Fight Aging! Newsletter, March 4th 2019

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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  • Request for Startups in the Rejuvenation Biotechnology Space, 2019 Edition
  • Upregulation of Autophagy to Treat Age-Related Disease
  • Upregulation of the Ubiquitin-Proteasome System as a Potential Mode of Therapy
  • Is Somatic Mosaicism in Brain Tissue an Important Contribution to Neurodegeneration?
  • Upregulation of Autophagy to Attenuate Age-Related Declines in Muscle Regeneration
  • Exercise Performance a Better Predictor of Mortality than Chronological Age
  • Greater Activity in Middle Age Correlates with Reduced Risk of Dementia
  • Narrowing Down the Senescent Cell Populations Responsible for Osteoporosis
  • Funding Development of Rejuvenation Therapies is the Most Effective Form of Altruism
  • A Higher Epigenetic Measure of Age Correlates with Increased Breast Cancer Risk
  • A Guide to Logical Fallacies for Rejuvenation Research Advocates
  • A More Serious Trial Failure for Gensight's Allotopic Expression Implementation
  • Clever-1 Inhibition Reduces the Subversion of the Immune System Carried Out by Tumor Associated Macrophages
  • Acid Sphingomyelinase in Age-Related Blood-Brain Barrier Dysfunction
  • Aneuploidy and Cellular Senescence in Aging

Request for Startups in the Rejuvenation Biotechnology Space, 2019 Edition

I am a little late with the 2019 list of projects in rejuvenation biotechnology that I'd like to see startups tackling sometime soon. In my defense, this year I have a startup of my own to keep up with, and the first part of 2019 was a wall to wall series of conferences alternating between the US and Europe. It continues to be the case that this is a new industry of near endless potential, yet little of that potential is under active development. This is the state of affairs despite the arrival of hundreds of millions in venture funds managed by the like of Juvenescence, Life Biosciences, and so on. The research community remains packed full of low-hanging fruit, potential approaches to rejuvenation that are barely even hidden; anyone with a modest knowledge of the field knows where they are. Anyone without that modest knowledge can find out easily enough - just send an email to Aubrey de Grey and the rest of the SENS Research Foundation crowd and ask for introductions. There has never been a better time to start a company focused on one or more aspects of rejuvenation biotechnology.

No More New Senolytics for a Little While

I know that many of you out there have the Best Idea Ever when it comes to ways to destroy senescent cells - but I think it best for everyone to sit back and let the existing set of senolytic therapies work their way closer to the clinic first. New senolytic companies are now competing with a dozen different approaches that are several years further along in their process of development. It is true that the world is a very large place, containing a great many old people who would benefit from senolytics, and there is plenty of room for a dozen competing ways to remove senescent cells as a part of a large medical ecosystem of rejuvenation. That said, there is the very real threat that failures on the part of any of the leading companies in this space will throw a pall over the funding environment. Start a senolytics company now, and you are at the mercy of Unity Biotechnology's trial results. This isn't fair, and Unity's programs are no reflection on the other, largely better approaches to clearance of senescent cells, but this is the way the world works. If Unity stumbles, investors will become nervous.

Deliver Existing Low Cost Senolytics to the Aged Masses

The most noteworthy point in all of the past five years of senolytic development is that the first compounds used as proof of principle in animal and human studies are actually pretty good at their job. They are also cheap and easily available. The dasatinib and quercetin combination, fisetin, and piperlongumine all have quite compelling animal data to support their senolytic effects, and all are very cheap. Why then are tens of millions of people in the US alone still suffering from arthritis and other inflammatory age-related conditions that have senescent cell accumulation as a significant cause? Why is it that no-one has yet stepped up to start a logistics company to improve all these lives considerably with one dose of senolytics that would cost something like 50-100 to manufacture and deliver at scale, and could be sold for twice that? This is a rare confluence of profit and public service.

Tailored Biological Age Assessment

Epigenetic clocks to assess biological age rather than chronological age are great in the abstract - except that no-one knows exactly what they measure, and thus they are useless at the present time for assessing the outcome of specific approaches to rejuvenation, such as senolytics. The technology is now far enough along that it is in principle possible to build a company based on supplying suitably tailored biological age assessment approaches that can be used to assess the results of a senolytic therapy, or other meaningful approach to aging. It is my belief that measures of biological age must be developed hand in hand with the therapies as they emerge, and only then can they be made useful. This is work that is presently not being accomplished in the for-profit marketplace, and thus here is opportunity.

A Competitor for Revel Pharmaceuticals in Glucosepane Cross-link Breaking

Revel Pharmaceuticals is the only company working on glucosepane cross-link breaking, emerging from the only lab that is working in a significant way on glucosepane cross-link breaking. These cross-links are a significant cause of loss of skin elasticity and loss of blood vessel elasticity. A success here will be as big as senolytics. I've spoken to more than one researcher who is either interested in this area, or has worked on this area, and would take funding to move ahead with their approach to the problem. So where are the competitors for Revel? This will be the next big thing in true rejuvenation therapies, I predict.

A Platform for Bacterial Enzyme Discovery to Break Down Metabolic Waste Targets

While I'm issuing predictions, here is another: the process of screening bacterial species from soil and seawater samples to find useful enzymes will prove to be far more cost effective than the present, or even machine-learning-enhanced, small molecule drug development process when it comes to establishing ways to break down harmful molecular waste in the human body. This is particularly true given the major advances in culturing bacterial species achieved in the past few years. So far as I know, no-one has started a company specifically to develop this approach as a platform for the many, many potential rejuvenation therapies that could result. There are a score of amyloids, numerous oxidized lipids, and countless components of lipofuscin to deal with just as a starting point. Companies such as LysoClear and Revel Pharmaceuticals found their lead compounds via mining the bacterial world, but have not made their process into a platform; the next generation of companies in this space should.

Make a Start on Interdiction of Telomere Lengthening as a Universal Cancer Therapy

Work in the laboratory to block lengthening of telomeres by telomerase is quite advanced - either close or ready to make the leap to a startup company. Someone should get out there, license one of these approaches, and get started on the process of bringing it to the clinic. The truly effective cancer therapies of the near future, those that will supplant immunotherapy because they are cheaper, more general, and more effective, will be based on suppression of telomere lengthening. All cancers must lengthen their telomeres, no cancer can avoid doing so, and if it is blocked, the cancer will wither. Any cancer, no matter what type, could be defeated by this single form of therapy, once implemented.

The Three Pillars of Immune System Rejuvenation

There are three vital initial components to the rejuvenation of the immune system, and this is a sufficiently important goal that there should be far more than the small number of companies presently working in this space. Firstly, the aged thymus must be regenerated in size and function; more competitors and more competing approaches than those of Repair Biotechnologies, Intervene Immune, and Lygenesis would be welcome. Secondly, a way to clear out and replace the damaged and malfunctioning cells of the aged peripheral immune system that does not involve the harsh, high-risk approaches of hematopoietic stem cell transplant and high dose chemotherapy. A kinder, more gentle targeted cell killing strategy that can be used in older, frail individuals is needed. Thirdly, the industry needs a way to introduce a new, functional, youthful hematopoietic stem cell population that, again, is kinder and more gentle than present transplant procedures, and can thus be used with older patients. Success in any one of these three will produce sizable gains, enough to help usher in the other two.

A Cell Therapy Platform to Reliably Deliver and Engraft New Stem Cell Populations

Stem cell decline is a major feature of aging. Existing stem cell therapies do little to nothing to address this issue. Aged stem cell populations must be supplemented or replaced with new, youthful stem cells. The surrounding niche and signaling must be adjusted to prevent the new cells from lapsing into inactivity. Platforms are needed that allow these goals to be achieved for arbitrary stem cell populations, or even just a majority of the most important stem cell populations. This is a path to delivering major gains in late life health and function.

An 80/20 Solution for Robust Gene Therapy

The community needs a gene therapy platform that works most of the time and for most tissues with minimal alteration, provides a high degree of cell coverage, and a high degree of configurable targeting by cell or tissue type. Perhaps this can be built atop the leading viral vector type, AAV, or perhaps it will emerge from some of the programmable gene therapy approaches, such as that of Oisin Biotechnologies. Regardless, it is very much needed. There is so much that could accomplished right now, today, it if wasn't necessary to build every new gene therapy completely from scratch, with years of work going into ways to obtain sufficient cell coverage, and to bypass the biggest obstacles, such as the patient's immune system. In the future, gene therapy will largely replace small molecule drugs for most uses - but that requires a great increase in the efficiency of development. The first 80/20 platforms that are good enough for most uses will drive the creation of an enormous amount of value.

Fix the Problems with Medical Tourism

Enhancement therapies, such as rejuvenation therapies, will be used by a hundred times as many people as presently undergo medical procedures. There are far more individuals who want to be enhanced than who have a medical condition and are at the point of needing treatment in the present system. The nature of the medical tourism industry will change dramatically given the much larger population of potential customers that will exist in a world of many novel enhancement therapies. There is an enormous opportunity here to solve the scattered, fraud-ridden nature of the existing marketplace, and to realize the full potential of regulatory arbitrage in responsibly bringing new therapies into trials and the clinic. Many companies present opt to take therapies into their first human trials in Australia because the cost is half or less of running through the standard process in the US or Europe. There is no reason why, in other jurisdictions, the cost couldn't be a tenth of that in the US and Europe, and a therapy deployed to the clinic entirely via medical tourism. That sort of competition is the only way to reduce the weight of the ball and chain of regulatory waste that holds back progress.

Methods of Outright Mitochondrial Repair

Loss of mitochondrial function occupies a central position in the declines of aging, implicated as a contributing cause of many age-related conditions. While mitochondrially targeted antioxidants that make the situation incrementally better are a going concern, with several products in the marketplace, much better approaches will be needed to deal with the issue of mitochondrial damage and decline with age. An implementation of the MitoSENS strategy of allotopic expression as a backup source of vital mitochondrial proteins, carried out for at least most mitochondrial genes, for example. Barring that, delivery of replacement mitochondria into tissues, perhaps engineered to be resistant to the signaling and damage that causes a general malaise in mitochondrial function and quality control. Or ways to robustly and completely restore the normal, youthful processes of mitophagy and mitochondrial fission in old tissues. This is a big problem and ambitious solutions are needed.

Upregulation of Autophagy to Treat Age-Related Disease

Regulation of autophagy has been a tremendously popular topic in the aging research community over the past twenty years, so much so that it is very surprising that little progress towards clinical therapies has been made. Search PubMed for autophagy and aging and you'll find a deluge of papers over this time frame, many of which express optimism on the topic of finding ways to upregulate autophagy to improve health and slow the aging process. It is the consensus in the research community that autophagy declines with age, and that there are benefits to be realized through increased autophagy. This may allow many age-related conditions to be treated, slowed, or postponed. All of this is taken as self-evident from the voluminous evidence accumulated to date.

What is autophagy? It is a collection of maintenance processes responsible for recycling broken or otherwise unwanted cellular structures and proteins. In the case of chaperone-mediated autophagy, target proteins are guided by a chaperone protein and imported into a lysosome for disassembly. For macroautophagy, an autophagosome membrane forms around the target structure, moves to a lysosome, and fuses with it. In microautophagy, a lysosome directly engulfs the target without assistance. In all cases, a lysosome is the final destination, a membrane packed with enzymes capable of taking apart near everything it will encounter inside a cell. The component parts are then released for reuse.

Many of the methods shown to slow aging and extend life span in short-lived laboratory species involve upregulation of autophagy. Calorie restriction is the canonical example, but increased autophagy is a common response to many forms of stress. Greater autophagy helps cells to survive, it reduces levels of cellular damage, it improves function. Brief stress can leads to lasting autophagy, and thus intermittent stresses tend to improve health and lengthen life - the process known as hormesis. That said, short-lived animals have much greater plasticity of life span than is the case for long-lived species such as our own. While calorie restriction, which arguably largely acts through autophagy, clearly improves human health significantly, we don't gain anywhere near the life extension observed in mice.

When are we going to see drugs that enhance autophagy? Calorie restriction mimetics such as mTOR inhibitors and the like work to some degree through upregulated autophagy. More rationally designed (rather than discovered) drugs aimed directly at the controlling mechanisms of autophagy are thin on the ground, however. If I'd been asked ten years ago how soon I thought that autophagy-targeted drugs of that sort would arrive on the scene, I'd have said imminently. Clearly I was wrong. The state of the research community on this topic looks exactly the same today as it did a decade ago, and no targeted autophagy enhancers are yet in evidence. About the only observable difference is that there might be one or two more companies working in this space, such as Selphagy Therapeutics, and a little more funding for those companies. I'd nonetheless throw up my hands and say I have absolutely no idea as to when targeting autophagy will become a going concern in the clinic.

Targeting Autophagy to Overcome Human Diseases

Autophagy is an evolutionarily conserved cellular process, through which damaged organelles and superfluous proteins are degraded, for maintaining the correct cellular balance during stress insult. It involves formation of double-membrane vesicles, named autophagosomes, that capture cytosolic cargo and deliver it to lysosomes, where the breakdown products are recycled back to cytoplasm. Dysregulation of autophagy can induce various disease manifestations, such as inflammation, aging, metabolic diseases, neurodegenerative disorders, and cancer. The understanding of the molecular mechanism that regulates the different phases of the autophagic process and the role in the development of diseases are only in an early stage. There are still questions that must be answered concerning the functions of the autophagy-related proteins.

Autophagy, Inflammation and Aging

Autophagy has been identified as main regulator of the inflammasome; a major innate immune pathway activated by exogenous stimuli, such as pathogenic microorganisms, or by endogenous mediators, such as reactive oxygen species (ROS), mitochondrial damage, and environmental irritants. Inflammasome activation involves formation and oligomerization of a protein complex, followed by release of proinflammatory cytokines, such as IL-1β and IL-18, from innate immune cells. In particular, when endogenous mediators induce massive inflammatory response, they can cause tissue damage and promote the onset of inflammatory diseases. Therefore, negative or positive regulation of inflammasome is essential to ensuring a good state of health.

As demonstrated by multiple studies, autophagy can negatively regulate inflammasome activation through different mechanisms, including by removing damaged organelles such as mitochondria, leading to reduced release of ROS and subsequent suppression of inflammasome activation. Autophagy deficiency causes inflammasome-related inflammatory diseases. Overall, data suggests that inflammasome and autophagy mutually regulate each other, favoring the balance between inflammatory response to defend itself from the host and prevention of excessive inflammatory response that can induce tissue damage and inflammatory disease. Recent studies have shown that the impaired autophagy activity that characterizes aging is due to accumulation of dysfunctional mitochondria, ROS, and NLRP3 inflammasome activation in macrophages. These factors predispose the cells to greater risk towards aging diseases, such as atherosclerosis and type 2 diabetes.

Autophagy and Neurodegenerative Disorders

The aggregation of misfolded proteins and some neuronal population losses are typical of the expression of pathological neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Autophagy has been reported to be involved in the occurrence of neurodegenerative disorders, being the main intracellular system for degrading damaged organelles and aggregated proteins. In neurodegenerative diseases, an alteration of the maturation mechanism of the autophagosome in the autophagolysosome has been found.

Moreover, autophagy plays an important role in the degradation of different proteins correlated with degenerative diseases, such as mutated α-synuclein in Parkinson's disease, mutant huntingtin in Huntington's disease, and the mutant TPD-43 in amyotrophic lateral sclerosis. In Alzheimer's disease, the presence of extracellular amyloid-β plaques and intracellular neurofibrillary tangles, composed of hyperphosphorylated tau proteins aggregates, has been revealed. In the healthy brain, the autophagosome vesicles are not very visible; instead, in the Alzheimer's disease brain, numerous autophagosomes are noticeable. Accumulation of autophagy vacuoles arises from impaired clearance rather than autophagy induction, suggesting the late stages of autophagy modulation as a possible therapeutic strategy for Alzheimer's disease.

The role of autophagy in Parkinson's disease has been demonstrated by the presence in neurons of lysosomal and autophagosomes alterations; to support this evidence, when the lysosome is functionally altered, the amount of α-synuclein is elevated, indicating an alteration of the autophagy pathway. TFEB has been identified as the factor that positively regulates genes related to formation of autophagosomes and the lysosome fusion, increasing the clearance of lysosomal exocytosis. Recently, it has been shown that its overexpression can reduce the lysosome damage and thus improve the neurological disorders related with α-synuclein.

Upregulation of the Ubiquitin-Proteasome System as a Potential Mode of Therapy

There are numerous cellular maintenance processes responsible for breaking down various component parts of the cell, proteins, and forms of metabolic waste. Autophagy, for example. Another is the ubiquitin-proteasome system. Broken or excess proteins are tagged with a ubiquitin molecule, which ensures they are broken up for raw materials by a proteasome. Proteasomes come in a variety of flavors, and all are very complex multi-protein structures. Like other forms of cellular maintenance, the pace at which the ubiquitin-proteasome system operates is regulated and responds to environmental cues such as lack of nutrients resulting from calorie restriction or the oxidative stress that results from mitochondrial activity during exercise.

Greater cellular maintenance leads to better cell function, a reduction in downstream damage caused by the presence of damaged proteins. Analogous to the search for ways to upregulate autophagy, factions within the research community have looked for ways to artificially boost the activity of proteasomes. Research programs tend to start by using exercise or calorie restriction to help understand how exactly the ubiquitin-proteasome system functions, and how proteasomal activity is regulated, and then proceed to find ways to intervene at the point of regulation. The research materials here are a snapshot of one such development program.

As is the case for upregulation of autophagy, we should expect upregulation of proteasomal activity to produce only modest benefits in humans. This is only one among many mechanisms by which exercise or calorie restriction produces benefits to health and longevity, and we know the scope of those interventions. While the health benefits in humans are certainly worth it when the treatment is free, it is arguably the case that we shouldn't be investing billions into this class of therapeutic development. We should prefer programs with a much greater potential benefit, those capable of rejuvenation rather than just a modest slowing of aging.

Exercise, fasting help cells shed defective proteins

Malfunctions in the cells' protein-disposal machinery can lead to the accumulation of misfolded proteins, which clog up the cell, interfere with its functions, and, over time, precipitate the development of diseases, including neurodegenerative conditions such as amyotrophic lateral sclerosis and Alzheimer's. The best-studied biochemical system used by cells to remove junk proteins is the ubiquitin-proteasome pathway. It involves tagging defective or unneeded proteins with ubiquitin molecules marking them for destruction by the cell's protein-disposal unit, known as 26S proteasome.

Past research has shown that this machinery can be activated by pharmacological agents that boost the levels of a molecule known as cAMP, the chemical trigger that initiates the cascade leading to protein degradation inside cells, which in turn switches on the enzyme protein kinase A. The lab's previous research found that cAMP-stimulating drugs enhanced the destruction of defective or toxic proteins, particularly mutant proteins that can lead to neurodegenerative conditions. The new findings, however, reveal that shifts in physiological states and corresponding changes in hormones can regulate this quality-control process independent of drugs.

The researchers analyzed the effects of exercise on cells obtained from the thigh muscles of four human volunteers before and after vigorous biking. Following exercise, the proteasomes of these cells showed dramatically more molecular marks of enhanced protein degradation, including greater levels of cAMP. The same changes were observed in the muscles of anesthetized rats whose hind legs were stimulated to contract repeatedly. Fasting - even for brief periods - produced a similar effect on the cells' protein-breakdown machinery. Fasting increased proteasome activity in the muscle and liver cells of mice deprived of food for 12 hours, the equivalent of an overnight fast.

Exposure to the fight-or-flight hormone epinephrine produced a similar effect. Epinephrine, also known as adrenaline, is responsible for stimulating the liver and muscle to mobilize energy reserves to boost heart rate and muscle strength during periods of physiologic stress. Liver cells treated with epinephrine showed marked increases in cAMP, as well as enhanced 26S proteasome activity and protein degradation. Taken together, these findings demonstrate that the rate of protein degradation can rise and fall swiftly in a variety of tissues in response to shifting conditions, and that such changes are mediated by fluctuations in hormone levels.

26S Proteasomes are rapidly activated by diverse hormones and physiological states that raise cAMP and cause Rpn6 phosphorylation

Most studies of proteolysis by the ubiquitin-proteasome pathway have focused on the regulation by ubiquitination. However, we showed that pharmacological agents that raise cAMP and activate protein kinase A by phosphorylating a proteasome subunit enhance proteasome activity and the cell's capacity to selectively degrade misfolded and regulatory proteins. We investigated whether similar adaptations occur in physiological conditions where cAMP rises. Proteasome activity increases by this mechanism in human muscles following intense exercise, in mouse muscles and liver after a brief fast, in hepatocytes after epinephrine or glucagon, and renal collecting duct cells within 5 minutes of antidiuretic hormone. Thus, hormones and conditions that raise cAMP rapidly enhance proteasome activity and the cells' capacity to eliminate damaged and preexistent regulatory proteins.

Is Somatic Mosaicism in Brain Tissue an Important Contribution to Neurodegeneration?

Somatic mosicism is a description of the pattern of different collections of mutations throughout the cells of a tissue. The vast majority of any given tissue is made up of somatic cells. These cells are limited in the number of times they can divide; initially created with long telomeres, they lose a little of their telomere length with each cell division. With short enough telomeres, the Hayflick limit is reached and cells become senescent and destroy themselves, or are destroyed by the immune system. New somatic cells with long telomeres, to replace the losses, are provided by the activity of much smaller populations of stem cells or progenitor cells. Thus any given tissue is in a state of turnover, though at a very different pace. The central nervous system has very little turnover, and many cells last a lifetime. The lining of the intestine turns over in a matter of days.

Mutations accumulate in cells constantly, but the vast majority are apparently harmless, at least over the timescale of the present human life span. Even if a mutation is problematic for cell function, and provided that it does not promotes cancerous behavior, then just how much damage can it do? When somatic cells become mutated in non-cancerous ways, that mutation will not spread far, since such cells are limited in the number of times they can divide. When stem cells or progenitor cells become mutated, however, there is the potential for mutations to become widely dispersed throughout a tissue. This is particularly true for the mutations that occur during embryonic development or in childhood. Those seem likely to be more influential in the brain, as only during development is there significant deployment of new cells.

There is an ongoing debate over the degree to which non-cancerous mutations to nuclear DNA contribute to degenerative aging. The expansion of mutations, via the processes noted above, to form somatic mosaicism is an important part of that debate, as illustrated by today's research materials. This is novel in the research I've seen on this topic, in that the absence of mosaicism is the interesting point. Younger people have more mosaicism in the brain than older people, at least in the few samples examined here. That suggests that cells with mutations are dying off on the way to old age, which in turn suggests a contribution to the processes of age-related neurodegeneration.

So far, however, I would say that there is no good evidence for raised rates of non-cancerous mutation to do all that much in animal studies, which suggests that perhaps this sort of molecular damage isn't as important as the other various forms of cell and tissue damage outlined in the SENS rejuvenation research proposals. Clearly at some point one must reach a harmful threshold of cellular dysfunction due to mutational damage, but the individuals of any given mammalian species may or may not be close to that point in later life. The presence of all of the other damage and dysfunction of aging obscures this specific contribution, and no-one has yet come up with a truly compelling, definitive way to isolate just non-cancerous mutational damage to nuclear DNA in a study.

Discovery May Explain a Great Mystery of Alzheimer's, Parkinson's

Scientists have identified a potential explanation for the mysterious death of specific brain cells seen in Alzheimer's, Parkinson's, and other neurodegenerative diseases. The new research suggests that the cells may die because of naturally occurring gene variation in brain cells that were, until recently, assumed to be genetically identical. This variation - called "somatic mosaicism" - could explain why neurons in the temporal lobe are the first to die in Alzheimer's, for example, and why dopaminergic neurons are the first to die in Parkinson's.

The finding emerged unexpectedly from investigations into schizophrenia. It was in that context that researchers first discovered the unexpected variation in the genetic makeup of individual brain cells. That discovery may help explain not just schizophrenia but depression, bipolar disorder, autism and other conditions. Researchers expected that this mosaicism would increase with age - that mutations would accumulate over time. What they found is exactly the opposite: younger people had the most mosaicism and older people had the least. Based on the finding, researchers believe that the neurons with significant genetic variation, known as CNV neurons, may be the most vulnerable to dying. And that could explain the idiosyncratic death of specific neurons in different neurodegenerative diseases. People with the most CNV neurons in the temporal lobe, for example, might be likely to develop Alzheimer's.

Neurons with Complex Karyotypes Are Rare in Aged Human Neocortex

Neocortical neurons are among the most diverse and longest-lived mammalian cells. Every human neocortical neuron may contain private somatic variants. Single nucleotide variants (SNVs) are especially common, with hundreds per neuron reported, and with frequencies of more than 3,000 SNVs per neuron observed in aged individuals. Endogenous mobile elements such as retrotransposons are also active during brain development. Mobile element activity has been linked to the generation of copy-number variants (CNVs). By contrast to other somatic variants, large CNVs almost always affect multiple genes. A reanalysis of published data herein found an average of 63 genes affected per neuronal CNV.

The most salient feature of the brain CNV atlas that we have produced is an anti-correlation between the age of an individual and the percentage of CNV neurons in the frontal cortex of that individual. By contrast, the initial assessment of CNV location finds evidence for the enrichment of a subset of long genes and neurally associated gene ontology categories only in aged brains. Given the enrichment of these CNVs in aged, not young, neurons, CNVs affecting some genomic loci may be more compatible with neural survival than others. We found similar rates of CNV non-neurons at different ages; however, it will be interesting to determine whether other long-lived cells (e.g., cardiomyocytes) show a similar change in mosaic composition during aging.

We provide evidence that a functional consequence of CNV neurons may be selective vulnerability to aging-related cell death. Age-related cognitive decline is associated with notable decreases in cerebral cortical thickness, myelination, and synapse number accompanied by ex vacuo enlargement in ventricular volume. Although neuronal cell death is generally considered to be minimal in the healthy mature brain, rates of ∼10% cerebral cortical neuron loss during adulthood are consistent with stereological counts in neurotypical individuals. The decline in CNV neuron prevalence that we observe between individuals younger than 30 years old and individuals older than 70 years old is also strikingly consistent with selective CNV neuron loss during a person's adult lifetime. We conclude that the most parsimonious interpretation of these data is that many, but not all, CNV neurons are selectively vulnerable to aging-associated atrophy.

Upregulation of Autophagy to Attenuate Age-Related Declines in Muscle Regeneration

As a companion piece to another recently published open access paper, noted earlier this week, today's review paper considers the therapeutic upregulation of autophagy as a possible approach to reduce the deleterious impact of aging on muscle regeneration. Autophagy is the name given to a collection of cellular housekeeping processes responsible for ensuring that excess and broken cellular components are transported to a lysosome for recycling. Lysosomes are membrane-bound vesicles packed with enzymes capable of breaking down near all structures and molecular waste they are likely to encounter. The remnant molecules are released back into the broader cell as raw materials.

Autophagy is known to decline with age. Many of the approaches shown to slow aging in short-lived laboratory species either involve increased autophagy, or, as is the case for calorie restriction, appear to depend on increased autophagy for the beneficial effects on health and life span. Increased autophagy is a feature of many forms of cellular stress response: heat, cold, lack of nutrients, oxidative damage, and so forth. Mild or short-lived stress or damage can provoke a reaction that lasts for a while and produces an overall gain in cell function. Since autophagy removes damaged components, it limits the opportunity for damage to spread and produce downstream effects. When that is happening in every cell in the body on a regular basis, the result is a longer life span.

Unfortunately, what we know of the effects of calorie restriction in mice and humans tells us that stress responses such as upregulated autophagy have a much larger effect on life span in short-lived species than they do in long-lived species such as our own. Calorie restriction can increase maximum mouse life span by 40%. In humans an effect size of more than five years would be surprising, given that any reliable gain much larger than that would have been discovered in antiquity and very well explored by now. Which is not to say that calorie restriction is worthless: it produces a larger reliable gain in long term health - for basically healthy people - than any readily available, well understood medical technology. Given the advent of senolytics as a rejuvenation therapy, that statement probably won't remain true for very much longer, but it is worth considering.

Autophagy as a Therapeutic Target to Enhance Aged Muscle Regeneration

Skeletal muscle has remarkable regenerative capacity, relying on precise coordination between resident muscle stem cells (satellite cells) and the immune system. The age-related decline in skeletal muscle regenerative capacity contributes to the onset of sarcopenia, prolonged hospitalization, and loss of autonomy. Although several age-sensitive pathways have been identified, further investigation is needed to define targets of cellular dysfunction. Autophagy, a process of cellular catabolism, is emerging as a key regulator of muscle regeneration affecting stem cell, immune cell, and myofiber function.

The pharmacological induction of autophagy represents a promising strategy to improve stress resistance and regeneration of skeletal muscle. Spermidine and rapamycin are two examples of drugs that have been studied for their autophagy-inducing effects and lifespan extension in rodent models. While rapamycin acts directly on mTOR, spermidine's polyamine effects on histone acetylation status upregulates various autophagy-related transcripts and suppresses necrosis. The positive benefits of spermidine in muscle tissues of mice and rats have been shown by mitigating age-related muscular atrophy as well as functional myopathies that originate from autophagy failure.

Spermidine also modulates macrophage polarization in mice towards reduced inflammation, though some evidence suggests the autophagy inducing effects of rapamycin more directly target T lymphocytes. Taken together, these agents act as "caloric restriction mimetics" to induce autophagy and contribute to improvements in lifespan of mice. Specifically, the effects of autophagy induction show promise as it related to therapies targeting muscle stem cell myogenic capacity.

Muscle stem cells and monocytes/macrophages are essential for skeletal muscle homeostasis and regeneration. A common theme among these cell populations is the idea that autophagy is a key process that is altered in aged cells leading to functional decline. Autophagy is no longer an emerging regulator of cellular function but has consistently been shown to play a central and important role, especially in the context of aging. Stem cells, in particular, show dysfunctional autophagy during initial stages of activation while caloric restriction and physical activity allow a sensitization to autophagy with beneficial outcomes in cellular activation and function. The exact role for autophagy in muscle regeneration will be complex considering the temporal nature and diverse cell types contributing to the regenerative program. However, global induction of autophagy appears beneficial to the regenerative capacity in the aged muscle. Continuing to uncover the molecular events responsible for age-related perturbations in these pathways is critical for exposing pharmaceutical targets to combat the aging process and improve tissue regeneration in aged individuals.

Exercise Performance a Better Predictor of Mortality than Chronological Age

Researchers here provide evidence to demonstrate that fairly standard exercise stress tests are better at predicting mortality in older individuals than chronological age. People age at different paces, and some portion of this variation is the secondary aging of lifestyle choices such as diet and physical activity or inactivity. The challenge with human studies of activity and aging is that they can really only provide evidence of correlation rather than causation. The animal studies are fairly compelling on causation when it comes to exercise and a lower rate of mortality in late life, however. It seems more plausible for humans to work much the same way than for there to be a major difference in the interaction between exercise and aging in humans versus other mammals.

Based on exercise stress testing performance, the researchers developed a formula to calculate how well people exercise - their "physiological age" - which they call A-BEST (Age Based on Exercise Stress Testing). The equation uses exercise capacity, how the heart responds to exercise (chronotropic competence), and how the heart rate recovers after exercise. "Telling a 45-year-old that their physiological age is 55 should be a wake-up call that they are losing years of life by being unfit. On the other hand, a 65-year-old with an A-BEST of 50 is likely to live longer than their peers."

The study included 126,356 patients referred between 1991 and 2015 for their first exercise stress test, a common examination for diagnosing heart problems. It involves walking on a treadmill, which gets progressively more difficult. During the test, exercise capacity, heart rate response to exercise, and heart rate recovery are all routinely measured. The data were used to calculate A-BEST, taking into account gender and use of medications that affect heart rate.

The average age of study participants was 53.5 years and 59% were men. More than half of patients aged 50-60 years - 55% of men and 57% of women - were physiologically younger according to A-BEST. After an average follow-up of 8.7 years, 9,929 (8%) participants had died. As expected, the individual components of A-BEST were each associated with mortality. Patients who died were ten years older than those who survived. But A-BEST was a significantly better predictor of survival than chronological age, even after adjusting for sex, smoking, body mass index, statin use, diabetes, hypertension, coronary artery disease, and end-stage kidney disease. This was true for the overall cohort and for both men and women when they were analysed separately.

Greater Activity in Middle Age Correlates with Reduced Risk of Dementia

It is well established that more physical activity correlates with reduced risk of mortality and age-related disease. The accumulated epidemiological evidence is mountainous in scope, and includes countless studies similar to the one noted here. It is hard, however, to prove causation in human studies. Are people more active because they happen to be more robustly resistant to the declines of aging for reasons entirely unrelated to physical activity, for example? In mice, yes, one can create groups at various levels of exercise and show that those who exercise to a greater degree have a longer span of healthy life (though not a longer life overall). The direction of causation can be established there, and exercise produces better health and lesser degrees of decline in aging. Health advice for humans leans heavily on the causation established in mice and other mammals. Reasonably so, I would say.

Keeping physically and mentally active in middle age may be tied to a lower risk of developing dementia decades later. The study involved 800 Swedish women with an average age of 47 who were followed for 44 years. At the beginning of the study, participants were asked about their mental and physical activities. Mental activities included intellectual activities, such as reading and writing; artistic activities, such as going to a concert or singing in a choir; manual activities, such as needlework or gardening; club activities; and religious activity.

Participants were given scores in each of the five areas based on how often they participated in mental activities, with a score of zero for no or low activity, one for moderate activity and two for high activity. For example, moderate artistic activity was defined as attending a concert, play or art exhibit during the last six months, while high artistic activity was defined as more frequent visits, playing an instrument, singing in a choir or painting. The total score possible was 10.

Participants were divided into two groups. The low group, with 44 percent of participants, had scores of zero to two and the high group, with 56 percent of participants, had scores of three to 10. For physical activity, participants were divided into two groups, active and inactive. The active group ranged from light physical activity such as walking, gardening, bowling or biking for a minimum of four hours per week to regular intense exercise such as running or swimming several times a week or engaging in competitive sports. A total of 17 percent of the participants were in the inactive group and 82 percent were in the active group.

During the study, 194 women developed dementia. Of those, 102 had Alzheimer's disease, 27 had vascular dementia, and 41 had mixed dementia, which is when more than one type of dementia is present, such as the plaques and tangles of Alzheimer's disease along with the blood vessel changes seen in vascular dementia. The study found that women with a high level of mental activities were 46 percent less likely to develop Alzheimer's disease and 34 percent less likely to develop dementia overall than the women with the low level of mental activities. The women who were physically active were 52 percent less likely to develop dementia with cerebrovascular disease and 56 percent less likely to develop mixed dementia than the women who were inactive.

Narrowing Down the Senescent Cell Populations Responsible for Osteoporosis

Given a sufficiently comprehensive method of destroying senescent cells, it doesn't much matter which populations of senescent cells contribute to which age-related diseases. None of these errant, lingering cells are wanted, and the agenda should be to get rid of them all. With the possible exception of Oisin Biotechnologies' platform, however, none of the existing approaches to senolytic therapies can kill even a majority of senescent cells in a majority of tissues. Small molecule drugs in particular tend to be tissue-specific to meaningful degrees.

In this context of imperfect and selective therapies, it is important to know the degree to which a targeted population of senescent cells is relevant to a specific age-related condition. The open access paper here is an example of this type of research, in which the authors rule out some of the possible contributing populations of senescent cells as causes of osteoporosis. It is interesting, but I feel that this sort of thing is a transitory concern, and will evaporate for all but academic interests given the advent of highly effective senolytic therapies that work in all tissues.

Soon after the attainment of peak bone mass, the balance between bone resorption and bone formation begins to progressively tilt in favor of the former, in both women and men. Age-related bone loss in mice is associated with an increase in the number of osteoclasts, the cells responsible for degrading the bone matrix. Nonetheless, a decline in bone formation is the seminal culprit of skeletal aging in both humans and rodents. A decrease in the number of osteoblasts, the cells that synthesize the bone matrix, underlies the loss of bone in aged mice. Osteoblasts differentiate from mesenchymal progenitors; the number of these osteoprogenitors declines with advancing age and this decline is associated with increased markers of cellular senescence.

Osteocytes, former osteoblasts buried in the bone matrix, are postmitotic and the most abundant cell type in bone. Osteocytes modulate bone resorption and formation. Earlier findings have elucidated that, like other postmitotic cells, osteocytes in the bone of aged female and male mice show markers of senescence. Several, but not all, senescent cell types exhibit high levels of the cyclin inhibitor p16. For example, senescent osteocytes have increased levels of p16, while senescent osteoblast progenitors have elevated levels of p21, but not p16.

Selective elimination of cells expressing p16 in mouse models increases life- and healthspan. Currently, two of such models have been described: the INK-ATTAC and the p16-3MR mice. Using the p16-3MR model, we have effectively depleted senescent cells in the skin, lungs, muscle, and bone marrow, including senescent hematopoietic and muscle stem cells, and suppressed the senescence-associated secretory phenotype (SASP) in aged mice. It has been found that elimination of p16-expressing cells in 20-month-old mice for a 4-month period, using the INK-ATTAC transgene, increases bone mass. These findings support the notion that senescent cells contribute to age-related bone loss.

However, the identity of the senescent cells that are responsible for skeletal aging remains unknown. Likewise, the extent to which elimination of p16-expressing cells rescues skeletal aging is unknown. Here, we investigated the skeletal effects of long-term ablation of senescent cells using p16-3MR mice - an alternative to the INK-ATTAC model of p16-expressing cell elimination. The key objectives of this work were two: first, to eliminate p16 senescent cells from 12 to 24 months of age, the time period during which C57BL/6 mice experience a dramatic age-related loss of bone mass, and determine whether the experimental maneuver could prevent the loss of bone. And second, to eliminate p16 senescent cells from 20 to 26 months of age in order to determine whether this intervention could restore bone mass in mice that had already lost it.

The activation of the p16-3MR transgene greatly diminished p16 levels in the brain, liver, and osteoclast progenitors from the bone marrow. The age-related increase in osteoclastogenic potential of myeloid cells was also abrogated. However, this did not alter p16 levels in osteocytes - the most abundant cell type in bone - and had no effect on the skeletal aging of p16-3MR mice. These findings indicate that the p16-3MR transgene does not eliminate senescent osteocytes but it does eliminate senescent osteoclast progenitors and senescent cells in other tissues. Elimination of senescent osteoclast progenitors, in and of itself, has no effect on the age-related loss of bone mass. Hence, other senescent cell types, such as osteocytes, must be the seminal culprits.

Funding Development of Rejuvenation Therapies is the Most Effective Form of Altruism

As our community grows, there are more of us in a position to push arguments directly into the media without having them distorted and mashed up via the average professional journalist's lack of specific knowledge and insight. The advent of earnest venture investment and numerous startup companies working on ways to treat aging means that the business press is where one might start to see more of this sort of thing. The example here is an opinion piece by Alex Zhavoronkov of small molecule infrastructure company In Silico Medicine, one of the first of the ventures emerging from our community to successfully align with major funding institutions and raise significant capital for further development of their vision. Zhavonokov presents some of the concepts that have been circulating in the broader advocacy community over the past year or so, considering the intersection of effective altruism and treating aging as a medical condition. It is an interesting topic, and one that I hope will lead to greater public support for the goal of human rejuvenation.

While there is a lot of talk about the growing income inequality and the increasing gap between the rich and the poor, the difference in overall utility one can get in this life is rapidly decreasing. The rich can get a slightly better package but the net gain in utility will be marginal. One does not fly business class to arrive earlier. The arbitrary separation of classes, ethnic groups, races, and nations is only drawing our attention away from the most important and unsolved challenge - aging. Regardless of how much money you have, you cannot live substantially longer or better. Aging does not discriminate and death comes to us all. Life does not provide a path for continuous improvement. Aging is a universal equalizer.

Effective altruism is the idea that doing good and donating money to worthy causes is really just the start. It is suggested that we use research and reason to make sure our help reaches the most people and has the most impact on their lives. One of the keys to effective altruism, therefore, is to work on the right problems. Imagine for a second that you are a character and life was a video game. How would you know if you're winning? Does your wealth really indicate whether you're good at the game, or just lucky? Can it tell you whether you're even enjoying the game? Would that score say anything about how you improved the game itself, or whether you improved the game for your fellow players?

A better way to check your score at life is a metric called QALY, or quality-adjusted life year. QALY can serve as a universal score because QALY measures both how long you live and how well you live. QALY represents a year of life lived in an optimal healthy state. QALY can also be shared and distributed. For each year that we remain healthy, our acts and our contributions - anything from giving birth to paying taxes to work on scientific advances - could raise their QALY of other people all around the world. We call this optimizing global QALY.

The traditional approach to altruism is to donate accumulated wealth to charities and worthy causes. However, a far more effective way to maximize global QALY is to stay healthy, live longer, direct your wealth intelligently and keep contributing to the world in all the other ways money can't count. So, that means the best way - in fact, the only way - to generate effective altruism and maximize global QALY is to focus on aging and longevity research.

For those of you who are driven to find the most effective way to maximize QALY on a global scale, becoming part of the growing movement to help people live longer and healthier lives is an obvious option. Personally engaging in longevity research, understanding the key concepts, and distributing the resources into longevity and aging projects that maximize global QALY may very well be the most altruistic endeavor you can embark on. The longevity biotechnology is rapidly emerging as an industry with the new funding sources, credible business models, and early successes. There are new ways to measure the rate of aging and new tools to understand the driving mechanisms behind the many debilitating processes will soon emerge as more experimental data becomes available.

A Higher Epigenetic Measure of Age Correlates with Increased Breast Cancer Risk

Epigenetic clocks use patterns of DNA methylation that correlate with age. Numerous studies have shown that people with epigenetic age higher than chronological age have a raised risk of disease. This works the other way as well; patient populations with a range of age-related diseases tend to have higher epigenetic age measures than their healthier peers of the same chronological age. The study noted here is the most recent in a growing body of evidence to suggest that epigenetic clocks measure something potentially useful about aging.

What exactly it is about aging that epigenetic clocks measure is still an open question, however. The patterns of DNA methylation were discovered by analysis of epigenetic data by age, not built from an understanding of the underlying processes. It is quite possible that they reflect only a fraction of the important processes in aging, which is fine when aging proceeds in a unified way, all processes roughly aligned with one another, but the utility of such clocks will end when it becomes possible to address any one specific process of aging via rejuvenation therapies. Take clearance of senescent cells, for example: at this point no-one has the first idea as to what that will do to epigenetic clock measures, and until data is established the clocks aren't all that helpful for developers working on senolytic therapies to selectively destroy senescent cells.

Scientists speculate that biologic age may be tied to environmental exposures. If so, it may be a useful indicator of disease risk. They used three different measures, called epigenetic clocks, to estimate biologic age. These clocks measure methylation found at specific locations in DNA. Researchers use these clocks to estimate biologic age, which can then be compared to chronologic age. The researchers used DNA from blood samples provided by women enrolled in the Sister Study, a group of more than 50,000 women in the U.S. and Puerto Rico. The study was specifically designed to identify environmental and genetic risk factors for breast cancer. The research team measured methylation in a subset of 2,764 women, all of whom were cancer-free at the time of blood collection.

"We found that if your biologic age is older than your chronologic age, your breast cancer risk is increased. The converse was also true. If your biologic age is younger than your chronologic age, you may have decreased risk of developing breast cancer. However, we don't yet know how exposures and lifestyle factors may affect biologic age or whether this process can be reversed. If you look at a group of people who are all the same age, some may be perfectly healthy while others are not. That variability in health may be better captured by biologic age than chronologic age."

A Guide to Logical Fallacies for Rejuvenation Research Advocates

The world has not yet rallied to the cause of defeating aging. Aging remains by far the greatest cause of suffering, pain, and death in this world, and yet it is accepted as set in stone by the vast majority of people. Few think of doing something about it. Little funding goes towards the research and development programs that could plausibly bring aging under medical control, indefinitely extending healthy life spans. Humanity spends more on sports stadiums than it does on addressing the impending death and drawn out, painful decline of everyone presently alive.

All of this is why, even as our community grows and we achieve success in spurring the start of a rejuvenation biotechnology industry, we must continue to aggressively advocate for the cause of rejuvenation research. It is why it is important to stand up and speak out, to argue in public, to make presentations and educate those who do not yet know that aging could be ended, if only sufficient resources were dedicated to that goal. Tools to aid in that work of advocacy and persuasion are always greatly appreciated - such as this long list of logical fallacies with specific examples for our field.

Alleged certainty: this fallacy consists of concluding something is true because "everybody knows" it is. "Everybody knows" that there are too many people on this planet and therefore rejuvenation is a bad idea; "everybody knows" that life-saving treatments, such as rejuvenation, will always be only for the rich; and so on. Whether or not everybody actually knows these things doesn't matter; what does matter is the evidence used to back them up. For example, overpopulation is not at all a black-and-white issue; whether we're overpopulated depends on the metrics that are taken into account. The best way to counter this fallacy may be simply asking for evidence and pointing out that simply claiming that everyone knows something isn't sufficient proof, especially if the topic is not at all uncontroversial.

Appeal to anger: this fallacy attempts to justify an argument based solely on negative emotions. In the context of life extension, this fallacy is rarely committed alone; it usually hinges on other fallacies or weak arguments that are used as premises. For example, someone might be outraged that you worry about life extension when, allegedly, there are much worse problems than aging in the world, and he might use the supposed outrageousness of life extension to gloss over the fact that aging is a problem, whether or not worse problems than it exist. If someone commits this fallacy, you should kindly point out that the way he feels about a statement or an idea is not what makes it true or false. Whether we're outraged by something doesn't mean that we can discount it.

Appeal to authority: the infamous appeal to authority involves believing a claim solely because the person who made it is in a position of authority or prestige. When discussing rejuvenation, the appeal to authority fallacy is sometimes observed when people say that rejuvenation isn't possible or that some possible negative consequences of it are certain because an expert said so. The expert in question might well be right, but in order to establish it, his evidence must be examined to make sure that he isn't genuinely mistaken or doesn't have some other reason to make an unsubstantiated claim. Explain that everyone can make a mistake, no matter how smart, authoritative, or knowledgeable he may be. You don't take for granted what Albert Einstein said because he was one of the greatest physicists of all time; his claims, too, need proof, and until said proof is presented and verified, you can't say whether the claim is true or false.

Appeal to motive: this fallacy consists of dismissing an idea on the grounds of the motives of its proponent. A typical life extension-related example is that of patient-funded clinical trials. At such an early stage, experimental rejuvenation therapies are indeed expensive, and governments may not be willing to pay for what seems like a moon shot. Thus, wealthy people willing to pay to try the therapies are effectively making it easier to test them. Some people may argue that wealthy people are doing this not to help the research but for their own benefit; consequently, they feel outraged and despise the idea of patient-funded trials entirely, deeming it nothing but proof that rejuvenation is only for the rich. Explain that anyone's motives for endorsing an idea are irrelevant when assessing whether the idea is good or not. It may help if you explain that you too disagree with the motives of people who push life extension only for their own interest but that life extension is a worthy goal per se.

Appeal to nature: the appeal to nature fallacy consists of implying that everything that is natural is better than everything that is not natural. In the context of life extension, you can expect to encounter this fallacy as the most classical of objections, the one and only "but aging is natural, while rejuvenation is not!" This fallacy is why people infer that aging is better or more desirable than using rejuvenative therapies to avoid it-which is not unlike saying that having cancer is better than using immunotherapy to cure it. The appeal to nature fallacy is easily countered with examples of undesirable yet perfectly natural things that we suffer from and desirable yet unnatural things that we use every day. Depending on how entrenched someone is, you can expect that person to resort to a double standard right after - "yes, but with aging, it's different." It is not. The bottom line is that naturalness is not a sufficient criterion to judge whether or not is something is good or desirable, regardless of what that thing may be.

A More Serious Trial Failure for Gensight's Allotopic Expression Implementation

Gensight Biologics uses allotopic expression of a mitochondrial gene, ND4, to attempt to treat the inherited blindness condition Leber hereditary optic neuropathy, in which this gene is mutated and dysfunctional. An altered copy of ND4 is introduced into the cell nucleus, and the protein produced is delivered back to the mitochondria where it is needed for correct function. A fairly standard gene therapy is used to deliver this payload into the retina. Unfortunately, after promising results from earlier trials and technology demonstrations, their late stage trials are failing.

It remains to be seen as to why this is the case. Earlier work makes it clear that the technology works in principle. It is possible that intervening too late cannot clear out enough of the damage already done, and that damage makes further decline inevitable, or recovery difficulty. This is a systemic problem for many conditions, given the way in which the structure and enormous cost of clinical trial regulation pushes companies towards the late stage of the disease, rather than earlier, preventative treatment. Equally, it may be that this formulation of the allotopic expression gene therapy isn't achieving a great enough coverage of retinal cells to produce reliable benefits. There are many possible reasons for failure.

A phase 3 trial of GenSight Biologics' Leber hereditary optic neuropathy (LHON) gene therapy has missed its primary endpoint. The AAV gene therapy was no better than placebo at improving vision at 48 weeks, leading GenSight to look to future updates to salvage the study. GenSight designed GS010 to improve the vision of patients with a particular mutation in the mitochondrial ND4 gene and moved the gene therapy into a pair of phase 3 trials in 2016. One trial enrolled patients who had suffered vision loss for 6 to 12 months. The other recruited people whose vision loss began less than six months ago. Both trials missed their primary endpoints.

The latest clinical setback involves LHON patients with six months or less of vision loss enrolled in the RESCUE trial. As in the other study, GenSight set out to link GS010 to a 15-letter improvement over placebo on a vision test. Each subject received GS010 in one eye and a sham injection in the other. This time around, the eyes treated with GS010 deteriorated by 19 letters over the first 48 weeks of the trial, compared to a 20-letter decline in the control cohort. The top-line figures hide a trend that shows vision in both arms of the trial declined before improving. Eyes treated with GS010 improved by 13 letters from their low point, while the placebo group recorded an 11-point improvement.

The trial failed to show GS010 is statistically superior to placebo against secondary endpoints, too. After 48 weeks, GS010 statistically had no more effect on the temporal retinal nerve fiber layer, papillomacular bundle thickness and ganglion cell volume than placebo. While GS010 outperformed the sham treatment on some other measures, the overall data set offers little encouragement that the gene therapy is effective at 48 weeks. The question is whether it will become effective as more weeks pass. GenSight thinks it will, in part because of its experience with the other phase 3 trial.

Clever-1 Inhibition Reduces the Subversion of the Immune System Carried Out by Tumor Associated Macrophages

Cancers subvert the immune system in order to protect themselves while they grow. One of the ways in which this happens is activities of macrophage cells that become associated with the tumor tissue. Cancer cells influence the macrophages into dampening the local immune response, preventing the immune system from effectively targeting the tumor. Researchers here find a way to reduce the impact of this process, and note that it synergizes well with the currently popular checkpoint inhibitor approach to rousing the immune system to attack cancerous cells.

One reason behind many unsuccessful cancer treatments is the cancers' ability to hijack the immune system to support its own growth. This is assisted by the so-called tumour-associated macrophages that can be educated by cancer cells to dampen anti-tumour immune responses. Macrophages are phagocytes that form the first line of defence towards invading pathogens and they have a crucial role in maintaining tissue homeostasis. Macrophages have a large repertoire of functions in immune activation and resolving inflammation.

Researchers investigated the possibility to utilise tumour-associated macrophages to increase the immunological detection and killing of cancer cells. Previously, it was observed that Clever-1 controls leukocyte trafficking between tissues. A new study found that blocking Clever-1 function on macrophages activated the immune system and was highly effective in inhibiting cancer progression. By inhibiting Clever-1 functions, tumour-associated macrophages that normally impair adaptive immune cell activation, such as cancer cell killing by cytotoxic T cells, were managed to be re-educated so that they had increased ability to present antigen and secrete pro-inflammatory cytokines leading to increased activation of killer T cells.

The antibody therapy targeting Clever-1 worked in the studied tumour mouse models as efficiently as the PD-1 antibody therapy that is in clinical use. The PD-1 antibody maintains the functionality of the killer T cells. It is notable that the Clever-1 antibody therapy targeting macrophages also increased the activity of the killer T cells efficiently. In certain mouse models of cancer, a combination of anti-Clever-1 and anti-PD-1 therapies prevented tumour growth and formation of metastases more effectively than either treatment alone.

Acid Sphingomyelinase in Age-Related Blood-Brain Barrier Dysfunction

The blood-brain barrier is a lining of specialized cells that wraps all blood vessels passing through the central nervous system. It allows only certain molecules to pass, keeping the biochemistry of the central nervous system distinct from that of the rest of the body. Unfortunately, the blood-brain barrier begins to leak in later life, and the inappropriate passage of cells and molecules into the brain results in both chronic inflammation and more subtle processes of damage and disarray. The consensus is that this contributes to the development of neurodegenerative conditions and consequent dementia, though there is some debate over where exactly this fits in the hierarchy and causality of effects.

What causes the blood-brain barrier to break down? That is a question without a definitive answer, as for so many of the manifestations of aging. Researchers here provide evidence for rising levels of acid sphingomyelinase (ASM) to be important, demonstrating this in mice via artificially increased and decreased levels of ASM. We might then ask what causes increased ASM in old mice, but it usually takes years for researchers to follow the chain of cause and consequence to to the next point of interest, when working backwards from the end state in this manner.

Aging is related to progressive deterioration of central nervous system function and contributes to the pathogenesis of neurodegenerative disease. Previous studies have implicated alterations in the molecular mechanisms of aging with changes in the brain environment such as abnormal aggregation of proteins, neuronal loss, neuroinflammation, and cognitive deficits. The dysfunctions in aging could lead to neurodegenerative disease including mild cognitive impairment, cerebrovascular disease, Parkinson's disease, and Alzheimer's disease. In particular, disruption of the blood-brain barrier (BBB) is one of several major pathological features of these age-related neurodegenerative diseases. Moreover, many studies have demonstrated that BBB dysfunction may be a cause or consequence of neurodegeneration.

Acid sphingomyelinase (ASM), encoded by the Smpd1 gene, plays an important housekeeping role in sphingolipid metabolism and is known to regulate cell apoptosis, proliferation, and differentiation. Although ASM is expressed in virtually all cell types under normal conditions, ASM secreted from endothelial cells (ECs) is significantly associated with numerous diseases. ECs are the major cell type forming the BBB, along with pericytes and astrocytes, and the interaction between ECs and other neuronal cells is critical for the maintenance of neurological health in the brain. Previous studies have suggested that an increase in ASM activity may contribute to age-related brain damage. Nevertheless, the specific role of ASM in maintaining the integrity of the BBB and/or age-related neurodegeneration remains unclear.

In a recent study, we for the first time demonstrated that ASM derived from ECs plays a central role in aging-induced BBB disruption and neurodegeneration. Higher ASM activity was detected in plasma from older individuals (65-90 years) compared with plasma from their younger counterparts (24-45 years). We also confirmed similar results in plasma derived from old mice (20-months). The robust elevation in ASM levels in the brains of old mice was associated with microvessels, and ECs derived from microvessels were the main contributors for elevated ASM activity. These results indicated that ASM activity increased in aged plasma and brain ECs, and could affect brain dysfunction in the process of aging.

Old Smpd1 +/- mice, in which ASM is genetically inhibited, exhibited a significant reduction in ASM activity in the plasma and brain ECs. In addition, capillary density in the brains of older mice was decreased by EC death, while old Smpd1 +/- mice exhibited higher capillary density. BBB permeability was also increased in the brains of old mice. In contrast, a substantial decrease in permeability in old Smpd1 +/- mice was observed. Moreover, the leakiest vessels in the brain did not exhibit an apoptotic signal in both old mice and old Smpd1 +/- mice, indicating that the death of ECs caused by ASM was not the main cause of BBB disruption in aging.

In conclusion, our findings suggest a central role for ASM as a regulator of BBB integrity and neuronal function in aging, as well as highlight the potential of ASM as a drug target for anti-aging. To date, few inhibitors that can directly inhibit ASM have been found; nevertheless, highly potent and selective ASM inhibitors are anticipated to be developed in the future. Therefore, further studies investigating the development of functional ASM inhibitors may be highly valuable for understanding the anti-aging process and for the treatment of various age-related neurodegenerative diseases.

Aneuploidy and Cellular Senescence in Aging

Aneuploidy is not very well studied in the context of aging, but at least a few research groups are looking into it. Aneuploidy describes the state of cellular dysfunction that arises from one or more missing or extra chromosomes, a problem that can occur as the result of malfunctions during cellular replication. Like all such issues in which an individual cell becomes damaged, the extent to which it causes downstream harm is largely governed by the degree to which a cell with aneuploidy can replicate, spreading its disordered state into a greater fraction of tissues. Alternatively, if aneuploidy occurs spontaneously with a great enough frequency, and also drives cells into senescence, then this might also be a path to significant harm in the course aging. Senescent cells contribute to aging via signaling, and even a comparatively small number of senescent cells can be very damaging.

This paper, I think, is an example of a fairly prevalent recent phenomenon: researchers retrofitting their current line of work on aging to more clearly build a link to cellular senescence. Cynically, I would say that this burst of rethinking is driven by the sizable influx of funding into the research and development of means to destroy or reprogram senescent cells. Now that it is broadly acknowledged that cellular senescence is a contributing cause of aging, there is funding for related projects, and the activities of researchers tend to be steered by the availability of funds.

Aging is characterized by a progressive loss of physiological integrity and function over time. Being the largest risk factor for the incidence of cancer, cardiovascular, and neurological diseases, it results from several interconnected molecular processes that decline with advancing age and that are commonly categorized in nine "aging hallmarks". Among these hallmarks, which are nevertheless interdependent, epigenetic alterations and cellular senescence have gained increased relevance, as they have been modulated by the current mainstream anti-aging therapies.

Although a single universal marker for cellular senescence is still to be unveiled, senescent cells present several distinguishing features in vitro, such as flattened morphology and enlarged nuclear size, and increased senescence-associated β-galactosidase (SA-β-Gal) activity. Moreover, cellular senescence is accompanied by the development of a senescence-associated secretory phenotype (SASP), a distinctive cell-specific secretome. There has been intensive research examining the regulatory mechanisms behind cellular senescence and SASP. It is now clear that this occurs on two fronts; while p53 and pRB are responsible for halting cell cycle progression during cell senescence, the regulation of the secretory component seems to be mainly mediated by the NF-κB signaling pathway.

For several decades, many observations have demonstrated an incidence of aneuploidy along human chronological aging. Aneuploidy is defined as an abnormal chromosome number resultant from chromosome mis-segregation during cell division, in both gametes and somatic cells. The molecular mechanisms behind the age-associated aneuploidy globally point to alterations in the expression levels of genes that are involved in the cell cycle and in the mitotic apparatus. Interestingly, genomic instability, telomere erosion, epigenetic drift, and defective proteostasis, which are the primary hallmarks of aging acting as initiating triggers leading to secondary hallmarks, have all been reported to induce mitotic defects and aneuploidization. Moreover, aneuploidy resulting from lagging chromosomes/weakened mitotic checkpoint has been associated with cellular senescence and premature aging.

While we are left to learn more what a truly senescent cell is, if there is the need of long- or short-term clearance from the organism, and, more importantly, if we can rescue the still proliferative "pre-senescent" cells. In this context, a new candidate hallmark for aging arises, aneuploidy, an abnormal chromosomal number that results from mis-segregation events during mitosis, which has been linked to normative aging and age-associated diseases, with the underlying mechanisms being poorly understood. Recently, aneuploidy was shown to increase with advancing age due to an overall dysfunction of the mitotic machinery. Furthermore, several reports have uncovered the impact of aneuploidy on cellular fitness and proliferative capacity, with several characteristics of aneuploid cells overlapping with those that are found in aged cells.

Our latest work provided insight as to how senescent cells arise, by demonstrating that elderly proliferative cells, primed with the expression of a senescence core gene signature, evolved into permanent cell cycle arrest (full senescence) following passage through a faulty mitosis. This further supports that improving mitotic fitness may be used as a potential anti-aging strategy, thereby counteracting the SASP-induced inflammatory microenvironment and helping to protect stem cell and parenchymal cell functions.


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