe the floor with every conceivable virus, you wouldn't call it an immortality drug, because right after leaving the doctor's office where you got your miracle shot, a grand piano might happen to crush you after a 50-story free fall, and the antiviral drug wouldn't be especially effective against that particular cause of death. Similarly, rejuvenation would save you from death by age-related diseases, but again not by falling grand pianos.

Yet, both people and the media keep talking about "curing death" and "immortality pills" when the actual topic is rejuvenation biotechnology; this is a cause of particular annoyance to Dr. Aubrey de Grey, whose pioneering work is constantly called an "immortality quest" and similar things. Since immortality reasonably seems a pipe dream, this results in a gross misrepresentation of the entire field and a lot of unwarranted bashing of completely legitimate medical research whose only fault is that it aims to prevent the diseases of aging rather than just coping with them.

The same story is true of negligible senescence. If a successful rejuvenation platform were implemented, people would still age biologically, but we would have therapies capable of undoing such aging. Through periodic reapplication of these therapies, the hallmarks of aging would always be kept well below the pathology threshold. In other words, we would still senesce (that is, age), but our level of senescence would stay negligible - that's where the term comes from. Yet, many people keep calling negligible senescence immortality just like they do rejuvenation biotechnology, whether deliberately or by genuine mistake, thereby providing an excellent strawman for needy critics to beat.

Negligible senescence is the expected result of truly comprehensive rejuvenation biotechnologies, and yes, if we got there, our healthspan would be vastly increased, and consequently, so would our lifespan; if you were in perfect health for longer than, say, 100 years, it is a disarmingly trivial consequence that you would live for longer than 100 years. However, whether a negligibly senescent person then lives on forever or not, or ten thousand years from now, someone beats the odds and comes up with a fancy immortality switch, is an entirely different matter that is beyond the scope of the field of rejuvenation biotechnology.