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Hematopoietic stem and progenitor cell populations are responsible for generating immune cells. Their decline is one of the causes of immune failure with age, as the pace at which new immune cells are created falters. There are other equally important issues in immune aging, such as the atrophy of the thymus, where T cells of the adaptive immune system mature, and the accumulation of malfunctioning immune cells in older individuals, but we'll put those to one side for this discussion.

Stem cell decline with aging is a complicated business with many contributing causes, and the relative importance of those causes seems to differ between populations and tissues. Few stem cell populations are very well studied when it comes to asking why exactly it is that they decline in activity with age. Those that are, such as muscle, hematopoietic, and neural populations all seem to be quite different. Muscle stem cells decline in activity but, given the right signals, appear quite ready to go back to work with minimal signs that they are greatly impacted by damage. Hematopoietic stem cells do appear to be more damage-limited, however.

In this open access paper, the authors look at the detrimental impact of cellular senescence on hematopoietic cells, and thus on the immune cells that they produce. Cellular senescence is a reaction to damage or excessive replication; senescent cells cease to replicate, and most such cells self-destruct or are destroyed by the immune system. Some linger, however, and the harmful, inflammatory mix of signals that they generate are implicated as a cause of degenerative aging. Studies in mice show that removing senescent cells improves health and extends life span. There are also populations of cells that show some of the markers and behaviors of senescence, but have yet to be definitively classified as senescent - nothing is simple when it comes to cellular biology. This pseudo-senescence or maybe-senesence may be the case here; more research will determine whether or not this is the case.

Elderly human hematopoietic progenitor cells express cellular senescence markers and are more susceptible to pyroptosis

Aging is associated with an increased prevalence of multiple comorbidities, including infectious and malignant diseases. Many of these disorders are thought to stem from old-age-related immune decline. Increasing efforts to characterize the immune system of elderly people in recent years have revealed that most immunocompetent cell compartments present profound quantitative as well as qualitative impairments. The cause of these impairments can vary, and is often related to the exhaustion of the cells or their functions over time in inflammatory settings.

The majority of mature blood cell compartments need, therefore, to be continuously replenished or replaced, which is the role of hematopoietic progenitor cells (HPCs) and, ultimately, hematopoietic stem cells (HSCs). While the self-renewal and differentiation potential of stem cells, along with their blood cell reconstitution capacity, have long been considered as infinite, increasing evidence indicates that this is not the case. Under conditions of stress, HSCs eventually exhibit several functional defects, including a diminished regenerative and self-renewal potential. Loss of stem cell activity is therefore a likely mechanism of impairment common to many mature cell types, thus representing a central cause of immune-competence decline.

Most studies on HSC aging have been carried out in mouse models, and have highlighted extrinsic and intrinsic factors affecting the function of HSCs. A recent study reveals that loss of autophagy in most HSCs from aged mice causes an activated metabolic state, which is associated with accelerated myeloid differentiation, and impairs HSC self-renewal activity and regenerative potential. In humans, much less information is available on the aged HSCs, due to the limited and challenging access to bone marrow samples of elderly humans, the niche of HSCs. Reduced transplantation success in patients receiving HSCs isolated from older (45 years and above) donor bone marrows indicates that human HSC regenerative capacity also declines with aging.

We performed here a comprehensive study of blood HPCs, as an alternative to bone marrow HSCs, to overcome the constraint of sample availability from elderly adults. Based on phenotypic analyses, in vitro T lymphocyte differentiation assays, and gene expression profiling of circulating HPCs from aged subjects, we demonstrate impaired lymphopoiesis and active cell cycling of HPCs with aging, and provide insights into their functional impairments. Our findings reveal that, while mobilized, elderly HPCs present evidence of cellular senescence and increased cell death by pyroptosis. Reduced telomere length and telomerase activity in old HPCs may affect the properties of their progeny, such as mature T lymphocytes. This pre-senescent profile is characteristic of the multiple intrinsic and extrinsic factors affecting HPCs in elderly individuals and represents a major obstacle in terms of immune reconstitution and efficacy with advanced age.

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Clearance of metabolic waste from the brain via fluid drainage pathways is becoming an important topic in the context of age-related neurodegeneration, as is noted by the authors of this open access review paper. There is good evidence to suggest that drainage of cerebrospinal fluid is a significant path for the removal of wastes, such as the protein aggregates associated with dementia, and that the relevant fluid channels atrophy and fail with age. That decline may well be an important contribution to the development of neurodegenerative disease in later life, and the first efforts to do something about it are now underway. Restoring drainage is the goal of Leucadia Therapeutics, for example, a company that will probably be joined by similar initiatives in the years ahead.

Waste removal from the central nervous system is essential for maintaining brain homeostasis across the lifespan. Two interconnected, dynamic networks were recently uncovered, which may provide new information concerning the conundrum of how the brain manages waste removal in the absence of authentic lymphatic vessels (LVs). The glymphatic system serves as the brain's "front end" waste drainage pathway that includes a perivascular network for cerebrospinal fluid (CSF) transport, which is connected to a downstream authentic lymphatic network associated with the meninges, cranial nerves, and large vessels exiting the skull. The anatomical and functional components of the two systems are complex, and the processes by which they physically interconnect are only partly understood.

The first pioneering studies documented that soluble amyloid beta (Aβ) protein and tau oligomers - metabolic waste products whose buildup is associated with Alzheimer's disease (AD) - were transported from the interstitial fluid (ISF) space and out of the brain via the glymphatic system. This information was followed by another hallmark study reporting that slow wave sleep enhanced glymphatic Aβ clearance from brain when compared to wakefulness. Collectively, this information was met with excitement in the neuroscience and clinical communities because maintaining efficient brain waste drainage across the lifespan - possibly by preserving normal sleep architecture - emerged as a novel therapeutic target for preventing cognitive dysfunction and decline.

The idea of maximizing brain "waste drainage" as a new preventive or therapeutic target for neurodegenerative disease states was further strengthened by animal studies providing evidence of declining glymphatic transport efficiency in healthy aging, AD models, traumatic brain injury, cerebral hemorrhage, and stroke. Considering the novelty of the glymphatic system concept, along with the rapidly emerging literature associating key physiological processes (e.g., vascular pulsatility, and sleep) with glymphatic transport function and waste solute outflow from brain, we decided it was timely to review this information cohesively. Hence, the goal of this mini-review is to provide a broad overview of the current data, controversies, and gaps in knowledge of the glymphatic system and waste drainage from the brain, while addressing potential consequences of aging as well as critically reviewing evidence for its existence in the human brain.

Link: https://doi.org/10.1159/000490349

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Researchers here report on a single gene alteration in fruit flies, increased levels of vinculin, that improves cardiovascular function in later life and increases life span. Effect sizes in flies are much larger than those in humans, where is is possible to directly compare interventions. Short-lived species have evolved to exhibit a far greater plasticity of longevity in response to environmental and genetic changes, at least in those methodologies tested to date. It remains to be seen as to whether the initial hypothesis on the important mechanisms linking vinculin levels to improved health turn out to be correct. Vinculin is involved in common cellular processes that in turn influence many aspects of tissue function. This is frequently the case in studies of slowed aging - finding out exactly how and why it works is a long and arduous process.

Our cells tend to lose their shape as we grow older, contributing to many of the effects we experience as aging. This poses particular problems for the heart, where aging can disrupt the protein network within muscle cells that move blood around the body. Researchers discovered that maintaining high levels of the protein vinculin - which sticks heart muscle cells to one another - confers health benefits to fruit flies. Their work shows that fruit flies bred to produce 50 percent more vinculin enjoyed better cardiovascular health and lived a third of their average life span longer.

Vinculin works at the intercalated disks that glue together heart muscle cells, called cardiomyocytes. As we age, cardiomyocytes make less vinculin. Vinculin organizes the heart's contractile proteins, so as vinculin levels fall our heartbeats become disorganized and less efficient. By breeding flies with complementary genes, researchers created a genetic switch that turned on extra copies of the vinculin-coding gene. To ensure that only cardiomyocytes were producing the protein, the group used the same activation machinery as a heart development gene called Tinman.

While typical fruit flies live for roughly six weeks, flies that made more vinculin survived up to nine weeks. Additionally, flies with a vinculin boost were more active and able to climb the walls of their enclosures, a test of fruit fly athletic ability. Researchers were surprised how much improving cardiac function also helped the flies maintain a healthier metabolism. To measure this improvement, researchers fed the flies a special form of glucose and detected how the flies modified and used the sugar. Flies with more vinculin broke down more glucose than their counterparts. The team concluded higher vinculin levels in the flies' hearts enabled other organs to efficiently get the nutrients they needed in the breakdown process.

Link: https://publishing.aip.org/publishing/journal-highlights/high-vinculin-levels-help-keep-aging-fruit-fly-hearts-young

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Oisin Biotechnologies is the company working on what is, to my eyes, the best of the best when it comes to the current crop of senolytic technologies, approaches capable of selectively destroying senescent cells in old tissues. Adding senescent cells to young mice has been shown to produce pathologies of aging, and removal of senescent cells can reverse those pathologies, and also extend life span. It is a very robust and reliable approach, with these observations repeated by numerous different groups using numerous different methodologies of senescent cell destruction.

Most of the current senolytic development programs focus on small molecules, peptides, and the like. These are expensive to adjust, and will be tissue specific in ways that are probably challenging and expensive to alter, where such alteration is possible at all. In comparison, Oisin Biotechnologies builds their treatments atop a programmable suicide gene therapy; they can kill cells based on the presence of any arbitrary protein expressed within those cells. Right now the company is focused on p53 and p16, as these are noteworthy markers of cancerous and senescent cells. As further investigation of cellular senescence improves the understanding of senescent biochemistry, Oisin staff could quickly adapt their approach to target any other potential signal of senescence - or of any other type of cell that is best destroyed rather than left alone. Adaptability is a very valuable characteristic.

The Oisin Biotechnologies staff are currently more than six months in to a long-term mouse life span study, using cohorts in which the gene therapy is deployed against either p16, p53, or both p16 and p53, plus a control group injected with phosphate buffered saline (PBS). Forty aged mice were randomly put into these groups, and dosed with the therapy once a month. The mice in which both p16 and p53 expressing cells are destroyed are doing very well indeed so far, in comparison to their peers. This is quite impressive data, even given the fact that the trial is nowhere near done yet.

The image presented here is taken from the Oisin Biotechnologies PDF that accompanies a presentation given at the recent ICSA meeting in Montreal. We should certainly hope to see more of this sort of thing in the years ahead as senolytic technologies improve.

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Researchers appear to have found a novel way to sabotage fibrosis, the condition in which regenerative processes run awry with age and cells begin building scar-like structures that disrupt normal tissue function. The approach involves blocking TLR4 signaling. Fibrosis is a feature of the decline of many organs; liver, lung, kidney, heart, and so forth. If it can be turned off comparatively simply, that would produce noteworthy gains for the health of older individuals, even when the underlying causes of regenerative disarray are not addressed. The question is always whether or not there is a good way to interfere without also altering other important cellular processes, of course.

An interesting broader context for this TLR4 signaling inhibition is the growing evidence that suggests senescent cells to be a significant contributing cause of fibrosis. Senescent cells secrete a great many disruptive, inflammatory signal molecules, and that changes the behavior of surrounding cells, usually for the worse when that signaling persists for a long time. It may or may not be the case that senescent cells directly cause increased TLR4 signaling, but it is worthy of note that TLR4 deficient mice exhibit a reduced level of cellular senescence than their peers. There are some dots yet to be joined here.

Fibrosis, the hallmark of systemic sclerosis (SSc), is characterized by excessive production and persistent accumulation of collagens and other extracellular matrix (ECM) molecules in skin, lungs, and other internal organs. The process underlies a large number of fibrotic diseases that, in aggregate, account for a considerable proportion of deaths worldwide. With no effective therapy to date, fibrosis therefore represents a significant unmet global health need.

TLRs and related pattern-recognition receptors represent the first line of host defense against microbial pathogens. Cell surface receptors such as TLR4 and endosomal receptors such as TLR3 recognize extrinsic pathogen-associated molecule patterns (PAMPs) such as LPS and virus-derived nucleic acids. Significantly, TLRs also recognize damage-associated molecule patterns (DAMPs) that arise endogenously during various forms of noninfectious tissue injury. Regulated PAMP sensing by TLR4 has a unique requirement of myeloid differentiation 2 (MD2), an accessory receptor that interacts with TLR4 to form the signaling-competent receptor. The requirement for MD2 as an accessory pattern-recognition receptor for PAMPs appears to be unique for TLR4.

We recently demonstrated that particular DAMPs are markedly upregulated in fibrotic skin and lungs in patients with SSc and largely colocalize with TLR4-expressing myofibroblasts. In mice, genetic ablation of either of two DAMPs prominently associated with SSc resulted in markedly attenuated skin and lung fibrosis and enhanced fibrosis resolution, suggesting a fundamental pathogenic role for DAMP-TLR4 signaling in driving persistent organ fibrosis.

We developed a small molecule that selectively blocks MD2, which is uniquely required for TLR4 signaling. Targeting MD2/TLR4 abrogated inducible and constitutive myofibroblast transformation and matrix remodeling in fibroblast monolayers, as well as in 3-D scleroderma skin equivalents and human skin explants. Moreover, the selective TLR4 inhibitor prevented organ fibrosis in several preclinical disease models and mouse strains, and it reversed preexisting fibrosis.

Link: https://doi.org/10.1172/jci.insight.98850

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Inhibitors of mechanistic target of rapamycin (mTOR) are arguably the most reliable of the current crop of compounds that slow aging by targeting stress response mechanisms, improving cellular health and resilience to some degree. The observed gain in life span in mice and lower species is likely to be much larger than the outcome achieved in longer-lived species such as our own, as that is unfortunately just the way things work for this class of approach to aging. Short-lived species evolved to have far greater plasticity of longevity in response to environmental circumstances.

The health benefits in old humans that can be obtained using mTOR inhibitors may well still be broad and sizable in comparison to most currently available medical technology for the treatment of age-related disease, but this is as much a suggestion that present technologies are not all that good, as it is a reflection of the utility of mTOR inhibitors. It seems likely that they won't hold a candle to approaches that are based on repair of underlying damage, such as those of the SENS portfolio.

The core challenge in developing therapies based on inhibition of mTOR is that mTOR forms two complexes, mTORC1 and mTORC2. These complexes have quite different roles in our cellular biochemistry; the unwanted side-effects of rapamycin stem from its inhibition of both complexes. Ideally, inhibiting mTORC1 but not mTORC2 is the way to go, but it has taken some years for drug candidates capable of this feat to be identified and progress through a development program. Here, one of these programs reports success in a human trial that targeted immune function in older individuals - and if you like the sound of the results here, just imagine how much more could be achieved through actually repairing the causes of immune failure with aging.

resTORbio today announced newly published data from a Phase 2a clinical trial demonstrating that target of rapamycin complex 1 (TORC1) inhibitor treatment improved immune function and decreased incidence of all infections, including respiratory tract infections (RTIs), in people aged 65 years and older. RTIs in particular are a significant health risk for the elderly with life-threatening consequences and few treatment options.

"Inhibition of TORC1 has extended both lifespan and healthspan in multiple pre-clinical species. The results of this Phase 2a trial raise the possibility that TORC1 inhibition also has health benefits in older humans. In the Phase 2a trial, TORC1 inhibitor treatment was associated with a clinically meaningful reduction in the incidence of infections in people aged 65 years and older and an enhancement in the function of the aging immune system as assessed by influenza vaccination response and antiviral gene expression. The results need to be validated in additional clinical trials, but may have broad implications for the treatment of diseases of aging that we are actively investigating with our TORC1 inhibitor program."

The data for this publication were gathered in a randomized, double-blinded, placebo-controlled Phase 2a study of 264 elderly volunteers at least 65 years of age without unstable medical conditions. Subjects were treated for 6 weeks with study drug and after a 2-week drug-free interval, were given a seasonal influenza vaccine. The incidence of infections was assessed for one year after initiation of study drug treatment. In the RTB101 monotherapy and RTB101+everolimus combination treatment arms, statistically significant and clinically meaningful reductions in the annual rate of infections of 33% and 38%, respectively, compared to placebo, were observed.

Link: http://ir.restorbio.com/news-releases/news-release-details/restorbio-announces-science-translational-medicine-publication

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A few recent papers have, collectively, added evidence for persistent viral infection to be a significant contributing cause of Alzheimer's disease. A number of viruses in the herpesvirus family are prevalent in the population but cause few obvious symptoms, such as HSV-1 and cytomegalovirus (CMV). Some of these, particularly CMV, are already under suspicion as being the cause of long-term dysfunction in the immune system. Viral infection is an attractive way to explain why only some of the people who exhibit all of the known risk factors for Alzheimer's disease actually go on to develop the full clinical manifestation of the condition. The proportion of the population with latent infection is high, but not too high: other candidate differentiating factors are a lot less convincing because either the population size is too small, or near everyone has it.

How can viral infections contribute to the development of Alzheimer's disease? The amyloid cascade hypothesis tells us that, in the first early stages of Alzheimer's disease, amyloid-β accumulates in the brain, producing only comparatively minor symptoms of degeneration. In later life, this accumulation reaches a critical point that causes tau protein to alter and form solid neurofibrillary tangles in significant amounts. It is this tau aggregation that causes the lion's share of the damage in the later stages of the condition - though a high enough level of amyloid-β can still be harmful in and of itself. Infection is important because amyloid generation is an innate immune mechanism that evolved to respond to viral infection. Thus infection speeds up the production and aggregation of amyloid-β in the brain, pushing things ever closer to the tipping point into pathology.

Herpes Viruses and Senile Dementia: First Population Evidence for a Causal Link

Authors have recently reported that infection with a different herpes virus, herpes simplex virus type 1 (HSV1), leads to a similarly increased risk of later developing senile dementia (SD). Further, when the authors looked at patients treated aggressively with antiherpetic medications at the time, the relative risk of SD was reduced by a factor of 10. It should be stressed that no investigations were made on subjects already suffering from SD, and that those treated were the few rare cases severely affected by HSV. Nonetheless, antiherpetic medication prevented later SD development in 90% of their study group. These articles provide the first population evidence for a causal link between herpes virus infection and senile dementia.

Multiscale Analysis of Independent Alzheimer's Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus

Investigators have long suspected that pathogenic microbes might contribute to the onset and progression of Alzheimer's disease (AD) although definitive evidence has not been presented. Whether such findings represent a causal contribution, or reflect opportunistic passengers of neurodegeneration, is also difficult to resolve. We constructed multiscale networks of the late-onset AD-associated virome, integrating genomic, transcriptomic, proteomic, and histopathological data across four brain regions from human post-mortem tissue. We observed increased human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) from subjects with AD compared with controls. These results were replicated in two additional, independent and geographically dispersed cohorts. We observed regulatory relationships linking viral abundance and modulators of APP metabolism.

Alzheimer's Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection

Amyloid-β peptide (Aβ) fibrilization and deposition as β-amyloid are hallmarks of Alzheimer's disease (AD) pathology. We recently reported Aβ is an innate immune protein that protects against fungal and bacterial infections. Fibrilization pathways mediate Aβ antimicrobial activities. Thus, infection can seed and dramatically accelerate β-amyloid deposition. Here, we show Aβ oligomers bind herpesvirus surface glycoproteins, accelerating β-amyloid deposition and leading to protective viral entrapment activity in mouse and human neural cell culture infection models against neurotropic herpes simplex virus 1 (HSV1) and human herpesvirus 6A and B. Herpesviridae are linked to AD, but it has been unclear how viruses may induce β-amyloidosis in brain. These data support the notion that Aβ might play a protective role in central nervous system innate immunity, and suggest an AD etiological mechanism in which herpesviridae infection may directly promote Aβ amyloidosis.

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Approaches to producing a biomarker of aging based on assessing levels of many proteins in the blood, and how those levels change with aging, are under development by a number of research groups. This paper should be considered a demonstration of methodology only, as a great deal of further work would be required to show that the relationships discovered here also apply across broader human populations. Still, it seems likely that proteomic analogies to the epigenetic clocks developed in recent years do in fact exist.

The challenge with all of these biomarkers and potential biomarkers is to connect them to the underlying causes of aging. If the end result of a test is just a number that represents how far removed one is from the average result across the population at a given age, then what action should be taken when that result shows a higher rather than lower physiological age? Presently there is no good answer to that question, and therein lies the problem.

Despite its importance for health, most epidemiological research considers aging merely as a confounder, a nuance dimension to be accounted for and then discarded, under the assumption that aging is unavoidable and unchangeable. This view is now changed. As the intrinsic biological mechanism of aging is slowly revealed, there is hope that interventions that slow aging and prevent or delay the onset of chronic disease and functional impairments can be discovered.

A critical goal in the field of aging biomarkers is to identify molecular changes that show robust patterns of change with normal aging, with the assumption that departures from this "signature" pattern provide not only information regarding future risk of pathology and functional decline but also clues on compensatory mechanisms by which our organism counteracts the effects of aging. Such a signature could be used both to identify individuals in the trajectory of accelerated aging and to track the effectiveness of interventions designed to slowdown biological aging.

The "epigenetic clock," a biomarker index that combines weighted information of a subset of DNA methylation sites raised great interest because it is strongly associated with chronological age and predicts multiple health outcomes, including cardiovascular disease, cancer, and mortality. These findings suggest that aging is associated with stereotyped and reproducible molecular changes that can potentially be used to identify individuals who are aging faster or slower than the average population. However, the underpinnings of these molecular changes have not been fully elucidated, at least in part because the effect of methylation on DNA function remains unclear.

A promising alternative to current methods may be to construct a similar aging biomarker clock based on circulating proteins. Proteins are attractive because they directly affect phenotypes and provide direct information on biological pathways that can be involved in many of the physiological and pathological manifestations of aging. We conducted proteomic analyses that measured 1,301 proteins in 240 adults aged 22-93 years, free of major chronic diseases, cognitive, and functional impairment. The goal was to identify proteins associated with chronological age avoiding as much as possible the effect of clinically detectable disease, examine their association with several clinical characteristics, and further compare our results to previous proteomic profile analyses that used the same technology.

We found 197 proteins were positively associated, and 20 proteins were negatively associated with age. The functional pathways enriched in the 217 age-associated proteins included blood coagulation, chemokine and inflammatory pathways, axon guidance, peptidase activity, and apoptosis. We created a proteomic signature of age based on relative concentrations of 76 proteins that highly correlated with chronological age. However, the generalizability of our findings needs replication in an independent cohort.

Link: https://doi.org/10.1111/acel.12799

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The Ichor Therapeutics contingent present at the Ending Age-Related Diseases conference in New York last week were quite pleased that the timing worked out to allow them to announce during the conference a $10 million investment from Juvenescence into a joint venture with their portfolio company Antoxerene. Antoxerene started as a protein biotechnology infrastructure company, but the staff are now turning that infrastructure to the discovery and development of senolytic compounds, those capable of selective destruction of senescent cells. Antoxerene joins a number of existing companies working on various approaches to this goal: this diversity bodes well for our future health and wellbeing, given that senescent cells are thought to be one of the root causes of aging.

As regular readers will recall, the Juvenescence principals intend their fund to be a sizable and long term player in the commercialization of longevity science. They are quite vocal, and their published materials and comments to date suggest that they are supportive of the SENS model of rejuvenation based on damage repair - which of course has included and advocated senescent cell clearance since day one, long prior to the present growth of interest in this line of research. It is a pity that it took so long for senolytic research to become widely appreciated; from a purely technical viewpoint, meaningful progress could have been made, albeit at much greater cost, twenty years ago or more.

Antoxerene, Inc., a portfolio company of Ichor Therapeutics, Inc., focused on small molecule drug discovery for pathways of aging, announced today the launch of a joint venture with Juvenescence Limited. The joint venture, called FoxBio, Inc., will develop Antoxerene's collection of small molecules that target senescent cells. Juvenescence will support the venture with $10 million in equity financing and drug development expertise.

"There has been a lot of interest surrounding the therapeutic applications of senolytic drugs - compounds that clear toxic senescent cells - particularly with respect to age-associated disease. As molecular pathways unique to senescent cells have begun to be identified, we can now develop drugs to target these pathways. We are eager to work with the Juvenescence team, whose experience in drug development, technical depth, and visionary leadership will help us to deliver on the immense potential of this field."

CEO of Juvenescence Dr. Bailey said, "this is one of the main focuses of Juvenescence - to modify aging through the clearance of senescent cells. FoxBio plays to both companies' strengths, which is why we are excited about working with the Antoxerene team. We are fascinated with the Antoxerene platform and its ability to discover intriguing compounds in the area of senescence. This is a great fit with Juvenescence's track record in drug development, so FoxBio is a very exciting new company in the area of longevity."

Link: https://www.businesswire.com/news/home/20180712005565/en/Antoxerene-Closes-10-Million-Deal-Juvenescence-Develop

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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

  • Blind Upon the Eve of Apotheosis
  • The Hedonistic Imperative, Followed to the Ends of Paradise Engineering
  • Adverse Interactions Between Natural Selection and the Modern Environment
  • Exosomes From Induced Pluripotent Stem Cells Make Skin Cells More Resilient
  • An Unconvincing Desire for Mortality
  • Chimeric Antigen Receptor Therapy, but Using Natural Killer Cells
  • Cleara Biotech Launches to Develop Senolytic Therapies Based on FOXO4-DRI
  • Senolytics Reduce Age-Related Dysfunction and Extend Remaining Life Span by 36% Following Administration to Old Mice
  • Endothelial Cell Dysfunction as the Early Manifestation of Small Vessel Disease
  • More than You Wanted to Know About NAD+ in Metabolism and Aging
  • A Life Lived is No Justification for a Death Unchosen
  • Activation of the Anaphase Promoting Complex to Enhance Genomic Stability
  • Upregulation of FGF21 to Prevent Visceral Fat Gain and Consequent Diabetes
  • Arguing that Cytomegalovirus is Beneficial for Old Immune Systems
  • Evidence to Show that Multivitamins Do Not Aid Cardiovascular Health

Blind Upon the Eve of Apotheosis
https://www.fightaging.org/archives/2018/07/blind-upon-the-eve-of-apotheosis/

Our present age of technology and accelerating progress is the first of its kind for our species. It commenced a few short centuries ago with subtle changes in wealth, agriculture, and life expectancy that compounded to form the foundations for the Industrial Revolution. It was a dramatic break with millennia in which stasis or the cyclic advance and retreat of applied knowledge - of civilization - were the norm. In our era, it is instead the case that progress today reliably creates the potential for greater and faster progress tomorrow. The most important consequence of this is arguably not that we now lead rich lives of greater wealth, capacity, and comfort, but that the technologies of tomorrow will radically transform our selves and our nature: these are the last decades of humanity as we know it. Human nature and the human condition as it has existed since the Great Leap Forward, some 50,000 years ago, will become malleable. We will be able to improve upon the human body and human mind. What comes next is something far greater than humanity, both for the billions of individuals who see the transformation from end to end and for our societies as a whole.

It has been argued that we have already changed ourselves greatly through technology. That the humans of Ur were far removed from the small and violently suspicious bands of humans who coexisted with their Neanderthal near relatives. That today's humans of internet and mobile phones are far removed from the humans of Ur and earlier cities. That technologies such as writing and global telecommunications, or even simply the size and density of population, leads to very different minds grown from the same genetic basis. On the face of it, this seems unlikely, however. Upon the eve of apotheosis, in a world linked by networks of communication and rapidly advancing technology, a glance at the activities of humanity finds any given populace worshipping civic idols and chieftains, in ways that are in essence little different from those of the ancient world, or reencting the politics of the greens and the blues of the Byzantine empire. Further, the past century has seen any number of small bands of humans brought into the modern era by neighboring peoples, with no signs of any fundamental difference in their human nature as a result of comparative isolation and lack of technology.

Past technological progress has not changed what it is to be human, the shape of our minds. What comes next will be very, very different in scope and outcome. It will start with some combination of a progressive reverse engineering of the brain, advanced biotechnology capable of altering and improving upon existing organ function, the development of interfaces between neural architecture and computing hardware, and software emulation of functional neural tissue. All of these lines of research are well established today, albeit in comparative infancy. They will converge into the ability to run minds in hardware and software, to alter the way in which minds function, to extend biological minds, and to move them into hardware, piece by piece. We presently forget 98% of everything we experience. That will go away in favor of perfect, controllable, configurable memory. Skills and knowledge will become commodities that can be purchased and installed. We will be able to feel exactly as we wish to feel at any given time. How we perceive the world will be mutable and subject to choice. How we think, the very fundamental basis of the mind, will also be mutable and subject to choice. We will merge with our machines, as Kurzweil puts it. The boundary between mind and computing device, between the individual and his or her tools, will blur.

Over the course of the 21st century, people will have access to an increasing array of options when it comes to enhancing the function of the mind and the body. The young of today will live to see all of that span, and more. Aging will soon become a treatable medical condition, its causes addressed by therapies that repair the molecular damage that accumulates in old tissues. The human genome will become fluid, the subject of any number of treatments that alter genes or gene expression in adult tissues in order to achieve specific benefits such as greater muscle mass or increased resistance to disease. Somewhere down the line, biotechnology and nanotechnology will merge to produce technologies such as artificial cells and cell-like machines, vastly more efficient at specific tasks than their biological counterparts. Biology will become an option, rather than the present mandate. People will be able to move to a more resilient vehicle for the brain than the present human body, and even the brain may be swapped out for better hardware, through a slow process of replacement and integration, one neuron at a time exchanged for a nanomachine.

Piece by piece, we will be able to choose physical immortality. Choose our physical forms. Choose exactly how our minds function. Choose how we think and feel. Choose exactly what being human is for each of us. A great branching in the diversity of minds and appearances will spring forth from our present uniformity in a matter of mere decades. The population may well expand greatly as well; minds in hardware and software can be copied. There are no limitations on the pace of reproduction in such a world, nor would such minds necessarily need to consume anywhere near the same resources as present humans. If we choose to believe that acceleration in technological development is, at root, largely a function of total human population and the degree to which people communicate with one another, then departing from our biological roots will enable the acceleration to continue far past its present limits.

That isn't just a matter of population, however. The pace of progress today bumps up against the limits imposed by organization of efforts, in that it takes a few years for humans to digest new information, talk to one another about it, decide on a course of action, gather together a group, raise funds, and start working. There is no necessary reason for any of these parts of the process to take more than a few seconds, however: consider a world in which human minds run far faster, because they run on something other than biological neurons, because they run hundreds of distinct streams of consciousness simultaneously, and because they are augmented by forms of artificial intelligence that take on some of the cognitive load for task assignment and decision making.

It is, frankly, hard to even speculate about the potential forms taken by society in such an environment. Technology clearly drives human organizational strategies and struggles, for all that the minds of prehistory, of Ur, and of our modern times are all the same. In the past, evolution of society was largely shaped by the ability to communicate over distances and by the size of the population. In the future it will be shaped to a far greater extent by the way in which intelligences think and feel, and the way in which their minds depart from the present standard for human nature. We struggle to model human action in the broadest sense of economic studies, and I suspect that this will be true for any society of minds, no matter how capable they are. The complexity of the group always exceeds the capabilities of any individual or research effort within that group. We can do little more than point out incentives and suggest trends that are likely to emerge from those incentives.

Nonetheless, the transition to what comes after humanity will come to pass, at some pace. Not as rapidly as some would like, in part because organizational matters will continue to happen slowly until minds are enhanced. Yet those of us who are young enough or fortunate enough to see the transition from end to end, perhaps with the aid of the first functional anti-aging therapeutics, will have the opportunity to become entities so capable, different, and vast in comparison to present humans that our ancestors would have called them gods or spirits. It will happen gradually, step by step, each such step forward a sensible choice to participate in an enhancement that brings benefits or a desired change, but in the end the sum of it will indeed be an apotheosis. Humans will become what they desire to become, leaving humanity as we presently understand it far behind. The present human condition is a seed, a childhood, and it will just as inevitably come to an end as we grow to reach our true potential.

The eyes of the world are by no means as closed to this future as was the case even a few short decades ago, when transhumanism was a niche vision. Posthumanity has been explored in fiction, discussion, and research far more extensively. Yet most people live in the here and the now, and act as though next year will be same as this year. It is a strange state of mind given that we are so evidently alive in a time of rapid change. Most of us have passed through the development of personal computing, the internet, and pervasive telecommunications, and have personal points of comparison for the enormous changes to habit and capabilities that have taken place. Equally, most of us squabble over politics, the blues and the greens again, save for retirement, and otherwise in thought and deed anticipate a life that has the same trajectory and span as that of our grandparents. Becoming gods is not on the agenda, not in the plan. It is still inevitable, however. Few will turn down longer lives, perfect memory, immunity to disease, the ability to run multiple streams of consciousness, and much more, when those capabilities exist. Scientists will build the basis for each incremental advance, entrepreneurs will bring it to the masses, and people will choose to better themselves.

Perhaps it will come slowly, perhaps rapidly. But insofar as there is godhood ahead, most will stumble into it without that ever being the intended goal. It is a strange thing to consider, this future of accidental deities, spawned from our largely blind society of people near entirely focused on unrelated minutiae. Does it even make much difference, we might ask, to stand with eyes open and see what is coming?

The Hedonistic Imperative, Followed to the Ends of Paradise Engineering
https://www.fightaging.org/archives/2018/07/the-hedonistic-imperative-followed-to-the-ends-of-paradise-engineering/

The two strongest urges are firstly to seek pleasure, in all its myriad forms, and secondly to evade suffering, in all its myriad forms. The primordial glass half full and glass half empty of the human condition. These are the two sides of the hedonistic imperative, and are perhaps the most important motivations guiding the development of technology. Technology, and I use the word in its broadest sense, can satisfy these urges either by helping to eliminate suffering or by helping to induce pleasure. Technology to reduce suffering has throughout history largely consisted of the vast and complex fields of medicine and agriculture. On the other side of the fence, for the induction of pleasure, we find intoxicants and pharmaceuticals of other classes, as well as, arguably, every technological development that can be turned to conquest and control. Not all pleasures are good in the moral sense, or perhaps it is better to say that given our deeper origins in an animal world that runs red in tooth and claw, many of the chemical incentives inherent to our biology are triggered only through selfish and damaging acts.

There are nonetheless many pleasures that can be attained without causing harm or resorting to advanced forms of technology. Completing challenging work, triggering the evolved response to pattern and surprise that is humor, simply being present in an attractive location, participating in the puzzle palace of human interactions, physical or otherwise, and so forth. Altering the operation of our brains to induce pleasure without the need to undertake much of that work was a fairly early innovation, however. The point of much of technological progress is to achieve better results with less effort, after all. The logical end of that line is wireheading or a life science equivalent yet to be designed: an augmentation in the brain, a button that you push, and the system causes you to feel pleasure whenever you want. There are numerous other alternatives in the same technological genre that seem plausible, such as always-on happiness, regardless of circumstances.

This sort of thing makes many people nervous, and, sadly, rarely for useful reasons. One doesn't have to look much further than the continued efforts to make mood-altering drugs illegal to see a panoply of bad motivations and perverse incentives exhibited front and center. Not every drug user becomes an addict, and self-destruction through addiction is clearly something that people do to themselves, only aided by the drug. A drug is an enabling technology, like a hammer, and neutral in and of itself. There remains considerable uncertainty today over who is more or less prone to addiction, and why, though there are plenty of addictive games against which you can test yourself in that way, such as those in which the makers gleefully exploit the effects of variable reinforcement on the human mind.

That said, I suspect that even the most self-controlled of individuals has sufficient self-doubt to be wary of the advent of implementations of wireheading that might be, say, a hundred times better, cheaper, and safer than today's most influential mood-altering drugs. What would you do in the presence of that potential option to substitute for the hedonic treadmill of work and reward? Little Heroes by Norman Spinrad is a worthy, albeit partial, fictional exploration of that question, and I recommend it. It is worth asking yourself "why not gain control of my mind in this way?" - and then follow your own answers to their logical ends. That exercise will probably reveal a great deal about how you view the world and your place in it.

Reliable, safe, on-demand pleasure (or confidence, or feelings of well-being, or happiness) achieved through technologies such as wireheading is a topic that has been comprehensively explored in fiction and philosophy, and is very slowly trickling into the real world via some forms of early, only weakly effective pharmaceutical products. There is little I can add to that library here that hasn't been said well many times over. What I will say is that to my eyes this is actually the less interesting and less consequential of the two sides of the hedonistic imperative. It is the elimination of suffering, not the gaining of pleasure, that, when taken to its conclusions, will lead to a world and a humanity changed so radically as to be near unrecognizable.

Paradise engineering is a catch-all term for the creation and large-scale use of technology to build a world that satisfies the hedonistic imperative. For me at least, pleasure on demand is a nebulous, potentially dangerous, and much less important goal when compared to the concrete list of forms of suffering that we might address, especially when given that for each of these pains and lacks we can envisage the necessary technologies and changes in some detail. The hedonic treadmill may well be inextricably tied to freedom in its purest sense: the freedom to make your own choices implies the freedom to make mistakes, and pleasure and its absence are an important part of the mental machinery by which we measure our use of time and effort. Suffering, however, is not necessary in this model. Thus I see the primary task of paradise engineers as being to take the list of suffering in some approximate order from greatest and most widespread harm to least and most localized harm, and work on solutions until such time as there is no more meaningful suffering. By this I mean solutions to the actual problems, the root cause of suffering, rather than any form of shortcut akin to wireheading or other forms of augmentation of feeling. Selectively blocking all unwanted physical pain is one response to the suffering caused by an incurable fatal degenerative disease, for example, but it isn't a good response.

It might surprise some that the greatest cause of human suffering is not the inhumanity with which all too many people treat one another, individually and collectively. Nor is it the related deficits in the organization of our societies: war, kleptocracy, repression, the enforced poverty that results when the bottom rungs of the ladder of growth are removed. The greatest cause of suffering receives the least attention. It is aging, the simple biological wear and tear of the body and the structures of the brain that support the mind. It affects everyone, and it causes drawn out pain, fear, and misery, alongside the loss of dignity, opportunity, and vigor - and ultimately the loss of the self as the mind decays. A staggering number of people are presently suffering in many ways because of aging. To the degree that we think of death as a loss and a form of suffering, then we should be prompted by the fact that aging is by far the greatest cause of death in our species.

This then, is the next goal for paradise engineering: to bring aging under medical control, and to reduce the cost of that control to the point at which everyone can live indefinitely in youthful health. It could be feasible within decades, given great enough support for the necessary research and development, as we all age for the same reasons, and identical mass therapies for billions could be produced with the greatest of economies of scale. Control of aging is not the first goal undertaken by paradise engineers, however, which is to say that paradise engineering has been taking place for some time. Many important incremental goals were achieved over the course of the past half century, for example: progress in agricultural technology sufficient to make famine impossible, save through human neglect and corruption; greater control over infectious disease; and many others.

After hunger and aging, there is still the other half of infectious disease to deal with, however. There are also the thousands of forms of internal failure of human biochemistry and biology unrelated to aging or infection. Ultimately the medical community seeks complete control over our molecular biochemistry, sufficient to eliminate all defects. At present a look to the future suggests that this goal will compete with the development of machine alternatives to biological systems, and humans will become hybrids of engineered, cultivated biology and artificial nanoscale machinery that will work with, enhance, or replace portions of our biology. Aging and disease will be banished, while malfunctions and breakages will be both far less common and cause only inconvenience when they do happen. We will have successfully defeated all of the most common sources of physical pain and dysfunction, either by remodeling the chassis of our biology, or by adding guards to protect it from harm.

Suffering is not only human, however. The natural world from which we evolved continues to be as bloody, terrible, and rife with disease as it ever was. Higher animal species are certainly just as capable of experiencing anguish and pain as are we humans, and the same is true far further down into the lower orders of life than we'd like to think is the case. We ourselves are responsible for inflicting great suffering upon animals as we harvest them for protein - an industry that is now entirely unnecessary given the technologies that exist today. We do not need to farm animals to live: the engineering of agriculture has seen to that. The future of paradise engineering could, were we so minded, start very soon with an end to the farming and harvesting of animals. That would be followed by a growing control over all wild animal populations, starting with the lesser numbers of larger species, in order to provide them with same absolute control of health and aging that will emerge in human medicine. Taken to its conclusions, this also means stepping in to remove the normal course of predator-prey relationships, as well as manage population size by controlling births in the absence of aging, disease, and predation.

Removing suffering from the animal world is a project of massive scope, as where is the line drawn? At what point is a lower species determined to be a form of biological machinery without the capacity to suffer? Ants, perhaps? Even with ants as a dividing line, consider the types of technology required, and the level of effort to distribute the net of medicine and control across every living thing in every ecosystem. Or consider for a moment the level of technological intervention required to ensure a sea full of fish that do not prey upon one another, and that are all individually maintained in good health indefinitely, able to have fulfilling lives insofar as it is possible for fish. Artificial general intelligences and robust molecular manufacturing technologies, creating self-replicating machinery to live alongside and inside every living individual in a vast network of oversight and enhancement might be the least of what is required.

At some point, and especially in the control of predators, the animal world will become so very managed that we will in essence be curating a park, creating animals for the sake of creating animals, simply because they existed in the past - the conservative impulse in human nature that sees us trying to turn back any number of tides in the changing world. It seems clear that the terrible and largely hidden, ignored suffering of the animal world must be addressed, but why should we follow this path of maintaining what is? What good comes from creating limited beings for our own amusement, when that same impulse could go towards creating intelligences..

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