Fight Aging! Newsletter, December 25th 2017

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

  • Final Reminder for 2017: Help Us Fund Rejuvenation Research, and Claim the Last of the Challenge Fund to Match Donations
  • The Calorie Restriction Issue of the Journals of Gerontology
  • Describing an Inflammatory Feedback Loop in Alzheimer's Disease
  • Reviewing the Mitochondrial Contribution to Aging and Age-Related Disease
  • AGEs and RAGE in the Aging Arteries
  • All of Medicine has a History of the Strange and the Wrong, Slowly Shed Over Time
  • Faustian Bargains Struck in Search of Life Extension
  • Brain Rhythms are Disrupted with Age, and this Causes Memory Dysfunction
  • Overexpression of FKBP1b Restores Lost Memory Function in Old Rats
  • The Advanced Regenerative Manufacturing Institute Works Towards the Mass Production of Organs
  • The Present Standard Cancer Therapies Increase Biological Age
  • IRF4 as a Discriminating Target for Selective Destruction of Immune Cells
  • A Class of Calorie Restriction Mimetic Targeting NRF2
  • A Demonstration of Evolutionary Optimization for Resilience Rather than Life Span
  • Immortality is a Distant Challenge, not the Immediate Issue

Final Reminder for 2017: Help Us Fund Rejuvenation Research, and Claim the Last of the Challenge Fund to Match Donations
https://www.fightaging.org/archives/2017/12/final-reminder-for-2017-help-us-fund-rejuvenation-research-and-claim-the-last-of-the-challenge-fund-to-match-donations/

This year's Fight Aging! challenge fund matches the next year of donations made by supporters of SENS rejuvenation research who sign up as monthly donors to the SENS Research Foundation. Josh Triplett, Christophe and Dominique Cornuejols, and Fight Aging! have put up 36,000 to encourage you to create a brighter future for medicine. The fund expires at the end of 2017, and with just two weeks left in this fundraiser, the final third of the challenge fund is yet to be claimed.

So please join us in helping to support the scientific research needed to build a comprehensive suite of therapies to reverse the causes of aging and bring an end to all age-related disease. The SENS Research Foundation is one of the most influential organizations in this field, having achieved tremendous progress using the donations of past years. Few other causes have the potential to produce so great a benefit at such a low cost. When we say that we want to change the world for the better, we mean it: the existence of rejuvenation therapies will touch everyone, bringing the capacity to greatly improve all lives.

This year has certainly been one of ups and downs in fundraising; a lot of new funding has poured into the for-profit ecosystem with the arrival of investors such as Jim Mellon's team and the launch of ventures such as the Methuselah Fund. We're now all looking for more credible companies to emerge, run by teams focused on SENS-relevant approaches to aging, ways to repair the cell and tissue damage that produces degeneration and age-related disease. At the same time, charitable fundraising has been tough in 2017; if we want to do better, the community must grow. We must reach new audiences and persuade them of the merits of rejuvenation research, that the construction of rejuvenation therapies is both relevant and plausible as a goal.

Yet we were still fortunate enough to see the Pineapple Fund choose the SENS Research Foundation as one of the recipients of 1 million in bitcoins just a few days ago. This was made possible by the thousands of supporters who, over the years, lead the way by making modest donations and talked about the prospects for rejuvenation research. The anonymous principal of the Pineapple Fund could look at the SENS Research Foundation, and all that has been written about it, and because of our actions see a small organization of sizable influence and importance. The larger our community of supporters, the more credible that SENS research becomes in the eyes of potential donors, and the more likely it is that large donations are made to support future research. We make a real difference - so join in and make a donation this year!

The Calorie Restriction Issue of the Journals of Gerontology
https://www.fightaging.org/archives/2017/12/the-calorie-restriction-issue-of-the-journals-of-gerontology/

Today I'll point out a recent collection of papers on calorie restriction from the Journals of Gerontology, including a report on the CALERIE human study in which algorithmic approaches to measuring biological age - constructing a measure from simple health metrics, such as the measures found in blood tests - indicate a slowing of aging in participants. Calorie restriction has been shown to slow aging in near all species and lineages tested to date, much more so in short-lived species than in long-lived species. Thus calorie restriction and methods of mimicking some of the cellular response to calorie restriction make up the present majority of initiatives among those scientists of the aging research community who have shown themselves willing to embrace the goal of treating aging as a medical condition. This encompasses investigations of mTOR, involving rapamycin and related compounds, slow steps towards any one of half a dozen approaches to autophagy enhancement, the long drawn-out dead end of sirtuin research programs, and many more lines of work.

Aubrey de Grey has called this a false dawn - a blossoming of research that accompanied a great change in the culture of the scientific community, as it transformed from a closed-mouth group whose members denied and discouraged all interest in treating aging, to one in which many researchers now talk openly and excitedly about extending healthy life spans. Yet they have largely settled upon a program of research and development, focused on calorie restriction, that cannot possibly produce sizable effects on human life span, and is in addition demonstrably expensive, slow, and challenging. It dovetails well with the urge to map metabolism in detail, however, which is perhaps why this field has expanded despite the poor prospects for benefits to health and longevity at the end of the day.

By any sensible cost-benefit analysis, the practice of actual calorie restriction is, like exercise, a great gift from our evolutionary history: a reliable and free way to improve long-term health to a greater degree than any presently available medical technology can achieve. It is a sound idea to adopt this proven approach as a health strategy; the evidence is compelling. A few additional years for free, and a lower risk of age-related disease? Sign me up. Yet spending billions and decades of researcher time to reproduce that in a pill? Not so great, when the alternative uses of that time and funding, such as pursuing the rejuvenation therapies of the SENS programs, could be expected to add decades of additional healthy years to our lives. The expected quality of the outcome matters greatly when choosing strategy, and currently most of the research community is choosing poorly.

In Delaying Aging, Caloric Restriction Becomes Powerful Research Tool as Human Studies Get Underway

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."

Caloric Restriction Research: New Perspectives on the Biology of Aging

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.

Change in the Rate of Biological Aging in Response to Caloric Restriction: CALERIE Biobank Analysis

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.

Describing an Inflammatory Feedback Loop in Alzheimer's Disease
https://www.fightaging.org/archives/2017/12/describing-an-inflammatory-feedback-loop-in-alzheimers-disease/

The research noted here improves the understanding of how inflammation acts to drive the progression of Alzheimer's disease, despite being secondary to the well-known deposition of amyloid-β observed in the condition. Alzheimer's disease is considered to be in part an inflammatory condition. Rising levels of chronic inflammation occur with aging, in the brain and elsewhere in the body, and there is plenty of evidence for inflammation to contribute to a good many age-related conditions. The ordering of cause and effect in Alzheimer's is still somewhat up for debate, but there is evidence for the cascade to begin with amyloid-β, that then produces inflammation as the immune cells of the brain react to it, which in turn leads to tau aggregation. The paper here adds nuance to that possible ordering, suggesting that amyloid-β and inflammation form their own feedback loop, spurring one another forward.

The immune system of the central nervous system is its own creature, quite different in its details from the immune system of the rest of the body, and arguably much more integrated and necessary for the correct function of the brain than is the case in other organs. Nonetheless, similar classes of age-related dysfunction arise, and inflammation is one of the results regardless of protein aggregation such as the formation of amyloid deposits. Immune cells become overly active, but at the same time less effective at carrying out their assigned tasks. Inflammation is a necessary part of the immune response to many of the issues it might have to deal with, typically those that involve destruction, as as removal of senescent or potentially cancerous cells, and mounting attacks upon the pathogens that constantly try to invade the body and brain. If permanently switched on, however, inflammation begins to disrupt all of the other necessary tasks of the immune system, such as those relating to regeneration or shepherding the correct function of brain cells.

For a number of years now, some researchers have departed a little way from the mainstream focus on removal of amyloid-β to consider an anti-inflammatory approach to building therapies for Alzheimer's, but this line of research hasn't made a sizable impact yet. Reducing inflammation in a usefully targeted way is still quite challenging, as the immune system is very complex, though promising noises are emerging from research groups investigating NLRP3 as a target. That also happens to show up in the research here as a part of the connection between immune cells, amyloid, and inflammation.

Inflammation drives progression of Alzheimer's

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."

Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer's disease

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.

Reviewing the Mitochondrial Contribution to Aging and Age-Related Disease
https://www.fightaging.org/archives/2017/12/reviewing-the-mitochondrial-contribution-to-aging-and-age-related-disease/

Today I'll point out a fairly readable review paper that walks through the high points of what is known of the mitochondrial contribution to degenerative aging and the common, well-studied age-related diseases that cause the greatest amounts of suffering and death. Every cell has a few hundred mitochondria swarming inside it, evolved descendants of ancient symbiotic bacteria that are now fully integrated components of the cell. They are highly active components: they replicate and fuse, pass molecular machinery between one another, are destroyed by cellular quality control mechanisms when they become damaged, and can even transfer between cells, all conducted at a rapid pace. Most of their DNA has moved into the cell nucleus, but a small number of genes remain to form the circular mitochondrial DNA. Mitochondria are primarily responsible for generating chemical energy stores, providing the power for cellular operations, but they also participate in many other fundamental cellular processes in one way or another.

There are two ways we might think of mitochondria in the context of aging. The first is the SENS view of the mitochondrial contribution to aging. The mitochondrial DNA becomes damaged, either through replication or because building energy store molecules is a process that generates potentially damaging, reactive molecules as a side-effect. Sometimes that damage cuts out an important part of the energy generation machinery, creating a mitochondrion that both runs hot, producing many more harmful molecules, but is also more competitive than its peers when it comes to replication within the cell. Perhaps it can evade quality control, perhaps it replicates more rapidly; whatever the cause, whenever this rare form of damage occurs, the descendants of the damaged mitochondrion very quickly take over the entire population within that cell.

The result is a pathological cell that churns out harmful reactive molecules in large amounts into the surrounding tissue. This can, for example, cause atherosclerosis through oxidative damage of lipids that end up in the bloodstream. There the damaged molecules irritate blood vessel walls, resulting in the lesions that will become atherosclerotic plaques and eventually rupture. This could be avoided via any reliably means of sabotaging this chain of events. The proposed SENS Research Foundation approach is to use gene therapy to copy mitochondrial DNA into the cell nucleus to provide a backup supply of protein machinery; if carried out, then it won't matter how ragged the mitochondrial DNA becomes. The mitochondria will still function correctly, and cells will remain unharmed.

The second way to think of mitochondrial in aging is given far more attention in the scientific mainstream. It is a sort of general malaise found in all cells in aged tissue, in which mitochondrial dynamics are altered, the size of mitochondria changes, and their ability to generate energy stores falters. The processes of cellular quality control responsible for destroying problematic mitochondria start to fail as well. This is well studied by researchers who specialize in neurodegenerative diseases, as the brain requires a great deal of energy to function, and lack of that energy is a real problem. Why does this happen? That remains a question; which of the forms of damage that drive aging lead to this reaction, and what exactly is the chain of cause and effect? Researchers are making some inroads in tinkering with this mitochondrial malaise, speeding it up and slowing it down somewhat, but the roots remain obscure.

The Mitochondrial Basis of Aging and Age-Related Disorders

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.

AGEs and RAGE in the Aging Arteries
https://www.fightaging.org/archives/2017/12/ages-and-rage-in-the-aging-arteries/

Below you will find a paper on advanced glycation end-products (AGEs) and their contribution to degenerative aging, with a focus on the vascular system. AGEs are the result of various chemical reactions involving sugars, many of which occur both inside the body in the normal course of metabolic operations and outside the body during food preparation. There are many different types of AGEs, most well-known to chemists, but the tools for working with AGEs and their precursors in a biological context are not that great in comparison to the rest of the biochemistry field, and as a consequence their study has lagged. You will still find many papers hedging or being carefully agnostic on the question of which AGEs are important in mammalian aging, and on their relative amounts and relevant mechanisms. That is the case here.

As is true of mitochondrial damage, there are two quite distinct ways of looking at AGEs in aging, two collections of processes, one of which offers worse prospects when it comes to producing gains in health and longevity, but is nonetheless the point of greatest mainstream research focus. This is, sadly, the story for much of the young field of rejuvenation research. We have a lot of work left to accomplish when it comes to driving the necessary interest and funding to make meaningful progress towards addressing the causes of aging. Not least of this is the matter of steering more of the research community in the right direction, towards high-yield rather than low-yield strategies.

The first, minority area of AGE research is focused on persistent cross-links formed by AGEs in the extracellular matrix. AGEs can bind to the matrix proteins, linking them together. Since the physical properties of tissue are determined by the arrangement of these proteins and their ability to move relative to one another, this process of cross-linking can corrode elasticity and strength. It makes bone brittle, skin wrinkled, and blood vessels stiff. The last of those starts the cascade leading to hypertension, heart disease, and death: even if there were no other processes in aging, it would kill you eventually.

Few AGEs are persistent, however. Most are like the sugars that formed them: here today, gone tomorrow, with current levels very dependent on the diet. It is thought that glucosepane makes up the overwhelming majority of all persistent cross-links in human tissues, but there is next to no funding for research into this compound and its role in aging. The SENS Research Foundation has been funding near all of the work aimed at the production of necessary scientific infrastructure and then AGE-breaker pharmaceuticals that can destroy cross-links. This is hopefully nearing fruition. That this is just a single type of target makes it a very promising line of work, hopefully soon to join senolytics as a rejuvenation therapy moving from theory to practice. Reversing blood vessel stiffness alone would have a profound effect on health for older individuals.

The second, majority area of AGE research is more focused on chronic inflammation, metabolic dysfunction characteristic of type 2 diabetes and obesity, and dietary intake of sugars and AGEs. It encompasses the short-lived AGEs, which are a much larger fraction of the AGE population than the rare, persistent AGEs that linger to accumulate slowly in tissues. A primary point of interest here is the interaction between AGEs and RAGE, the receptor for AGEs. RAGE is a mediator of inflammation, and high levels of AGEs trigger it relentlessly; it also has a number of other roles that are poorly cataloged, but the general consensus is that these probably don't benefit from continual activation either. This is thought to be one of the ways in which diabetes and excess fat tissue result in high degrees of chronic inflammation, and all of the downstream consequences of that inflammation. That means higher rates of age-related disease, greater immune dysfunction, more tissue damage, and so forth. At least until quite late in old age, much of this is the result of lifestyle choices, and can be avoided or reversed through choice in diet and weight.

The paper here is focused on a future of therapies that interfere in the interaction between AGEs and RAGE. The author dismisses AGE-breakers due to past failures, which I think is an incorrect conclusion. The past failures were failures because they targeted forms of AGE that are noteworthy in short-lived rodent species, but unfortunately not all that relevant in humans. The types of AGE that cause pathology vary considerably by species and species life span. No past initiative ever targeted glucosepane. Meanwhile, efforts to target the AGE / RAGE interaction are probably best thought of as belonging to the same class of strategy as other attempts to block the inflammatory consequences of fat tissue or diabetes. It is an effort to compensate for a problem, not repair the cause of the problem.

The AGE-RAGE Axis: Implications for Age-Associated Arterial Diseases

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.

All of Medicine has a History of the Strange and the Wrong, Slowly Shed Over Time
https://www.fightaging.org/archives/2017/12/all-of-medicine-has-a-history-of-the-strange-and-the-wrong-slowly-shed-over-time/

All fields of medicine are characterized by a history of wrong ideas, many of them very strange from a modern viewpoint. These ideas were slowly winnowed out as technology advanced to the point of being able to prove them wrong, and as the culture of science advanced to the point of being taken seriously. Considerations of aging are no exception, and like most of the very complex issues in biology, this is arguably one in which the wrong and the strange persisted to a later date than was the case for other areas of medical science.

Many early theories of aging revolved around loss of some form of resource: that people were born with a given amount, that it was needed for life, and the process of living depleted it. No such resource exists, of course. Rate of living theories of aging might be seen as the more modern final last gasp of that sort of thinking regarding fixed limits and the passage of time. In reality, life span is fluid, determined by the accumulation of cell and tissue damage that arises as a side-effect of the normal operation of cellular metabolism, by the rising mortality rate caused by the presence of that damage and its consequences. It is the damage that is important, not the time spent alive. Repair the damage and people will live for longer in good health; the first rejuvenation therapies, such as those that destroy senescent cells, should prove that point in the years ahead.

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."

Faustian Bargains Struck in Search of Life Extension
https://www.fightaging.org/archives/2017/12/faustian-bargains-struck-in-search-of-life-extension/

It helps to know a little bit about the views of the author S. Jay Olshansky when reading this piece. He is one of the scientists behind the Longevity Dividend initiative, the goals of which can be summarized as greatly increasing government funding for current mainstream programs at the National Institute on Aging, with the aim of adding a few years to life expectancy over the next few decades. For those of us who seek far larger outcomes, and a way to turn back aging rather than merely slowing it down, he wishes us luck, but doesn't seem convinced that the goal of additional decades through rejuvenation research after the SENS model is practical.

Olshansky has long been vitriolically opposed to the "anti-aging" marketplace of the past few decades, packed as it is sellers of fraudulent pills and potions, and believes it a baleful influence that damages the prospects for serious science. You might look at the Silver Fleece awards that he conducted for some years, for example. I think that went a long way to determining his early position of opposition to SENS rejuvenation research and related advocacy for actuarial escape velocity, the unbounded increase in life span that would follow any meaningful first implementation of rejuvenation therapies. That is an opposition that has mellowed somewhat, though Olshansky clearly still strongly dislikes talk of radical life extension.

From my point of view, this unwillingness to seriously consider sizable outcomes and potentials is a part of the problematic legacy of the last generation of researchers in this field. It is why they suppressed interest in efforts to treat aging as a medical condition. It is why they failed to make significant progress despite all the evidence in hand pointing to the causes of aging. It is why people like Aubrey de Grey and others involved in SENS had to come in from outside the field to shake things up.

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.

Brain Rhythms are Disrupted with Age, and this Causes Memory Dysfunction
https://www.fightaging.org/archives/2017/12/brain-rhythms-are-disrupted-with-age-and-this-causes-memory-dysfunction/

The popular science article noted here covers a recent advance in the understanding of brain waves and their interaction with memory. The damage done to the brain over the course of aging produces functional decline of a variety of forms. One of the many systems in which this decline becomes apparent is in the generation of brain waves. These are coherent oscillating patterns of activity in neurons, important to the higher level functions of the brain. Unfortunately, definitively linking specific physical, cell and tissue damage to brain wave changes is one of the many areas of aging research in which the chain of cause and effect is yet to be filled out.

On that topic, note that the researchers involved in the research here venture to suggest a compensatory therapy rather than a therapy that addresses root causes. This is all too often the case in the research community, and it is something that must change if we are to see meaningful progress towards an end to aging. Comprehensively filling in the links between this finding and the many forms of physical damage found in the aging brain remains a matter for future research, but the fastest way forward to those answers, I believe, is to fix the known forms of damage that cause aging and then see what happens. Compensatory approaches will never be all that effective, as they fail to address the underlying damage that will continue to cause degeneration and eventual death.

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.

Overexpression of FKBP1b Restores Lost Memory Function in Old Rats
https://www.fightaging.org/archives/2017/12/overexpression-of-fkbp1b-restores-lost-memory-function-in-old-rats/

Here, researchers demonstrate restoration of lost memory function in old rats though increased levels of FKBP1b in the hippocampus. This is a very intriguing paper, firstly for the size of the effect, and secondly because it touches on the question of the degree to which dysfunction in the aging brain is damage versus inappropriate cellular reactions to damage. Inappropriate reactions can be overridden, at least for a time. Ever-increasing damage always wins in the end, however, which is why damage repair after the SENS model should be more efficient and cost-effective as an approach. Further, repairing damage doesn't require researchers to learn how to safely manipulate a very complex disease state, or even to learn exactly how the damage produces that disease state; it is a reversion to a known good state. Given this, it is either a tragedy or a hidden benefit that sometimes overriding an inappropriate reaction looks good enough to justify the expenditure of serious effort on development of a therapy. Which of those two options is the case is really only possible to determine in hindsight.

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.

The Advanced Regenerative Manufacturing Institute Works Towards the Mass Production of Organs
https://www.fightaging.org/archives/2017/12/the-advanced-regenerative-manufacturing-institute-works-towards-the-mass-production-of-organs/

It seems that more members of the high profile entrepreneur segment are starting to consider mass manufacture of tissue engineered organs as an area to put time and effort into. The publicity article here offers one example. While the research community has yet to produce a robust means of creating the microvasculature needed to sustain larger tissue sections, that absence is really the only serious roadblock standing between the state of the science today and a manufactured, patient-matched kidney or liver a few years from now. It is high time to consider moving the technology from laboratory to manufactory.

Even lacking the ability to lace tissue with tiny blood vessels, researchers can still create small organoids that exhibit the correct structure and function of their tissue type. In large numbers, organoids could be used instead of a full organ transplant, the aim being to patch a damaged organ with scores of tiny organoids that will integrate with the tissue and augment its failing function. That is a practical vision, just as soon as the ability to mass-manufacture organoids comes to pass. Creating the proof of concept in the laboratory is one thing; creating ten thousand of them to order, and within tight quality constraints, is quite another. A company that succeeds in that goal over the next decade or so will be ready to start on full-sized organs when the blood vessel problem is finally solved.

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."

The Present Standard Cancer Therapies Increase Biological Age
https://www.fightaging.org/archives/2017/12/the-present-standard-cancer-therapies-increase-biological-age/

The current standard treatments for cancer, chemotherapy and radiotherapy, are quite unpleasant and harmful; no-one would voluntarily undergo them given a better alternative. In fact, treatment makes people physically older, accelerating the processes of aging. There is evidence to suggest that this is due to an added burden of senescent cells. Cells become senescent in response to damage or a toxic environment, and there is plenty of that going around in any earnest attempt to treat cancer with radiation or chemical agents; in fact, many cancer therapies are intended to aggressively induce senescence in tumor cells.

The presence of senescent cells is one of the causes of aging. These cells remove themselves from the usual cycle of replication, and in normal circumstances near all self-destruct or are destroyed by the immune system. Unfortunately, enough linger to contribute to aging. They produce harm through inflammatory signaling, the senescence-associated secretory phenotype (SASP), that corrodes tissue structure and disrupts tissue function - insignificant in small amounts, but very damaging given a sizable number of such cells. There are no doubt other mechanisms by which present cancer therapies touch on the causes of aging, however; given that aging is damage, and cancer treatments are damaging in many ways, we should probably not be surprised to find that aging is accelerated.

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.

IRF4 as a Discriminating Target for Selective Destruction of Immune Cells
https://www.fightaging.org/archives/2017/12/irf4-as-a-discriminating-target-for-selective-destruction-of-immune-cells/

There are many issues that might be solved by destroying a sufficiently large number of immune cells. Take autoimmune disease, for example, in which the immune system attacks tissues. This is a configuration problem, and that configuration is entirely contained in immune cells. If those cells are removed, autoimmunity is cured. The age-related decline in the immune system, similarly, is in part a problem of too many unhelpful, over-specialized, or damaged, senescent, and exhausted immune cells cluttering up the body.

The only currently working approach involves high doses of harsh immune suppressant drugs to clear out near all immune cells, accompanied by some form of cell therapy to speed replenishment. It has been used to cure multiple sclerosis and type 1 diabetes in trials, but is hard on the patients. This isn't something that would be risked in anything other than a severe condition, and is probably too dangerous for older, less robust individuals. Better, safer methods of shutting down or destroying the unwanted parts of the immune system are needed.

In the research noted here, the authors have identified IRF4 as a single target protein that can disable active T cells, and thus potentially shut off many forms of autoimmunity. Quite aside from that, it has the look of a suitable target for the Oisin Biotechnologies cell-killing gene therapy that is triggered by the presence of specific proteins inside a cell, as IRF4 only occurs in immune cells. The researchers will no doubt pursue a pharmacological option for inhibition, but it is worth keeping in mind that this is only one of an expanding number of options nowadays.

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."

A Class of Calorie Restriction Mimetic Targeting NRF2
https://www.fightaging.org/archives/2017/12/a-class-of-calorie-restriction-mimetic-targeting-nrf2/

NRF2, or SKN-1 in the nematode worm Caenorhabditis elegans, is one of the many coordinating stress response genes activated by calorie restriction or a range of other forms of mild cellular stress. Part of the way in which this results in improved health and extended life span in a range of species is through activating cellular protection and repair mechanisms. Researchers are interested in ways to recapture this reaction to stress via pharmaceuticals rather than diet, and so are working their way through the drug databases in search of prospects. The results here are an example of the sort of thing they are looking for: a drug already approved for use that might be adapted as a calorie restriction mimetic treatment.

Sadly this is marginal work; calorie restriction does have very positive effects on human health, but only small effects on human life span. Short-lived species have a much greater plasticity of life span in response to environmental circumstances than is the case for long-lived species such as our own. So calorie restriction is worth pursuing as something that is free, but it is not worth billions in research and development investment when there are other, potentially far more effective ways forward. Why tinker with adjusting metabolism for tiny gains when we could follow the SENS rejuvenation research road and add decades of health life with the same investment in time and funding? The real battle in aging research these days is shifting from convincing people it is worth doing at all to convincing people to adopt strategies that will produce large results: human rejuvenation, the reversal of aging, not just a modest slowing of the underlying processes.

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 Demonstration of Evolutionary Optimization for Resilience Rather than Life Span
https://www.fightaging.org/archives/2017/12/a-demonstration-of-evolutionary-optimization-for-resilience-rather-than-life-span/

We see the current survivors of the relentless evolutionary process of winnowing and change all around us, and near all are examples of the point that greater life span is all too rarely a winning trait. Look at how easy it is for our early biotechnology to engineer longer lives in near all animal species. Small genetic tweaks suffice in most cases. Why were those genetic alterations not selected for long ago, given that longer-lived individuals can produce more progeny than their shorter-lived rivals? The study here provides one example of the many reasons for the current state of life span in most species: the present outcome for any given species is a balance between resistance to stress and ability to live longer, in this case mediated by the way in which the immune system acts in response to circumstances.

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.

Immortality is a Distant Challenge, not the Immediate Issue
https://www.fightaging.org/archives/2017/12/immortality-is-a-distant-challenge-not-the-immediate-issue/

The media throws around the term "immortality" when talking about efforts to extend healthy life, with little concern for the dictionary definition. Advocates for radical life extension have in the past used physical immortality as a alternative term for the concept of agelessness, in which aging is controlled but all other causes of death still exist - which is another change of meaning. Some people find this a distraction, an annoyance, something that makes it harder to conduct advocacy and fundraising for current and prospective longevity science. Convincing the world that rejuvenation therapies are a viable near term prospect, given sufficient funding, is challenge enough without the peanut gallery.

It isn't clear whether or not dictionary definition immortality is possible in this universe, and if it was the entities enjoying it would be very different from the present human model of existence. Even scaling up to a reliable life expectancy of a million years would require considerable technology-assisted change and expansion. Such long-lived beings would probably be something akin to distributed collections of hardened, space-faring, automated computational factories. In that sense, we stand a long way removed from even the lesser challenges of living for a very, very long time. The problems of today, in which we take the first steps towards treating aging as a medical condition, so as to add the first few additional decades of healthy life, are those of the first rung on an extremely long ladder - and they are hard problems. If we don't focus on them, there is every chance of failure to progress soon enough to matter for most of us.

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.

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