Fight Aging!

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Contents

• When Will the Cryonics Industry Arrive at a Tipping Point in Growth?
• An Example of a Harmful Metabolite Generated by the Aging Gut Microbiome
• Inflammaging as a Contributing Factor in the Development of Cardiovascular Disease
• Butyrate Produced by the Gut Microbiome Encourages Favorable Macrophage Polarization
• Lyfspn Working on Clinical Trials of Plasmapheresis
• Inflammation Accelerates Mesenchymal Stem Cell Aging
• Fecal Microbiota Transplantation Improves Ovarian Function in Old Mice
• On the Large Scale Plans of the Hevolution Foundation
• Vision Influences Circadian Rhythms to Interact with Calorie Restriction and Aging
• A Hostile Environment for Neurogenesis in the Aging Hippocampus
• DNA Gaps as a Protective Mechanism that Limits DNA Damage
• Towards Scaffold-Based Regeneration of Dental Pulp
• Clozapine Treatment Reduces Epigenetic Age in Male Psychiatric Patients
• Engineering Therapeutic Mesenchymal Stem Cells to Overexpress HIF1α
• USP16 Inhibition May Produce Benefits in an Alzheimer's Mouse Model by Lowering the Burden of Cellular Senescence

When Will the Cryonics Industry Arrive at a Tipping Point in Growth?
https://www.fightaging.org/archives/2022/06/when-will-the-cryonics-industry-arrive-at-a-tipping-point-in-growth/

Twenty years ago, there wasn't all that much of a difference between the public view of rejuvenation research and the cryonics field. Both were mocked by the mainstream media, marginal areas of human endeavor out on the fringes of society, supported by very little funding and a handful of dedicated supporters. Yet in both cases, compelling research existed to support the goals - of the treatment of aging, of reversible cryopreservation - and was largely ignored, or even actively derided by the academic mainstream, worried about appearances.

A great deal has changed since then for the field of rejuvenation research. In the early 2000s, patient advocates were delighted and surprised by the rare occasion on which a six or seven figure check arrived from a philanthropist. It didn't happen often! Twenty years down the line, however, and billions in funding from philanthropists, research institutions, and venture funds are now devoted to the development of in vivo epigenetic reprogramming as an approach to the treatment of aging. Similarly, hundreds of millions have been invested in the development of senolytic therapies to clear senescent cells. The treatment of aging as a medical condition and the goal of reversal of aging is no longer mocked, it is taken seriously, and both funding and the number of ventures are increasing at a rapid pace.

How did this change happen? It was a mix of networking, advocacy, philanthropy, and compelling advances in the science, such as the development of the first senolytics and many consequent studies showing rapid, profound rejuvenation in mice. A tipping point was reached after years of a long, slow grind of bootstrapping: a little more progress, a little more support, a little more progress. Once past that tipping point, matters moved much more rapidly year after year, and the acceleration continues today.

I recently attended the 50th anniversary conference for the Alcor Life Extension Foundation, celebrating the lengthy run of one of the oldest cryonics providers. A good deal of the discussion there orbited around the usual questions asked by a small and passionate community: how does the cryonics field become larger, more robust? How does it achieve greater funding and faster progress towards widespread use? Fifty years on from the very early days of improvised equipment, ad hoc science, and regulatory opposition, the field of cryonics now looks a lot like the field of rejuvenation biotechnology did fifteen or twenty years ago. Slow progress is underway, the organizations are far more professional, and a few visionary philanthropists are putting in six or seven figure checks occasionally. Compelling advances in research exist, and are not receiving the widespread attention that they deserve. New organizations for advocacy and research are being founded with small budgets and big visions. Some of the technology waiting in the wings, such as reversible vitrification of human organs, may help to reach the tipping point once they are fully realized and in widespread use.

Given this, I would not be surprised to see the cryonics field becoming much larger and more commercial, growing suddenly and rapidly, in the mid-to-late 2030s. By that time, I would expect that reversible vitrification of organs will be a going concern, radically changing the economics and viability of organ donation, and adopted as a core enabling technology by the new industry focused on manufacturing patient-matched organs to order. The widespread recognition of this technological capability will bring many more people to the realization that cryopreservation on clinical death is a viable approach to saving lives that would otherwise be lost, and matters will proceed ever more rapidly from there on.

An Example of a Harmful Metabolite Generated by the Aging Gut Microbiome
https://www.fightaging.org/archives/2022/06/an-example-of-a-harmful-metabolite-generated-by-the-aging-gut-microbiome/

The gut microbiome changes in detrimental ways with age. Beneficial populations decline in numbers while harmful populations gain ground at their expense. A large part of the harm done results from an increased burden of inflammatory microbes that aggravate the immune system, resulting in chronic inflammatory signaling that degrades tissue function throughout the body. But the loss of beneficial metabolites generated by microbial species is also increasingly well studied. Butyrate, for example, helps with cognitive function by upregulating BDNF expression, which in turn increases levels of neurogenesis.

In today's open access paper, researchers note an example of the opposite case, a harmful metabolite, isoamylamine, that produces cell death in microglia, a population of supporting immune cells in the brain. Production increases with age, and in aged mice at least, reducing levels of this one metabolite produces gains in cognitive function. We might take this as yet another piece of evidence supporting the value of rejuvenation of the gut microbiome, a goal that can be achieved all at once, rather than bit by bit, via strategies such as flagellin immunization or fecal microbiota transplantation. These approaches should receive more attention from the clinical community, as they can be carried out with little effort at the present time. Running small clinical trials to prove efficacy in human patients is a very feasible prospect, given funding for that project.

Gut bacterial metabolite promotes neural cell death leading to cognitive decline

Prior research has suggested a strong link between gut bacteria and brain health. In this new effort, the researchers looked into the possible impact on the brain of just one metabolite, isoamylamine (IAA), produced by one family of bacteria in the gut, Ruminococcaceae. They found first that IAA becomes more prevalent in the gut as people age due to the presence of more Ruminococcaceae. Their interest in IAA grew when they learned it could pass through the blood-brain barrier. They found the metabolite binds to a promoter region of the gene S100A8, which allowed for expression of the gene, resulting in production of apoptotic bodies, which lead to cell death. To learn more about what happens when such bindings occur, the researchers fed IAA to young healthy mice and determined that this resulted in a loss of cognitive function. They next blocked production of the metabolite in the guts of older mice and found that it led to improvements in cognitive performance.

Gut bacterial isoamylamine promotes age-related cognitive dysfunction by promoting microglial cell death

The intestinal microbiome releases a plethora of small molecules. Here, we show that the Ruminococcaceae metabolite isoamylamine (IAA) is enriched in aged mice and elderly people, whereas Ruminococcaceae phages, belonging to the Myoviridae family, are reduced. Young mice orally administered IAA show cognitive decline, whereas Myoviridae phage administration reduces IAA levels. Mechanistically, IAA promotes apoptosis of microglial cells by recruiting the transcriptional regulator p53 to the S100A8 promoter region. Specifically, IAA recognizes and binds the S100A8 promoter region to facilitate the unwinding of its self-complementary hairpin structure, thereby subsequently enabling p53 to access the S100A8 promoter and enhance S100A8 expression. Thus, our findings provide evidence that small molecules released from the gut microbiome can directly bind genomic DNA and act as transcriptional coregulators by recruiting transcription factors. These findings further unveil a molecular mechanism that connects gut metabolism to gene expression in the brain with implications for disease development.

Inflammaging as a Contributing Factor in the Development of Cardiovascular Disease
https://www.fightaging.org/archives/2022/06/inflammaging-as-a-contributing-factor-in-the-development-of-cardiovascular-disease/

Inflammaging is the name given to the decline of the aging immune system into a state of constant, unresolved inflammation. Inflammatory signaling in the aged body arises in part because of an increased burden of senescent cells. These cells secrete a potent mix of pro-inflammatory signals, disrupting tissue function. This is one of the reasons why removal of lingering senescent cells produces such rapid rejuvenation, as these errant cells actively maintain a portion of the degradation of function and environment in aged tissues. Beyond senescent cells, the broad molecular damage and cellular dysfunction of aging produces circulating DNA debris, and similar outcomes, that are recognized by the innate immune system as indicative of infection or injury, leading to inflammatory behavior.

Beyond the removal of senescent cells, current approaches to suppression of inflammation, largely developed as treatments for autoimmune conditions, are crude and have significant long-term side-effects. Because they rely on suppression of specific signal molecules or their recognition, they inhibit not only excessive and inappropriate unresolved inflammation, but also the necessary short-term inflammation that is needed for regeneration, defense against pathogens, and elimination of damaged and potentially cancerous cells. More sophisticated approaches are needed, but given the overlap in signals and signal transduction between desirable and undesirable inflammation, it is unclear that anything will work really well other than removing the triggers that cause unresolved inflammation, as illustrated by the dramatic benefits observed in animal models following the removal of senescent cells.

Modern Concepts in Cardiovascular Disease: Inflamm-Aging

Under physiological conditions, inflammation protects against external pathogens and intrinsic degenerative processes. Nevertheless, dysregulation of the immune system, as seen during aging, triggers a persistent state of low-grade inflammation, which has been recognized as an important driver for the development of age-related diseases. This phenomenon, referred to as inflamm-aging, has been linked to a higher risk of cardiovascular (CV) events and has been increasingly recognized as a determinant of CV outcomes. Since CV disorders are the leading cause of death in industrialized countries, improving the treatment of these diseases implies prolonging the average lifespan. Furthermore, acute CV events, particularly stroke, are associated with long-term disability, inevitably resulting in a worsening of quality of life. Long-term disability, dependence on daily living, and reduced quality of life are the most relevant backlashes of aging; thus, addressing those aspects is pivotal in promoting healthy aging. Finally, inflamm-aging is also involved in other age-related disorders, like sarcopenia, cancer, and neurocognitive impairment, all having a heavy impact on lifespan and quality of life of elderly people. Therefore, targeting inflamm-aging may prolong lifespan and promote successful aging by acting on multiple levels.

Inflamm-aging was firstly theorized in the 2000s as a phenomenon involved in the age-related deterioration of physiological processes. Defined as a chronic low-grade sterile inflammation, inflamm-aging was suggested to result from persistent antigenic load and stress. Since then, this concept has been intensively studied to identify its molecular mechanisms and how it contributes to age-dependent diseases. Even though the exact mechanisms of inflamm-aging are not yet fully elucidated, some pathologic features have been identified.

Inflamm-aging develops due to senescent cell accumulation, altered function of immune cells, and increased inflammasome activity due to incremented levels of damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). To date, wide experimental evidence validated the importance of inflamm-aging in the pathophysiology of CV diseases and the potential of targeting inflammation as pharmacological therapy. Nevertheless, none of the tested anti-inflammatory agents has yet been implemented in everyday clinical cardiology; thus, more work remains to be done to optimize these promising interventions. Ultimately, future studies are encouraged to discover further potential therapeutic targets involved in the complex mechanism of inflamm-aging. Along with other treatment strategies against different age-related alterations in molecular pathways, inflamm-aging targeted approaches will intently endure the burden of CV disease in the growing aging population.

Butyrate Produced by the Gut Microbiome Encourages Favorable Macrophage Polarization
https://www.fightaging.org/archives/2022/06/butyrate-produced-by-the-gut-microbiome-encourages-favorable-macrophage-polarization/

The gut microbiome produces a broad range of necessary, beneficial metabolites, but the effects of only a few are well understood. Butyrate is one of the better studied of these metabolites, particularly in the context of cognitive function. Butyrate encourages BDNF expression, which in turn upregulates neurogenesis. Butyrate also upregulates expression of FGF21, which adjusts metabolism in ways that mimic some of the beneficial effects of calorie restriction. Unfortunately, shifts in the balance of populations in the gut microbiome take place with age, and butyrate production decreases as a result.

The innate immune cells called macrophages adopt packages of behaviors known as polarizations in response to circumstances. In today's open access paper, researchers note that butyrate adjusts the polarization of macrophage cells, from the pro-inflammatory M1 polarization to the anti-inflammatory, pro-regenerative M2 polarization. This is generally advantageous in the context of aged, inflamed tissue that tends towards fibrosis. Fibrosis is a malfunction of normal tissue maintenance that leads to scar-like deposition of collagen extracellular matrix, degrading tissue function. Organs such as the heart and kidney suffer fibrosis in later life, and there is presently little that can be done about that after the fact. A number of lines of work have shown that adjusting macrophage polarization towards M2, to dampen inflammation, can be beneficial in fibrotic tissues, however, and hence the interest here in the effects of butyrate on these cells.

Butyric Acid Ameliorates Myocardial Fibrosis by Regulating M1/M2 Polarization of Macrophages and Promoting Recovery of Mitochondrial Function

Myocardial fibrosis (MF) refers to various quantitative and qualitative changes in the myocardial interstitial collagen network. It is mainly manifested by the proliferation of myocardial fibroblasts, which secretes extracellular matrix proteins to replace damaged tissues. It is a common pathological manifestation in the end stage of many cardiovascular diseases and is the result of imbalance of collagen synthesis and metabolism. When MF occurs, it will damage the myocardial structure and promote arrhythmia and ischemia, thus affecting the evolution and outcome of heart disease.

Recent studies have shown that gut microbiota has a variety of effects on the host. Indeed, the functions of gut microbiota like an endocrine organ, producing bioactive metabolites that affect the physiological function of the host. There is growing awareness of the importance of the gut in many cardiovascular health and diseases, of which the role of the "gut-heart" axis is particularly important. Butyric acid is a short-chain fatty acid (SCFA) from the microbial community that involves in a series of cellular processes in a concentration-dependent manner. It is a multifunctional molecule produced by the fermentation of dietary fiber in the intestinal tract of mammals.

Macrophages are key cells in the immune inflammatory response. Activated macrophages are generally differentiated into M1 and M2 phenotypes. In addition to playing a role in host defense, macrophages also ensure tissue homeostasis and inhibit inflammatory responses. In order to perform these seemingly opposite functions, macrophages show high plasticity and adopt a spectrum of polarized states, where M1 macrophages and M2 macrophages are extreme. Both M1 macrophages and M2 macrophages are closely related to the inflammatory response, among which M1 macrophages are mainly involved in the pro-inflammatory response, and M2 macrophages are mainly involved in the anti-inflammatory response. Functionally, M2 macrophages inhibit M1-driven inflammation and promote tissue repair.

We hypothesized that M1-related mitochondrial oxidative phosphorylation inhibition is the factor that prevents M1 from repolarization to M2. Increasing the plasma concentration of butyric acid helps to protect the mitochondria, thereby repolarizing M2 from M1 to inhibit the progression of MF. To this end, we constructed a rat model of MF and fed rats with butyric acid. Our results suggested that butyric acid ameliorated MF by regulating M1/M2 polarization of macrophages and promoting recovery of mitochondrial function.

Lyfspn Working on Clinical Trials of Plasmapheresis
https://www.fightaging.org/archives/2022/06/lyfspn-working-on-clinical-trials-of-plasmapheresis/

Parabiosis studies involve connecting the circulatory systems of two genetically identical mice, resulting in modest rejuvenation in the older mouse of the pair. The path from those animal studies to age-modifying therapies in humans has been one of twists and turns. At first, the research community focused on potentially beneficial factors in young blood. Elevian's work on GDF11 is still ongoing as an outcome of that research. Over the same period of time, plasma transfusions from young to old humans have produced a lack of convincing data.

Later experiments strongly suggested that the real benefit was dilution of harmful factors in old blood, and it remains to be seen as to where that leaves Elevian. Of late, further evidence has arisen to point to the quality of albumin in blood as an important factor, with the hypothesis that dilution works because it usually involves delivery of albumin along with saline or plasma, and thus reduces the amount of harmfully modified albumin already in circulation, rather than for any other reason. Dilution is fairly easy to carry out, and physicians are already doing this for self-experimenters. It still needs a reasonably sized human trial, however, to confirm the beneficial results observed in animal studies.

Lfyspn is a new company set up to run exactly this sort of clinical trial, to establish plasma dilution, or albumin replacement, or both, as simple means to improve late life health. Their view is that this is an approach that should be considered immunomodulatory in nature, leading to a reduction in inflammatory signaling and improvements in tissue function downstream of that primary effect. More research is needed in order to understand the details, but benefits to health in humans can still be quantified well in advance of that work.

A new clinical trial is hoping to move the needle on therapeutic plasma exchange - and is looking for participants

Plasmapheresis is a procedure that removes plasma from whole blood, swapping out unhealthy plasma and replacing it with healthy donor plasma or a plasma substitute. Plasma is part of blood, a fluid made up of water, proteins, and essential nutrients. In certain diseases, as well as in aging individuals, certain harmful substances accumulate in plasma and may lead to organ damage. Lyfspn, a company backed by Khosla Ventures, is conducting a plasmapheresis trial in the Bay Area for longevity benefits - and is actively seeking trial participants, particularly those from the biohacking community.

The idea that plasmapheresis could aid longevity started, as is so often the case, in mice, in an experiment called parabiosis. It was shown that when two mice - one old, one young - are connected through their skin, the end result is common circulation, with the blood of each animal, in effect, diluted by 50% and the young mouse experiencing accelerated aging and the older mouse benefiting from rejuvenation. Experiments over the last seven or eight years to discover exactly what it is in the blood that causes this rejuvenation have failed at a cost of millions. A change of approach was needed. "Last year we published other experiments in mice, that didn't involve connecting two mice. Instead, we transfused blood from mice into another - a process we call dilution - and we saw the same beneficial effects occurring."

"What else became obvious from the original research is that the effect isn't just the removal of bad substances from the blood. This is something people don't pay close attention to, but plasmapheresis, probably by the removal of certain substances, actually causes immunomodulation - the whole immune system functions differently, and, for the most part it functions better after plasmapheresis, with an increase in certain beneficial factors in the blood. This is one of the most exciting findings, but it's a complex process that warrants this further research."

Lyfspn

Lyfspn is a physician-led venture-backed startup company working to invent novel therapies that will allow us live longer, healthier lives. The Lyfspn team is passionate about bringing therapies to the world that find their basis in basic science research. Lyfspn is currently planning to carry out a pilot study of our lead longevity promoting therapy candidate, a novel apheresis-based treatment. Apheresis is an existing therapeutic modality which plays an important role in the management of many diseases including more than 50 autoimmune disorders, a number of rare neurologic conditions, and Alzheimer's disease. Apheresis is emerging as a prevention and therapy for other age related medical conditions.

Inflammation Accelerates Mesenchymal Stem Cell Aging
https://www.fightaging.org/archives/2022/06/inflammation-accelerates-mesenchymal-stem-cell-aging/

Chronic inflammation disrupts tissue function throughout the body, contributing to the onset and progression of age-related conditions. One of the wide variety of ways in which this happens is via detrimental changes in stem cell populations and their activities. Researchers here focus down on mesenchymal stem cells in bone marrow as one example of many that might be considered. That senescent cells act to maintain an inflammatory environment is one of the reasons why removal of senescent cells produces profound and rapid rejuvenation in animal studies. More methods of cleanly reducing chronic inflammation with minimal side-effects are very much needed, a necessary part of the toolkit of rejuvenation therapies presently under development.

Mesenchymal stem cell (MSC) senescence is considered a contributing factor in aging-related diseases. We investigated the influence of the inflammatory microenvironment on bone marrow mesenchymal stem cells (BMSCs) under aging conditions and the underlying mechanism to provide new ideas for stem cell therapy for age-related osteoporosis. The BMSCs were cultured until passage 3 (P3) (young group) and passage 10 (P10) (aging group) in vitro. The supernatant was collected as the conditioned medium (CM). The young BMSCs were cultured in the CM of P3 or P10 cells. The effects of CM from different groups on the aging and stemness of the young BMSCs were examined. An inflammation assay was conducted on serum extracts from young (aged 8 weeks) and old (aged 78 weeks) mice, and differentially expressed factors were screened out.

We discovered that the CM from senescent MSCs changed the physiology of young BMSCs. Systemic inflammatory microenvironments changed with age in the mice. In particular, the pro-inflammatory cytokine IL-6 increased, and the anti-inflammatory cytokine IL-10 decreased. The underlying mechanism was investigated, and there was a change in the JAK-STAT signaling pathway, which is closely related to IL-6 and IL-10. Collectively, our results demonstrated that the age-related inflammatory microenvironment has a significant effect on the biological functions of BMSCs. Targeted reversal of this inflammatory environment may provide a new strategy for stem cell therapy to treat aging-related skeletal diseases.

Fecal Microbiota Transplantation Improves Ovarian Function in Old Mice
https://www.fightaging.org/archives/2022/06/fecal-microbiota-transplantation-improves-ovarian-function-in-old-mice/

Fecal microbiota transplantation from a young individual to an old individual has been shown in animal studies to reset the aging gut microbiome to a more youthful configuration for a lasting period of time. The gut microbiome changes in detrimental ways with age, as harmful and inflammatory populations grow to displace beneficial populations that produce needed metabolites. A fecal microbiota transplant removes these changes, improving health, reducing inflammation, and extending life span in short-lived species. It is a procedure already used in humans, and which should be further developed as a means to improve the health of all older people.

Advanced maternal age is characterized by declines in the quantity and quality of oocytes in the ovaries, and the aging process is accompanied by changes in gut microbiota composition. However, little is known about the relationship between gut microbiota and ovarian aging. By using fecal microbiota transplantation (FMT) to transplant material from young (5-week-old) into aged (42-week-old) mice, we find that the composition of gut microbiota in FMT-treated mice presents a "younger-like phenotype" and an increase of commensal bacteria, such as Bifidobacterium and Ruminococcaceae. Moreover, the FMT-treated mice show increased anti-inflammatory cytokine IL-4 and decreased pro-inflammatory cytokine IFN-γ.

Fertility tests for assessing ovarian function reveal that the first litter size of female FMT-treated mice is significantly higher than that of the non-FMT group. Morphology analysis demonstrates a dramatic decrease in follicle atresia and apoptosis as well as an increase in cellular proliferation in the ovaries of the FMT-treated mice. Our results also show that FMT improves the immune microenvironment in aged ovaries, with decreased macrophages and macrophage-derived multinucleated giant cells (MNGCs). These results suggest that FMT from young donors could be a good choice for delaying ovarian aging.

On the Large Scale Plans of the Hevolution Foundation
https://www.fightaging.org/archives/2022/06/on-the-large-scale-plans-of-the-hevolution-foundation/

There have been signs that Saudi Arabian interests are considering putting significant amounts of funding into accelerating progress towards the treatment of aging, though it is entirely unclear as to whether any of that investment will be targeted towards the more useful areas of research and development, those focused on repair and reversal of age-related damage. This article is a decent high level summary of what may or may not come to pass via the Hevolution Foundation as a vehicle for the deployment of sovereign wealth into geroscience. The present accelerating trajectory for increased funding of translational aging research is clearly heading in this direction. Consider the few billion in funding devoted to reprogramming in just the last year or two. If not Saudi Arabia, then other countries will sooner or later devote large-scale funding towards the treatment of aging, in the hopes that it will prevent the collapse of entitlement systems due to the rising average age of the population.

Anyone who has more money than they know what to do with eventually tries to cure aging. Google founder Larry Page has tried it. Jeff Bezos has tried it. Tech billionaires Larry Ellison and Peter Thiel have tried it. Now the kingdom of Saudi Arabia, which has about as much money as all of them put together, is going to try it. The Saudi royal family has started a not-for-profit organization called the Hevolution Foundation that plans to spend up to 1 billion a year of its oil wealth supporting basic research on the biology of aging and finding ways to extend the number of years people live in good health, a concept known as "health span."

The foundation hasn't yet made a formal announcement, but the scope of its effort has been outlined at scientific meetings and is the subject of excited chatter among aging researchers, who hope it will underwrite large human studies of potential anti-aging drugs. The idea, popular among some longevity scientists, is that if you can slow the body's aging process, you can delay the onset of multiple diseases and extend the healthy years people are able to enjoy as they grow older. The fund is going to give grants for basic scientific research on what causes aging, just as others have done, but it also plans to go a step further by supporting drug studies, including trials of "treatments that are patent expired or never got commercialized."

The fund is authorized to spend up to 1 billion per year indefinitely, and will be able to take financial stakes in biotech companies. By comparison, the division of the US National Institute on Aging that supports basic research on the biology of aging spends about 325 million a year. Hevolution hasn't announced what projects it will back, but people familiar with the group say it looked at funding a 100 million X Prize for age reversal technology and has reached a preliminary agreement to fund the TAME trial, a test of the diabetes drug metformin in several thousand elderly people.

Vision Influences Circadian Rhythms to Interact with Calorie Restriction and Aging
https://www.fightaging.org/archives/2022/06/vision-influences-circadian-rhythms-to-interact-with-calorie-restriction-and-aging/

Circadian mechanisms have been found to influence aging in short-lived species, though the degree to which this is relevant to treating aging in longer-lived species such as our own is up for debate. All too much of the metabolic response to stress, and items such as circadian rhythms that have an impact on that response, have far larger effects on the pace of aging in short-lived species than in long-lived ones. The work here, in which vision is found to alter circadian mechanisms and thus also the beneficial calorie restriction response, is interesting in the academic sense, in the same way that it is interesting that scent can disrupt the calorie restriction response, but most likely of little to no practical use.

Researchers conducted a broad survey to see what genes oscillate in a circadian fashion when flies on an unrestricted diet were compared with those fed just 10 percent of the protein of the unrestricted diet. Immediately, they noticed numerous genes that were both diet-responsive and also exhibiting ups and downs at different time points, or "rhythmic." They then discovered that the rhythmic genes that were activated the most with dietary restriction all seemed to be coming from the eye, specifically from photoreceptors, the specialized neurons in the retina of the eye that respond to light.

This finding led to a series of experiments designed to understand how eye function fit into the story of how dietary restriction can extend lifespan. For example, researchers set up experiments showing that keeping flies in constant darkness extended their lifespan. "That seemed very strange to us. We had thought flies needed the lighting cues to be rhythmic, or circadian." They then used bioinformatics to ask: Do the genes in the eye that are also rhythmic and responsive to dietary restriction influence lifespan? The answer was yes they do.

The biggest question raised by this work as it might apply to humans is, simply, do photoreceptors in mammals affect longevity? Probably not as much as in fruit flies, said Hodge, noting that the majority of energy in a fruit fly is devoted to the eye. But since photoreceptors are just specialized neurons, "the stronger link I would argue is the role that circadian function plays in neurons in general, especially with dietary restrictions, and how these can be harnessed to maintain neuronal function throughout aging."

A Hostile Environment for Neurogenesis in the Aging Hippocampus
https://www.fightaging.org/archives/2022/06/a-hostile-environment-for-neurogenesis-in-the-aging-hippocampus/

Neurogenesis, the creation of new neurons and subsequent integration into neural circuits, is necessary for maintenance and function of the brain, particularly in connection to memory. Unfortunately, neurogenesis declines with age. Here, researchers add to the existing body of evidence for chronic inflammation in the brain to contribute to this decline. Unresolved inflammation is considered to contribute to neurodegeneration in general, not just loss of neurogenesis. Finding ways to safely suppress excessive inflammation in the aging body and brain is a high priority in the treatment of aging as a medical condition.

Using brain tissues from non-human primates (NHPs), the ideal model to mimic human hippocampal aging, scientists have established the first single-nucleus transcriptomic landscape of primate hippocampal aging. In this study, the aged NHP hippocampus was found to demonstrate an array of aging-associated damages, including genomic and epigenomic instability, loss of proteostasis, as well as increased inflammation.

To explore unique cellular and molecular characteristics underlying these age-related phenotypes, scientists generated a high-resolution single-nucleus transcriptomic landscape of hippocampal aging in NHPs. It is composed of the gene expression profiles of 12 major hippocampal cell types, including neural stem cells, transient amplified progenitor cells (TAPC), immature neurons, excitatory/inhibitory neurons, oligodendrocytes, and microglia. Among them, TAPC and microglia were most affected by aging, as they manifested the most aging-related differentially expressed genes and those annotated as high-risk genes for neurodegenerative diseases.

In-depth analysis of the dynamic gene-expression signatures of the stepwise neurogenesis trajectory revealed the impaired TAPC division and compromised neuronal function, underlying the early onset and later stage of dysregulation in adult hippocampal neurogenesis, respectively. This landscape also helps to unveil contributing factors to a hostile microenvironment for neurogenesis in the aged hippocampus, namely the elevated pro-inflammatory responses in the aged microglia and oligodendrocyte, as well as dysregulated coagulation pathways in the aged endothelial cells. This may aggravate the loss of neurogenesis in the aged hippocampus, and may lead to the further decline of cognitive function and the occurrence of neurodegenerative diseases.

DNA Gaps as a Protective Mechanism that Limits DNA Damage
https://www.fightaging.org/archives/2022/06/dna-gaps-as-a-protective-mechanism-that-limits-dna-damage/

This fascinating paper discusses the phenomenon of DNA gaps, essentially a double strand break in which the break is hidden from the usual mechanisms that respond to and repair such damage. The authors present evidence for these DNA gaps to be protective against DNA damage, noting that a loss of DNA gaps is associated with degenerative aging in animal models, both induced aging and natural aging. It is a little early to speculate on what can be done with this information, but it is interesting to join the dots with other research into DNA damage conducted in recent years.

The endogenous DNA damage triggering an aging progression in the elderly is prevented in youth, probably by naturally occurring DNA gaps. Decreased DNA gaps are found during chronological aging in yeast. So we named the gaps "Youth-DNA-GAPs." The gaps are hidden by histone deacetylation to prevent DNA break response and were also reduced in cells lacking either the high-mobility group box (HMGB) or the NAD-dependent histone deacetylase, SIR2. A reduction in DNA gaps results in shearing DNA strands and decreasing cell viability. The number of Youth-DNA-GAPs were low in senescent cells, two aging rat models, and the elderly. HMGB1 acts as molecular scissors in producing DNA gaps. Increased gaps consolidated DNA durability, leading to DNA protection and improved aging features in senescent cells and two aging rat models similar to those of young organisms.

Similar to other DNA modifications such as 5-methylcytosine that can be either epigenetic marks or DNA damage, both pathological DNA breaks and physiological DNA gaps are DNA modifications with the same DNA structure; however, pathological DNA breaks are DNA damage, and the physiological DNA gaps are epigenetic marks. By evaluating the correlation between Youth-DNA-GAPs and age, we concluded that Youth-DNA-GAPs are a ubiquitous DNA change existing in a wide range of eukaryotic cells, including yeast, rodents, and humans. Additionally, the reduction of Youth-DNA-GAPs varies based on the aging degree and this decrease can result from chemical-induced or natural aging. The reduction of Youth-DNA-GAPs was associated with aging phenotypes regardless of cause. In rats, decreased DNA gaps were found in both natural and D-gal-induced aging groups.

In yeast, a strong correlation was observed between the reduction in Youth-DNA-GAPs and viability in aging yeast cells. So the gap reduction is rather a marker of biological than chronological aging. This study showed a negative relationship between the gaps and the number of senescence cells. Moreover, we found a similar reduction in 30-month-old naturally and 7-month-old D-gal-induced aging rats. Given these consistent data from different eukaryotic organisms, it suggests that the Youth-DNA-GAP is a marker of phenotype-related aging degree

Towards Scaffold-Based Regeneration of Dental Pulp
https://www.fightaging.org/archives/2022/06/towards-scaffold-based-regeneration-of-dental-pulp/

Researchers are working towards the ability to regenerate the dental pulp inside teeth. Full regeneration of teeth has seemed perpetually on the verge of success for a decade or so now; it has been achieved as a proof of concept in rats, for example. Restoration of dental pulp is a more viable, less complex project, given the present state of research into the use of scaffolds to provoke regrowth.

Researchers have proposed an alternative to root canals in dentistry: restoring the lost tissue in the tooth cavity by inducing the body to regenerate it. Their goal is to develop a materials-based therapy that does not contain live cells and therefore could be sold off-the-shelf. It would be the first of its kind. The team has created an injectable hydrogel designed to recruit a person's own dental pulp stem cells directly to the disinfected cavity after a root canal. Composed of biocompatible peptides that aggregate into fibers, the hydrogel delivers biological cues to direct tissue growth, as well as a scaffold structure to support it.

A procedure known as over-instrumentation is performed on children's immature permanent teeth with necrotic pulp, prompting new growth of the still-forming root by eliciting a healing response. The tissue outside of the emptied canal, when poked, forms blood clots that secrete a growth factor that signals cells to produce new tissue to support the root. While some regrows, it is disorganized, lacks the needed tissue differentiation - including nerve cells - and fails to mimic soft tissue. By contrast, the team's hydrogel therapy mimics the body's own growth factor signaling, and, coupled with known antimicrobial mechanisms engineered into those materials, is capable of promoting tissue healing and regeneration.

In early animal studies, dogs injected with the team's hydrogels formed soft tissue from the tooth apex to the crown in just under a month. "We saw a lot of different tissues, including blood vessels, nerve bundles and pulp-like cells. One of the primary goals of this project is to determine the type of cells that reorganize and repopulate the regenerated tissue." One of the core challenges tissue engineers face is creating blood vasculature, the plumbing that delivers nutrients to regenerated cells. To address the problem, the team's hydrogel contains a protein known as vascular endothelial growth factor that stimulates the growth of new blood vessels.

Clozapine Treatment Reduces Epigenetic Age in Male Psychiatric Patients
https://www.fightaging.org/archives/2022/06/clozapine-treatment-reduces-epigenetic-age-in-male-psychiatric-patients/

Researchers are beginning to apply epigenetic clocks to known cases in which drug treatment is associated with a longer life expectancy, even less unusual ones, such as this case. Patients treated with the antipsychotic drug clozapine exhibit a longer life expectancy, and epigenetic clock data now shows that male patients in addition experience a lowered epigenetic age. Whether any of this data proves useful at the end of the day is an open question. The challenge in the use of epigenetic clocks is that researchers don't yet understand how specific epigenetic marks connect to the underlying mechanisms of aging. Therefore clocks become unreliable in the context of interventions that address a given mechanism of aging: the clock may be biased towards or against that mechanism, and without calibrating the therapy against the clock in life span studies, it is impossible to draw conclusions from the data.

Long-term studies have shown significantly lower mortality rates in patients with continuous clozapine (CLZ) treatment than other antipsychotics. We aimed to evaluate epigenetic age and DNA methylome differences between CLZ-treated patients and those without psychopharmacological treatment. The DNA methylome was analyzed in 31 CLZ-treated patients with psychotic disorders and 56 patients with psychiatric disorders naive to psychopharmacological treatment. Delta age (Δage) was calculated as the difference between predicted epigenetic age and chronological age. CLZ-treated patients were stratified by sex, age, and years of treatment. Differential methylation sites between both groups were determined using linear regression models.

The Δage in CLZ-treated patients was on average lower compared with drug-naive patients for the three clocks analyzed; however, after data-stratification, this difference remained only in male patients. Additional differences were observed in Hannum and Horvath clocks when comparing chronological age and years of CLZ treatment. We identified 44,716 differentially methylated sites, of which 87.7% were hypomethylated in CLZ-treated patients, and enriched in the longevity pathway genes. Moreover, by protein-protein interaction, AMPK and insulin signaling pathways were found enriched. CLZ could promote a lower Δage in individuals with long-term treatment and modify the DNA methylome of the longevity-regulating pathways genes.

Engineering Therapeutic Mesenchymal Stem Cells to Overexpress HIF1α
https://www.fightaging.org/archives/2022/06/engineering-therapeutic-mesenchymal-stem-cells-to-overexpress-hif1%ce%b1/

Reseachers here demonstrate that engineering the mesenchymal stem cells provided in a cell therapy to overexpress HIF1α produces regeneration in a pig model of heart failure. The mechanisms involved are up for debate, as they may or may not involve an extension of survival of the stem cells following transplant, versus a shift in cell signaling. Mesenchymal stem cells do not survive long in most such treatments, and their beneficial effects are the result of signals secreted in the short time they are present in tissues. Given the feasibility of engineering cells in vitro in any number of ways, this is a logical next step for the industry, now that first generation cell therapies are so well established.

Recent preclinical investigations and clinical trials with stem cells mostly studied bone-marrow-derived mononuclear cells (BM-MNCs), which so far failed to meet clinically significant functional study endpoints. BM-MNCs containing small proportions of stem cells provide little regenerative potential, while mesenchymal stem cells (MSCs) promise effective therapy via paracrine impact. Genetic engineering for rationally enhancing paracrine effects of implanted stem cells is an attractive option for further development of therapeutic cardiac repair strategies. Non-viral, efficient transfection methods promise improved clinical translation, longevity and a high level of gene delivery.

Hypoxia-induced factor 1α (HIF1α) is responsible for pro-angiogenic, anti-apoptotic and anti-remodeling mechanisms. Here we aimed to apply a cellular gene therapy model in chronic ischemic heart failure in pigs. A non-viral circular minicircle DNA vector was used for in vitro transfection of porcine MSCs (pMSC) with HIF1α (pMSC-MiCi-HIF-1α). pMSCs-MiCi-HIF-1α were injected endomyocardially into the border zone of an anterior myocardial infarction one month post-reperfused-infarct.

Animals underwent treatment one month after infarction, which more aptly reflects realistic clinical application, but arguably complicates successful outcomes, because the initial repair and immunological processes start immediately at the onset of infarction. Nonetheless, pMSC-MiCi-HIF-1α significantly reduced myocardial scar size and improved cardiac output. Our results thus underline the potential as a therapeutic concept.

USP16 Inhibition May Produce Benefits in an Alzheimer's Mouse Model by Lowering the Burden of Cellular Senescence
https://www.fightaging.org/archives/2022/06/usp16-inhibition-may-produce-benefits-in-an-alzheimers-mouse-model-by-lowering-the-burden-of-cellular-senescence/

Previous studies have shown benefits in some mouse models of Alzheimer's disease (not the one chosen here) via clearance of senescent cells. These cells produce chronic inflammation, and that inflammation is thought to be influential in driving the pathology of Alzheimer's disease. One caveat is that these models are highly artificial, but nonetheless, there is good evidence for the human condition to involve cellular senescence and otherwise inflammatory behavior in the supporting cells of the brain.

Researchers here note that USP16 inhibition improves function in an Alzheimer's mouse model; this acts to downregulate Cdkn2a, one of the gene loci involved in the onset of cellular senescence. The results here are supportive of a role for cellular senescence in neurodegeneration, but suppression of the onset of cellular senescence may or may not be the best approach. Where inflammation is driving undamaged cells into senescence, then it could be beneficial. But there is always the risk of suppressing senescence for cells that really should become senescent, to protect against potentially cancerous damage. Where the balance of benefit and risk falls can only really be determined by experiment.

Alzheimer's disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. Therefore, we set out to identify a potential earlier targetable phenotype. Utilizing a mouse model of AD and human fetal cells harboring mutant amyloid precursor protein, we show cell intrinsic neural precursor cell (NPC) dysfunction precedes widespread inflammation and amyloid plaque pathology, making it the earliest defect in the evolution of the disease.

We demonstrate that reversing impaired NPC self-renewal via genetic reduction of USP16, a histone modifier and critical physiological antagonist of the Polycomb Repressor Complex 1, can prevent downstream cognitive defects and decrease astrogliosis in vivo. Reduction of USP16 led to decreased expression of senescence gene Cdkn2a and mitigated aberrant regulation of the Bone Morphogenetic Signaling (BMP) pathway, a previously unknown function of USP16. Thus, we reveal USP16 as a novel target in an AD model that can both ameliorate the NPC defect and rescue memory and learning through its regulation of both Cdkn2a and BMP signaling.