Fight Aging!

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.

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.

Link: https://www.utu.fi/en/news/press-release/antibody-therapy-training-phagocytes-to-destroy-tumours-now-tested-on-patients

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.

Link: https://www.fiercebiotech.com/biotech/gensight-s-vision-loss-gene-therapy-again-fails-phase-3

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.

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.

Link: https://www.leafscience.org/the-life-extensionists-guide-to-logical-fallacies/

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."

Link: https://www.niehs.nih.gov/news/newsroom/releases/2019/february22/

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.

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.

Link: https://www.forbes.com/sites/cognitiveworld/2019/02/20/how-to-live-this-life-better-effective-altruism-in-the-context-of-longevity/

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.

Link: https://doi.org/10.1111/acel.12923

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 of dollars 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.

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.

Link: https://www.aan.com/PressRoom/Home/PressRelease/2694

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.

Link: https://www.escardio.org/The-ESC/Press-Office/Press-releases/What-s-age-got-to-do-with-it

Naked mole-rats exhibit exceptional longevity in comparison to other rodent species. They can live nine times longer than similarly sized mice, for example. There are no doubt a sizable number of distinct mechanisms that contribute to this difference in species life span, and the existence of mammals with widely divergent life spans acts as a natural laboratory for researchers interested in better understanding aging. If one species lives a much longer life than another, then using their differences in order to identify the more important aspects of cellular metabolism in the matter of aging may well be a faster approach than other strategies that aim to reverse engineer the workings of aging. Thus research groups have been energetically investigating the biochemistry of naked mole-rats for many years now.

Naked mole-rats are exceptionally resistant to cancer, to the point at which for all of the populations maintained across the years in laboratories and zoos, only a few cases of cancer have ever been reported. Of late the ability of naked mole-rats to suppress cancerous mutations and cancerous cells has become one of the primary areas of study when it comes to their metabolic peculiarities. Avoiding death by cancer probably isn't one of the most important contributions to naked mole-rat longevity, however.

Instead, it seems likely that at least some of the major determinants of longevity relate to mitochondrial function and cellular resistance to oxidative damage. The horde of mitochondria in every cell act as power plants, but also as a source of oxidative molecules. These are generated as a byproduct of the energetic chemical reactions needed to package up the adenosine triphosphate (ATP) used as fuel for cellular processes. The presence of too many oxidative molecules are harmful to cells, and mitochondria themselves can be damaged by oxidative molecules in ways that contribute to aging. The situation is far from simple, however: oxidative molecules are used as signals for cellular maintenance, and thus small or brief increases are in fact beneficial. Further, antioxidant processes in mitochondria act to clean up much of the exhaust of new oxidative molecules. This is a complex, dynamic system of oxidants and reactions to oxidants that does not lend itself to easy predictions of outcomes.

The membrane pacemaker hypothesis suggests that the important factor in all of this, when considering differences between species, is the composition of cell membranes, particularly those of mitochondria. Different cell membrane lipids are more or less vulnerable to oxidative reactions and consequent functional damage. Species like naked mole-rats, with very high levels of all of the markers of oxidative stress, yet few to no apparent consequences, are perhaps a good argument for the membrane pacemaker way of looking at things. Equally, the research here makes a different argument - that this is all about the degree to which mitochondria can direct their own antioxidant processes to consume oxidizing molecules, and naked mole-rats are much better at this than mice. It is known that raising levels of mitochondrial antioxidants, either via gene therapy or by delivering artificial antioxidants that localize to mitochondria, appears to slow aging in a number of different species. The question, as always, is the size of any specific contribution to the overall outcome.

The exceptional longevity of the naked mole-rat may be explained by mitochondrial antioxidant defenses

Naked mole-rats (NMRs; Heterocephalus glaber, Rodentia) are mouse-sized eusocial mammals native to Eastern Africa that live in large subterranean colonies. Individuals of this species can live for longer than 30 years in laboratory conditions, and also exhibit a remarkably long health span; typical signs of senescence seen in old rodent are mostly absent in NMRs. Conversely, the common mouse (Mus musculus, Rodentia) lives less than 4 years and is highly susceptible to aging-related diseases and physiological decline. As a result, comparisons between these two species are considered to be a "gold standard" in mammalian studies of aging.

According to the oxidative stress theory of aging, senescence is caused by the gradual accumulation of oxidative damage to cells, inflicted by reactive oxygen species (ROS) of mitochondrial origin. However, previous comparative studies of NMR biology mostly provided evidence that contradicted this theory. For example, comparisons of isolated heart mitochondria found no difference in the rate of H2O2 efflux (i.e., the proportion of H2O2 not consumed by the mitochondrion before detection) between NMRs and mice. In addition, extensive oxidative damage and limited antioxidant capacity have been reported in the cytosol of NMR hepatocytes. Taken together, these findings led to the conclusion that the longevity of NMRs occurs independently of enhanced protection against oxidative damage, and this conclusion has been used repeatedly to refute the oxidative stress theory of aging.

More recently, however, the mitochondrial oxidative stress hypothesis of aging has gained empirical support; however, this hypothesis remains controversial, and has not yet been investigated in NMRs. This refined hypothesis stems from the fact that mitochondrial ROS are mostly released inside the mitochondrion (i.e., within the mitochondrial matrix), thereby directly exposing mitochondrial biomolecules to oxidative damage. According to the mitochondrial stress hypothesis, cellular senescence is primarily driven by loss of mitochondrial function with age. A central step toward testing this hypothesis would be to measure the balance between internal production and internal consumption of ROS within mitochondria themselves.

We have recently shown that traditional methodologies for detecting the rate of H2O2 formation from isolated mitochondria underestimate ROS generation because of the remarkable endogenous capacity of matrix antioxidants to consume H2O2. For example, this underestimation can reach 80% or more in rat skeletal muscle with certain respiratory substrates. Moreover, mitochondria can consume far more H2O2 than they generate; therefore, this capacity of mitochondria to consume H2O2 putatively represents a novel and widely underappreciated test of the mitochondrial oxidative stress theory of aging in of itself. We hypothesized that differences in the capacity of mitochondria to eliminate H2O2 might solve the apparent NMR oxidative stress/longevity-conundrum.

To test our hypothesis, we took advantage of antioxidant inhibition methods that we developed previously to measure H2O2 formation rates without the confounding influence of internal consumption. We also compared mitochondrial H2O2 clearance (i.e., maximal consumption) rates between these two species in functional isolated mitochondria. Our results support the mitochondrial oxidative stress hypothesis of aging via a mechanism that has not been previously demonstrated: NMRs and mice do not differ in their rate of H2O2 formation, but rather in the markedly greater capacity of NMR mitochondria to consume H2O2.

There is an enormous difference in logistics and cost between cell therapies that must use a patient's own cells and cell therapies that arise from a single universal cell line that can be used in any patient. While in principle it is perfectly possible to reprogram a patient's cells into induced pluripotent stem cells, differentiate those cells into the desired cell type, and then even grow functional organoids, that all takes a lot of time and effort, and is as yet far from reliable. It would be much cheaper and much faster to have a factory producing cell lines and organs that can be universally used. When organs and other large tissue sections can be reliably grown from cells in the laboratory, this point will also apply there.

Given that, it is interesting to see signs of progress towards the production of induced pluripotent stem cells that lack the features that would cause a recipient immune system to attack them, but can nonetheless survive in the body. Achieving this goal is the basis for a much more cost-effective regenerative medicine and tissue engineering industry.

The immune system is unforgiving. It's programmed to eradicate anything it perceives as alien, which protects the body against infectious agents and other invaders that could wreak havoc if given free rein. But this also means that transplanted organs, tissues or cells are seen as a potentially dangerous foreign incursion, which invariably provokes a vigorous immune response leading to transplant rejection. When this occurs, donor and recipient are said to be - in medical parlance - "histocompatibility mismatched."

In the realm of stem cell transplants, scientists once thought the rejection problem was solved by induced pluripotent stem cells (iPSCs), which are created from fully-mature cells - like skin or fat cells - that are reprogrammed in ways that allow them to develop into any of the myriad cells that comprise the body's tissues and organs. If cells derived from iPSCs were transplanted into the same patient who donated the original cells, the thinking went, the body would see the transplanted cells as "self," and would not mount an immune attack. But in practice, clinical use of iPSCs has proven difficult. For reasons not yet understood, many patients' cells prove unreceptive to reprogramming. Plus, it's expensive and time-consuming to produce iPSCs for every patient who would benefit from stem cell therapy.

Scientists wondered whether it might be possible to sidestep these challenges by creating "universal" iPSCs that could be used in any patient who needed them. In their new paper, they describe how after the activity of just three genes was altered, iPSCs were able to avoid rejection after being transplanted into histocompatibility-mismatched recipients with fully functional immune systems. The researchers first used CRISPR to delete two genes that are essential for the proper functioning of a family of proteins known as major histocompatibility complex (MHC) class I and II. MHC proteins sit on the surface of almost all cells and display molecular signals that help the immune system distinguish an interloper from a native. Cells that are missing MHC genes don't present these signals, so they don't register as foreign. However, cells that are missing MHC proteins become targets of immune cells known as natural killer (NK) cells.

The team found that CD47, a cell surface protein that acts as a "do not eat me" signal against immune cells called macrophages, also has a strong inhibitory effect on NK cells. Believing that CD47 might hold the key to completely shutting down rejection, the researchers loaded the CD47 gene into a virus, which delivered extra copies of the gene into mouse and human stem cells in which the MHC proteins had been knocked out. CD47 indeed proved to be the missing piece of the puzzle. When the researchers transplanted their triple-engineered mouse stem cells into mismatched mice with normal immune systems, they observed no rejection.

Link: https://www.ucsf.edu/news/2019/02/413311/crispr-gene-editing-makes-stem-cells-invisible-immune-system

Hutchinson-Gilford progeria syndrome (HGPS), or simply progeria, is a very rare condition caused by mutation in the lamin A gene. Patients exhibit a condition that superficially resembles greatly accelerated aging. They typically die very young from forms of cardiovascular disease usually only found in much later life. Lamins are important structural proteins, and the broken form of lamin A in progeria patients, known as progerin, results in cells with misshapen nuclei and significant dysfunction. In the sense that aging is an accumulation of damage and dysfunction, progeria can thus resemble aging, but the type of damage and the details of its progression bear little resemblance to normal aging.

In the research noted here, scientists report the interesting finding that progeroid mice are actually better off with lamin A disabled than they are with progerin in circulation; this can be achieved via gene therapy. We watch work on progeria because researchers have determined that progerin is present to some degree in normal aged individuals. It remains an open question as to the degree to which this contributes to the dysfunction of aging: is it significant in comparison to all of the other forms of molecular damage that degrade cell and tissue function? We will probably not gain an answer to that question until such time as a therapy to eliminate progerin is deployed and then tested in old people as well as in progeria patients. The example here is most likely not that therapy: I would expect disabling lamin A entirely to cause more harm than help in old people who only exhibit small amounts of progerin.

With an early onset and fast progression, progeria is one of the most severe forms of a group of degenerative disorders caused by a mutation in the LMNA gene. Both mice and humans with progeria show many signs of aging, including DNA damage, cardiac dysfunction, and dramatically shortened life span. The LMNA gene normally produces two similar proteins inside a cell: lamin A and lamin C. Progeria shifts the production of lamin A to progerin. Progerin is a shortened, toxic form of lamin A that accumulates with age and is exacerbated in those with progeria.

The researchers utilized the CRISPR/Cas9 system to deliver the gene therapy into the cells of the progeria mouse model expressing Cas9. An adeno-associated virus (AAV) was injected containing two synthetic guide RNAs and a reporter gene. The guide RNA ushers the Cas9 protein to a specific location on the DNA where it can make a cut to render lamin A and progerin nonfunctional, without disrupting lamin C. The reporter helps researchers track the tissues that were infected with the AAV.

Two months after the delivery of the therapy, the mice were stronger and more active, with improved cardiovascular health. They showed decreased degeneration of a major arterial blood vessel and delayed onset of bradycardia (an abnormally slow heart rate) - two issues commonly observed in progeria and old age. Overall, the treated progeria mice had activity levels similar to normal mice, and their life span increased by roughly 25 percent.

Link: https://www.salk.edu/news-release/putting-the-brakes-on-aging/

Many research groups have published evidence to suggest that age-related mitochondrial dysfunction is an important aspect of neurodegenerative conditions such as Alzheimer's disease. The brain is an energy-hungry organ and mitochondria are the power plants of the cell, responsible for producing the chemical energy store molecules that power cellular activity. It is well known that mitochondrial function declines with age; mitochondria in old tissues are structurally different, and less effective at their jobs.

The research results here suggest that this mitochondrial decline has a lot to do with the fact that the cellular housekeeping processes of autophagy falter with age, and in particular mitophagy, the autophagic recycling of damaged or dysfunctional mitochondria. The degree of benefit seen from boosted mitophagy indicates that perhaps it is higher rather than lower in the hierarchy of mechanisms. That said, there is good evidence from other studies for lapsed mitophagy to be a consequence of deeper changes in mitochondrial dynamics that make it harder for the autophagic processes to operate. The question of the best place to intervene is probably one best settled by trying the various potential approaches in order to see how well they work.

A point worth noting, as for all Alzheimer's research, is that the animal models of this condition are highly artificial. Old mice do not normally undergoing anything even remotely akin to the processes underlying Alzheimer's disease, and thus there is always the question of whether or not the results in a mouse model have anything to do with the way in which the condition proceeds in humans. One can be reasonable confident that mitochondrial dysfunction is similar between mammalian species, based on the past few decades of research, but it is the linkage of that dysfunction to either Alzheimer's or the faux-Alzheimer's of the model that is the thorny point. I do think it reasonable to believe that improved autophagy (in general) or mitophagy (in specific) will produce some degree of benefits across the board in human cellular biochemistry - but will the benefits for Alzheimer's patients be of the same order as those observed in mice?

'Lack of Cleaning' in Brain Cells is Central to Alzheimer's Disease

Researchers have come closer to a new way of attacking Alzheimer's disease. They target the efforts towards the cleaning process in the brain cells called mitophagy. "When the cleaning system does not work properly, there will be an accumulation of defective mitochondria in the brain cells. And this may be really dangerous. At any rate, the poor cleaning system is markedly present in cells from both humans and animals with Alzheimer's. And when we improve the cleaning in live animals, their Alzheimer's symptoms almost disappear."

The researchers have looked more closely at mitophagy in brain cells from deceased Alzheimer's patients, in Alzheimer's-induced stem cells and in live mice and roundworms with Alzheimer's. In addition, they have also tested active substances targeted at mitophagy in the animal models. The mitochondria lie inside the cell and can be seen as the cell's energy factories. Mitophagy breaks down defective mitochondria and reuses the proteins that they consist of. It is known from previous research that dysfunctional mitophagy is associated with poor function and survival of nerve cells, but so far, the connection with Alzheimer's is unclear.

In both Alzheimer's and other states of dementia, there is an accumulation of the proteins tau and beta amyloid in the brain, leading to cell death. In the new animal models, the researchers show that when boosting the mitophagy, such accumulation will slow down. The researchers believe that altogether their findings indicate that mitophagy is a potential target for the treatment of Alzheimer's, which should be further investigated. They therefore plan to start clinical trials in humans in the near future.

Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease

Accumulation of damaged mitochondria is a hallmark of aging and age-related neurodegeneration, including Alzheimer's disease (AD). The molecular mechanisms of impaired mitochondrial homeostasis in AD are being investigated. Here we provide evidence that mitophagy is impaired in the hippocampus of AD patients, in induced pluripotent stem cell-derived human AD neurons, and in animal AD models.

In both amyloid-β (Aβ) and tau Caenorhabditis elegans models of AD, mitophagy stimulation (through NAD+ supplementation, urolithin A, and actinonin) reverses memory impairment through PINK-1, PDR-1, or DCT-1 dependent pathways. Mitophagy diminishes insoluble Aβ1-42 and Aβ1-40 and prevents cognitive impairment in an APP/PS1 mouse model through microglial phagocytosis of extracellular Aβ plaques and suppression of neuroinflammation. Mitophagy enhancement abolishes AD-related tau hyperphosphorylation in human neuronal cells and reverses memory impairment in transgenic tau nematodes and mice. Our findings suggest that impaired removal of defective mitochondria is a pivotal event in AD pathogenesis and that mitophagy represents a potential therapeutic intervention.

The age-related degeneration of joint cartilage is a strongly inflammatory condition, in which the accumulation of senescent cells plays an important role. Senescent cells produce potent inflammatory signaling that harms the local environment in a range of ways. Systemic inflammation is also thought to be a meaningful contribution to osteoarthritis, however. The immune system becomes dysfunctional throughout the body with age, becoming more active and inflammatory even as it becomes ever less capable of defending against pathogens and errant cells. Minimizing joint issues with aging will no doubt require dealing with both local and systematic sources of chronic inflammation.

Aging is an inevitable process in the human body that is associated with a multitude of systemic and localized changes. All these conditions have a common pathogenic mechanism characterized by the presence of a low-grade proinflammatory status. Inflammaging is systemic, chronic, and asymptomatic. It has a multifactorial aetiology including an increased number of proinflammatory cytokines, oxidative stress, immunosenescence, autophagy, or cellular DNA damage.

The incidence of osteoathritis (OA) is steadily increasing, especially among the elderly. The mechanism of articular cartilage degeneration is not necessarily the consequence of aging, but aging is considered to be a risk factor for the occurrence of OA. There is a close relationship between chondrocyte activity and local articular environment changes due to cell senescence followed by secretion of inflammatory mediators. Furthermore, systemic inflammaging can lead to cartilage destruction, pain, disability, and an impaired quality of life.

The term "chondrosenescence" refers to all age-dependent deterioration of chondrocytes as a consequence of replicative (intrinsic) and stress-induced (extrinsic) factors. There is a strong correlation between inflammaging, the presence of inflammasomes, autophagy, and chondrosenescence. Intrinsic factors in the aging process in association with extrinsic factors such as mechanical overload or different chemical stimuli act on articular cartilage. As a consequence, an inflammatory environment characterized by increased proinflammatory cytokines, chemokine, and activated proteinase occurs locally. All these lead to the aging process of chondrocytes (chondrosenescence), which favors the appearance of degenerative joint modifications.

Link: https://doi.org/10.3390/ijms20030614

The immune cells of the brain are somewhat different in character and function from those of the body. They have a greater portfolio of tasks beyond chasing down pathogens, clearing out waste, and assisting in regeneration. For example, the immune cells known as microglia are involved in the maintenance of synaptic connections between neurons. Interestingly, microglia are not produced in the bone marrow by stem cells or progenitor cells, so in the research here in which young bone marrow is transplanted into old mice, one can be fairly sure that any beneficial effects on microglia result from signaling differences on the part of the rest of the immune system.

At the surface, this seems like a case of improvement in function resulting from a reduction in chronic inflammation. That is perhaps reasonable to expect if the immune system becomes less damaged by age, is given more competent cells capable of managing the inflammatory process. Inflammation without end is very problematic in all tissues, the brain included, and is a significant contributing factor in the many dysfunctions of aging. It disrupts the normal behavior of near all cell types. Microglia in particular are prone to behaving unhelpfully in an inflamed environment, contributing to damage rather than helping to repair it or maintain normal function.

Surgically attaching old mice to young mice so that they share a circulatory system (heterochronic parabiosis) has been reported to rejuvenate old mice and accelerate aging in young mice. Rejuvenation of the brain, heart, liver, and pancreas of old parabionts by young blood is thought to be partly due to effects on stem cell populations. In particular, improved cognitive function has been attributed to increased neurogenesis and synaptic plasticity, as well as better brain vascularization and myelination. A single blood exchange between old and young mice, which replaces the blood without organ sharing or complications associated with the parabiosis procedure, has also recently been reported to have similar effects.

Circulating levels of CCL11 and β2-microglobulin have previously been reported to increase with age in mice and humans, and shown to promote brain aging when administered to young mice. Both CCL11 and β2-microglobulin can be produced by a diverse range of cell types, and the tissues or organs responsible for their elevated levels during aging have not been defined. Thus, the role of the hematopoietic system in these effects is unclear. CCL11 and β2-microglobulin are thought to act by suppressing neurogenesis in the hippocampus. However, the role of neurogenesis in the adult brain is controversial. Thus other mechanisms may be responsible for the rejuvenated cognitive function in old mice undergoing heterochronic parabiosis or plasma transfer. Indeed, while stem cell populations in the neurogenic niche have been closely examined, it is not known whether aging-associated changes in glial cells are also reversed.

We therefore established a heterochronic bone marrow transplant (BMT) model to determine the specific influence of systemic hematopoietic aging on cognitive function, including glial cells in the hippocampus. This approach also allowed us to evaluate the long-term beneficial impact of a young hematopoietic system on the aging brain, and define the role of the hematopoietic system in aging-associated elevation of circulating levels of CCL11 and β2-microglobulin. We found that reconstitution of old mice with young, but not old, hematopoietic cells prevented cognitive decline. BMT achieved preservation of cognitive function for at least 6 months. Microglial activation was reduced, and synaptic connections were maintained. Our data also attribute the aging-associated elevation of circulating β2-microglobulin levels to non-hematopoietic cells. In contrast, the increased CCL11 appears either to be of hematopoietic origin or to be produced by non-hematopoietic cells under hematopoietic control, and our data implicate CCL11 in aging-associated microglial activation and synaptic loss.

Link: https://doi.org/10.1038/s42003-019-0298-5

Epigenetic clocks are a weighted combination of DNA methylation at specific sites on the genome. Modern processing power allowed the association between these algorithms and aging to be reverse engineered, but it remains an open question as to what exactly is being measured. What underlying processes of aging are reflected by these characteristic epigenetic changes? All of them? Some of them? Some more than others? No-one knows in certainty, though the specific genes and proteins involved offer some suggestions. Until researchers have a better idea on that front, it is hard to use these clocks in the way we all want them to be used: to greatly speed up development of rejuvenation therapies. If it was possible to take a measure, apply a therapy, and then within days or a month at most take a second measure, and on that basis declare whether or not a particular approach works, then the assessment of potential methods of rejuvenation could proceed quite rapidly indeed.

Epigenetic clocks are evolving as researchers explore this association between DNA methylation and aging. The most interesting aspect of the new clock noted below is that only a tiny portion of the genome is involved. Even though it is apparently very similar in diverse species, to me this sounds like there is an even greater risk that the clock only measures a small slice of the many important processes of aging, and thus won't be all that helpful for the development of rejuvenation therapies. In a world without the ability to intervene in specific processes of aging, all of those processes in any given individual tend to be aligned with one another. But if just one of those processes is reversed - such as by clearance of senescent cells - then assessment will become a problem if epigenetic clocks behave unpredictably in this sort of scenario.

In practice, what is going to happen is that measures of aging and rejuvenation will be developed in parallel to the development of rejuvenation therapies. Perhaps epigenetic clocks will be increasingly calibrated to report on the outcome of clearance of senescent cells, for example. This seems likely, as the industry will want something more than just counts of cells and reversal of symptoms for one specific age-related disease to show that they are affecting the course of aging in a profound way. But that tailored epigenetic clock may well turn out to be useless for, say, assessing the effects of cross-link breaking on the progression of aging. Nothing is simple in biochemistry. We might hope for a universal assessment of age to turn up sometime soon, to speed up research and development, but it may well be the case that the only practical way to build such a measure is to first make significant progress in all of the areas of the full SENS program of rejuvenation therapies.

Uncovering a "smoking gun" of biological aging

Researchers looked at ribosomal DNA (rDNA), the most active segment of the genome and one which has also been mechanistically linked to aging in a number of previous studies. They hypothesized that the rDNA is a "smoking gun" in the genomic control of aging and might harbor a previously unrecognized clock. To explore this concept, they examined epigenetic chemical alterations (also known as DNA methylation) in CpG sites, where a cytosine nucleotide is followed by a guanine nucleotide. The study homed in on the rDNA, a small (13 kilobases) but essential and highly active segment of the genome, as a novel marker of age.

Analysis of genome-wide data sets from mice, dogs, and humans indicated that the researchers' hypothesis had merit: numerous CpGs in the rDNA exhibited signs of increased methylation - a result of aging. To further test the clock, they studied data from 14-week-old mice that responded to calorie restriction, a known intervention that promotes longevity. The mice that were placed on a calorie-restricted regimen showed significant reductions in rDNA methylation at CpG sites compared with mice that did not have their caloric intake restricted. Moreover, calorie-restricted mice showed rDNA age that was younger than their chronological age.

The researchers were surprised that assessing methylation in a small segment of the mammalian genome yielded clocks as accurate as clocks built from hundreds of thousands of sites along the genome. They noted that their novel approach could prove faster and more cost effective at determining biological and chronological age than current methods of surveying the dispersed sites in the genome. The findings underscore the fundamental role of rDNA in aging and highlight its potential to serve as a widely applicable predictor of individual age that can be calibrated for all mammalian species.

Ribosomal DNA harbors an evolutionarily conserved clock of biological aging

The ribosomal DNA (rDNA) is the most evolutionarily conserved segment of the genome and gives origin to the nucleolus, an energy intensive nuclear organelle and major hub influencing myriad molecular processes from cellular metabolism to epigenetic states of the genome. The rDNA/nucleolus has been directly and mechanistically implicated in aging and longevity in organisms as diverse as yeasts, Drosophila, and humans. The rDNA is also a significant target of DNA methylation that silences supernumerary rDNA units and regulates nucleolar activity.

Here, we introduce an age clock built exclusively with CpG methylation within the rDNA. The ribosomal clock is sufficient to accurately estimate individual age within species, is responsive to genetic and environmental interventions that modulate life-span, and operates across species as distant as humans, mice, and dogs. Further analyses revealed a significant excess of age-associated hypermethylation in the rDNA relative to other segments of the genome, and which forms the basis of the rDNA clock. Our observations identified an evolutionarily conserved marker of aging that is easily ascertained, grounded on nucleolar biology, and could serve as a universal marker to gauge individual age and response to interventions in humans as well as laboratory and wild organisms across a wide diversity of species.

There is plenty of evidence for progressive dysfunction in neurotransmission related to GABA to be important in forms of cognitive decline, particularly relating to memory. A number of approaches to treat this loss have been considered, with the one noted here the most recent of the type. Exactly why GABA-related dysfunction occurs in the brain is a matter for debate; as for so much of aging, there is no well-mapped line of cause and consequence leading from the fundamental damage that causes aging to the observed changes in cell behavior the aging brain. There are two approaches to dealing with this ignorance. The first is to repair the well-known forms of damage, and see what happens - the SENS rejuvenation biotechnology methodology. The second, far more popular, approach is to try to compensate for the late stage, downstream dysfunction in some way, without addressing the causes.

This second strategy, the far worse strategy, describes near all of the development of medicine for age-related disease over the past century, and its dominance in the research community is why little progress has been made. There is nothing harder than trying to keep a damaged machine running without repairing the damage. Nonetheless, as capacities in biotechnology grow, these attempts do become incrementally better. It is still absolutely the wrong approach to the challenge, but people continue to be lured back in by the steady improvement in outcomes. Of course, given that most prior outcomes are marginal at best, it doesn't take much for new initiatives to look better in comparison.

New therapeutic molecules show promise in reversing the memory loss linked to depression and aging. What's unique and promising about these findings, in the face of many failures in drug development for mental illness, is that the compounds are highly targeted to activate the impaired brain receptors that are causing memory loss. Researchers first identified the specific impairments to brain cell receptors in the GABA neurotransmitter system. Then they showed that these impairments likely caused mood and memory symptoms in depression and in aging.

The new small molecules were invented to bind to and activate this receptor target. The idea was that they would exert a therapeutic effect by "fixing" the impairment, resulting in an improvement in symptoms. The molecules are chemical tweaks of benzodiazepines, a class of anti-anxiety and sedative medications that also activate the GABA system, but are not highly targeted.

A single dose of these new molecules was administered in preclinical models of stress-induced memory loss. Thirty minutes later, memory performance returned to normal levels, an experiment that was reproduced more than 15 times. In another experiment involving preclinical models of aging, memory declines were rapidly reversed and performance increased to 80 per cent after administration, essentially reaching levels seen in youth or earlier stages of adulthood. This improvement lasted over two months with daily treatment.

Link: http://www.camh.ca/en/camh-news-and-stories/new-molecules-reverse-memory-loss-linked-to-depression-aging

The same underlying molecular and cellular damage of aging contributes to both calcification of blood vessel walls and the development of atherosclerosis, but researchers here argue that calcification can be considered on its own, an independent risk factor for cardiovascular dysfunction and mortality in later life. The presence of senescent cells is one of the common underlying factors that accelerates the progression of both atherosclerosis and calcification of blood vessels. This is due to the inflammatory signaling produced by these cells. That signaling distorts the behavior of macrophages trying to clear up deposits of cholesterol in blood vessel walls, but also makes other cells in the wall behave as though they are osteoblasts in bone, laying down mineral deposits.

Calcification, like the creation of cross-links or degradation of elastin in the extracellular matrix, is harmful because it reduces elasticity in blood vessels. That loss of elasticity breaks the feedback mechanisms that control blood pressure, and the result is the development of hypertension. Hypertension causes structural damage throughout the body: small blood vessels rupture at an accelerated rate in the delicate tissues of the brain, kidney, and other organs, killing tiny sections of tissue. Further, hypertension accelerates the progression of atherosclerosis, and increases the chance of a fatal breakage in blood vessels weakened by atherosclerotic lesions.

In 1903, scientists described typical concentric calcifications in the medial arterial wall as a distinct phenomenon from atherosclerotic plaques. These medial arterial calcifications (MAC) have long been considered as innocent normal aging. Current treatments for cardiovascular disease target luminal thrombosis and atherosclerosis in the intimal layer. Despite widespread preventative efforts, residual cardiovascular disease burden remains high. We hypothesize that arterial calcification, especially in the medial arterial layer, contributes to this residual cardiovascular risk.

Testing this hypothesis is relevant given the high prevalence of arterial calcifications in the population. Causal investigation, independent of inflammation, dyslipidaemia, and thrombosis is difficult and the diagnosis of MAC is challenging as intimal and medial calcification often co-occur. In the human body a complex network of calcification promoters and inhibitors is precisely tuned to inhibit MAC. Inorganic pyrophosphate (PPi) is one of the most potent calcification inhibitors in humans. It binds to hydroxyapatite crystals, thereby inhibiting further growth of the calcifications. The consequences of disrupted PPi homeostasis are shown in genetic disorders. These patients suffer from accelerated aging which results in severe visual impairment, peripheral arterial disease, gastric bleeding, ischemic stroke, and cerebral white matter lesions.

How relevant can this be for patients with diabetes, chronic kidney disease, and for aging in the general population? It is clear that the residual burden and health care costs for cardiovascular disease are huge. MAC contributes to arterial stiffening which results in hypertension and heart failure, but also to pulse pressure-related damage in susceptible high flow end-organs like the kidney and the brain. Indeed increased arterial stiffness is associated with worsening of chronic kidney disease and microvascular brain damage and might therefore contribute to the development and progression of cognitive decline.

In the general population, MAC is shown to be the predominant type of calcification in leg arteries and probably also in the intracranial carotid artery. In the femoral and crural arteries of leg amputees, 71% of the arteries contained MAC whereas in only 31% calcified atherosclerotic lesions were seen. These calcifications are the strongest predictor of major cardiovascular events such as stroke and leg amputation and also linked to dementia, heart failure, and kidney failure. Probably, these ectopic calcifications have evolved as a defence mechanism against resistant infections and, in a pre-antibiotic era with a much shorter life expectancy, have aided survival and population growth. In our era, preventing and removing MAC maybe essential for healthy vascular aging, prevention of chronic cardiovascular events and multi-organ failure and might contribute to further decrease of residual cardiovascular risk.

Link: https://doi.org/10.18632/aging.101821

Some of the voices of the past can appear entirely contemporary, because they saw further and with greater clarity than most of their peers. John W. Campbell, editor of Astounding Science-Fiction Magazine, died of heart disease at age 61 in 1971. In 1949 he wrote an editorial on the future of medicine, aging, and longevity that wouldn't seem out of place today. He anticipated what we presently call actuarial escape velocity, or longevity escape velocity, the idea that gains in life span through progress in medical technology allow greater time to benefit from further gains - and eventually, we are repaired more rapidly than we are damaged, escaping from aging. These commentaries of past years, printed on paper, often vanish into the void. Fortunately this one remains.

As was the case for Timothy Leary in the 1970s, Campbell in 1949 overestimated what could be achieved with the technology of his near future. They were not the first to do so. Thus those of us who have advocated and raised funds for the rejuvenation biotechnology of today must have an argument as to why this decade is different, why we are not doomed to a certainty of aging to death just like Leary and Campbell. That argument must be detailed, robust, and heavily scientific.

That argument exists! Look no further than the SENS rejuvenation research programs and the extensive supporting evidence for the effectiveness of working to repair the root cause molecular damage of aging. This approach is different from the hypothetical approaches to intervene in aging that were proposed in the past - though Campbell is closer to it than Leary. The SENS thesis on aging predicted that senolytics to clear senescent cells from old tissues would be effective as a means of rejuvenation, and now we are finding that this is in fact the case. Senolytics robustly turn back all manner of measures of aging and age-related disease in animal studies. Implementing the rest of the SENS agenda, to repair or work around the molecular damage at the root of aging, is the way to demonstrate that, yes, it is different this time around.

Oh King, Live Forever!... - Astounding Science-Fiction Magazine, Vol. 43, No. 2, April, 1949

At some point in the history of the world and the history of medical science, a point will be reached such that a child born at that time can, if he chooses - and has reasonable luck so far as mechanical damage goes - live practically forever. This point in time will be some forty or more years before the perfection of the full requirements for continuous life - and this point may already have passed, without our knowing it.

For it is inherent in the nature of things that the critical birth-period can not be known until after the event - until after the perfection of the final techniques. Modern medical techniques have been developed to a high point - and on an exponential curve of progress, as is normal in an advancing science - with a view to keeping children and young adults happy, healthy and reasonably sane. The rise in the average-age-at-death statistics has been largely influenced by the diminution of infant and young-adult mortality; medical science has been devoting the greater measure of its efforts to that end of the problem.

Now, with an increasingly older population group, with increasing masses of people in the older age brackets as their biggest problem, systemic failure type medical problems, rather than acute infectious problems will predominate. Heart disease takes the place of diphtheria; cancer replaces tuberculosis. Childbirth fever is vanquished - the problem is hardening of the arteries. Pediatrics is a well-advanced science; gerontology, its opposite number, is practically an unexplored field.

The first achievements of an advancing study of "old age and why is it" will naturally be concentrated on the typical conditions that kill the aged - systemic failure troubles such as heart and artery breakdowns. Of course, the only real cure for the systemic failures of the aged is the very simple and obvious one - youth. Not chronological youth, but metabolic youth. Research must be done on that problem, and is being done. The efforts being made at any time will, of course, be basically palliative - treatments that are primarily symptomatic. The obvious symptom of trouble is heart disease; the cause is old age. The medical profession assures itself that it isn't out to find the secret of eternal youth - simply to cure heart disease. But if it succeeds in cleaning up all the symptoms, one by one, the sum total of the results must, necessarily, be metabolic youth.

Some of the more forthright researchers are headed directly toward the more all-inclusive goal of extended maturity - i.e., extended youth. The two groups of researches will, inevitably, meet on a middle ground of success, sooner or later. For the present and near-future, say twenty years hence, we can expect some very real extensions in active life span, before the onset of the symptoms which, collectively, are termed "old age", and, simultaneously, a successful attack on the more outstanding problems of old age. The combined effect may be to extend the useful period of life as much as thirty years. Certainly not a figure to be confused with "eternal youth" - but pleasant none the less.

During the next succeeding years, incidentally, progress may well be at a faster rate. If the maturity extension techniques are applied to the research workers themselves - naturally! - the experience and ability gained in the previous years of work will be available to aid in further advances. Instead of spending thirty-five years learning how, and then twenty-five years doing research, a man with an added thirty years of life would be a far more efficient unit of civilization; a non-producer for thirty-five years, he could be a producer for fifty-five!

And the great problem really can't be very extreme: the human metabolism is already so nearly perfectly balanced that it takes many decades of very slow accumulation of imbalances to bring on old age. So small a factor of failure certainly should be correctable - and a small advance should mean a large improvement. With the accumulated knowledge and techniques of the previous research, the second twenty years of work might well see a further extension of maturity by another couple of decades.

The first advance of thirty years would be no "eternal youth" treatment. But - science tends to advance exponentially. That thirty-year reprieve might give just the time needed for research to extend your life another forty years. And that forty years might ... We don't know, nor can we guess now, when in time that critical point will arrive - or has arrived. But somewhere in history there must come a point such that a child born then will be just passing maturity when the life-extension techniques will reach the necessary point. They will grant him a series of little extensions - each just sufficient to reach the next - until the final result is achieved. I wonder if that point has been passed? And my own guess is - it has.

In old tissues, stem cell activity is much reduced relative to youthful activity. This is thought to be the most important contribution to loss of muscle mass and strength with age, leading to the condition known as sarcopenia. It also diminished the ability to regenerate after muscle injury. Numerous studies in the regenerative medicine community have demonstrated that while this loss of stem cell function may be a defense against cancer, reducing the activity of cells that may bear potentially dangerous molecular damage, there appears to be a fair amount of room to push the balance towards greater activity without large increases in cancer risk. In mice, anyway.

Researchers here demonstrate a novel way of increasing muscle stem cell activity, to add to a number of others that have been shown to work to some degree in animal studies. The mechanism is arguably somewhat related to work on ways to increase levels of NAD+ so as to enhance mitochondrial activity in old tissues. Here the effect size on muscle regeneration in mice is certainly large enough to be interesting. We'll no doubt see what it does in humans fairly soon, even ahead of human trials, as the self-experimentation community decides to try this out. One would hope they would go about it more carefully than is usually the case in body building circles.

Aging is accompanied by progressive declines in skeletal muscle mass and strength and impaired regenerative capacity, predisposing older adults to debilitating age-related muscle deteriorations and severe morbidity. Muscle stem cells (muSCs) that proliferate, differentiate to fusion-competent myoblasts, and facilitate muscle regeneration are increasingly dysfunctional upon aging, impairing muscle recovery after injury. While regulators of muSC activity can offer novel therapeutics to improve recovery and reduce morbidity among aged adults, there are no known muSC regenerative small molecule therapeutics.

We recently developed small molecule inhibitors of nicotinamide N-methyltransferase (NNMT), an enzyme overexpressed with aging in skeletal muscles and linked to impairment of the NAD+ salvage pathway, dysregulated sirtuin 1 activity, and increased muSC senescence. We hypothesized that NNMT inhibitor (NNMTi) treatment will rescue age-related deficits in muSC activity to promote superior regeneration post-injury in aging muscle.

24-month old mice were treated with saline (control), and low and high dose NNMTi for 1-week post-injury, or control and high dose NNMTi for 3-weeks post-injury. In vivo contractile function measurements were conducted on the injured tibialis anterior (TA) muscle and tissues collected for ex-vivo analyses, including myofiber cross-sectional area (CSA) measurements to assess muscle recovery. Results revealed that muscle stem cell proliferation and subsequent fusion were elevated in NNMTi-treated mice, supporting nearly 2-fold greater CSA and shifts in fiber size distribution to greater proportions of larger sized myofibers and fewer smaller sized fibers in NNMTi-treated mice compared to controls.

Prolonged NNMTi treatment post-injury further augmented myofiber regeneration evinced by increasingly larger fiber CSA. Importantly, improved muSC activity translated not only to larger myofibers after injury but also to greater contractile function, with the peak torque of the TA increased by ∼70% in NNMTi-treated mice compared to controls. Taken together, these results provide the first clear evidence that NNMT inhibitors constitute a viable pharmacological approach to enhance aged muscle regeneration by rescuing muSC function.

Link: https://doi.org/10.1016/j.bcp.2019.02.008

Senescent cells are a major problem in our bodies, in that their growing presence over the years is an important cause of degenerative aging. Unfortunately, the research community can't just prevent cells from ever becoming senescent, even were the capacity to do that in hand today, because transient senescence serves many useful, even necessary purposes in our biochemistry. It is only the lingering senescent cells that are the problem. Periodically removing these unwanted, harmful cells is a very viable way forward, however, and a new biotechnology industry is springing up to do just that.

One very interesting point about senescent cells is that they are notably larger than normal cells. One research group has produced a way of counting senescent immune cells from a blood sample based on sorting by size. Another measured the sizes of cells in old hearts, before and after clearing out senescent cells with a senolytic treatment, showing that the senescent cells were larger. I have to think that there is something useful, potentially even important, that can be done with this feature of senescent cells - the clever implementation just hasn't arrived yet.

In multicellular organisms, cell size ranges over several orders of magnitude. This is most extreme in gametes and polyploid cells but is also seen in diploid somatic cells and unicellular organisms. While cell size varies greatly between cell types, size is narrowly constrained for a given cell type and growth condition, suggesting that a specific size is important for cell function. Indeed, changes in cell size are often observed in pathological conditions such as cancer, with tumor cells frequently being smaller and heterogeneous in size. Cellular senescence in human cell lines and budding yeast cells is also associated with a dramatic alteration in size: senescing cells become exceedingly large. Cell size control has been studied extensively in a number of different model organisms, but why cell size may need to be tightly regulated is not known.

Several considerations argue that altering cell size is likely to have a significant impact on cell physiology. Changes in cell size affect intracellular distances, surface to volume ratio and DNA:cytoplasm ratio. It appears that cells adapt to changes in cell size, at least to a certain extent. During the early embryonic divisions in C. elegans, as cell size decreases rapidly, spindle size shrinks accordingly. Other cellular structures such as mitotic chromosomes, the nucleus and mitochondria have also been observed to scale with size in various organisms. Similarly, gene expression scales with cell size in human cell lines as well as in yeast.

However, not all cellular pathways can adapt to changes in cell size. For example, signaling through the spindle assembly checkpoint, a surveillance mechanism that ensures that cells enter anaphase only after all chromosomes have attached to the mitotic spindle, is less efficient in large cells in C. elegans embryos. In human cell lines, maximal mitochondrial activity is only achieved at an optimal cell size. Finally, large cell size has been shown to impair cell proliferation in budding yeast and human cell lines.

Here we identify the molecular basis of the defects observed in cells that have grown too big. We show that in large yeast and human cells, RNA and protein biosynthesis does not scale in accordance with cell volume, effectively leading to dilution of the cytoplasm. This lack of scaling is due to DNA becoming rate-limiting. We further show that senescent cells, which are large, exhibit many of the phenotypes of large cells. We conclude that maintenance of a cell type-specific DNA:cytoplasm ratio is essential for many, perhaps all, cellular processes and that growth beyond this cell type-specific ratio contributes to senescence.

Link: https://doi.org/10.1016/j.cell.2019.01.018

Now that senescent cells are widely acknowledged as a cause of aging and age-related disease, and now that a large industry is forming to find ways to destroy or otherwise render harmless these cells, a great deal more investigative work into the biochemistry of senescence is taking place than was the case in earlier years. While destruction is very straightforward, and certainly easier to engineer at the present time, a sizable faction of scientists are interested in finding ways to turn off the harmful signals secreted by senescent cells. It is this signaling, the senescence-associated secretory phenotype (SASP), that causes all of the damage: chronic inflammation; destructive remodeling of the surrounding tissue structure; encouraging nearby cells to also become senescent; and so forth.

Because the SASP is complicated and poorly mapped, and no doubt depends on the operation of scores of interacting mechanisms inside a cell, and few of those mechanisms are particularly well mapped in this context, it seems to me that investigating ways to modulate the SASP is more of an academic exercise than a road to therapies at the present time. It cannot possibly compare in efficiency to destroying senescent cells. The only reason to avoid destroying these cells would be the discovery of essential senescent populations, such as neurons in the brain that are both senescent and carrying out vital functions, perhaps. So far that hasn't been the case: old mice do just fine when given senolytic therapies to destroy senescent cells throughout the body, including the brain.

Nonetheless, we might ask whether or not there are master regulators of the SASP yet to be discovered. If so, their existence might make SASP suppression a more viable proposition in the future. The open access research results below may represent a step in that direction. The researchers have found what looks like a fairly important point of control for the SASP, or at least a point of dependency, and that suggests the possibility of a master regulator, even if the exact mechanism examined here turns out to be infeasible as the basis for a point of intervention (which seems quite likely to be the case at first glance).

Study sheds light on damage linked to ageing

Some of the damaging cell effects linked to ageing could be prevented by manipulating tiny parts of cells, a study shows. Scientists have shed light on how the harm caused by senescence - a vital cell process that plays a key role in diseases of ageing - could be controlled or even stopped. Researchers say the findings could have relevance for age-related diseases, although they caution that further research is needed.

During senescence, cells stop dividing. This can be beneficial in assisting wound-healing and preventing excessive growth. Some aspects of senescence are also harmful and can lead to tissue damage and the deterioration of cell health as seen in diseases of older age. Researchers focused on a chain of harmful processes triggered by senescence, known as the senescence-associated secretory phenotype (SASP). The SASP is a cascade of chemical signals that can promote damage to cells through inflammation. The researchers showed that manipulating a cell's nuclear pores - gateways through which molecules enter the heart of the cell - prevented triggering of the SASP. Findings also show that DNA had to be reorganised in space within in the cell nucleus in order for the SASP to be triggered.

Nuclear pore density controls heterochromatin reorganization during senescence

Three-dimensional (3D) genome organization is governed by a combination of polymer biophysics and biochemical interactions, including local chromatin compaction, long-range chromatin interactions, and interactions with nuclear structures. One such structure is the nuclear lamina (NL), which coats the inner nuclear membrane and is composed of lamins and membrane-associated proteins, such as Lamin B receptor (LBR). Large blocks of heterochromatin are associated with the nuclear periphery, and mapping genome interactions with laminB1 identifies more than 1000 lamina-associated domains (LADs).

One situation in which there is a dramatic reorganization of heterochromatin is in oncogene-induced senescence (OIS) - a cell cycle arrest program triggered by oncogenic signaling. OIS cells undergo striking chromatin reorganization with loss of heterochromatin and constitutive LADs from the nuclear periphery and the appearance of internal senescence-associated heterochromatin foci (SAHFs). SAHFs are not observed in nontransformed replicating cells.

The nuclear envelope is perforated by nuclear pores that control transport between the cytoplasm and nucleus. The nuclear pore complex (NPC) is a large transmembrane complex consisting of ∼30 proteins called nucleoporin. The nuclear area underneath nuclear pores is devoid of heterochromatin. The nucleoporin TPR has been shown to be responsible for heterochromatin exclusion zones at the NPC.

The composition and density of the NPC change during differentiation and tumorigenesis. We therefore hypothesized that the NPC could contribute to global chromatin organization and that, specifically, heterochromatin organization could result from a balance of forces attracting heterochromatin to the NL and forces repelling it away from the NPC. In support of this hypothesis, we show here that nuclear pore density increases during OIS and that this increase is necessary for heterochromatin reorganization into SAHFs. We identified TPR as a key player in this reorganization. Furthermore, we demonstrated the functional consequences of heterochromatin reorganization in OIS for the programmed activation of inflammatory cytokine gene expression: the senescence-associated secretory phenotype (SASP).

Ichor Therapeutics, led by Kelsey Moody, was one of the first companies to emerge from the core SENS Research Foundation community. The company has grown over the years and is now at the head of a collection of spin-out startups focused on a variety of approaches to aging, such as senolytic therapies to destroy senescent cells (Antoxerene), and clearance of a form of metabolic waste that contributes to macular degeneration (LysoClear). The influx of funding in this field that has taken place over the past couple of years is now powering Ichor Therapeutics forward towards the clinic.

Ichor and its portfolio companies have been very busy over the last year, so I thought it was time that we caught up on progress. Can you tell us how things are going for the Ichor group?

Ichor really had a good year in 2018. We raised over $16 million across our portfolio, and that's allowed us to scale up all aspects of our operations. We're at over 50 employees now, mostly bench scientists and research technicians, and we're really delivering on our goal of being a vertically integrated biopharmaceutical company. What that means is we want to be able to take any idea, regardless of what it is, such as a type of compound or therapeutic indication, and rapidly turn it from the discovery stage, through the pipeline, into the first demand studies. The additional capital that we've raised and the infrastructure that we're putting online are really allowing us to put that all together to support the field of longevity.

Juvenescence and you made a collaborative project called FoxBio. How's that going?

Unfortunately, I can't say a whole lot about the progress on FoxBio, except to say that I'm very, very bullish on it and very excited about the prospects and implications. We are very excited to partner with Juvenescence due to the depth of experience that they bring to the drug discovery process and the insights that they have about creating not just strong drug development and discovery programs but also company structures and platforms that allow entities to raise the large amount of capital that is necessary for clinical trials, as it's just a huge value add to the core portfolio. We found them to be great to work with, and we're really excited to expand the scope of that relationship over time.

What's the news on Lysoclear, the therapy for adult age-related adult blindness?

Again, I can't talk a whole lot about the specifics, but we did close a financing round in December of 2018 to move from our proof-of-concept lead drug candidate to a clinical candidate that would be suitable for first-demand studies. We're in the process of putting together our plan to reach IND (investigational new drug) status. IND in the US system is the point at which you're able to go into human trials for the first time. That requires all kinds of backend support, from manufacturing your product under good manufacturing processes (GMP) to toxicology studies and so forth. We were very fortunate last year to recruit a chief medical officer who has a lot of experience in drug development and discovery. He's got about 12 drugs and medical devices under his belt and about 185 clinical trials in the macular degeneration space. We're very enthusiastic to have someone with that depth of expertise, really taking the reins on our clinical planning and making sure that when we're ready with our candidate to pull the trigger, we're able to navigate clinical and regulatory issues that might arise.

An area that has been problematic in the past has been taking the research from a basic stage to a translational point where it can then go to market. Has that improved in the last few years?

Yeah, I think so. I think there's a lot of academic labs in particular now that have an eye for spinning out companies, particularly with new groups emerging in the area. Juvenescence, of course, is licensing different types of technology and having a partnership with the Buck Institute, for example, and Life Biosciences, a new player in the space, is bringing in substantial amounts of capital to assist academic labs with translating programs. What's really exciting about all of this is when you bring these sophisticated drug developers into this space, you're adding a certain level of robustness to the discovery process that might not necessarily exist in a traditional academic setting. It really allows you to combine the best of both worlds.

How did you develop your career from someone who was a high school and college athlete to where you are now?

Well, like a lot of people that are really trying to start companies and do things in this space, I started by reading a book, Aubrey de Grey's book, in fact, Ending Aging, which I think was published a little over a decade now. I told myself that I'm going to switch to biochemistry as a major, and I'm going to pursue this line of work until I am certain that Aubrey is wrong. Despite my very best efforts, I have not been able to get to any sort of definitive conclusion on that. He still might be, and many have tried to prove him wrong, but the trend is in his favor. That, of course, took me to work with Aubrey at SENS Research Foundation and various startups in Silicon Valley and then eventually become a medical student where I currently am.

One of the really interesting things that I think is underappreciated about the SENS paradigm, and is a central component to how we're structuring our companies, is really this damage repair approach. A lot of people like the SENS damage repair approach that Aubrey put forth because it's something that we can understand and the whole argument of sidestepping the ignorance of metabolism, and so forth. What's underappreciated by most people that do drug development, that I think is worth highlighting here, is that the sorts of therapies that would emerge from this line of thinking are therapies that are going to be used intermittently, and that is hugely beneficial from a development perspective. That creates a huge opportunity for drug developers to bring in whole new classes of drugs that are actually able to mitigate many of these diseases of aging in a way that's rather unprecedented and very much defies the chronic-administration sort of model that we're familiar with in this space.

Link: https://www.leafscience.org/an-interview-with-kelsey-moody-developing-a-company-to-end-age-related-diseases/

Researchers here outline a new discovery regarding the origin of reduced blood flow in the aging brain; white blood cells are clogging up capillaries. It is well known that the supply of blood is reduced in tissues with age; this is studied in muscles and the brain, among other tissue types. Some researchers blame a reduction in capillary density in later life, others consider reduced capacity of the heart to pump blood uphill to the brain. A lesser flow of blood in any specific tissue will affect its function, especially in energy-hungry tissues such as the brain, as the supply of oxygen and nutrients is reduced.

In the case of the results reported here, I have to wonder whether this might tie in some way to the observed reduction in capillary density with age; does blockage by white blood cells result in significant capillary atrophy at the smallest scale of blood vessels? There are certainly other mechanisms by which that outcome could occur, and this may not be an important contribution even it does produce atrophy to some degree.

The existence of cerebral blood flow reduction in Alzheimer's patients has been known for decades, but the exact correlation to impaired cognitive function is less understood. "People probably adapt to the decreased blood flow, so that they don't feel dizzy all of the time, but there's clear evidence that it impacts cognitive function." A new study offers an explanation for this dramatic blood flow decrease: white blood cells stuck to the inside of capillaries, the smallest blood vessels in the brain. And while only a small percentage of capillaries experience this blockage, each stalled vessel leads to decreased blood flow in multiple downstream vessels, magnifying the impact on overall brain blood flow.

The work began with a study in which researchers were attempting to put clots into the vasculatures of Alzheimer's mouse brains to see their effect. "It turns out that the blockages we were trying to induce were already in there. It sort of turned the research around - this is a phenomenon that was already happening." The researchers determined that only about 2 percent of brain capillaries had "stalls" (blockages), but the cumulative effect of that small number of stalls was an approximately 20 percent overall decrease in brain blood flow, due to the slowing of downstream vessels by the capillaries that were stalled.

Recent studies suggest that brain blood flow deficits are one of the earliest detectable symptoms of dementia. To test the effect of the stalls on performance of memory tasks in Alzheimer's mice, they were given an antibody that interfered with the adhesion of white blood cells to capillary walls, which caused the stalled capillaries to start flowing again and thus increased overall brain blood flow. Memory function was improved within a few hours, even in aged mice with more advanced stages of Alzheimer's disease.

Link: http://news.cornell.edu/stories/2019/02/brain-blood-flow-finding-gives-hope-alzheimers-therapy

To my mind far too much effort is expended on trying to figure out the epidemiology of the tiny fraction of humans who manage to live a fair way past one hundred years of age. For one, there just aren't enough of them to generate truly robust data from which conclusions can be drawn. People are still arguing over the legitimacy of many of the cases, including Jeanne Calment. Gathering and vetting data on the age of very old people is inherently challenging in its own ways. As the authors of today's paper point out, we should be more suspicious than we are of claims of extreme longevity. You might compare their position with another recent discussion on this topic that presents similar conclusions - the quality of the data on ages of extremely old people just isn't great. But beyond legitimacy, small data sets naturally come with all sorts of other problems. The law of small numbers applies: a low number of data points tends to exhibit false trends that will vanish given more data points.

The more important issue here, however, is that this simply doesn't matter! It really is of little importance as to the statistics of how the small number of oldest humans age to death in the absence of rejuvenation therapies. It is unimportant because rejuvenation therapies will soon arrive in the clinic. The first experimental rejuvenation therapies worthy of the name are available now for the adventurous to try. It won't be long before near everyone who reaches old age will have undergone one or more forms of treatment to slow or reverse the progression of aging. The world of natural aging, in which there were no deliberate attempts to intervene in the mechanisms that cause aging, is soon to vanish. In this environment of rapid progress in biotechnology, the demographics of unmodified aging are of increasingly little importance. Instead, the focus must be on forging ahead with the development of rejuvenation biotechnology, the means to prevent and reverse the suffering and disease of aging.

Late-life mortality is underestimated because of data errors

The world longevity record for Jeanne Calment (122 years) is widely cited with great pride as the gold standard of the highest data quality for many decades. Yet even for this best documented longevity claim, some early doubts were expressed of her suspicious extremely outlying age. Still, most scientists and the public believe in the validity of the Calment longevity record. The situation is even more serious-our studies found that many longevity records for ages 105 years and older are often incorrect (see later). After age 105 years, longevity claims should be considered as extraordinary claims that require extraordinary evidence. Traditional methods of data cleaning and data quality control are just not sufficient. New, more strict methodologies of data quality control need to be developed and tested. Before this happens, all mortality estimates for ages above 105 years should be treated with caution.

Knowledge of true mortality trajectory at extreme old ages is important not only for actuaries but also for biologists who test their theories of aging with demographic data. Studies conducted in the 1990s suggest that the exponential growth of human mortality with age (the Gompertz law) is followed by a period of deceleration, with slower rates of mortality increase. These early studies, as well as studies on insects, convinced researchers of the universality of the mortality deceleration phenomenon, and until recently, there was no doubt among biodemographers and gerontologists that mortality slows down after the age of 80 years. At that time, several biological explanations of mortality deceleration and late-life mortality plateau were suggested. Reliability models of aging also suggest mortality plateau at advanced ages when assuming random loss of functional cells and other essential elements over time.

Recently, the common view about mortality deceleration at advanced ages has been challenged using both theoretical and empirical considerations. It was found that mortality of US extinct cohorts born after 1889 demonstrated the Gompertz-like trajectory in the age interval 85 to 106 years. In the study of old-age mortality in 15 low-mortality countries, Gompertz-like mortality growth was found at older ages for Australia, Canada, and the US and mortality deceleration for other studied countries.

It should be noted that hazard rate estimation at very old ages faces difficulties because of very small number of survivors to these ages, and age misreporting by older persons. Age misreporting is a big problem affecting estimates of mortality at advanced ages. It was found that even a small percentage of inaccurate data can greatly distort mortality trajectories at advanced ages and that age misreporting at older ages results in mortality underestimation. Taking into account that the accuracy of age reporting is positively correlated with education, it is reasonable to expect improvement in age reporting over time and less prevalent mortality underestimation or mortality deceleration at older ages for more recent birth cohorts. Indeed, it was found that late-life mortality in historically older US birth cohorts demonstrates stronger mortality deceleration compared to more recent birth cohorts. These results suggest that mortality deceleration observed in early studies of old-age mortality may be caused by age misreporting at older ages.

Funding is pouring into the commercial development of the first rejuvenation therapies, largely meaning senolytic treatments at the present time, alongside various ways of upregulating beneficial stress responses in order to modestly slow aging. As this progresses, we will see an accompanying growth in advocacy for the treatment of aging as a medical condition. The announcement noted here is an example of the type, somewhat analogous to the Longevity Dividend initiative of the past decade, but hopefully more energetic and more focused on strategies such as clearance of senescent cells that are likely to produce larger gains in human health and life span.

A group of leading scientists devoted to research on the mechanisms of biological aging today announced the formation of the Academy for Health and Lifespan, the first global non-profit group focused on accelerating breakthroughs in the expansion of the human health span. The Academy's mission is to set the public stage for the transformation society must make, as health span extension means a growing population fully able to live healthier lives longer. The group's plan is to accomplish its goals through awareness and education, by giving new research a platform for dissemination, and by organizing conferences and forums where the world's leaders in the study of health span and longevity will gather and share research and insights. Ultimately, the Academy will provide grants to fund promising research from established and emerging scientists.

"We believe we are at a threshold moment in the research of age-related decline, which is the timing that inspired the creation of the Academy. Our shared belief is that science shows that we can age later. The Academy is a think tank seeking to speed the rate of discoveries to expand our health spans. Our 16 founders are among the leading geroscientists in the world. In addition to raising awareness of research advances among the general public, we will encourage increased public and private investment in health span and longevity research throughout the globe."

The Academy embraces a 4C mission: First to Catalyze the world's ongoing research to accelerate the development of life-changing enhancements of healthy aging. Second to Connect our founders to each other through the auspices of the academy. The third C: Convene experts and authorities around the world to advance their missions and that of the Academy's in public and private settings. Finally, we shall Communicate with the public at large to educate them about this new generation of health span and longevity research, what it means and what it doesn't mean, and to engage in constructive conversations. "As founders of AHLR, we believe that, as the field rapidly advances, we must help bridge the gap between science and public understanding. We believe that while death is inevitable, aging need not be."

Link: https://www.ahlresearch.org/news/2019/2/13/16-longevity-scientists-have-a-valentines-day-message-for-the-world-announcing-thenbspacademy-fornbsphealth-and-lifespan-researchnbsp

Since ketosis is argued to be a component of the effects of calorie restriction, responsible in some part for the reliable benefits to health and longevity that result, some research groups have investigated ways to induce ketosis via treatment rather than via diet. This is a subset of broader efforts to produce calorie restriction mimetic drugs that mimic some of the effects of a low calorie diet on cellular metabolism. With the funding now pouring into the biotech startup arena, it was inevitable that some of it would make its way towards work on aspects of calorie restriction that was ready to make the leap to commercial development, and here Juvenescence and the Buck Institute have chosen to wrap a company around some of their work on ketosis.

I will say that I think the scope of benefits that can be produced via calorie restriction mimetic development is limited. We know what calorie restriction itself does in humans: it is significantly beneficial for long-term health, reduces risk of age-related disease, but doesn't extend human life span by more than a few years. We don't know just how many years, but we do know that it can't be a very large number of years, because otherwise that outcome would have been discovered long ago. Further, mimetics only capture a fraction of the benefits; calorie restriction works through countless changes to the operation of metabolism.

Thus I believe that working in this field will do little to nothing to change the shape of human life. It will produce only an incremental improvement above the state of medicine and aging that presently exists - and is unlikely to produce a larger effect than the actual practice of calorie restriction. In an age of biotechnology, with clear guides to ways in which to produce reversal of aging via repair of molecular damage, we can and should aim to achieve far more than mimicking the effects of a good diet.

Jim Mellon's crew at Juvenescence has found its latest venture idea in a popular diet making its rounds in biotech circles. Once again teaming up with the Buck Institute for Research on Aging, Juvenescence has launched BHB Therapeutics to explore preventative medicines that have potential to protect against age-related disease by inducing a state of ketosis, where the body burns fat instead of carbohydrates, spurring the production of anti-inflammatory ketone bodies. In particular, the biotech startup will focus on the ketone body beta-hydroxybutyrate, or - you guessed it - BHB.

Eric Verdin, the Buck president and CEO whose research inspired another Juvenescence spinout, has discovered that BHB helps the body respond to stress. A ketogenic diet - which has been heralded for its effects in weight loss, hunger suppression as well as concentration - and the consequent long-term exposure to ketone bodies can also extend healthy lifespan in model systems. Buck researchers have generated "hard scientific data" in mice that show ketosis can be cardio-protective. "The reason we think that cardio-protection may translate to humans is because if given sugar or ketones, many people's hearts prefer ketones, whereas the brain is the opposite. If given the option between sugar or ketones, the brain will take sugar. Unfortunately, individuals when they hit 50 (plus or minus a couple years) they become insulin resistant - and then the sugar can go seriously high in a variety of organs and that leads to a variety of different pathologies."

Just days ago, Juvenescence unveiled the first $46 million tranche of a promised $100 million raise that's designed to bankroll longevity projects with the collective goal of extending the human lifespan to 150 years. So far, it's ticked off stem cell tech and organ regeneration among the fields it's established itself through joint ventures with AI groups - Insilico and Netramark - and controlling interests in AgeX and LyGenesis. The goal is to have 18 projects underway by the end of the year. Look for two or three of them to be announced over the next few weeks.

Link: https://endpts.com/keto-in-a-pill-juvenescence-debuts-anti-aging-joint-venture-with-the-buck-dedicated-to-inducing-ketosis/

Today's open access paper is well worth reading through completely; the middle sections are a good consideration of how specific mechanisms and diseases in aging feed upon themselves to progress ever faster over time. Aging is a process of damage accumulation. The damage itself is comparatively simple; aging is complex because cellular biology is complex, not because its causes are complex. Consider rust in a baroque metal structure of many parts. Rust is very simple, but the way in which the structure falls apart over time is not simple. That is a function of the structure, not the rust. This is why I favor developing means to repair damage, as close to the root causes of aging as possible, rather than trying to adjust the operation of metabolism to resist the damage. Repair is an easier task, and should also be more effective when successful.

Anyone who has owned, used, and maintained machines has a good idea of the pattern of aging of any complicated system. Wear is slow at the outset, and then it accelerates into consequences and dysfunction quite quickly at the end of the machine's working life. Damage causes further damage, and different types of damage interact to produce a worse outcome than would be the case for either on its own. Aging is a feedback loop, an accelerating process of breakage causing further breakage. This is true in something as simple as a hammer. It is true in something as complex as our bodies, capable of self-repair.

Beyond the conclusion that addressing damage through repair is better than trying to compensate for damage, another obvious consequence of this view of aging is that prevention in the early stages is far better as a strategy than waiting until matters progress. Since damage spawns further, more complicated forms of damage, and the process accelerates, then it will be many times more costly and challenging to reverse later stages of aging. Start the repair therapies early. That is easier said than done in the present stage of development of rejuvenation therapies, of course. The first treatments worthy of the name are still uncertain, where they exist at all. Early treatment even with highly effective rejuvenation therapies means small benefits, hard to measure, and for most intents and purposes it will be indistinguishable from a treatment that didn't work at all.

Molecular mechanisms behind the rapid progression of age-related diseases

Statistical data indicate that the mortality rates due to all major age-related diseases increase exponentially with age. Researchers have hypothesized that the reason behind this self-aggravating disease progression is the indefinite repetition of reaction cycles, which increases the harm from the initially noncritical changes in the body manyfold. It is these cycles that prospective therapies might address. "Investigating the mechanisms behind age-related disease progression, one concludes that by the time the disease has been diagnosed, it is too late to address the triggering factors. Apparently the most effective strategy is to interrupt the known vicious cycles by blocking certain stages in them. Drugs doing just that are already being developed."

Researchers examined the mortality rates of patients with five most widespread diseases that tend to affect elderly people more often, leading these diseases to be widely regarded as age-related: atherosclerosis, hypertension, diabetes, Alzheimer's, and Parkinson's diseases. Mortality statistics are the most powerful and least biased tool for studying diseases, since they account for the natural progression of a disease under various life conditions across a large population. A detailed analysis of age-related diseases revealed that they progress exponentially due to reactions on the molecular or cellular level producing pathogenic products which in turn initiate the very reactions that produced them. That way the harmful products quickly multiply, and the disease progresses at an ever increasing rate, like an avalanche.

For example, nerve cells in the brain contain a small amount of a protein called alpha synuclein, which is involved in nerve impulse transmission. It may happen that the gene encoding alpha synuclein is mutated, duplicated, or triplicated in a genome. This leads to multiple protein molecules sticking to one another, forming so-called toxic oligomers, which then grow in size by attaching other alpha synuclein molecules. This process produces fibrils, which from time to time break up into oligomers, each of which eventually grows into a new fibril, etc. This chain reaction causes the number of toxic alpha synuclein oligomers to grow exponentially.

Age-related diseases as vicious cycles

Nationwide mortality and disease incidence statistics are perhaps the most powerful and least biased datasets on human diseases that we currently have. These data are derived from humans living in the complex environment and developing diseases naturally, and not from distantly related animals contained in laboratory conditions under disease-inducing regimens. I decided to use disease statistics to elucidate the underlying nature of five major ARDs: atherosclerosis, hypertension, diabetes, Alzheimer's and Parkinson's. As large-scale incidence data for these diseases is not readily available, I have instead evaluated the age distribution of mortality.

It can be seen that the exponential function provides a reasonable approximation for mortality from atherosclerosis, diabetes and Alzheimer's, but is inadequate for mortality from essential hypertension and Parkinson's. The slightly more complex but mathematically correct logistic function provides the fits that are at least as good as for the exponential function, and in addition provides the perfect fit for Parkinson's disease mortality. Finally, the sum of two logistic functions is required for the adequate fit to mortality from essential hypertension. This may indicate that essential hypertension is a heterogeneous disease composed of two major subtypes with different mortality kinetics.

This study showed that potential vicious cycles underlying ARDs are quite diverse and unique, triggered by diverse and unique factors that do not usually progress with age, thus casting doubts on the possibility of discovering the single molecular cause of aging and developing the single anti-aging pill. Rather, each disease appears to require an individual approach. However, it still cannot be excluded that some or all of these cycles are triggered by fundamental processes of aging, such as chronic inflammation or accumulation of senescent cells. Nevertheless, experimental data showing clear cause and effect relationships between fundamental aging processes and ARDs are still missing.

It could also be that the above-mentioned fundamental aging processes themselves are mediated by positive feedback loops. For example, chronic inflammation can amplify itself similarly to autoimmune diseases via cytokines and epitope spreading. Cellular senescence can propagate from cell to cell in a chain-reaction fashion via cytokines and reactive oxygen species. DNA damage may amplify by affecting the genes of more and more DNA repair enzymes. Accumulating intracellular garbage may impair the lysososmal function, leading to ever-accelerating garbage accumulation. However, to test these propositions, longitudinal data on the kinetics of corresponding processes should be obtained.

It seems reasonable to think that sabotaging the lengthening of telomeres might prove to be the basis for a universal cancer therapy, capable of shutting down all cancers. Unfettered telomere lengthening is required by all cancers in order to permit rampant replication and growth. Without that capability, the cancer will wither. Telomere length is a part of the mechanism limiting cell replication; cells lose a little of that length with each cell division, and short telomeres force senescence or self-destruction via programmed cell death. In normal tissues only stem cells use telomerase in order to maintain lengthy telomeres. Cancer cells abuse telomerase and the normally silent alternative lengthening of telomeres (ALT) mechanisms in order to bypass the usual restrictions on cell replication. Given this, we should all be most interested in any signs of a way to safely suppress telomerase, as in the research reported here.

The ends of chromosomes are covered with a kind of safety caps - telomeres. These are compact DNA sequences that stabilize chromatin structure. With each cell division telomeres become shorter, and the older a cell, the shorter are the telomeres of its chromosomes. However, certain types of cells (e.g. germ cells, stem cells, and lymphocytes) have an active immortality enzyme called telomerase. It compensates for the shortening of telomeres and allows the cells to divide practically endlessly. The highest telomerase activity is observed in cancer cells - this is one of the factors that makes them malignant.

Biochemists have now demonstrated that the activity of telomerase may be reduced using specific oligonucleotides (short DNA fragments). "We wanted to find out whether the oligonucleotides in charge of splicing shift (splicing is the process of cutting and reattaching of mRNA segments) are able to slow down the activity of telomerase. We studied it on the example of human T-lymphocytes. As a result, we managed to find an oligonucleotide able to actively suppress telomerase and slow down cell proliferation without killing the cells."

The main way of influencing the activity of telomerase is associated with the inducing of alternative splicing of its mRNA. As a result of this process several non-active protein forms are synthesized in a cell. The biochemists affected the alternative splicing using three types of oligonucleotides specific for different regulatory areas of telomerase mRNA. They were injected into human T-lymphocyte cells, and the activity of telomerase was measured after one day. It turned out that individual oligonucleotides did not influence the enzyme considerably, but the combination had a profound effect: the activity of telomerase reduced to 50% within the first 24 hours, to 18% - within the second, and to 10% - within the third.

Link: https://www.eurekalert.org/pub_releases/2019-02/ru-rbf021119.php

Hematopoietic stem cell transplant (HSCT) is, in essence, a way to replace a person's immune system. These stem cells give rise to all of the immune cells in the body. There are numerous reasons why HSCT is a traumatic procedure, with a comparatively high risk of death, and thus only widely used for very severe diseases. One of them is the struggle to rebuild the immune system rapidly enough for the patient not to succumb to infection; this is particularly challenging in old patients, where the thymus is much diminished and the pace of T cell creation is slowed in comparison to youth. The thymus is where thymocytes produced by hematopoietic stem cells go to mature into T cells, and the rate of production depends on the amount of active thymic tissue that remains. Another issue is the need for aggressive chemotherapy to clear out the existing population of hematopoietic stem cells prior to transplantation, which in and of itself bears risk, particularly to older, frail individuals.

Nonetheless, swapping out the existing immune system for a new one is has many potential uses, far more than are presently actively addressed by the medical community. It is a way to control autoimmunity, suppressing that condition for years, based on results from trials against type 1 diabetes. Of greater interest to our community, rebuilding the damaged immune system of an older person via HSCT should be capable of reversing many of the issues associated with immune aging. (Though it really should be combined with some way of restoring the thymus to greater levels of T cell production). If there was a way to make HSCT safer, to remove the risk and side-effects, then many more people could undergo the procedure whenever issues of aging or autoimmunity made it beneficial.

An antibody-based treatment can gently and effectively eliminate diseased blood-forming stem cells in the bone marrow to prepare for the transplantation of healthy stem cells. The researchers believe the treatment could circumvent the need to use harsh, potentially life-threatening chemotherapy or radiation to prepare people for transplant, vastly expanding the number of people who could benefit from the procedure.

The study is one of two indicating that an antibody targeting a protein called CD117 on the surface of blood-forming, or hematopoietic, stem cells can efficiently and safely eliminate the cells in mice and non-human primates. CD117 is a protein found on the surface of the stem cells. It regulates their growth and activity; the antibody, called SR1, binds to the protein and prevents its function. The results of these studies set the stage for a clinical trial of the antibody in children with an immune disorder called severe combined immunodeficiency.

Often the best chance for a cure for this and other diseases originating in the bone marrow is to eliminate the patient's own defective hematopoietic stem cells and replace them with healthy stem cells from a closely matched donor. But in order to do so, the patient must be able to withstand the pre-treatment, known as conditioning. Most conditioning regimens consist of a combination of chemotherapy and radiation in doses high enough to kill stem cells in the marrow. The researchers studied a mouse model of a class of human diseases called myelodysplastic syndromes, or MDS. People with MDS are unable to make mature, properly functioning blood cells and the only cure is a stem cell transplant. The disease primarily affects older adults, who are more likely than younger people to have additional, complicating medical factors and who are less likely to withstand the conditioning regimen.

The anti-CD117 antibody SR1 recognizes CD117 on the surface of hematopoietic stem cells isolated from either healthy donors or from patients with MDS. The researchers found that the antibody blocked the growth of both healthy and diseased stem cells in a laboratory setting. Then, the researchers investigated the effect of SR1 treatment on mice that were engineered to have a hybrid blood systems consisting of both human and mouse hematopoietic stem cells. They found in the mice that SR1 quickly and efficiently eliminated both healthy human hematopoietic stem cells and cells isolated from low-risk MDS patients. In those animals with diseased human stem cells, SR1 pre-treatment significantly improved the ability of healthy hematopoietic stem cells to engraft after transplantation.

Link: http://med.stanford.edu/news/all-news/2019/02/antibody-could-increase-cure-rate-for-blood-immune-disorders.html

Farming animals is morally dubious, to say the least, but we live in a world in which most people are accepting of this practice. That doesn't make it right, and I think that this will change in the future. For now, however, anyone who finds farming animals for meat ethical should also consider it ethical to create genetically altered animals that contain either human organs or organs that can be humanized. The purpose in doing this is to provide a large supply of organs for transplantation, alleviating the present shortage of organs for that purpose. This is not the only approach, of course. Many research groups are working towards the growth of new organs from tissue samples, where the creation of blood vessel networks sufficient to support larger tissue sections is the biggest challenge. Others are investigating the use of decellularization to expand the pool of donor organs by recovering those that are damaged and would normally be discarded.

But back to sourcing organs from animals, there are a number of ways to obtain organs for transplantation in this way. The first is to use decellularization with an appropriately sized organ, and pigs are a useful species in this respect. The pig cells are stripped away, leaving the extracellular matrix and its biochemical cues. Human cells of the necessary types, derived from the transplant recipient, are introduced to repopulate the organ. This line of development is still somewhere in progress, as other species have a handful of problematic proteins in the extracellular matrix. At least one group is farming genetically engineering pigs that lack these proteins.

The other approach is noted in the research materials here, which is to create animal lineages in which human organs are growing. This may also require some additional work to remove problem proteins before an organ can be transplanted, and is further behind the decellularization and genetically engineered pigs approach. Nonetheless, it seems equally viable. It is an open question as to which of these various lines of research and development will prosper in the clinic, and when, in the years ahead. Still, I would say that farming organs is a stop-gap technology, something that will be replaced with the creation of organs from patient cells.

Researchers one step closer to growing made-to-order human kidneys

For patients with end-stage renal disease, a kidney transplant is the only hope for regaining quality of life. Yet many of these patients will never undergo transplant surgery thanks to a chronic shortage of donor kidneys. But researchers have been working on ways to grow healthy organs outside the human body. One such method, called blastocyst complementation, has already produced promising results. Researchers take blastocysts, the clusters of cells formed several days after egg fertilization, from mutant animals missing specific organs and inject them with stem cells from a normal donor, not necessarily of the same species. The stem cells then differentiate to form the entire missing organ in the resulting animal. The new organ retains the characteristics of the original stem cell donor, and can thus potentially be used in transplantation therapy.

Initial attempts by the researchers to grow rat kidneys in mice proved unsuccessful, as rat stem cells did not readily differentiate into the two main types of cells needed for kidney formation. However, when the reverse scenario was attempted, mouse stem cells efficiently differentiated inside rat blastocysts, forming the basic structures of a kidney. After being implanted into pseudo-pregnant rats, the complemented blastocysts matured into normal fetuses. Remarkably, more than two thirds of the resulting rat neonates contained a pair of kidneys derived from the mouse stem cells. Further screening showed that all of the kidneys were structurally intact, and at least half could potentially produce urine. "Our findings confirm that interspecific blastocyst complementation is a viable method for kidney generation. In the future, this approach could be used to generate human stem cell-derived organs in livestock, potentially extending the lifespan and improving the quality of life of millions of people worldwide."

Generation of pluripotent stem cell-derived mouse kidneys in Sall1-targeted anephric rats

Regeneration of human kidneys in animal models would help combat the severe shortage of donors in transplantation therapy. Previously, we demonstrated by interspecific blastocyst complementation between mouse and rats, generation of pluripotent stem cell (PSC)-derived functional pancreas, in apancreatic Pdx1 mutant mice. We, however, were unable to obtain rat PSC-derived kidneys in anephric Sall1 mutant mice, likely due to the poor contribution of rat PSCs to the mouse metanephric mesenchyme, a nephron progenitor.

Here, conversely, we show that mouse PSCs can efficiently differentiate into the metanephric mesenchyme in rat, allowing the generation of mouse PSC-derived kidney in anephric Sall1 mutant rat. Glomerular epithelium and renal tubules in the kidneys are entirely composed of mouse PSC-derived cells expressing key functional markers. Importantly, the ureter-bladder junction is normally formed. This data provides proof-of-principle for interspecific blastocyst complementation as a viable approach for kidney generation.

The role of oxidized lipids in aging is often studied in the context of comparative biology, comparing different species with divergent life spans in order to try to identify the properties of cellular metabolism that are most influential on life span. It appears that the degree to which lipids are resistant to oxidative reactions is an important factor, and this has given rise to the membrane pacemaker hypothesis. There is something in mitochondrial function and resilience of lipids in mitochondrial membranes to forms of damage that is important in life span, at least at the scale of differences between species. Do lipid variations have a noteworthy effect on aging and longevity within a species, however? The evidence here suggests that there is an effect, but says little about the size of the effect.

Maximum lifespan (MLSP) is a species-specific feature that may differ more than 5000-fold among animal species being about 120 years in humans. Centenarians are considered an exceptional human model of healthy aging and extreme longevity. Available evidences reveal the existence of a link between MLSP and lipids. Thus, the findings from several studies demonstrate that the membrane fatty acid profile differs between animal species (including vertebrates, invertebrates, and exceptionally long-lived animal species) and that cell membrane susceptibility to lipid peroxidation is inversely related to MLSP. Furthermore, a recent phylogenomic approach showed that genes involved in lipid metabolism have undergone an increased selective pressure in long-lived species, reinforcing the idea that cell membrane lipid profile has been an optimized evolutionary adaption.

The physiological role of ether lipids, and specially plasmalogens, is essentially linked to their function as membrane components. Thus, plasmalogens seem to play a key role in specific properties of cell membrane. Interestingly, an antioxidant effect has also been ascribed to plasmalogens. Effectively, the vinyl-ether linkage of the plasmalogens is particularly susceptible to oxidation by reactive species such as reactive oxygen species and hypochlorous acid, and thus, like a scavenger, could protect unsaturated membrane lipids (as well as lipoproteins) against oxidation.

Consequently, plasmalogens could have a modulatory effect on oxidative stress, lipid-derived inflammation and cell signalling mechanisms. Lipidomic studies reveal that ether lipids are inversely associated with genetic peroxisomal disorders, and also suggest that they are negatively associated with prevalent disease states such as obesity, prediabetes, type 2 diabetes mellitus, cardiovascular disease, cancer and Alzheimer's disease, among others. Notably, these pathological states share as common trait an increased oxidative stress, and a potential mechanistic role for plasmalogens.

Although the fact that systems biology-based approaches allow a comprehensive molecular characterization of complex biological systems, up to date no targeted lipidomic studies investigating differences in plasma of exceptionally long-lived humans have been reported. To this end, we have designed a study that represents the most detailed lipidomic analysis of plasma ether lipids associated with human longevity. We discovered a particular ether lipid signature related to the condition of extreme longevity, allowing the identification of potential mechanisms and biomarkers of healthy aging.

Link: https://doi.org/10.1016/j.redox.2019.101127

The blood-brain barrier lines the blood vessels of the brain, and only very selectively allows passage of molecules to and from the brain. As is the case for all tissue structures, it fails with age. Molecular damage and cell dysfunction causes it to become leaky, and as a consequence all sorts of cells and proteins make their way into the brain to cause damage. One of these is fibrinogen, which appears toxic to brain cells. Here, researchers elaborate on previous findings, suggesting that this is an immune activation problem, and may be a significant cause of neurodegenerative conditions that exhibit significant loss of synapses, such as Alzheimer's disease.

Researchers used state-of-the-art imaging technology to study both mouse brains and human brains from patients with Alzheimer's disease. They also produced the first three-dimensional volume imaging showing that blood-brain barrier leaks occur in Alzheimer's disease. They found that fibrinogen, after leaking from the blood into the brain, activates the brain's immune cells and triggers them to destroy important connections between neurons. These connections, called synapses, are critical for neurons to communicate with one another.

Previous studies have shown that elimination of synapses causes memory loss, a common feature in Alzheimer's disease and other dementias. Indeed, the scientists showed that preventing fibrinogen from activating the brain's immune cells protected mouse models of Alzheimer's disease from memory loss. "We found that blood leaks in the brain can cause elimination of neuronal connections that are important for memory functions. This could change the way we think about the cause and possible cure of cognitive decline in Alzheimer's disease and other neurological diseases."

The team showed that fibrinogen can have this effect even in brains that lack amyloid plaques, which are the focus of diverse treatment strategies that have failed in large clinical trials. The researchers showed that injecting even extremely small quantities of fibrinogen into a healthy brain caused the same kind of immune cell activation and loss of synapses they saw in Alzheimer's disease. Interestingly, researchers recently developed an antibody that blocks the interaction between fibrinogen and a molecule on the brain's immune cells. In a previous study, they showed this antibody protected mouse models of Alzheimer's disease from brain inflammation and neuronal damage.

Link: https://gladstone.org/about-us/press-releases/new-culprit-cognitive-decline-alzheimers-disease

Scarring is an unfortunate fact of mammalian life, both following injury and throughout inner organs in old age, when the processes of regeneration and tissue maintenance run awry. Wound healing, or indeed any form of regeneration, is enormously complex. It is a dance of signals and actions carried out between numerous cell populations: various stem cells and progenitor cells; immune cells; somatic cells. These processes are similar at the high level in different tissues, but the details vary. It is far from completely mapped by the research community, as is true of most of cellular metabolism, particularly when multiple cell types are coordinating with one another.

Today's research is a good illustration of the complexities of regenerative biochemistry. When focusing down on even one class of cell in one tissue, fibroblasts in the skin, a wide variety of phenotypes and activities is revealed. Some of these apparently similar cells have arrived from far away in the body, and have very different roles from their peers of a similar type. If the mechanisms of scarring can be more carefully mapped in this way, there is perhaps the potential to reduce or prevent scars from forming. That would be a powerful technology, and probably more so for the ability to ameliorate some of the downstream damage of aging in organs rather than allowing better healing of injuries.

Study Reveals How Blood Cells Help Wounds Heal Scar-Free

Skin injuries activate rapid wound repair, which often culminates with the formation of scars. Unlike normal skin, scars are devoid of hair follicles and fat cells, and creating new hair and fat is necessary for regenerating an equivalent of normal skin. In 2017 researchers identified that adult mice can naturally regenerate nearly normal-looking skin when new hair follicles and fat cells form in healing wounds. New fat cells regenerate from myofibroblasts, a type of wound fibroblast that was previously not thought to be capable of converting into other cell types. This discovery brought renewed attention to wound fibroblasts as attractive targets for anti-scarring therapies. In the current study, the research team sought to further characterize wound fibroblasts and determine if they're all the same and equally capable of regenerating new fat cells.

"We saw that wound fibroblasts are surprisingly very diverse and that there are as many as twelve different cell sub-types. We understand their molecular signatures and are beginning to learn about their unique biology. For example, we already know that distinct fibroblast sub-types 'prefer' only certain parts of the wound. This suggests that they play specific roles in different locations within the wound, and possibly at different times during the repair process. Molecular profiling of wound fibroblasts strongly suggests that as many as 13% of them at some point in their past were blood cells that converted into collagen-producing fibroblasts, but kept residual blood-specific genes still turned on."

"What is truly novel about our observation is that these fibroblast-making blood cells, which are called myeloid cells, can reprogram into new fat cells. In essence, we observed that for wounds to achieve scar-less regeneration, the body must mobilize multiple cellular resources, which includes remotely circulating blood progenitors." Because myeloid cells can be fairly easy to harvest and enrich using existing techniques, the new findings open the exciting possibility that the skin's healing ability can be enhanced via delivery of regeneration-competent blood-derived progenitors to the site of the wound.

Single-cell analysis reveals fibroblast heterogeneity and myeloid-derived adipocyte progenitors in murine skin wounds

Traditionally, adult mammals are considered to have limited regenerative abilities and scarring is thought to be the default repair response. The notable exceptions to this rule are digit tip regeneration after amputation and neogenesis of hair follicles and fat in the center of large excisional wounds. Intriguingly, lineage studies reveal important differences in the regenerative strategies between these two systems. Epithelial and mesenchymal structures in the digit tip regenerate from several types of fate-restricted progenitors and no multipotent progenitors or lineage reprogramming events are observed. In contrast, large skin wounds demonstrate broadened lineage plasticity. Although progeny of preexisting hair-fated bulge stem cells migrate into wound epidermis, they do not partake in hair follicle neogenesis. Instead, new hair follicles regenerate from non-bulge epithelial stem cells, among other sources. Fat neogenesis is driven by lineage reprogramming of non-adipogenic wound myofibroblasts. Dermal papilla neogenesis also likely relies on myofibroblast reprogramming strategy.

Are all wound myofibroblasts identical or heterogeneous in terms of their origin, properties, and morphogenetic competence? Here, we studied fibroblast heterogeneity in the mouse model for wound-induced regeneration at 12 days post-wounding when wound re-epithelialization is completed and preceding hair follicle neogenesis. We show that wound fibroblasts can be broadly classified into two major populations on the basis of their transcription factor signatures and PDGF receptor expression patterns. Prominent additional heterogeneity exists within both populations.

Bone-marrow-derived progenitors, including myeloid cells, endothelial progenitors, and circulating mesenchymal stem cells can contribute new stromal cells toward injured tissues in various organs. In skin, studies document bone marrow giving rise to fibroblasts at the injury sites. Our data from large excisional wounds shows that the contribution from myeloid cells to wound fibroblasts is small yet significant, between 6% and 11.3%, depending on the assessment method. We also showed that at least a portion of these cells can convert into de novo adipocytes around neogenic hair follicles.

Researchers here present an interesting approach to regeneration of the brain. Rather than spur greater creation of new neurons, or delivering neurons via cell therapy, they find a way to persuade supporting cells near damaged areas to convert themselves into neurons. They have not yet demonstrated that this will work in animals to restore lost function. In situ cell reprogramming is a part of the field that has a lot of promise, but much of the experimentation has yet to be accomplished. "Reprogramming" covers a wide range of possible goals, from minor changes to encourage cells into greater activity or altered behavior within their type, to the more radical adjustments such as change of type or inducement of pluripotency. It remains to be seen which of these approaches will turn out to be viable in the near term of the next decade or so.

A simple drug cocktail that converts cells neighboring damaged neurons into functional new neurons could potentially be used to treat stroke, Alzheimer's disease, and brain injuries. A team of researchers identified a set of four, or even three, molecules that could convert glial cells - which normally provide support and insulation for neurons - into new neurons. The team previously published research describing a sequence of nine small molecules that could directly convert human glial cells into neurons, but the large number of molecules and the specific sequence required for reprogramming the glial cells complicated the transition to a clinical treatment.

In the current study, the team tested various numbers and combinations of molecules to identify a streamlined approach to the reprogramming of astrocytes, a type of glial cells, into neurons. By using four molecules that modulate four critical signaling pathways, they could efficiently turn human astrocytes - as many as 70 percent - into functional neurons. The resulting chemically converted neurons can survive more than seven months in a culture dish in the lab. They form robust neural networks and send chemical and electrical signals to each other, as normal neurons do inside the brain.

The researchers had previously developed a gene therapy technology to convert astrocytes into functional neurons, but due to the excessive cost of gene therapy - which can cost a patient half a million dollars or more - the team has been pursuing more economical approaches to convert glial cells into neurons. The delivery system for gene therapies is also more complex, requiring the injection of viral particles into the human body, whereas the small molecules in the new method can be chemically synthesized and packaged into a pill.

Link: http://science.psu.edu/news-and-events/2019-news/Chen2-2019

This fascinating open access paper investigates a role in aging for DNA fragments that have escaped the cell nucleus, for underlying reasons probably related to stochastic nuclear DNA damage, but yet to be comprehensively explored. They may contribute to cellular senescence and the chronic inflammation generated by senescent cells, and this is accomplished by activating an innate immune sensor, cGAS-STING. This innate immune mechanism is already strongly linked to the bad behavior of senescent cells. The most interesting portion of the work here is the prospect for cleaning up extranuclear DNA fragments via some form of molecular therapy, and therefore dampening the consequence. The researchers demonstrate a proof of principle, and it would be interesting to see this explored further in naturally aging mice.

Subclinical but heightened inflammation is observed in aging tissues, and in the blood of older adults in large epidemiologic studies, with consistently higher basal levels of C-reactive protein and abundant pro-inflammatory cytokines. Such alteration is often viewed as non-cell autonomous, for example senescent cells, which increase with aging, may modulate inflammation through secretion of cytokines (i.e., senescence-associated secretory phenotype, SASP. The intrinsic processes that initiate this inflammation in aging remain largely unknown.

We previously described a cell-autonomous process in which damaged nuclear DNA is trafficked to the cytosol, transported via autophagy, and degraded by lysosomal nuclease DNASE2A. Excess DNA accumulated under conditions of increased damage, defective degradation, or autophagy blockade can activate the STING pathway leading to inflammation. DNA damage has been postulated to be a major cause of cellular aging. We hypothesize that cumulative damage may generate excess DNA leading to persistent inflammation in aging cells through a similar mechanism. Several observations in senescence seem to agree with our prediction. Unrepaired or persistent double-stranded breaks (DSBs) can be found in senescing cells, and cells are known to senesce upon DNA damage. Senescent nuclei also undergo dramatic chromatin changes with fragments budding off the nucleus.

We found that older cells harbored higher levels of extranuclear DNA compared to younger cells. Extranuclear DNA was exported by a leptomycin B-sensitive process, degraded through the autophagosome-lysosomal pathway and triggered innate immune responses through the DNA-sensing cGAS-STING pathway. Patient cells from the aging diseases ataxia and progeria also displayed extranuclear DNA accumulation. Removing extranuclear DNA in old cells using DNASE2A reduced innate immune responses and senescence-associated β-gal enzyme activity. We hypothesize a direct role for excess DNA in aging-related inflammation and in replicative senescence, and propose DNA degradation as a therapeutic approach to remove intrinsic DNA and revert inflammation associated with aging.

Link: https://doi.org/10.1111/acel.12901

Cells become senescent in response to a toxic environment, or during regeneration, or when damaged in ways that may increase cancer risk, but the vast majority are created when cells reach the end of their replicative life span, the Hayflick limit. Senescence is irreversible, and a senescent cell is blocked from further replication. In all these cases, near all newly senescent cells are soon destroyed, either by their own programmed cell death mechanisms, or by the immune system. A tiny fraction lingers, however. Senescent cells are very metabolically active, secreting a potent mix of molecules that disrupts tissue structure, produces chronic inflammation, and encourages nearby cells to also become senescent. This is just fine in the short-term context in which a cell becomes senescent: it assists regeneration, or helps protect against cancer, and so forth, and then it is gone when the senescent cells are destroyed. But when a small but growing number of senescent cells remain alive, and their secretions continue, day in and day out, their presence becomes very harmful. In fact, long-lasting senescent cells are one of the causes of aging and age-related disease.

Senolytic therapies are those that can selectively destroy senescent cells without impacting normal cells to the level of producing significant unwanted side-effects. A number of chemotherapeutics appear safely senolytic when taken as a single dose or in short dosing periods. Since the therapy destroys all of the problem cells it can reach immediately, and senescent cells accumulate only very slowly, treatment can be very intermittent. The research community has demonstrated senolytic therapies to extend life in mice, and to reverse measures of many age-related diseases.

The paper here is one example of many lines of work focused on understand exactly how senescent cells are harming tissues, and the degree to which senolytic therapies can reverse this process. The authors are focused on the aging of the heart, something that senescent cells appear to contribute to significantly. There are a number of very interesting observations in this data. Firstly, the evidence strongly suggests that senescent cells in the heart are larger than their normal peers. You might recall that a research group last year produced a method of counting senescent cells in a blood sample that worked via size-grading, as senescence immune cells are larger than normal immune cells. It is interesting to see this phenomenon in another senescent cell type, and makes me ponder how to build a decent clinical assay based on cell size for other tissues. Secondly, removing senescent cells from the heart reversed cardiac hypertrophy. I think that this is a big deal. The growth and weakening of heart muscle that occurs in response to the damage of aging was one of the line items that I suspected would be hard to repair once it had happened. If this problem to even some degree fixes itself, given a more youthful tissue environment, that is very pleasing to hear.

Scientists are killing zombie cells to reverse age-related damage in the heart

Ageing is one of the main risk-factors for heart failure, as older people are more likely to develop heart disease and don't recover as well following a heart attack. New research explores how senescent cells - also known as zombie cells - form in the heart during ageing and lead to heart failure. Zombie cells occur all over the body as it ages. They get their nickname from the fact that although they are not dead they do not function correctly and can cause other cells around them to become senescent (or zombiefied!) Elsewhere in the body, zombie cells are usually caused by the shortening of structures found at the end of chromosomes called telomeres, which happens progressively each time a cell divides. But as heart cells - cardiomyocytes - rarely divide it was not known if or how these cells could become senescent.

"Previously, it was believed that senescence occurs only as a result of a lifetime of cell division and the shortening of telomeres. Our data support the very exciting idea that heart cells can become senescent due to stress that damages their telomeres rather than the process of division. This mechanism could also explain how other non-dividing cells in our bodies age. We saw that removing senescent cardiomyocytes from the hearts of aged mice, both genetically and using drugs, was able to restore cardiac health - essentially removing the damage caused by ageing. This data provides critical support for the potential of using medicines to kill zombie cells. If this is validated through clinical trials it would provide us with a new way of treating cardiac diseases.

Length-independent telomere damage drives post-mitotic cardiomyocyte senescence

To investigate further the therapeutic impact of targeting senescent cells to counteract cardiac ageing, we treated aged wild-type mice with the previously described senolytic drug, ABT263 (navitoclax) intermittently for 2 weeks. We found that navitoclax reduced telomere dysfunction in cardiomyocytes without affecting telomere length. Similarly, to genetic clearance of p16Ink4a cells in INK-ATTAC mice, we found that navitoclax significantly reduced hypertrophy and fibrosis in aged wild-type mice. However, navitoclax had no significant impact on cardiac function, left ventricle mass and ventricle wall rigidity.

The decrease in mean cardiomyocyte size without significant changes in left ventricle mass suggested a compensatory increase in overall cardiomyocyte number. Supporting de novo cardiomyocyte proliferation, we observed that frequency distribution analyses of cardiomyocyte cross-sectional area suggested that the decrease in mean cardiomyocyte area following navitoclax treatment is a function of both an elimination of the largest cardiomyocytes, presumably as these are senescent, and the appearance of a "new" population of small cardiomyocytes.

A number of research programs in recent years have pointed to an increased level of retrotransposon activity with aging. Retrotransposons are DNA sequences that can copy themselves to different locations in the genome, a parasitic addition that originated deep in evolutionary history. Retrotransposons are normally suppressed in youth, but increased retrotransposon activity occurs in later life, and is thought to bring disarray to cellular function. As is the case for most observed aspects of aging, there is plenty of room to debate just where retrotransposon activity sits in the complex web of cause and consequence.

Researchers here note that one class of retrotransposons escapes suppression in senescent cells, and this increased activity is important to the senescence-associated secretory phenotype (SASP) by which lingering senescent cells cause great harm to surrounding tissues. The SASP is highly inflammatory, and chronic inflammation is responsible for much of the downstream harms of aging. Removing senescent cells is the present preferred approach to building rejuvenation therapies capable of turning back age-related inflammation, but a sizable contingent of researchers are nonetheless interested in finding ways to dial down the SASP. This seems a more challenging task, one that will proceed increment by increment, as this is a very complex phenomenon.

Retrotransposons are related to ancient retroviruses that, when left unchecked, can produce DNA copies of themselves that can insert in other parts of a cell's genome. Cells have evolved ways to keep these "jumping genes" under wraps, but as the cells age, the retrotransposons can escape this control. A research team has now shown that an important class of retrotransposons, called L1, escaped from cellular control and began to replicate in both senescent human cells - old cells that no longer divide - and old mice. Retrotransposon replication, specifically the DNA copies of L1, is detected by an antiviral immune response, called the interferon response, and ultimately triggers inflammation in neighboring cells.

These retrotransposons are present in every type of tissue, which makes them a compelling suspect for a unified component of cellular aging. Understanding that, the team uncovered the interferon response, the potential mechanism through which these jumping genes may cause cellular inflammation without necessarily causing damage to the genome. The interferon-stimulating copies of L1 DNA require a specific protein called reverse transcriptase. HIV and other retroviruses also require reverse transcriptase proteins to replicate. In fact, AZT, the first drug developed to treat HIV/AIDS, halts HIV reverse transcriptase. Researchers thought that this class of drugs may keep the viral-like L1 retrotransposon from replicating and thereby prevent the inflammatory immune response.

One generic HIV drug, lamivudine, stood out because of its activity and low side effects. Growing human cells in the presence of lamivudine did not impact when the cells reached senescence or kill the senescent cells. But lamivudine did decrease the interferon response and the late-stage senescence-associated secretory phenotype (SASP) - the important characteristics of senescent cells that promote inflammation in their neighbors. "When we started giving this HIV drug to mice, we noticed they had these amazing anti-inflammatory effects. Our explanation is that although L1s are activated relatively late in senescence, the interferon response reinforces the SASP response and is responsible for age-associated inflammation."

Link: http://news.brown.edu/articles/2019/02/aging

The largest institutions are always the most conservative, late to the party. Even now, as clearance of senescent cells is shown in mice to increase life span and reverse measures of aging and many age-related diseases, and an industry of senolytic therapies is pulling in hundreds of millions in venture funding, support from the major institutions of aging research for targeting the causes of aging is lukewarm and very carefully worded. This is the way of things, unfortunately. Still, there is clearly movement in the right direction.

Medical care for older adults has long focused on preventing and treating chronic diseases and the conditions that come with them. But now, geriatrics researchers and clinicians hope a new understanding - one honed at a conference hosted by the American Geriatrics Society (AGS) and the National Institute on Aging (NIA) - can lead to better and more effective interventions by targeting the aging process itself rather than discrete conditions or concerns. "Aging is complex and varies from one person to the next, but there's a growing body of evidence that aging itself is driven by interconnected biological factors we call 'hallmarks' or 'pillars'. We believe disrupting these hallmarks - which cover everything from the stability of our genes to ways our cells communicate - can contribute to chronic disease and frailty, which is why a better understanding of how they work is so important."

Rather than beginning with the discrete health conditions and concerns common among older adults, conference organizers took the unique approach of focusing on aging itself as a primary factor impacting multiple chronic diseases and the declining ability to rebound from health challenges (also known as "resilience"). In doing so, scholars advanced our understanding of the concept that targeting age-related mechanisms might delay, prevent, or even reverse geriatric syndromes, age-related chronic diseases, and declines in resilience. Conference sessions also focused on new methods and strategies for studying these aspects of aging, and reviewed the challenges of studying age when older people often have been excluded from medical research.

Link: https://www.americangeriatrics.org/media-center/news/report-prestigious-nih-funded-conference-looks-biological-pillars-aging-better

Senolytic compounds selectively destroy senescent cells to some degree, and thus achieve a narrow form of rejuvenation, as accumulation of senescent cells is one of the root causes of aging. Senolytics produce a reliable reversal of age-related disease and extension of life in mice. As in all such things, quality varies widely: there will be a very large number of marginal senolytics that we should all ignore by the time the first enthusiastic wave of research, exploration, and clinical development is done. Of the senolytic compounds that do have sizable enough effects to care about, and for which there is published data, their effect sizes are at present all in the same ballpark - up to 50% clearance of lingering senescent cells, varying widely tissue by tissue. Another interesting point to consider is that data on senolytic effects in cell cultures is a poor guide as to how well these compounds do in mice. Further, we don't yet know how much variation in effectiveness to expect going from mice to humans.

Fisetin is a supplement that is widely used. Given the recent discovery that fisetin is significantly senolytic in mice - about as good as the dasatinib and quercetin combination - at doses that are ten to twenty times higher than the usual supplement dose used by a great many humans, how should we adjust our expectations regarding the wide range of natural compounds that have been shown in the past to very modestly slow aging or reduce risk of age-related disease in mice? How many of those are in fact senolytic? How many will become meaningfully senolytic if used at much higher doses than is common? These are questions without answers at the present time; the odds are unknown. In the case of curcumin and its analogs, however, I'm much more dubious than I am regarding whether or not fisetin will turn out to be usefully senolytic in humans. Curcumin has a much longer history of widespread use, and it seems unlikely that humanity would have failed to discover that high doses were a reliable treatment for age-related disease, were it as senolytic in humans as fisetin is in mice.

Nonetheless, researchers are now investigating a range of natural compounds and their derivatives that have been claimed to affect aging in mice, even to only very small degrees, and curcumin and its analogs are in that list. This is one of many programs of dubious utility that obtain far too much funding and interest in comparison to the benefits they might plausibly delivery. My suspicion is that this will turn out to be an exercise of largely academic interest, better categorizing a range of marginal ways to influence aging, but until such time as fisetin is rigorously tested in humans, there is always that to point to as a counterargument. Further, since it is much cheaper to develop natural compounds, there will always be those who choose to fish in the shallows just because it is easier to fish in the shallows, regardless of the fact that the rewarding catches are only found further out. This is exactly why we have more research into curcumin than into many of the branches of SENS rejuvenation research. It is a waste in the grand scheme of things, a distraction, but it will nonetheless occupy a great deal of time and resources.

The curcumin analog EF24 is a novel senolytic agent

The mechanisms by which senescent cells (SCs) accumulate with aging have not been fully understood but may be attributable in part to immune senescence that decreases the ability of the body to clear SCs. Although cellular senescence is a tumor-suppressive mechanism, SCs can play a causative role in aging and age-related diseases when they accumulate. This suggestion is supported by the finding that genetic elimination of SCs in naturally aged mice through a transgene can delay various age-dependent deterioration in tissues and organs and extend their lifespan.

This seminal finding stimulates research to identify small molecules termed senolytic agents that can selectively kill SCs as potential therapeutics for age-related diseases. To date, several classes of senolytic agents have been identified, and most of them are natural compounds such as quercetin, fisetin, and piperlongumine. Because natural senolytic compounds have the advantages of low toxicity, they may have a better chance to be translated into clinic to treat age-related diseases or can be used as a lead for the development of more specific and potent senolytic agents.

Curcumin, a natural compound extracted from turmeric, has a broad range of biological and pharmacological activities, including antioxidant, anti-inflammatory, antimicrobial, and anti-cancer activities. Numerous studies suggest that curcumin has some health benefits in delaying aging and may be useful in preventing and treating age-related diseases. For example, curcumin was shown to prolong lifespan and extend healthspan in Drosophila melanogaster and Caenorhabditis elegans. To improve the bioavailability and biological activity of curcumin, many curcumin analogs were developed, including EF24, HO-3867, 2-HBA, and dimethoxycurcumin, which have been demonstrated to be more active than curcumin in preventing and treating various diseases and reducing age-dependent deterioration. However, the mechanisms of their anti-aging action have not been fully elucidated.

We hypothesized that curcumin and its analogs may increase healthspan in part by functioning as novel senolytic agents. Therefore, in this study, we examined the senolytic activity of several curcumin analogs and found that EF24 is a novel potent and broad-spectrum senolytic agent in cell culture. We show that EF24 can selectively reduce the viability of human SCs from different tissue origins and induced by different stresses. Its senolytic effect is likely attributable to the induction of apoptosis via proteasome-mediated downregulation of the Bcl-2 anti-apoptotic family proteins such as Bcl-xl. These findings provide new insights into the mechanisms by which curcumin and its analogs function as anti-aging agents and suggest that the curcumin analog EF24 has the potential to be used as a novel senolytic agent for the treatment of age-related diseases.

Some of the Life Extension Advocacy Foundation folk were at the recent Longevity Leaders conference in London, and wrote up a report on the event. The conference split up into three streams later in the day, one of which is followed here. Being focused on the pensions and life insurance industries as much as biotechnology, there were a lot of people present with minimal exposure to the prospects for rejuvenation and slowing of aging. It was noteworthy to see so many there being newly interested in the topic of treating aging as a medical condition, and motivated to learn more because it is important to their work in other areas of endeavor.

The conference was quite broad in scope and included people from the aging research community, the pharmaceutical industry, general healthcare, and the business and insurance fields. Speaking of insurance companies, it was interesting that the large insurance companies Prudential and Legal & General were both sponsoring the event; Prudential had even produced an interesting booklet for guests with the title "Prepare for 100" boldly on the cover. The book went on to talk about the changes coming to medicine and how people could soon be living longer than ever before thanks to the new medical approaches that are currently being developed.

Dr. Aubrey de Grey was in fine form as usual during the keynote panel discussion at the start of the event, just as he was when, later that day, I had the opportunity to interview him about progress with SENS. While we will be publishing the interview I did with Aubrey later, it's a good time to share the interesting concept of damage crosstalk now. It turns out that Aubrey has become more optimistic about the medical control of age-related damage and has moved his prediction of longevity escape velocity down from 20 years to 18. Quite simply, there is increasing evidence that the different aging processes have a lot more influence and interaction with each other (crosstalk) than previously thought.

Lynne Cox, a biochemist from the University of Oxford, chaired a discussion panel with Brian Delaney, president of the Age Reversal Network and who serves on our Industry Advisory Board, and Tristan Edwards, the CEO of Life Biosciences. The discussion topics were "What's at the cutting edge of aging research and development?" and "How can we accelerate research and development and the advancement of new therapies to address aging and age-related disease?" The panel was in a round table format, and attendees were also able to directly join the discussion, which proved lively and interesting. Lynne Cox, in particular, provided some very informative details about aging research.

There was considerable discussion about senescent cell clearing therapies as well as touching upon the topic of biohacking. The general feeling was that biohacking had the potential to set the field back if people conduct it in an unscientific manner and harm themselves in the process. Indeed, this echoes our sentiment that people who self-test at home should be very careful and apply a science-based approach to what they are doing. The bottom line is that if you are not recording your biomarkers and doing things scientifically, you risk hurting yourself and are taking things on faith rather than evidence; this also has potential to harm the field and set research back, so please hack responsibly.

On a more positive note, the panel was in favor about science doing something about aging and age-related diseases, and discussion of senolytics, senomorphics (therapies that block senescent cell inflammation), and cellular reprogramming were all enthusiastically discussed, especially by the academics present. This is very welcome, and it was great to see so many academics being frank about the potential of medicine to bring aging under medical control in order to prevent age-related diseases, which is in stark contrast to a decade ago, when suggesting the idea could harm your career and get you mocked by your peers. Times have certainly changed, as more and more researchers are now focusing on how we can rise to the challenge that aging presents.

Link: https://www.leafscience.org/longevity-leaders-conference/

Apollo Ventures is one of the first wave of investor concerns focused on the treatment of aging, and the principals and staff have put a fair amount of work into building a model for finding and commercializing promising research. They also publish the Geroscience popular science site, which is a helpful act of advocacy for the wider cause. As is the case for near all bigger venture funding organizations, they have a senolytics company (Cleara Biotech) in their portfolio, and thus the SENS model for rejuvenation is advanced.

What initially attracted you to aging as a general discipline?

Through multiple, orthogonal, potentially synergistic interventions, we are able to extend the healthy lifespan of model organisms. In mice, the ablation of senescent cells can extend median lifespan by 30%. The augmentation of autophagy and the transient re-activation of telomerase yield similar rejuvenating effects. These interventions should be combined, as they may be synergistic. It is only a matter of time before these interventions are working in the clinic. This kind of evidence was enough for me to commit my career to geroscience because, many years ago, I saw that the 'writing is on the wall' - thanks to advances in molecular biology, healthy life extension is no longer science fiction. This century, geroscience will be a paradigm shift comparable to the antibiotics revolution in the last century.

What is the main challenge you have faced as a longevity investor?

Most geroscientists are not working on translational research. They are basic scientists. Basic science is the bedrock of everything we do, but it's not enough. Pharma has dropped the ball in drug discovery and development, and there is a major gap in the pipeline between academic proof-of-concept and drug development. There is not enough collaboration between biologists, chemists, and drug hunters. The transition through the 'valley of death' of drug development is where company-building venture capital firms such as Apollo Ventures can step in. For example, there are many biologists with data showing that gene X or protein Y, when modulated, has salutary effects. They might even identify a 'hit' molecule, such as a natural product or library compound that modulates the target or mechanism of action, but they usually don't partner with chemists to perform medicinal chemistry optimization, pharm/tox, and validation in multiple animal models of disease.

The other challenge is that, as investors, we don't see many established, aging-focused biotechs that satisfy our investment criteria. The science may be solid, but the team is lacking, or vice versa. There are not many experienced C-level biotech managers out there, and few understand geroscience. This will change once the field has a few clinical successes. Then the floodgates will open.

What can we expect from you and Apollo Ventures in 2019?

We will unveil a few more geroscience companies that are currently in stealth mode. Apollo will continue to build our internal team as well. We are looking for people with talent in both geroscience and biotech business management. Apollo was founded by a partnership of successful entrepreneurs and aging scientists with expertise in the biopharma and management consulting businesses. The depth of scientific expertise and biopharma business acumen within Apollo is unique in the geroscience space. Another distinguishing feature is that Apollo is focused more heavily on company building than other investors who are oriented toward investing in pre-established companies.

Link: https://www.leafscience.org/longevity-investor-network-member-spotlight-sebastian-aguiar/

LSX, a life science and biotechnology business networking organization, runs a yearly conference that took place in London this week. As a part of the festivities this year, the organizers added the Longevity Leaders event. This is one of a number of new conference series recently launched, in response to the great influx of funding and interest in the development of means to treat aging. Not all of that is rejuvenation biotechnology after the SENS model of damage repair, but a growing percentage is, even if that is near all a growing fleet of senolytics startups. A few years from now, we'll all have lost count of myriad methods of achieving rejuvenation via removal of senescent cells, scores of small molecule drug candidates and numerous startup companies. Even this first thin slice of the full rejuvenation biotechnology industry ahead of us will be massive and energetic.

The community of supporters and folk interested in the intersection of biotechnology and aging are getting quite organized; since this conference was on a Monday and thus going to see a lot of people flying in a day or two beforehand, the Aikora Health principals organized a large meet and greet for investors, entrepreneurs, and others on Sunday night. It went very well, and was a most useful addition to the normal conference schedule. I don't get over to the other side of the pond all that often, and met many new and interesting people. I came away with a great sense of anticipation on the part of the business community: they expect big things from the treatment of aging. We could all learn from this pre-conference meeting exercise, and try to make it a more commonplace occurrence in the community.

Each of the conference series related to biotechnology and aging has its own focus. Undoing Aging is the SENS rejuvenation biotechnology conference; the Ending Age-Related Diseases series has a focus on investor and entrepreneur networking in the context of scientific and technical goals; the Longevity Forum engages the broader public and has explicitly non-profit goals in advancing treatments for age-related disease; and so forth. The Longevity Leaders event was distinguished by a focus on bringing in medical insurance, life insurance, and pension industry people, particularly those who recognize that they have major, systemic, costly problems that could be solved by either (a) grasping the true scope of gains in healthy and overall life span that are possible and plausible in the near future, or (b) the introduction of partially effective treatments to control or reverse mechanisms of aging that produce gains in healthy life span.

The pensions and insurance industries could be strong allies, given the right frame of mind. They have deep pockets, and parts of the industry are capable of spending comparatively large amounts on treatments for older individuals, provided that those treatments saved them from greater losses further down the line. Given that aging produces immense costs, there must be a way to restructure these industries to both fund and benefit from any approach to rejuvenation in the old. Sadly the conference broke out into three groups for much of the day, and since I was presenting in the startup-focused group, I couldn't listen in on the insurance-focused presentations.

A number of biotechnology startup and other companies presented at the event. Insurance giant Prudential was one of the larger ones; they are clearly very engaged with this business of aging. The widely distributed Prudential advertising materials that encouraged people to think about radical life extension, living to 150, are clearly not a flash in the pan. This is an organization in which many groups understand the scope of the change that is coming, and at least some are on their way to being appropriately concerned and active. Among the startups there were Oisin Biotechnologies, Ichor Therapeutics, Repair Biotechnologies (the company Bill Cherman and I founded last year), Cleara Biotech, Senolytx, and many others. When I was up on stage to talk about Repair Biotechnologies, I was actually following right on the heels of three senolytics companies presenting in sequence: perhaps feeling a little subtle peer pressure there, given that I was discussing rejuvenation biotechnologies that had absolutely nothing to do with senescent cells.

I also participated in a very interesting round table discussion on the challenges to commercial development of therapies to treat aging at the present time - and of course what we might do to address those challenges. It was led by Sree Kant of Life Biosciences, and once again the senolytics contingent was the largest distinct group at the table. (This is something of a taste of what is to come; it seems that every group capable of the work is moving towards launching a small molecule senolytic treatment. A few years from now there will be many more startup companies in this space). Now, it is my contention that we have two major issues in development of rejuvenation therapies: (a) all of the entities involved - universities, researchers, entrepreneurs, investors - generally do a poor job of identifying and nurturing highly promising technologies that are currently in the late stages of research, but ready for the leap to a startup company, and (b) there are too few entrepreneurs capable of taking on this work, possibly an order of magnitude too few.

What leads me to this conclusion is that, as a result of my years of watching the field, I know of at least a score of languishing technologies that should be moving ahead. They are easy to find if you have a grasp of the areas of development relevant to aging. Repair Biotechnologies is working on two of them, and we obtained the rights (where that is even needed) very easily. One of them could have been developed in the 1990s, and has failed to make the leap from the labs at least twice that we know of. This sort of situation is enormously frustrating, and worse, deadly. Countless people have suffered and died of age-related diseases younger than might have been the case over the last century, and at root this is because institutions and communities are just not good at the technology transition from laboratory research to corporate development.

Considered as a model of organization, Life Biosciences is an approach to trying to make things better, though as ever I would say that many of the technologies they focus on have limited upside in the matter of human longevity. They are a structure that creates companies around research projects where the researchers have no entrepreneurial leanings, and then provides all of the support and advice to help those companies succeed. Juvenescence represents a different model, in which the companies are more independent, but the principals are still very energetically trying to solve the challenge of identifying the technical opportunities. Another approach is to build an industry-wide culture of companies that run multiple distinct projects, encapsulating each in a subsidiary company structure to obtain funding and become independently run when it achieves success, but at the head is a single team of entrepreneurs. Ichor Therapeutics, for example, now has several spin-off companies, but all of their work is managed by the founders of the original parent company. Many other groups could do this.

Overall, we seem to be in a period of acceleration, of a great influx of venture funding, almost with the tenor of optimism of the early internet years. This year is far more active than last. The people who were convinced early on that the treatment of aging will be a vast industry are well into their land-grab activities, using large funds to engage all the more obvious and high-profile research groups and funding the most evident startups. Their activities act as a signal to other capital ventures, which gravitate towards this space. That in turn will help raise the profile of the treatment of aging with other large industries, such as insurance and pensions. This is all very rewarding and sudden for those of us who went through the past twenty years of slow, incremental advocacy, one day at a time. We chipped away at the flood gates, and now they are breaking, and the speed is surprising when seen at first hand, even given that we knew intellectually that this outcome was exactly the goal.

A new fund to invest in companies working on aging recently launched, the $100 millions Longevity Vision Fund. From what has been said, and what was presented at the Longevity Leaders conference, it sounds very much as though the Longevity Vision Fund principals wish to follow in the footsteps of Juvenescence, with an initial focus on small molecule drug discovery infrastructure. Unlike Juvenescence, it will probably continue to focus on established infrastructure technologies related to age-related disease, such as diagnostics, and fairly safe work with modest benefits, such as stem cell therapies, rather than invest in any of the current attempts to produce rejuvenation therapies. Whether the strategy changes later, to shift to be more in line with the rhetoric on the fund website, remains to be seen. Such a shift looks somewhat unlikely based on what is said in the article here, though the details given at the conference were more nuanced.

Inspired by British billionaire Jim Mellon, chairman of anti-aging upstart biotech venture Juvenescence, Sergey Young unveiled a $100 million fund on Monday to catalyze the development of a comprehensive solution to counteract the damaging consequences of aging. The 47-year-old considers himself a product of Peter Diamandis - the man behind the non-profit XPRIZE and venture capital fund BOLD Capital Partners - and is in charge of all things longevity at both organizations. Like Mellon, who penned Juvenescence: Investing in the Age of Longevity prior to the launch of the company Juvenescence, Young is in the embryonic stage of writing his own book designed to decode the science of aging for the masses. Meanwhile, his $100 million Longevity Vision Fund will back organizations who are working on technology to reverse the aging process and prolong healthy human life.

"We are currently working on 6 deals ... and are looking at all the usual suspects in terms of themes." These areas include early detection of serious diseases using ultrasound technology; early diagnostics for heart, cancer, and neurodegenerative diseases; stem-cell and microbiome-based therapeutics; and big data as well as AI-based applications. Unsurprisingly, Young is in dialogue with Alex Zhavoronkov's AI shop at Insilico Medicine. Zhavoronkov has deep connections in the R&D space - last year he raised funds at the behest of Shanghai high-flyer WuXi AppTec, Singapore's Temasek, Peter Diamandis, and Juvenescence.

For long-time investor and venture capitalist Young, who has insight into the aging research and development effort within the US and to a lesser extent in the UK, China and India's sizable populations pose compelling prospects for deals for his fund. "In the next decade, advancements will allow us to be a lot more predictive and preventative in the most damaging diseases. I'm thinking AI-enabled medicine will empower doctors .. technological advances to improve sleeping and meditation will emerge - and these are an essential part of a healthy, long life, along with a plant-based diet."

Link: https://endpts.com/peter-diamandis-right-hand-man-sergey-young-wants-to-reverse-aging-via-his-100m-longevity-vision-fund/

Here, an update on the MouseAGE project from the popular science press. This initiative aims to produce a viable biomarker of aging based on visual inspection of mouse faces. Since age-related mortality in humans correlates fairly well with apparent age of the face, and since machine learning techniques can be used to assess aging from photographs in an automated fashion, it seems reasonable to think that it might be possible to achieve a similar analysis in mice. If successful, it might by used to speed up the assessment of potential rejuvenation therapies, a faster alternative to running life span studies. Given the low cost of development, it is worth a try as an alternative approach to the epigenetic clock and other biomarkers of aging under development. The project was crowdfunded in 2017 and data collection began last year.

Vadim Gladyshev is asking lab scientists to whip out their smartphones and take photos. Not selfies, exactly, but snapshots of their lab mice. It's a fiddly task, Gladyshev admits: mice move fast, and need to be kept still for the camera. He suggests grabbing them with one hand or taking them by the tail while they use their front paws to hold a rod. The impromptu photo shoots are all part of a crowdsourced effort to develop an algorithm that can help predict the biological age of a mouse from its mug shot - information that could help researchers studying aging understand the connection between a person's biology and how old he or she looks.

Scientists now know, for example, that people who look younger than their years tend to live longer than people whose appearance more closely matches the time they've been alive. People are surprisingly good at predicting biological age when it comes to fellow Homo sapiens. But pinpointing the biological age of mice is far more challenging. Instead, assessing the effect of anti-aging drugs in lab mice often involves taking blood samples and running expensive tests. Biomarkers such as DNA methylation signatures and analyses of metabolites and biochemical measurements consume resources and run up costs. Alternatively, researchers may need to sacrifice mice in order to examine the internal effects of a compound.

The idea for a cheap and less wasteful alternative came to Gladyshev and Alex Zhavoronkov, founder of Insilico Medicine, a company specializing in artificial intelligence (AI) for aging research and drug discovery, a couple of years ago. The pair got to chatting and came up with the idea of using a mouse's appearance as a marker of biological age - just as developers have attempted to do for humans. Mouse photo shoots have already been staged in labs across the US and Europe, and around 500 lab mice are in the catalog. The team plans to release the algorithm publicly a few months from now and allow researchers to use it for free. But the project is still in the image-collection stage, as the more reference images it has, the better the algorithm will perform. The team aims to collect images of 1,000 mice by March, but Gladyshev is planning to continue collecting until the project has sourced at least 10,000. "Future programs would tell whether one group of mice is biologically younger than another, allowing us to more easily test interventions. Instead of waiting for mice to die, they can be quickly assessed for their potential to live longer."

Link: https://www.the-scientist.com/notebook/photographing-the-aging-process-65353

Researchers who work on autophagy might well feel justified in issuing the claim that the processes of autophagy are involved in near every aspect of aging. Autophagy is cellular housekeeping, the recycling of damaged or unwanted structures and molecules inside the cell. In chaperone-mediated autophagy, very selective chaperone proteins pick up other molecules and carry them to lysosomes. In macroautophagy, materials to be broken down are engulfed in an autophagosome, which then travels to the lysosome and fuses with it. In microautophagy, the lysosome engulfs materials directly. In all cases, the lysosome is the end of the journey, where a mix of enzymes will slice up the waste material into parts suitable for reuse. The result of smoothly running autophagy is a cell that is less cluttered with damaged parts and waste, and thus a cell that causes fewer issues to the tissue it is a part of.

This business of keeping molecular wear and tear inside cells to a minimal level appears a noteworthy determinant of aging. Many of the methods shown to slow aging in laboratory species such as flies, nematodes, and mice involve increased autophagy. Cells react to stress by increasing autophagy, largely regardless of the type of stress. This is one of the reasons why short and mild exposure to stress improves health, the process known as hormesis. Radiation, lack of nutrients, heat, cold ... it all can lead to improved long-term health and lengthened life span. Autophagy is an important part of this outcome, and in some cases it is a necessary part: animals with disabled autophagy do not gain the benefits to health and longevity provided by calorie restriction, for example.

In the open access paper here, the authors walk through the Hallmarks of Aging, linking them to autophagy. While, yes, one can link autophagy to near everything in aging, and particularly given that autophagy declines with age, it is important to remember that there is a limited upside to increased autophagy as a therapeutic approach. The rough location of that limit is illustrated by calorie restriction; one can imagine a therapy that does twice as well as calorie restriction at upregulating autophagy, but that isn't going to add decades to the human life span. In fact stress responses in our species have only small effects on life span in comparison to those observed in mice. Calorie restriction may increase maximum life span by 40% in mice, but it certainly doesn't do that in our species. Five years of additional life expectancy would be about the upper limit of what we might expect - though the health benefits along the way are certainly well worth having.

Hallmarks of Aging: An Autophagic Perspective

Loss of Proteostasis

Proteostasis is one of the major functions of autophagy in normal tissues. Imbalance of proteostasis due to aging leads to protein aggregation, accumulation of misfolded proteins and in the end to cellular dysfunction, among others. Notably, carbonylation due to oxidative stress is one of the changes that leads to loss of proteostasis. To avoid cell death or dysfunction, numerous homeostatic mechanisms turn on, mainly autophagy and the Ubiquitin-Proteasome-System (UPS). Because autophagy is considered one of the most important intracellular homeostatic processes, an alteration or deterioration of this pathway could modify the normal cell functioning, including a variety of diseases and normal cell physiology declination.

Mitochondrial Dysfunction

Mitophagy is a basal process involved in the autophagic degradation of mitochondria. It is necessary in normal differentiation of certain cell types such as red blood cells, in embryogenesis, immune response, cell programming, and cell death. Mitophagy is required not only to remove damaged mitochondria, but also to promote the biosynthesis of new ones, supporting the mitochondrial quality control. Given that mitochondria are implicated in bioenergetics and ROS production, the mitophagy plays an important role in cell homeostasis. Additionally, a decrease in mitophagy is observed in aged animals and this contributes to aging phenotypes.

Deregulated Nutrient Sensing

Because autophagy is a catabolic mechanism, it can be assumed to be implicated in cellular and systemic metabolism. Metabolic stress responses could be compromised due to a decline in autophagic activity. As an important process regulating the general cellular status, autophagy can also link metabolic pathways to maintain homeostasis under a variety of conditions. In this sense, it has been demonstrated that, after nutrient or growth factor deprivation, ULK1 and ULK2 are activated, and these kinases phosphorylate and activate several glycolytic enzymes as well as autophagic proteins. This makes it possible to obtain metabolites thanks to glucose uptake, gluconeogenic pathway blockage, and autophagic degradation of cytosolic components. Supporting this, mTOR hyperactivation was found in several diseases such as obesity, metabolic syndrome, and type 2 diabetes, which highlights the importance of a tight regulation of autophagy as well as the nutrient sensing pathway.

Genomic Instability

In the last decade, several studies have demonstrated that autophagy or autophagic-related molecules act as a "safeguard" of genome stability both directly (DNA repair modulation) and indirectly (by acting as a homeostatic response). Several mouse models have provided substantial information regarding genomic instability and its connection with healthy and pathological aging.

Epigenetic Alterations

Taken together, organismal models as well as in vitro studies highlight the importance of epigenetics throughout life. The relationship between epigenetic changes and autophagy needs to be deeply studied in order to understand the regulatory loop that seems to be involved in development and aging.

Telomere Attrition

Telomerase activity can support cell cycle progression by preventing the arrest due to short telomeres, leading to a putative malignancy. Remarkably, overexpression of Beclin1 in HeLa cells revealed that telomerase activity is reduced after autophagy induction. This approach argues in favor of the hypothesis that autophagy plays an important tumor suppressor role by the modulation of telomerase activity in somatic cells. This autophagic response arises in order to avoid genome instability and telomeric dysfunction, thus promoting cell survival.

Cellular Senescence

Autophagy regulates the senescence of vascular smooth muscle cells. Intriguingly, autophagy can mediate the transition to a senescent phenotype in oncogene-induced senescence fibroblasts, making possible the protein remodeling needed to establish the senescent phenotype under oncogene activation. It is proposed that type of autophagy, the exact moment when it acts, and the place where it occurs can define the pro or anti-senescence role of autophagy.

Stem Cell Exhaustion

Self-renewal is important to maintain the population of tissue-specific stem cells throughout life. Importantly, as we age, stem-cell activity decreases. It has been shown that autophagy is necessary for preservation and quiescence of hematopoietic stem cells (HSCs). Autophagy is also important to maintain stemness in bone marrow-derived mesenchymal stem cells. In addition, Atg7 loss in aged muscle stem cells (satellite cells) of transgenic mice caused altered mitophagy and an accumulation of ROS, all features of senescence that diminish the regenerative potential of aged satellite cells.

Calorie restriction, also known as dietary restriction in the scientific community, is the practice of consuming up to 40% fewer calories than usual, while still obtaining optimal levels of micronutrients. It produces sweeping changes in the operation of cellular metabolism, slows near all measures of aging, and extends life in mice. Thus for any particular aspect of aging, and here the focus is on chronic inflammation in the brain that accelerates progression of age-related neurodegeneration, it is possible to invest a great deal of time and effort into investigating just how calorie restriction slows it down.

This sort of work is of great scientific interest, as it will help researchers to build a comprehensive map of cellular metabolism and the changes that take place over the course of aging. It is not, however, a road to rejuvenation. Calorie restriction, like all approaches involving upregulation of cellular stress responses, has a much smaller effect on life span in humans than in short-lived species such as mice. There isn't a way to conjure a reversal of aging in the elderly from this biochemistry. That requires a completely different strategy, based on identification of root cause damage, and repair of that damage, as outlined in the SENS roadmap for development of rejuvenation therapies.

A growing body of evidence demonstrates that dietary restriction (DR) exerts its beneficial effects on brain aging at multiple levels. Although there is some degree of discrepancy across studies, likely due to the difference in the model organisms and experimental design, DR appears to mitigate all of the morphological and functional alterations in the brain associated with aging. A major hallmark of aging is systemic, low-grade chronic inflammation throughout the body, termed inflammaging. Notably, these inflammatory signs are similar to the ones associated with obesity and metabolic diseases, providing a possible glimpse into why DR exerts anti-inflammatory effects on aging-associated inflammation.

As with other organs, chronic low-grade inflammation is a common feature of the aged brain. Neuroinflammation is a host defense mechanism against harmful stimuli and damage in the brain. However, chronic inflammation can be deleterious in normal aging as well as in pathological aging related to neurodegenerative diseases. The central nervous system (CNS) is composed of heterogeneous cell types, including neurons, microglia, astrocytes, and oligodendrocytes. Although two major glial cell types, astrocytes and microglia, are known to be key players in inflammatory responses in the brain, it is now well recognized that all neural cells participate to some degree in the neuroinflammatory responses.

Neuroinflammation often manifests as astrogliosis, microgliosis, and an increase in secreted inflammatory mediators, such as cytokines, chemokines, and complement proteins. Accumulating evidence from clinical and basic research suggests that neuroinflammation is tightly connected to the decline in brain function during aging. Although the precise mechanisms of DR's neuroprotective functions are not fully elucidated, it has been suggested that DR exerts neuroprotective effects through multiple pathways, such as modulating metabolic rates, reducing oxidative stress, increasing anti-inflammatory responses, regulating insulin sensitivity, and improving synaptic plasticity and neurogenesis. All of the molecular changes induced by DR may directly or indirectly contribute to the regulation of neuroinflammation associated with aging and neurodegenerative diseases. DR may directly mitigate activation of glial cells and modulate expression of inflammatory cytokines and indirectly regulate neuroinflammation by reducing inflammatory stresses, such as accumulation of toxic proteins and oxidative stress.

Link: https://doi.org/10.3390/ijms20030464

Aging is a process of damage accumulation in cells and tissue structures, followed by reactions to that damage, some of which are compensatory and some of which make matters worse, and lastly the consequent failure of biological systems necessary to support health and life. Age-related diseases are names we give to some of the aspects of system failure, but they are not distinct from aging. One cannot draw a line between aging and age-related disease; it is a futile endeavor, and that the medical industry and regulatory bodies are set up to do so is one of the major challenges facing those who want to develop commercial rejuvenation therapies based on clearance of senescent cells or other recent scientific advances.

This point about aging and age-related disease is somewhat reinforced by the genetic analysis noted here, though I'm yet to be convinced of the utility of this sort of research beyond gaining a purely curiosity-driven scientific understanding of how aging progresses in detail. Since we all age for the same reasons, the same underlying damage, and since rejuvenation therapies will repair that damage in the same way in all patients, and since we have a good list of that damage, there are certainly days when it seems to me that anything other than just building the repair therapies and testing their effects is something of a sideline.

"According to Gompertz mortality law, the risk of death from all causes increases exponentially after the age of 40 and doubles approximately every 8 years. By analyzing the dynamics of disease incidence in the clinical data available from the UK Biobank, we observed that the risks of age-related diseases grow exponentially with age and double at a rate compatible with the Gompertz mortality law. This close relation between the most prevalent chronic diseases and mortality suggests that their risks could be driven by the same process, that is aging. This is why healthspan can be used as a natural proxy for investigation of the genetic factors controlling the rate of aging, the 'holy grail' target for anti-aging interventions."

To find genetic factors associated with human healthspan, the researchers studied the genomes of 300,477 British individuals. Overall, 12 genetic loci affecting healthy life expectancy were discovered. To confirm that these results hold true for other ethnicities, they used genetic data of UK Biobank participants with self-reported European, African, South Asian, Chinese and Caribbean ancestry. Of the 12 single nucleotide polymorphisms (SNPs), 11 increased risk both in discovery and in replication groups. Three of the genes affecting healthspan, HLA-DQB, LPA, and CDKN2B, were previously associated with parental longevity, a proxy for overall life expectancy.

At least three genetic loci were associated with risk of multiple diseases and healthspan at the same time and therefore could form the genetic signature of aging. HLA-DQB1 was significantly associated with COPD, diabetes, cancer, and dementia in this study and was demonstrated to be associated with parental survival earlier. The genetic variants near TYR predict death in the prospective UKB cohort and are involved in the earlier onset of macular degeneration. The chromosome 20 locus containing C20orf112 was not associated with the incidence of any of the diseases at the full-genome level, and yet was affecting the healthspan of studied individuals.

Link: https://www.eurekalert.org/pub_releases/2019-01/g-aac012919.php

Accumulation of lingering senescent cells is one of the causes of aging; these cells secrete a potent mix of molecules that produce inflammation, disrupt tissue structure and function, and alter the behavior of other cells for the worse. This signaling is useful during wound healing, where senescent cells are created and then destroyed once they have served their purpose, but like most such processes it becomes quite harmful when sustained over the long term. Researchers are presently hotly engaged in developing senolytic therapeutics to destroy senescent cells, and thereby achieve a narrow form of rejuvenation.

Prior to the present focus on senescent cells in aging, most work on cellular senescence was carried out in the context of cancer research. Senescent cells have quite the interesting relationship with cancer. While the state of senescence is an anti-cancer mechanism, shutting down replication in cells that are damaged and may become cancerous, the presence of too many senescent cells makes the tissue environment more hospitable to cancer, more amenable to cancer growth and survival. Along with the age-related decline of the immune system, this is one of the reasons why cancer is an age-related condition.

The work here demonstrates an addition complexity to the relationship between cancer and senescence. Since senescence is contagious to some degree, meaning that a senescent cell can drive nearby cells into senescence as well, why not a cancer that co-opts that mechanism in order to make the local environment more conducive to its growth? That is what researchers observe here in the case of acute myeloid leukemia (AML). This suggests that, for at least some cancers, senolytic treatments capable of destroying senescent cells might be a useful a way to weaken the cancer, make it more vulnerable to other therapies. Existing standard treatments such as chemotherapy and radiotherapy will create numerous further senescent cells, either forcing cancer cells into senescence, or damaging bystander cells that become senescent as a consequence. Senolytics will be useful after the fact as well, cleaning tissues of therapy-induced senescence to prevent the long-term harm to the patient that results from cancer treatments.

Cancer causes premature ageing

New findings show that healthy bone marrow cells were prematurely aged by cancer cells around them. It is well known that ageing promotes cancer development. But this is the first time that the reverse has been shown to be true. Importantly, the aged bone marrow cells accelerated the growth and development of the leukaemia - creating a vicious cycle that fuels the disease. The study also identified the mechanism by which this process of premature ageing occurs in the bone marrow of leukaemia patients and highlights the potential impact this could have on future treatments.

NOX2, an enzyme usually involved in the body's response to infection, was shown to be present in acute myeloid leukemia (AML) cells - and this was found to be responsible for creating the ageing conditions. The research team established that the NOX2 enzyme generates superoxide which drives the ageing process. By inhibiting NOX2, researchers showed the reduction in aged neighbouring non-malignant cells resulted in slower cancer growth.

Acute myeloid leukemia induces pro-tumoral p16INK4a driven senescence in the bone marrow microenvironment

Acute myeloid leukemia (AML) is an age-related disease that is highly dependent on the bone marrow microenvironment. With increasing age, tissues accumulate senescent cells, characterized by an irreversible arrest of cell proliferation and the secretion of a set of pro-inflammatory cytokines, chemokines, and growth factors, collectively known as the senescence-associated secretory phenotype (SASP). Here, we report that AML blasts induce a senescent phenotype in the stromal cells within the bone marrow microenvironment. We report that the bone marrow stromal cell senescence is driven by p16INK4a expression. The p16INK4a-expressing senescent stromal cells then feedback to promote AML blast survival and proliferation via the SASP.

Importantly, selective elimination of p16INK4a-positive senescent bone marrow stromal cells in vivo improved the survival of mice with leukemia. Next, we find that the leukemia-driven senescent tumor microenvironment is caused by AML induced NOX2-derived superoxide. Finally, using the p16-3MR mouse model we show that by targeting NOX2 we reduced bone marrow stromal cell senescence and consequently reduced AML proliferation. Together, these data identify leukemia generated NOX2 derived superoxide as a driver of pro-tumoral p16INK4a-dependent senescence in bone marrow stromal cells. Our findings reveal the importance of a senescent microenvironment for the pathophysiology of leukemia. These data now open the door to investigate drugs which specifically target the 'benign' senescent cells that surround and support AML.

Our community has undertaken years of advocacy for rejuvenation research, with the aim of developing ways to reverse age-related disease and disability, and thus greatly extend healthy life spans. The first concrete results are emerging from the research community, the result of philanthropy and persuasion, then the incremental accretion of funding to programs that showed promising initial data. So now we have senolytics, and I would hope not too many years from now we'll have glucosepane cross-link breakers - and then more thereafter.

But have we persuaded the broader public at all? Have we convinced more than a small number of people of the plausibility of the goal of human rejuvenation? Of the merits of ending aging, of eliminating the enormous scope of suffering and death that is all around us? At the large scale, and over decades, progress requires public support. Aging research as a whole needs the same widespread, overwhelming support enjoyed by HIV or cancer research programs; the history of both of those vast patient advocacy initiatives is well worth studying. We are not there yet. But are we further along than was the case at the turn of the century? You might compare the results of the survey noted here with another survey conducted last year; while it certainly looks like progress, I think it is far from clear as to where exactly things stand.

People generally do not believe in the plausibility of targeting the mechanisms of aging in order to slow down and reverse age-related damage. After so many millennia of fruitless dreams, with so many powerful psychological defenses that protect our state of mind when we face the idea of inevitable death by aging, becoming hopeful is usually too much to ask. This can explain why most people, when asked about their desired lifespan, add only a few years to the life expectancy of their given countries.

However, in the last few years, things have apparently started to change. In 2015, in a study by Donner et al, it was found that given perfect mental and physical health, 797 out of 1000 participants wanted to live to 120 or longer; over half of these 797 people desired unlimited lifespans (around 40% of all participants). A new study by YouGov shows even more impressive results. We at Lifespan.io generally stay away from strong statements such as "living forever" or "immortality", because these expressions are hardly scientific and have a religious background. The notion of immortality even seems to scare some people because it seems to limit their freedom and because immortals are pictured by pop culture as criminals, crazy, or morally inferior. Therefore, people often reject the idea of extended life without perfect health.

However, in a new study by YouGov that included around 1200 participants, one in five (19%) people agreed with the statement "I want to live forever" without any promises related to perfect health. 42% of the participants chose "I want to live longer than a normal lifespan, but not forever", while 23% said, "I don't want to live longer than a normal lifespan." People in different age groups reacted to this survey differently; it turns out that the idea of radical life extension was more supported by young people (24%) than by people over 55 (13%), while support for the status quo was the opposite (19% of young people didn't want to live longer than a normal lifespan, while this position was shared by 29% of people aged 55 and older).

The YouGov survey participants were randomly selected, and few of them will be regularly exposed to news about aging and longevity research. However, over 60% explicitly expressed a desire for radical life extension. That is a big jump from the Pew Research study from 2013, where only 38% of the participants expressed the desire to undergo medical treatments to slow aging and live to be 120 or more. Of course, the questions in these surveys were formulated differently, so we cannot directly compare them. However, looking at various, similar studies, it appears that, in the last 5 years, 20% more Americans have become aware that something serious is going on in the rejuvenation biotechnology industry.

Link: https://www.leafscience.org/the-american-public-increasingly-desires-life-extension/

Researchers here investigate the mechanisms by which senescent cells are created during acute kidney injury (AKI). Senescent cells are usually created as a part of the injury and regeneration process, and then destroyed quickly afterwards, but there is more to it in this case. The senescent cells linger and their signaling causes fibrosis, a form of scarring that further harms the injured kidney. The researchers find that some (but not all) senolytic drugs can clear out these senescent cells, reducing fibrosis. However, introducing this treatment after AKI failed to lead to regeneration of damage to the tubule structures of the kidney. That only some senolytics work for this particular type of senescent cell and tissue is perhaps the most interesting finding here: it reinforces the developing thesis that there are significant differences between senescent cells in different tissues and circumstances, and thus variety is desirable in the development programs for small molecule senolytic drugs.

Tubule repair is a common event after kidney injury, but is frequently associated with interstitial inflammation and maladaptive processes that lead to fibrosis, the hallmark of all forms of kidney disease and a reliable predictor of progression to chronic kidney disease(CKD). Recently, multiple studies identified multipotent mesenchymal stromal progenitor cells (pericytes) as the cell population that is responsible for collagen deposition after injury. Kidney fibrosis has also been correlated with arrest of tubular epithelial cells (TECs), which suggests that the epithelium plays a primary role in the progression of kidney disease. However, the factors that contribute to the cell cycle arrest are not known. Cell cycle arrest is a universal marker of cellular senescence and is evoked by a variety of stressors.

Several studies have reported a correlation between the presence of senescent cells and kidney fibrosis both during the aging process and in the context of disease, but a systematic study of cellular senescence after AKI and its potential contribution to the progression of tubular damage and fibrosis is lacking. Here, we show that in mice TECs commonly become senescent after various types of kidney injury, and that this occurs surprisingly early after injury. We show that senescent TECs express higher levels of proinflammatory factors of the SASP as a result of cell-autonomous control by the TLR/IL-1R-mediated innate immune signaling pathway, and that senescent TECs are a source of the mesenchymal progenitor-activating ligands.

Tubule-specific inhibition of TLR/IL-1R signaling by conditional inactivation of the Myd88 gene prior to senescence not only reduced the levels of epithelial cell-derived proinflammatory cytokines, interstitial infiltration, and fibrosis, but also decreased the accumulation of senescent cells and ameliorated tubular damage. Whereas inactivation soon after injury was equally effective in decreasing the number of senescent TECs, inflammation, and fibrosis, it did not protect from tubular damage. Similarly, eliminating p16+ senescent cells, but not senescent cells by FOXO4-DRI inhibitory peptide, which induces apoptosis of senescent cells by disrupting the interaction between FOXO4 and p53, reduced kidney fibrosis without reducing tubular damage.

Our results indicate that TEC senescence is a common and early event after kidney injury, and that signaling by the TLR/IL-1R pathway within the epithelium controls this phenomenon. Our findings also suggest that early intervention after injury is likely required to reduce organ damage after AKI. Furthermore, this study reveals what we believe is a novel function of the epithelial TLR/IL-R1 signaling in controlling the onset of TEC senescence in a cell-autonomous manner, consistent with the concept that the tubular epithelium triggers kidney disease following injury and also drives its progression.

Link: https://doi.org/10.1172/jci.insight.125490

I attended the small Longevity Therapeutics conference in San Francisco last week, there to talk a little about the work taking place at Repair Biotechnologies. This was another first conference of a forthcoming series, but, unlike most of the prior conferences in our community, this was organized by Hanson-Wade, a company that specializes in hosting conferences. The company finds areas of growing interest in business and science, sets up conferences, and tries to make a business out of that process. It is a sign of growth that companies of this nature are arriving in our community to launch conferences relating to the development of treatments to enhance longevity and slow or reverse aging. Greater funding is flowing, more people are participating, and more outsiders are paying attention.

The other attendees were largely a mix of researchers, entrepreneurs, businesspeople from larger companies, and individuals in the process of transition from one of those categories to another. As one researcher-soon-to-be-entrepreneur I spoke to noted, the tone of the conference was one of optimism, of the desire to make progress towards concrete benefits for patients - and this is quite different to what one might find at scientific community events. I think that this is a good thing. The drive and the vision is necessary for progress to occur. Despite the tremendous influx of capital and interest into the field of longevity science and development of therapies to treat aging, it remains a backwater of development, underfunded by several orders of magnitude in comparison to its importance and potential.

As one might expect, there was a sizable senolytics contingent at the conference to discuss their various approaches and the state of the field. This is an exciting topic, and we're going to see a big jump in both the number of companies and potential senolytic therapies and mechanisms over the next year. It is already the case that when I turn up at one of these events, there is a company or two I hadn't heard of, involved in some form of senolytics development I was unaware of. This growth will be coupled with results from the first human trials over the next year, hopefully repeating the robust, positive results on a range of age-related diseases achieved in mice in recent years. For better or worse, senolytics will be the flagship of the rejuvenation biotechnology community for the next decade: as senolytics succeed, there will be more interest for the development of other rejuvenation therapies; as any specific company or development program stumbles, it will harm the industry as a whole.

Beyond senolytics, the topics varied widely, from fundamental science related to known drugs (such as metformin or mTOR inhibitors) that slow aging to some degree, to more recently discovered mechanisms yet to produce therapies, such as splicing factor changes in older individuals, to efforts on biomarker development that are aimed at making biomarkers of aging practical to use in evaluation of therapies. The machine learning contingent had their representatives as well. As I've mentioned in the past, a sizable fraction of present investment in the field of therapeutics for aging relates to the use of machine learning methodologies to improve the efficiency of small molecule drug discovery programs. The larger investors seem most interested in setting up an initial presence in the field that is based on producing large numbers of small molecule drug candidates: new senolytics, new mTOR inhibitors, and the like.

Mixed in with these topics were presentations from a number of noteworthy individuals from the field presenting; people from Unity Biotechnology and Life Biosciences, for example, and well known scientists such as Judith Campisi and Aubrey de Grey. A wide range of views on aging and the prospects for development were represented, from people who see metformin as ambitious new technology, and adding a few years to be the greatest that can be achieved in the near future, to people who wish to see true rejuvenation biotechnology after the SENS model realized, and would aim at decades and more added to the human life span.

A topic that came up in several discussions is the challenge (the present failure) of moving basic science to the clinic. All of the players in this process do things poorly: the scientists are bad at packaging up research for commercialization; the funding entities and universities fail to identify, cultivate, and fund truly valuable, novel work; the venture industry and entrepreneurs fail to reach into the research community in any systemic way to identify new technologies that can be development. The Life Biosciences representative argued that their way of doing things is a model that can help to address this problem, and it may well be a good attempt, even given my disagreement with the value of some of the programs they have chosen to support. I am given to think the onus largely falls on the venture and corporate world to do this work, as they have the resources and the will.

On the whole, I think this event worked well. The conference organizers profit, and people came to find their own benefits via networking and discussion of the state of the field. I met some new faces, and had a chance to pitch the primacy of damage repair as an approach to aging. We will see more of this in the years ahead, as the community continues to grow rapidly, driven by clinical success in the first attempts at generating rejuvenation in human patients.

In this open access paper, the authors argue that exercise (and particularly strength training) remains the best therapy for sarcopenia, the age-related loss of muscle mass and strength, because exercise improves mitochondrial function and other attempted treatments do not. This seems a reasonable position. There are many, many possible contributing causes of sarcopenia, all with accompanying evidence, but the most compelling in my opinion is stem cell dysfunction. Even so, one still needs to offer an explanation as to why exactly stem cell activity in muscle tissue declines with age, a way to link it to the root cause molecular damage of aging listed in the SENS research proposals. Perhaps faltering mitochondrial function is a noteworthy underlying cause.

Resistance exercise continues to be the most effective intervention against sarcopenia. In addition, maintenance of physical activity can delay the progression of sarcopenia. Despite the strong support for maintaining an active lifestyle, adherence to physical activity guidelines remains low. The traditional therapeutic focus of sarcopenia treatment is to target growth-related pathways to increase muscle mass. Here, we discuss the positives of these strategies, but also build a case for targeting mitochondrial bioenergetics as a way to maintain muscle mass and function with age.

The vast majority of adults fail to meet physical activity guidelines. While 60% of adults, both European and American, self-report that they meet guidelines, objectively measured physical activity reveals that fewer than 10% of adults in the United States meet physical activity guidelines. Moreover, sedentary behavior alone increases the risk for sarcopenia. While there are few trials in humans on the effects of lifelong sedentary behavior, studies in mice reveal lifelong sedentary behavior impairs mitochondrial function.

It was thought that resistance exercise training had little or no effect on mitochondrial biogenesis or function. However, recent studies have shown that resistance exercise training increases mitochondrial protein fractional synthesis rates (FSRs) and improves mitochondrial function. Young adults engaged in a resistance exercise program showed increases in mitochondrial enzyme activity and respiration. While the changes in mitochondrial respiration are modest in comparison to endurance exercise, improvements in in vivo phosphocreatine recovery rates and oxidative capacity appear comparable in older adults engaged in either exercise intervention.

Aerobic exercise is generally not appreciated as a stimulator of hypertrophy; however, there is evidence that it can lead to muscle hypertrophy. Nearly half a century ago, it was first documented that aerobic exercise increases mitochondrial content. Since then, research has consistently documented that aerobic exercise improves both mitochondrial content and function. Aerobic exercise increases mitochondrial turnover since it increases both mitochondrial biogenesis (protein synthesis) and mitophagy (mitochondrial-specific autophagy). The improvement in the rate of ATP production from aerobic exercise training suggests that more energy is available to maintain proteostasis. Additionally, improvement in mitochondrial efficiency (reduction in ROS generated per oxygen consumed or ATP generated) suggests that there is less oxidative stress and damage, which would in turn improve the quality of the proteome. In all, aerobic exercise mediated improvements in mitochondrial function likely protects against sarcopenia.

Link: https://doi.org/10.3389/fphys.2018.01883

Researchers here suggest that PU.1 is a master regulator of fibrosis, and thus inhibition could be an effective treatment for the various fibrotic diseases that presently lack good options for patients. Fibrosis is a dsyregulation of the normal processes of tissue maintenance, in which scar-like deposits of collagen are formed, disrupting tissue structure and function. When this progresses far enough, it is ultimately fatal: consider the fibrotic diseases of heart, lungs, and kidney, for example. There is evidence for the presence of senescent cells to contribute to fibrotic diseases. Given this new information about PU.1 it, it will be interesting to see if the mechanisms by which scarring forms can be traced back to specific signaling on the part of senescent cells, and thus further reinforce senolytics as a therapy for fibrosis.

In connective tissue diseases such as systemic sclerosis, referred to collectively as 'fibrosis', excessive activation of connective tissue cells leads to hardening of the tissue and scarring within the affected organ. In principle, these diseases can affect any organ system and very often lead to disruption of organ function. Connective tissue cells play a key role in normal wound healing in healthy individuals. However, if the activation of connective tissue cells cannot be switched off, fibrotic diseases occur, in which an enormous amount of matrix is deposited in the tissue, leading to scarring and dysfunction of the affected tissue. Until now, scientists did not fully understand why repair processes malfunction in fibrotic diseases.

Researchers now been able to decipher a molecular mechanism responsible for the ongoing activation of connective tissue cells. In experimental studies, the researchers targeted the protein PU.1. In normal wound healing, the formation of PU.1 is inhibited by the body so that at the end of the normal healing process the connective tissue cells can return to a resting state. "We were able to show that PU.1 is activated in various connective tissue diseases in the skin, lungs, liver and kidneys. PU.1 binds to the DNA in the connective tissue cells and reprograms them, resulting in a prolonged deposition of tissue components."

PU.1 is not the only factor involved in fibrosis, as factors that are involved in the deposition of scar tissue have already been identified in the past. What has been discovered now, however, is that PU.1 plays a central role in a network of factors controlling this process. "PU.1 is like the conductor in an orchestra. If you take it out, the entire concert collapses." This approach has already been tested using an experimental drug, fuelling the hope that clinical trials on inhibiting PU.1 may soon be able to be launched, aimed at better treating fibrosis.

Link: https://www.eurekalert.org/pub_releases/2019-01/uoe-cto013119.php

Being physically fit is very much better for long term health than being unfit. But in this era of cheap and attractive calories, it is quite possible to be both physically fit and overweight to some degree. Many people are. Unfortunately, being fit doesn't meaningfully protect against the detrimental effects of excess fat tissue on health and disease risk. If you are carrying more visceral fat tissue, then you have a higher risk of all of the common age-related diseases, when compared with someone of the same level of fitness with less visceral fat tissue.

Not so many years ago, metrics based on the ratio of height to waist circumference - such as the simple waist-stature ratio - began to appear in epidemiological studies as a replacement for the time-worn use of body mass index. The waist-stature ratio correlates more closely than body mass index with risk of disease, mortality, and other unfortunate aspects of aging. This points to the importance of visceral fat in disease processes. Even so it will take some time to percolate through the research community. Epidemiology doesn't move rapidly, and older data sets often lack the necessary information for use of waist-stature ratio, while most include body mass index.

How does visceral fat cause harm over the long term? Chronic inflammation is likely the primary mediating mechanism. Visceral fat cells are metabolically active, and when present in large numbers secrete signals that rouse the immune system. In addition, excess visceral fat appears to generate senescent cells at an accelerated rate, and these also secrete a mix of molecules that cause chronic inflammation. Fat cell debris further contains DNA fragments that aggravate the immune system in a different way. The inflammation generated by fat tissue disrupts processes of regeneration, and accelerates the progression of age-related diseases such as atherosclerosis and dementia.

Waist-stature ratio can indicate the risk of cardiovascular disease even in healthy men

Researchers have found that physically active men who were not overweight but whose waist-stature ratio (WSR) was close to the risk threshold were also more likely to develop heart disorders than individuals with lower WSRs. Recent research suggests that the WSR (waist circumference divided by height) is a more accurate predictor of cardiovascular risk than the body mass index (BMI), a widely used measure of body fat.

The researchers further investigated this hypothesis by analyzing the autonomic recovery of heart rate after aerobic exercise in healthy men with different WSRs. To this end, 52 physically active healthy men aged 18-30 were divided into the following three groups according to WSR: between 0.40 and 0.449, which is below the risk threshold for cardiovascular disease; between 0.45 and 0.50, which is close to the threshold; and between 0.50 and 0.56, which is above the threshold. The participants were tested on two separate days with a 48-hour interval between the two tests. Their heart rate and heart rate variability were measured while at rest and six times during a recovery hour to assess their speed of autonomic recovery after physical activity.

Analysis of the measurements showed that the autonomic recovery was slower in the groups with WSRs close to and above the risk threshold for heart disease after both the maximum effort test and moderate aerobic exercise. "We found that volunteers in the group with WSRs close to the risk limit were also more likely to develop cardiovascular disorders." The results of the statistical analyses suggested that two factors were most significantly correlated during the first ten minutes of the postexercise recovery period, when the parasympathetic nervous system (PNS) was being reactivated. Among other functions, the PNS, one of the three divisions of the autonomic nervous system, slows heart rate, and reduces blood pressure via the release of hormones.

Waist-Stature Ratio And Its Relationship With Autonomic Recovery From Aerobic Exercise In Healthy Men

Amongst the indicators of abdominal obesity, body mass index (BMI), waist circumference (WC), hip circumference (HC), conicity index (CI), waist-stature ratio (WSR) have been studied and are widely accepted in disease assessment, management and predictions in clinical practice and public health surveillance. Lately, WSR has been widely applied as it is simple, easy to measure and calculate. It is obtained by dividing the WC by height, in which WC demonstrates abdominal obesity and height remains constant in adults, which allows the possibility for direct comparisons in the general population.

Although the research literature has focused on obese patients with increased risk based on the WSR, it lacks evidence in subjects with values closer to the limit, herein moderate risk. In this sense, we appraised autonomic recovery after aerobic exercise in healthy men with different ranges of WSR. We found that healthy men with higher WSR accomplished delayed autonomic recovery following maximal effort exercise. Our results draw attention to the importance of cardiovascular prevention in the population within WSR values above 0.45, since we established that physically active men in this group offered slower autonomic recovery following aerobic exercise.

Data from a large human trial has shown that control of blood pressure in older individuals, achieved through lifestyle changes and medication, reduces the risk of mild cognitive impairment by 20% or so, but not the risk of dementia. This is a nuanced result; given what is known of the way in which blood pressure interacts unfavorably with a range of mechanisms related to the development of dementia, it is certainly easier to blame the study design, as the authors do here. There is plenty of evidence to show that hypertension damages the brain directly, causing a greater incidence of ruptured capillaries and tiny areas of dead tissue. It may also cause removal of metabolic waste to decline, contributing to the buildup of protein aggregates that progressively impairs the operation of the mind. It may change the behavior of immune cells in the brain for the worse. Further, the epidemiological data also exhibits a very good correlation between hypertension and dementia. So on the whole, the outcome of this study is a puzzle, and doesn't fit well with the established data on the subject.

Intensive lowering of blood pressure did not significantly reduce dementia risk but did have a measurable impact on mild cognitive impairment (MCI), according to the final, peer-reviewed results from the Systolic Blood Pressure Intervention Trial (SPRINT) Memory and Cognition in Decreased Hypertension (SPRINT MIND). SPRINT MIND secondary results are the first to show an intervention that significantly reduces the occurrence of MCI, which is a well-established precursor of dementia. MCI is a condition in which people have more difficulty with cognition, thinking, remembering, and reasoning, than normal for people their age. Dementia is a more severe form of loss in cognitive functions that interferes with daily life. Alzheimer's disease is the most common type of dementia. High blood pressure, or hypertension, is very common in persons over the age of 50 and a leading risk factor for heart disease, stroke, kidney failure, and a growing body of research suggests that it may increase risk for dementia later in life.

The participants in SPRINT were adults 50 years and older at high risk for cardiovascular disease. Results of the SPRINT trial, which ended early, showed that intensive blood pressure control, i.e., a systolic blood pressure target of less than 120 mmHg, compared to a standard target of less than 140 mmHg, reduced cardiovascular events and overall mortality. Between November 2010 and March 2013 more than 9,300 participants were randomized to the two target groups with nearly 4,700 in each group. In August 2015, the SPRINT trial was stopped after 3.3 years of treatment when the major beneficial effects of intensive blood pressure management on mortality and cardiovascular disease were discovered. Assessment for development of dementia and MCI continued for the full planned five years.

SPRINT MIND aimed to address whether intensive blood pressure control would also reduce the risk of developing dementia and cognitive impairment over the ensuing five years. Cognitive assessments were given to participants who had high blood pressure but no history of stroke or diabetes at the start of the trial, and over 91 percent had at least one follow up. Participants were classified into one of three categories: no cognitive impairment, MCI, or probable dementia.

The primary results of this analysis found no statistically significant difference between standard and intensive treatment in the proportion of participants that were diagnosed with dementia. The study, however, had fewer cases of dementia than expected. Nevertheless, the secondary results suggested that the intensive treatment reduced the risk of MCI and the combined risk of MCI and dementia. Due to the success of the SPRINT trial on the cardiovascular outcomes, the study intervention was stopped early; as a result, participants were treated for a shorter period than originally planned. The authors concluded that the shorter time and the unexpected fewer cases of dementia may have made it difficult to determine the role of intensive blood pressure control on dementia.

Link: https://www.nia.nih.gov/news/does-intensive-blood-pressure-control-reduce-dementia

Regular aerobic exercise, like calorie restriction, improves near all aspects of health throughout the life span. Unlike calorie restriction, exercise doesn't slow aging in the sense of improving life span. It does reduce incidence of many age-related diseases, extending the proportion of life spent in good health, however. Aging is a complicated many-faceted web of cause and consequence, and these two very robust metabolic alterations, exercise and calorie restriction, illustrate this point by the different character of the alterations in aging and age-related disease they produce. That it is possible to have less of most age-related disease but not live longer is a peculiarity of the distribution of affected mechanisms. It would be interesting to look at the set of calorie restriction associated mechanisms that are not also touched on by exercise, and vice versa, but that is (a) poorly mapped at this time, and (b) both sets are very large and incompletely understood. The memo for humans is to practice both interventions.

Biological aging is associated with progressive damage accumulation, loss of organ reserves, and systemic inflammation ('inflammaging'), which predispose for a wide spectrum of chronic diseases, including several types of cancer. In contrast, aerobic exercise training (AET) reduces inflammation, lowers all-cause mortality, and enhances both health and lifespan. In this study, we examined the benefits of early-onset, lifelong AET on predictors of health, inflammation, and cancer incidence in a naturally aging mouse model.

Lifelong, voluntary wheel-running (O-AET; 26-month-old) prevented age-related declines in aerobic fitness and motor coordination vs. age-matched, sedentary controls (O-SED). AET also provided partial protection against sarcopenia, dynapenia, testicular atrophy, and overall organ pathology, hence augmenting the 'physiologic reserve' of lifelong runners. Systemic inflammation, as evidenced by a chronic elevation in 17 of 18 pro- and anti-inflammatory cytokines and chemokines, was potently mitigated by lifelong AET, including master regulators of the cytokine cascade and cancer progression (IL-1β, TNF-α, and IL-6).

In addition, circulating SPARC, previously known to be upregulated in metabolic disease, was elevated in old, sedentary mice, but was normalized to young control levels in lifelong runners. Remarkably, malignant tumours were also completely absent in the O-AET group, whereas they were present in the brain (pituitary), liver, spleen, and intestines of sedentary mice. Collectively, our results indicate that early-onset, lifelong running dampens inflammaging, protects against multiple cancer types, and extends healthspan of naturally-aged mice.

Link: https://doi.org/10.1371/journal.pone.0210863