Fight Aging! Newsletter, September 5th 2022

Fight Aging! Newsletter
September 5th 2022

Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter, please visit: https://www.fightaging.org/newsletter/

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Contents

Fecal Microbiota Transplantation Improves Cognition in Older C. Difficile Patients Engineering an Increase in Retrotransposon Activity Accelerates Aspects of Aging in Flies Lifelong Exercise Considerably Reduces Sarcopenia in Mice Two Year Update on a Study of One with Flagellin Immunization to Adjust the Gut Microbiome Transplanting B Cells from Old Mice to Young Mice to Investigate Details of B Cell Aging A Better Way of Measuring Senescent Cell Burden Across Tissues and Species The Popular Press May Be Improving in Coverage of the Treatment of Aging Mitochondrial Mutator Mice Exhibit Accelerated Nuclear DNA Damage Treatments for Cellular Senescence as a Path to Reduced Age-Related Inflammation A Short Tour of Scientific Thought on Vascular Aging Searching for Age-Slowing Drugs in the Antidiabetic Portfolio Improving Hematopoietic Stem Cell Transplants Senolytics, a Promising New Field of Medicine in the Treatment of Aging Elongated Isoform of Aquaporin-4 Can Enhance Clearance of Amyloid-β from the Brain More Data on Plasma Dilution in Humans

Fecal Microbiota Transplantation Improves Cognition in Older C. Difficile Patients
https://www.fightaging.org/archives/2022/08/fecal-microbiota-transplantation-improves-cognition-in-older-c-difficile-patients/

Fecal microbiota transplantation from young individuals to old individuals reduces inflammation, improves health, and extends life span in killifish, a short lived species. It at least reduces inflammation and improves health in mice. Despite being used to treat C. Difficile infections, in which the gut microbiome is overtaken by that unwelcome species of bacteria, there is next to no data in humans on the very interesting question of whether the gut microbiome, and the many declines in health that are associated with age-related shifts in the microbiome, can be improved by transplanting a sample of youthful gut microbes.

The study reported in today's open access paper doesn't help in providing an answer, I think. It is good to see that old people with C. Difficile infections resistant to other treatments can be helped by fecal microbiota transplantation. It is good to see that the patients experience an improved cognitive function. But one can't separate the unpleasant effects of C. Difficile from the unpleasant effects of gut microbiome aging in this small study in that respect, and the choice of antibiotics for a control group, who were actually worse off after the treatment, just muddies the water, given the effects of antibiotics on the broader gut microbiome. The outcomes do not allow us to say all that much about how healthy older humans will benefit from the transplantation of a young gut microbiome, other than it appears safe to undertake.

In particular, we might look at chronic inflammation as one of the more relevant outcomes of gut microbiome aging. Inflammatory populations expand in number, perhaps because they are no longer adequately restrained by the immune system as it ages into immunosenescence. Chronic inflammation is strongly implicated in the progression of neurodegeneration and cognitive decline. Runaway C. Difficile infection is a highly inflammatory condition, however. Thus getting rid of the C. Difficile population obscures the question of whether and how the transplant is also improving the gut microbiome more generally in these older patients.

Fecal microbiota transplantation can improve cognition in patients with cognitive decline and Clostridioides difficile infection

After fecal microbiota transplantation (FMT) to treat Clostridioides difficile infection (CDI), cognitive improvement is noticeable, suggesting an essential association between the gut microbiome and neural function. Although the gut microbiome has been associated with cognitive function, it remains to be elucidated whether fecal microbiota transplantation can improve cognition in patients with cognitive decline. The study included 10 patients (age range, 63-90 years; female, 80%) with dementia and severe CDI who were receiving FMT. Also, 10 patients (age range, 62-91; female, 80%) with dementia and severe CDI who were not receiving FMT. They were evaluated using cognitive function tests (Mini-Mental State Examination [MMSE] and Clinical Dementia Rating scale Sum of Boxes [CDR-SB]) at 1 month before and after FMT or antibiotics treatment (control group). The patients' fecal samples were analyzed to compare the composition of their gut microbiota before and 3 weeks after FMT or antibiotics treatment. Ten patients receiving FMT showed significantly improvements in clinical symptoms and cognitive functions compared to control group. The MMSE and CDR-SB of FMT group were improved compare to antibiotics treatment (MMSE: median 16.00 vs 10.0; CDR-SB: median 5.50 vs 8.0). FMT led to changes in the recipient's gut microbiota composition, with enrichment of Proteobacteria and Bacteroidetes. Alanine, aspartate, and glutamate metabolism pathways were also significantly different after FMT. This study revealed important interactions between the gut microbiome and cognitive function. Moreover, it suggested that FMT may effectively delay cognitive decline in patients with dementia.

Engineering an Increase in Retrotransposon Activity Accelerates Aspects of Aging in Flies
https://www.fightaging.org/archives/2022/08/engineering-an-increase-in-retrotransposon-activity-accelerates-aspects-of-aging-in-flies/

One has to be somewhat careful when declaring that an intervention produces accelerated aging. Interventions that reduce health and life span in ways that mimic aspects of aging tend to be narrow in effect, causing elevated levels of a specific form of molecular damage, often one of those thought to be involved in natural aging. DNA repair deficiencies cause what looks a lot like accelerated aging, but should really be thought of as an excess of only one type of age-related damage, nuclear DNA damage. It might be possible to learn things from this type of malfunction, but given that it is very unlike natural aging, it is more likely that a close inspection of the cellular biochemistry and tissue dysfunction involved would be misleading. One can make similar, more difficult arguments regarding whether or not excess visceral fat tissue produces accelerated aging by increasing the burden of cellular senescence, or whether this should be viewed in much the same way as DNA repair deficiencies.

In today's open access paper, researchers note that engineering a greater activity of retrotransposons, in effect producing DNA damage as the transposable elements replicate themselves to break the parts of the genome they copy into, accelerates aspects of aging in flies. This is a closer analogy to DNA repair deficiencies than the question of obesity, again a way to amplify natural processes of DNA damage with consequences that can mimic natural aging in some ways. Retrotransposons are tightly controlled in youth, but epigenetic aging allows them ever greater freedom to replicate in later life. There is a fair amount of evidence to implicate this process in age-related disease and loss of function, but as is the case for so much of aging it is hard to pin down exactly how much harm is caused by this one process, versus all of the other processes of aging. Speeding it up in isolation of other mechanisms is one way to make an estimate, but it is nowhere near as compelling as the much harder demonstration, yet to be achieved, of slowing it down.

Artificially stimulating retrotransposon activity can increase mortality and accelerate a subset of aging phenotypes in Drosophila

Transposable elements (TE) are mobile sequences of DNA that can become transcriptionally active as an animal ages. Whether TE activity is simply a byproduct of heterochromatin breakdown or can contribute towards the aging process is not known. Here we place the TE gypsy under the control of the UAS GAL4 system to model TE activation during aging. We find that increased TE activity shortens the lifespan of male D. melanogaster. The effect is only apparent in middle aged animals. The increase in mortality is not seen in young animals. An intact reverse transcriptase is necessary for the decrease in lifespan implicating a DNA mediated process in the effect. The decline in lifespan in the active gypsy flies is accompanied by the acceleration of a subset of aging phenotypes. TE activity increases sensitivity to oxidative stress and promotes a decline in circadian rhythmicity. The overexpression of the Forkhead-box O family (FOXO) stress response transcription factor can partially rescue the detrimental effects of increased TE activity on lifespan. Our results provide evidence that active TEs can behave as effectors in the aging process and suggest a potential novel role for dFOXO in its promotion of longevity in D. melanogaster.

Lifelong Exercise Considerably Reduces Sarcopenia in Mice
https://www.fightaging.org/archives/2022/08/lifelong-exercise-considerably-reduces-sarcopenia-in-mice/

In today's study, researchers report on a comparison between mice undergoing life-long exercise (a wheel in their cage) versus more sedentary mice (no wheel). The authors note that the age-related onset of sarcopenia is much reduced in the exercising mice, which we could perhaps take as more of an indication of the harms of a lack of exercise than of the benefits of exercise per se. This is perhaps the least interesting part of the data and discussion, however. One of the points being made by the researchers is that the effects of life-long exercise are underestimated by the research community, because this intervention is not well studied in either mice or humans, at least in comparison to shorter periods of exercise commencing in old age.

The other point being made is that while it is known that exercise helps to blunt the loss of capillary density with age, the markers that the researchers assessed for cellular biochemistry related to angiogenesis, the creation of blood vessels, are not telling a story that matches up with the observed outcome. Thus the present understanding of the way in which exercise interacts with maintenance of capillary networks over the long term is probably incomplete, and there are other pathways to discover and investigate.

Capillary density is important in the operation of energy-hungry tissues such as muscle and the brain, being the road by which nutrients reach cells. Fewer capillaries means a lesser supply of nutrients and a consequent stress on cells and loss of tissue function. This issue of capillary densitry is probably a useful point of intervention, given safe strategies to adjust the operation of angiogenesis, such as VEGF gene therapy or CXCL12 upregulation via small molecule drugs.

Effects of lifelong spontaneous exercise on skeletal muscle and angiogenesis in super-aged mice

The effect of endurance exercise on sarcopenia is underestimated compared to that of resistance exercise. The reason for this is that the studies so far have mainly focused on therapeutic approaches after the onset of sarcopenia. In addition, large-scale epidemiological studies are difficult to control for variables that directly or indirectly affect endurance exercise. In the case of clinical studies, it is difficult to obtain various physiological phenotypes in the muscles following endurance exercise through research because long-term endurance exercise intervention over a lifetime is virtually impossible. Our previous study indirectly demonstrated that the risk of premature death can be lowered by maintaining energy homeostasis in super-aged mice subjected to lifelong spontaneous exercise (LSE). Therefore, it was expected that the onset of sarcopenia caused by aging would be delayed or the risk of sarcopenia occurring during aging would be lowered if LSE that mimics endurance exercise is performed. We aimed to investigate the quantity and quality of skeletal muscle in 25-month-old super-aged mice (99-week-old, corresponding to a human age of at least 70 years), which corresponds to the later life of naturally aging mice used as a rodent model for sarcopenia. In particular, one of the key points of this study was to explain capillary density (expression of angiogenesis-related genes and angiogenic capacity), which is known to be closely related to endurance exercise, by integrating the results of our previous study. Our findings show that LSE could maintain skeletal muscle mass, quality, and fitness levels in super-aged mice. In addition, ex vivo experiments showed that the angiogenic capacity was maintained at a high level. However, these results were not consistent with the related changes in the expression of genes and/or proteins involved in protein synthesis or angiogenesis. Based on the results of previous studies, it seems certain that the expression at the molecular level does not represent the phenotypes of skeletal muscle and angiogenesis. This is because aging and long-term exercise are variables that can affect both protein synthesis and the expression patterns of angiogenesis-related genes and proteins. Therefore, in aging and exercise-related research, various physical fitness and angiogenesis variables and phenotypes should be analyzed.

Two Year Update on a Study of One with Flagellin Immunization to Adjust the Gut Microbiome
https://www.fightaging.org/archives/2022/09/two-year-update-on-a-study-of-one-with-flagellin-immunization-to-adjust-the-gut-microbiome/

This post is an update for an earlier report on a self-experiment with flagellin immunization, tested as an approach to adjust the balance of microbial populations in the aging gut microbiome in a favorable, more youthful direction. Commentary and data from the earlier report are repeated, with the addition of a new assessment of the gut microbiome taken two years after the end of the experiment. In summary, changes from this short and simple intervention were largely favorable, and largely sustained over this period of time.

Flagellin is the protein that makes up bacterial flagellae, and it is hypothesized that there is a sizable overlap between populations of gut microbes that possess flagellae and populations of gut microbes that are harmful rather than helpful. The harmful microbes are largely a problem because they contribute to chronic inflammation, while helpful microbes are largely beneficial due to the metabolites that they produce. The gut microbiome changes with age, shifting towards more harmful and fewer helpful microbes.

If the immune system can be roused to do a better job of eliminating the problem microbes, then perhaps this could lead to improved health. Flagellin immunization has been trialed in humans as a vaccine adjuvant, and shown to be safe in the small studies conducted to date. In recent years, researchers tested its ability to adjust the gut microbiome in mice, with favorable results. In 2020, I posted a potential study outline for a self-experiment in flagellin immunization as a prompt for discussion, and in 2021 I published a report from one adventurous self-experimenter who gave it a try.

Setting Expectations

The motivation for this self-experiment was curiosity: would human data be similar to the mouse data? After a couple of years, the results continue to be, on balance, positive. The mouse data doesn't cover this sort of time span, but it is worth noting that in killifish adjustments to the gut microbiome made by fecal microbiota transplant are lasting, at least on the relatively short scale of a killifish life span. The question of whether results from an intervention to change the gut microbiome will last is of course quite an important one! A useful, lasting intervention is a great deal more valuable than one that does not last. This is a self-experiment in which there is an unusually clear readout for the outcome of interest, in the form of the Viome gut microbiome assay. This is nonetheless a study population of one. The results should be taken as interesting, but not supportive of any particular conclusion beyond the desire to run a larger and more formal study.

Schedule for the Self-Experiment

The self-experiment ran for ten weeks. Weekly intramuscular injections of 10 μg flagellin in 0.5ml phosphate-buffered saline were used, with Viome gut microbiome assays performed (a) beforehand, (b) at 10 weeks, (c) at 8 months, (d) and finally at 28 months.

Week 1: Viome gut microbiome assessment. Week 1: Intramuscular injection of 10 μg of flagellin. Week 2: Intramuscular injection of 10 μg of flagellin. Week 3: Intramuscular injection of 10 μg of flagellin. Week 4: Intramuscular injection of 10 μg of flagellin. Week 5: Intramuscular injection of 10 μg of flagellin. Week 6: Intramuscular injection of 10 μg of flagellin. Week 7: Intramuscular injection of 10 μg of flagellin. Week 8: Intramuscular injection of 10 μg of flagellin. Week 9: Intramuscular injection of 10 μg of flagellin. Week 10: Intramuscular injection of 10 μg of flagellin. Week 10: Viome gut microbiome assessment. Week 34: Viome gut microbiome assessment. Week 122: Viome gut microbiome assessment.

Subject Details

The subject for the self-experiment was in the 45-55 age range, healthy and without chronic conditions, with a BMI of ~22 throughout the duration of the experiment. Diet and exercise were described as "relatively consistent" across this time, including the six month and two year follow up assessments. I feel that one should always be relatively skeptical of that sort of claim, however, no matter how formal or informal the study.

Summary of Results

Viome does not provide raw data on species and prevalence of gut microbes and their biochemistry, but rather a set of scores derived from that raw data. The algorithm used isn't public, meaning that one can't really dispute any of their choices or the studies used to support those choices, unfortunately. The algorithm is, nonetheless, consistent between assays at different times, and so can be used as a point of comparison for the purposes of a self-experiment, at least.

Over the course of the self-experiment, Viome summary scores improved for Inflammatory Activity, Digestive Efficiency, Gut Lining Health, Protein Fermentation, and Gas Production. The summary scores declined for Metabolic Fitness and Active Microbial Diversity. The gains (largely bad scores transforming into good scores) were larger than the declines (bad scores becoming worse scores). Some of these areas of function are likely more important than others to health, though expect arguments over which and why. My bias would be to prioritize Inflammatory Activity and Gut Lining Health when it comes to interactions between the gut microbiome and the processes of aging, but this is certainly a viewpoint that could be challenged.

Viome Data - Overall Score

Gut Microbiome Health:
Before: 27
After: 43
Week 34: 49
Week 122: 42

Viome Data - Summary Scores

Inflammatory Activity (lower is better):
Before: 50
After: 45
Week 34: 28
Week 122: 31

Metabolic Fitness (higher is better):
Before: 25
After: 29
Week 34: 21
Week 122: 25

Digestive Efficency (higher is better):
Before: 0
After: 57
Week 34: 68
Week 122: 52

Gut Lining Health (higher is better):
Before: 12
After: 64
Week 34: 69
Week 122: 75

Protein Fermentation (lower is better):
Before: 87
After: 49
Week 34: 33
Week 122: 54

Gas Production (lower is better):
Before: 83
After: 48
Week 34: 35
Week 122: 35

Active Microbial Diversity (higher is better):
Before: 34
After: 15
Week 34: 15
Week 122: 5

Viome Data - Other Ratings

Ammonia Production Pathways
Before: Not Optimal
After: Average
Week 34: Good
Week 122: Not Optimal

Bile Acid Metabolism Pathways
Before: Average
After: Good
Week 34: Good
Week 122: Average

Biofilm, Chemotaxis, and Virulence Pathways
Before: Not Optimal
After: Not Optimal
Week 34: Good
Week 122: Not Optimal

Butyrate Production Pathways
Before: Average
After: Average
Week 34: Not Optimal
Week 122: Average

Flagellar Assembly Pathways
Before: Not Optimal
After: Not Optimal
Week 34: Average
Week 122: Average

LPS Biosynthesis Pathways
Before: Average
After: Average
Week 34: Average
Week 122: Average

Methane Gas Production Pathways
Before: Good
After: Not Optimal
Week 34: Good
Week 122: Average

Oxylate Metabolism Pathways
Before: Average
After: Not Optimal
Week 34: Not Optimal
Week 122: Not Optimal

Putrescine Production Pathways
Before: Not Optimal
After: Not Optimal
Week 34: Average
Week 122: Average

Salt Stress Pathways
Before: Average
After: Average
Week 34: Average
Week 122: Average

Sulfide Gas Production Pathways
Before: Not Optimal
After: Average
Week 34: Average
Week 122: Good

TMA Production Pathways
Before: Good
After: Good
Week 34: Good
Week 122: Average

Uric Acid Production Pathways
Before: Not Optimal
After: Not Optimal
Week 34: Not Optimal
Week 122: Good

Anecdotal Notes

The first few injections of flagellin produced a minor injection site reaction that lasted a few days: red and tender. That was reduced with each injection, and later injections produced no reaction. Beyond that, no perceptible change in health or digestion, positive or negative, was observed as a result of the self-experiment.

Conclusion

Coupled with the animal data, and the existing human trial data for safety, the results here suggests that someone should run a formal, controlled trial of flagellin immunization in older people, 65 and over. The goal would be to see whether (a) this sort of outcome holds up in a larger group of people, and (b) there is a meaningful impact on chronic inflammation and other parameters of health that are known to be affected by the aging of the gut microbiome.

The most interesting part of the data is perhaps the decline in microbial diversity, when considered against the gains elsewhere. Microbial diversity correlates with better health in epidemiological studies, but there isn't a good mechanistic understanding as to why this is the case, or what factors provoke diversity versus a lack of diversity.

Transplanting B Cells from Old Mice to Young Mice to Investigate Details of B Cell Aging
https://www.fightaging.org/archives/2022/09/transplanting-b-cells-from-old-mice-to-young-mice-to-investigate-details-of-b-cell-aging/

The varieties of B cell in the immune system participate in the immune response to pathogens by creating antibodies to match specific antigens, and spreading the information represented by that antibody to portions of the adaptive immune system capable of attacking threats. This is a very crude, high level summary of an enormously complex system. The fine details of how subsets of the B cell population generate suitable antibodies, and then communicate with one another and the rest of the immune system, are complicated indeed, involving many different subsets of cell, different paths of activation, and different mechanisms.

Aspects of B cell function are known to decline with age, contributing to the broader loss of efficacy in the immune response, the onset of immunosenescence. Is this a problem with the B cells themselves becoming changed or damaged, or is it a problem of the broader system within which B cells function? This sort of question is always hard to answer in the study of aging. Biology is very complicated, and everything interacts with everything else. Isolating the specifics of any one mechanism amidst all of that is very challenging. There are always avenues by which to make some progress, however. In today's open access paper, researchers analyze the behavior of B cells transplanted from old mice into young mice, using this as a strategy to obtain some insight into which aspects of B cell function decline due to intrinsic defects in the aged cells, and which are due to age-related deficiencies in other parts of the immune system.

Interestingly, other work shows that B cells can be readily cleared from the body in old animals, and regenerate rapidly following this intervention. Immune function is improved as a result. Thus while the work here shows that old B cells remain surprisingly functional if only given a young immune system to work with, there is in fact a degradation of function that is distinct from any problem in the hematopoietic cell populations responsible for creating B cells. Some populations of problem B cells have been identified, described as age-associated B cells in the literature, and it seems we'd all be better off for their removal from the aging body.

B cell-intrinsic changes with age do not impact antibody-secreting cell formation but delay B cell participation in the germinal centre reaction

Vaccines typically protect against (re)infections by generating pathogen-neutralising antibodies. However, as we age, antibody-secreting cell formation and vaccine-induced antibody titres are reduced. Antibody-secreting plasma cells differentiate from B cells either early post-vaccination through the extrafollicular response or from the germinal centre (GC) reaction, which generates long-lived antibody-secreting cells. As the formation of both the extrafollicular antibody response and the GC requires the interaction of multiple cell types, the impaired antibody response in ageing could be caused by B cell intrinsic or extrinsic factors, or a combination of the two. Here, we show that B cells from older people do not have intrinsic defects in their proliferation and differentiation into antibody-secreting cells in vitro compared to those from the younger donors. However, adoptive transfer of B cells from aged mice to young recipient mice showed that differentiation into extrafollicular plasma cells was favoured at the expense of B cells entering the GC during the early stages of GC formation. In contrast, by the peak of the GC response, GC B cells derived from the donor cells of aged mice had expanded to the same extent as those from the younger donors. This indicates that age-related intrinsic B cell changes delay the GC response but are not responsible for the impaired antibody-secreting response or smaller peak GC response in ageing. Collectively, this study shows that B cells from aged individuals are not intrinsically defective in responding to stimulation and becoming antibody-secreting cells, implicating B cell-extrinsic factors as the primary cause of age-associated impairment in the humoral immunity.

A Better Way of Measuring Senescent Cell Burden Across Tissues and Species
https://www.fightaging.org/archives/2022/08/a-better-way-of-measuring-senescent-cell-burden-across-tissues-and-species/

Researchers here propose a better way of measuring the burden of cellular senescence in aged tissues, one that works well across different tissues and species. It is complicated, involving expression of many genes, but the existing simple metrics, such as measurement of senescence-associated beta-galactosidase levels, are increasingly thought inadequate to the task. Senescent cells likely vary in character and metabolism between tissues in ways that have become meaningful now that researchers are past the period of early validation of therapies targeting senescent cells. Now it is important to obtain a much better idea as to the effectiveness of various potential treatments in mice or humans than is presently the case.

Cellular senescence is now recognized as a fundamental mechanism of aging in animals and humans. Senescent cells can develop a senescence-associated secretory phenotype (SASP), consisting of pro-inflammatory cytokines, chemokines, extracellular matrix-degrading proteins, and other factors that have deleterious paracrine and systemic effects. Further, because senescent cells accumulate in multiple tissues in temporal and spatial synchrony with age-associated functional decline in both animals and humans, they have been hypothesized to drive the deterioration linked to numerous chronic diseases. Importantly, the SASP as a feature of cellular senescence represents not just a locally or systemically detrimental set of factors that, in the aging organism, cause physical, metabolic, and cognitive decline, but is also a therapeutic target of interest. Thus, given the broad availability of next-generation sequencing, there is considerable interest in monitoring responses to senolytic treatments. However, this has been challenging, especially at the single cell level. In part, this is due to an imprecise definition of the heterogeneous population of senescent cells and their associated SASP which complicates appropriate monitoring of senescent cell clearance. Due to variations in the composition of a "senescence gene set" in the current literature, in the present study we sought to identify commonly regulated genes in various age-related datasets in a transcriptome-wide approach that included whole-transcriptome as well as single cell RNA-sequencing (scRNA-seq). Based on an extensive review of the literature, we defined a panel of 125 genes as our senescence gene set ("SenMayo"), which we then validated in our own as well as publicly available datasets of tissues from aged humans and mice, including changes in this gene set following the clearance of senescent cells. Recognizing the difficulty of identifying senescent cells within scRNA-seq analyses, we next applied SenMayo to available scRNA-seq data from human and murine bone marrow/bone hematopoietic and mesenchymal cells, ascertained the identity of the senescent cells in these analyses, and characterized the communication patterns of senescent hematopoietic or mesenchymal cells with other cells in their microenvironment. Finally, we experimentally validated key predictions from our in silico analyses in a mouse model of aging and following genetic clearance of senescent cells.

The Popular Press May Be Improving in Coverage of the Treatment of Aging
https://www.fightaging.org/archives/2022/08/the-popular-press-may-be-improving-in-coverage-of-the-treatment-of-aging/

These days, articles in the popular, non-scientific media on the topic of treating aging as a medical condition tend towards being something other than terrible. This is a considerable improvement over the state of affairs a decade ago, and night and day in comparison to the press attitudes towards aging research in the early years of this century. There is always room for improvement, and journalists are near always ill-informed about near everything they commit to paper, but nonetheless the tone is heading in the right direction: that the treatment of aging is a project, it is underway, there are many competing approaches and opinions, and, given the importance of the resulting therapies to all of our lives, this part of the scientific endeavor should not be ignored.

For all the advances in medical technology humans have developed, there is one thing it hasn't been able to do: stop us from getting old. We've managed to extend the human lifetime dramatically in the last couple of centuries, greatly diminishing infant and child mortality and pushing back on disease with antibiotics and vaccines. But the general trajectory of life endures: once we get into the last quarter of our lives, our health gradually declines. That may soon change, as researchers focus on treating the diseases and conditions that plague us as we get older. It's not impossible that we might soon see medicines that greatly improve and maintain our health and independence as we head into our golden years. "Until now, we've been treating medicine in this very unsystematic way. In a sense, we've been picking off the endpoints of aging, things like cancer and heart disease, without actually addressing the fundamental underlying causes that are resulting in those diseases. So what we could do by understanding these hallmarks of aging, is potentially come up with treatments to intervene in them directly. And that means preventative treatments, treatments can go in earlier and stop people getting ill in the first place." There are already treatments for cellular senescence, drugs that target these redundant cells and remove them, along with the toxic cocktail of molecules that accompany them and contribute to heart disease and cancer. Using these treatments on mice essentially made the mice biologically younger. "It's not as though they were hobbling along in a sort of geriatric state, which has somehow been extended by this anti-aging treatment. What they found is that the mice were healthier too. So they got less cancer, they got less heart disease, they got fewer cataracts, they were less frail." That's an important concept to get across. Most people, when they think of increasing human lifetimes from, say, 80 to 120 years, assume that this means we'll just be very old for a longer time, which doesn't hold a lot of appeal. But if we could live to 120 and be healthy and active until we're, say, 118, then that's a much more attractive proposition.

Mitochondrial Mutator Mice Exhibit Accelerated Nuclear DNA Damage
https://www.fightaging.org/archives/2022/08/mitochondrial-mutator-mice-exhibit-accelerated-nuclear-dna-damage/

Mice in which the POLG genek critical to repair of mitochondrial DNA, is disabled via genetic engineering exhibit accelerated aging. Researchers here show that these mice also show an accelerated rate of nuclear DNA damage and shorter telomere length. Telomeres shorten with each cell division in somatic cells, eventually reaching the Hayflick limit and senescence or programmed cell death, while stem cells produce daughter cells with long telomeres to replace losses. Average telomere length is thus, loosely, a measure of stem cell function, though since it is normally measured in immune cells from a blood sample, it also reflects immune system stress. The raised rate of nuclear DNA strand breaks may be the more interesting correlation here, given recent work suggesting that this repeated cycles of damage and repair of this sort results in epigenetic changes characteristic of aging.

Mitochondrial dysfunction plays an important role in the aging process. However, the mechanism by which this dysfunction causes aging is not fully understood. The accumulation of mutations in the mitochondrial genome (or "mtDNA") has been proposed as a contributor. One compelling piece of evidence in support of this hypothesis comes from the PolgD257A/D257A mutator mouse (Polgmut/mut). These mice express an error-prone mitochondrial DNA polymerase that results in the accumulation of mtDNA mutations, accelerated aging, and premature death. In this paper, we have used the Polgmut/mut model to investigate whether the age-related biological effects observed in these mice are triggered by oxidative damage to the DNA that compromises the integrity of the genome. Our results show that mutator mouse has significantly higher levels of 8-oxoguanine (8-oxoGua) that are correlated with increased nuclear DNA (nDNA) strand breakage and oxidative nDNA damage, shorter average telomere length, and reduced mtDNA integrity. Based on these results, we propose a model whereby the increased level of reactive oxygen species (ROS) associated with the accumulation of mtDNA mutations in Polgmut/mut mice results in higher levels of 8-oxoGua, which in turn lead to compromised DNA integrity and accelerated aging via increased DNA fragmentation and telomere shortening. These results suggest that mitochondria play a central role in aging and may guide future research to develop potential therapeutics for mitigating aging process.

Treatments for Cellular Senescence as a Path to Reduced Age-Related Inflammation
https://www.fightaging.org/archives/2022/08/treatments-for-cellular-senescence-as-a-path-to-reduced-age-related-inflammation/

The accumulation of senescent cells in aged tissues is an important contributing cause of aging, but it is only one cause of many. Nonetheless, removing even just a third of lingering senescent cells in some tissues produces a degree of rejuvenation in old mice that is large enough to be very interesting. Much of this effect appears mediated by a reduction in inflammatory signaling and thus in the chronic inflammation that disrupts tissue function in later life. We can hope that clinical trials and the ongoing development of first and second generation senolytic therapies to clear senescent cells will demonstrate similar benefits to health in humans.

Chronic inflammation, one of the major hallmarks of aging, is thought to be partly caused by senescent cells that may accumulate in older individuals. As we age, a small number of cells in tissues throughout our body become senescent. These cells undergo irreversible cell cycle arrest - in other words, they can no longer divide. The unique cells may have some evolutionary benefit. Rapid cell division, for example, can lead to cancer, and senescence may be an evolutionary adaptation that reduces the risk of certain cells becoming cancerous. However, senescent cells also produce inflammatory cytokines that accelerate the process of aging. Researchers hypothesize that through targeting senescent cells, they could potentially reign in chronic inflammation in aging individuals. To study senescence in mice, the researchers will mark various cells with fluorescent markers to track how the cells age over time and to see if they become senescent. Next, they will use unbiased transcriptional sequencing and spatial sequencing approaches - techniques used to help researchers generate a map of the cell they are sequencing - to try and discover new markers that are unique to senescent cells. The team hopes their work will lead to the development of approaches to target senescent cells in a way that reduces the inflammation they produce. Some researchers, for example, are studying ways to eliminate senescent cells using drugs known as senolytics. However, the use of these drugs is controversial because current senolytic drugs aren't specific to just getting rid of senescent cells and may harm other cells as well. The workcould potentially help scientists identify senescent cells causing chronic inflammation and develop newer, more precision drugs targeting these cells.

A Short Tour of Scientific Thought on Vascular Aging
https://www.fightaging.org/archives/2022/08/a-short-tour-of-scientific-thought-on-vascular-aging/

The aging of the vasculature, set aside from any other part of the body, arguably kills the largest fraction of humanity at the present time. It isn't just the dysfunctions of macrophages that lead to atherosclerotic plaque, and the narrowing of blood vessels and stroke and heart attack. It isn't just the declining density of capillary networks, reducing blood supply to energy-hungry tissues. It isn't just blood-brain barrier leakage and the consequent inflammation of the brain, or the stiffening of arteries that causes hypertension and remodeling of the heart. The vasculature is so vital that a great many mechanisms compete in their ability to cause harm with advancing age and the growing burden of cell and tissue damage.

Aging represents the main risk factor for cardiovascular disease (CVD) which carries the highest burden for the older population and is the leading cause of death worldwide. Vascular aging is a gradually developing process characterized by alterations in the properties of the vascular wall that start very early in life. In fact, it has been documented that the architecture of the vascular system is programmed in utero and most of the elastin, the major structural component underlying arterial wall elasticity, is synthesized and deposited during that period. The phenotype of vascular aging in adults will be identified by certain vascular alterations which result in vascular dysfunction and development of a wide range of age-related vascular pathologies. These alterations are divided into structural changes which include the progressive thickening of the vascular wall along with vascular smooth muscle cell (VSMC) migration and proliferation, namely vascular remodeling, and the functional changes which include endothelial dysfunction, loss of arterial elasticity and reduced arterial compliance, all of which result in increased arterial stiffness. The pathogenesis behind these changes in vascular aging involves multiple complex cellular and molecular mechanisms such as mitochondrial dysfunction and oxidative stress, inflammation, loss of proteostasis, genomic instability, cellular senescence, increased apoptosis and necroptosis, epigenetic alterations, and extracellular matrix (ECM) remodeling. As many age-related cardiovascular and cerebrovascular diseases are due to alterations in vascular function or are exacerbated by vascular functional and structural changes, it is important to thoroughly elucidate those fundamental pathophysiological mechanisms underlying the vascular aging process, in an attempt to develop novel treatments to reduce age-associated mortality. In this review, we describe the fundamental cellular and molecular mechanisms of aging: oxidative stress, chronic low-grade inflammation, cell matrix injury, epigenetic alterations, telomere length, cellular senescence and autophagy, considering in vitro and in vivo preclinical research and clinical studies.

Searching for Age-Slowing Drugs in the Antidiabetic Portfolio
https://www.fightaging.org/archives/2022/08/searching-for-age-slowing-drugs-in-the-antidiabetic-portfolio/

Data for the ability of metformin to slow aging has researchers looking at other antidiabetic drugs these days, even given that the evidence for metformin to have a meaningful impact on aging in non-diabetic animals is not great, very mixed, and even the human data for a modest addition of a few years in type 2 diabetes patients is most likely not as good as the impact of exercise and control of weight. Still, repurposing drugs to produce modest effects in a different condition has long been a going concern; regulators make it so hard to develop new drugs that it makes economic sense to repurpose existing drugs, even when the likely gains for patients are marginal. The research noted here is par for the course in this respect, finding a gender-specific modest effect on mouse life span for an antidiabetic. Generally, effect sizes in mice for near all metabolism-altering approaches that slow aging are much larger than in humans, so the result here is not all that exciting.

Canagliflozin (Cana), a clinically important anti-diabetes drug, leads to a 14% increase in median lifespan and a 9% increase in the 90th percentile age when given to genetically heterogeneous male mice from 7 months of age, but does not increase lifespan in female mice. A histopathological study was conducted on 22-month-old mice to see if Cana retarded diverse forms of age-dependent pathology. This agent was found to diminish incidence or severity, in male mice only, of cardiomyopathy, glomerulonephropathy, arteriosclerosis, hepatic microvesicular cytoplasmic vacuolation (lipidosis), and adrenal cortical neoplasms. Protection against atrophy of the exocrine pancreas was seen in both males and females. Thus, the extension of lifespan in Cana-treated male mice, which is likely to reflect host- or tumor-mediated delay in lethal neoplasms, is accompanied by parallel retardation of lesions, in multiple tissues, that seldom if ever lead to death in these mice. Canagliflozin thus can be considered a drug that acts to slow the aging process and should be evaluated for potential protective effects against many other late-life conditions.

Improving Hematopoietic Stem Cell Transplants
https://www.fightaging.org/archives/2022/09/improving-hematopoietic-stem-cell-transplants/

One of the causes of immune system aging is the growing dysfunction of hematopoietic stem cell populations, responsible for the production of immune cells. While some of this degeneration comes from the aging of the bone marrow niche, some it appears to be intrinsic to the cells themselves, and thus there may be benefits to be found in transplantation of functional hematopoietic stem cells derived from a patient's own cells. This would be the case if these cells could be made to reliably survive and engraft in any reasonable number, however. That is a challenging prospect, but it is worth keeping an eye on the cancer field, where transplantation of donor stem cells is used to attack leukemias, for signs of promising advances such as the one noted here.

Hardly a day goes by without someone receiving an infusion of healthy donor-derived hematopoietic stem cells (HSCs) to replace those lost or damaged by disease. But the types of stem cells contained in such a transplant are not all the same. The majority are "short-term" HSCs. These cells can give rise to all manner of white blood cells, thus offering a reprieve from cancer or disease. But the cells have limited capacity for self-renewal, a biological weakness that constrains the duration of their therapeutic benefit. A different population of rare stem cells has the potential for prolonged reconstitution of the blood-forming system. These "long-term" HSCs can both sustain the stem cell pool and differentiate into their short-term kin, which makes them ideal from a therapeutic standpoint. But long-term HSCs have their own drawback: they are not particularly adept at engraftment, the process of taking root in recipient individuals - and researchers have now discovered why. Researchers showed that, compared to short-term HSCs, the reduced expression of key adhesion molecules in long-term HSCs explained their poor engraftment ability. The researchers then found a type of drug commonly used to treat diabetes; when added to long-term HSCs, this drug altered the dynamics of cell surface adhesion molecules in ways that improved uptake of the cells in mice. Another type of adhesion-targeted treatment also augmented the engraftment potential of short-term HSCs - and, as an added bonus, it made the cells behave more like their long-term counterparts. Researchers next hope to test the strategy with human stem cells and human recipients.

Senolytics, a Promising New Field of Medicine in the Treatment of Aging
https://www.fightaging.org/archives/2022/09/senolytics-a-promising-new-field-of-medicine-in-the-treatment-of-aging/

It is becoming harder for the world at large to ignore the field of senolytics, the large number of research groups and companies working towards therapies that clear a fraction of senescent cells from aged tissues. Senescent cells accumulate in later life, likely because the immune system becomes less able to remove them promptly. Lingering senescent cells actively disrupt normal tissue function and provoke chronic inflammation, thus contributing to age-related degeneration. Scores of mouse studies conducted over the last decade demonstrate that senolytic treatments produce rapid, reliable reversal of many age-related conditions and extension of healthy life span. Most interestingly, the best of the early senolytic treatments, the dasatinib and quercetin combination, is cheap, readily available, and in human clinical trials with promising initial results. The opening decades of the 21st century are the start of a golden future, in which none of us will have to be as impacted by aging and age-related disease as our parents and grandparents were.

Cells eventually stop dividing and enter a "senescent" state in response to various forms of damage. The body removes most of them. But others linger like zombies. They aren't dead. But they can harm nearby cells like moldy fruit corrupting a fruit bowl. They accumulate in older bodies, which mounting evidence links to an array of age-related conditions such as dementia, cardiovascular disease, and osteoporosis. But scientists wonder: Can the zombie cell buildup be stopped? "The ability to understand aging - and the potential to intervene in the fundamental biology of aging - is truly the greatest opportunity we have had, maybe in history, to transform human health. Extending the span of healthy years impacts quality of life, public health, socioeconomics, the whole shebang." "When you're young, your immune system is able to recognize these senescent cells and eliminate them. But when we start getting old ... the activity of our immune system also gets diminished, so we're losing the capacity to eliminate them." Senescent cells resist apoptosis, or programmed cell death, and characteristically get big and flat, with enlarged nuclei. They release a blend of molecules, some of which can trigger inflammation and harm other cells - and paradoxically can also stimulate the growth of malignant cells and fuel cancer. Experimental drugs designed to selectively clear senescent cells have been dubbed "senolytics." In mice, they've been shown to be effective at delaying, preventing, or easing several age-related disorders. Possible benefits for people are just emerging. Researchers undertook a pilot study providing initial evidence that patients with a serious lung disease might be helped by pairing a chemotherapy drug with a plant pigment. Another pilot study found the same combination reduced the burden of senescent cells in the fat tissue of people with diabetic kidney disease. At least a dozen clinical trials with senolytics are now testing things like whether they can help control Alzheimer's progression, improve joint health in osteoarthritis, and improve skeletal health. Scientists say serious work to improve human health could also bring fringe benefits - like reducing skin wrinkling. "I tell my lab that if we find a drug that clears the bad senescent cells and not the good ones and we cure Parkinson's disease and Alzheimer's and osteoporosis and macular degeneration, it would be wonderful. But if we cure wrinkles, we'll be rich, and I'll never have to write another grant. We know that senolytics work pretty well in mice. We're still really figuring out the basics with people."

Elongated Isoform of Aquaporin-4 Can Enhance Clearance of Amyloid-β from the Brain
https://www.fightaging.org/archives/2022/09/elongated-isoform-of-aquaporin-4-can-enhance-clearance-of-amyloid-%ce%b2-from-the-brain/

Researchers here report on an interesting discovery relating to the way in which aquaporin-4 functions in clearance of molecular waste from the brain. An uncommon isoform of aquaporin-4 has a role in clearing excess amyloid-β, and possibly many other forms of molecular waste. Given that a failure of clearance of molecular waste from the brain is apparently involved in many neurodegenerative conditions, approaches that enhance clearance are promising. Increased amounts of this more effective isoform can be achieved via a variety of strategies in mice, and in mice engineered to generate excess amyloid-β, this results in a reduction of amyloid-β in the brain. This is quite interesting, but further work is required to determine a useful way to implement this shift in protein isoforms in humans.

Every once in a while, the brain protein aquaporin 4 is synthesized with an extra little tail on the end. Scientists already knew that the cell's protein-building machinery occasionally fails to stop where it should. When the machinery doesn't stop - a phenomenon known as readthrough - it creates extended forms of proteins that sometimes function differently than the regular forms. "At first, we thought it couldn't possibly be relevant. But then we looked at the gene sequence, and it was conserved across species. And it had this really striking pattern in the brain: it was only in structures that are important for waste clearance. So that's when we got excited." Researchers found the long form - but not the short one - in the so-called endfeet of astrocytes. Astrocytes are a kind of support cell that help maintain the barrier between the brain and the rest of the body. Their endfeet wrap around tiny blood vessels in the brain and help regulate blood flow. Astrocytic endfeet are the perfect place to be if your job is to keep the brain free of unwanted proteins by flushing waste out of the brain and into the bloodstream, where it can be carried away and disposed of. Thinking that increasing the amount of long aquaporin 4 might increase waste clearance, researchers screened 2,560 compounds for the ability to increase readthrough of the aquaporin 4 gene. They found two: apigenin, a dietary flavone, and sulphaquinoxaline, a veterinary antibiotic. Sulphaquinoxaline is not safe for use in people. Apigenin is available as a dietary supplement, but it's not known how much gets into the brain. The researchers studied mice genetically engineered to have high levels of amyloid in their brains. They treated the mice with apigenin; sulphaquinoxaline; an inert liquid; or a placebo compound that has no effect on readthrough. Mice treated with either apigenin or sulphaquinoxaline cleared amyloid beta significantly faster than those treated with either of the two inactive substances. "There's a lot of data that says reducing amyloid levels by just 20% to 25% stops amyloid buildup, at least in mice, and the effects we saw were in that ballpark. This could be a novel approach to treating Alzheimer's and other neurodegenerative diseases that involve protein aggregation in the brain. There's nothing that says this process is specific for amyloid beta. It may be enhancing, say, alpha-synuclein clearance, too, which could benefit people with Parkinson's disease."

More Data on Plasma Dilution in Humans
https://www.fightaging.org/archives/2022/09/more-data-on-plasma-dilution-in-humans/

Diluting blood plasma in old individuals reduces circulating levels of harmful signals, such as pro-inflammatory proteins and debris, for long enough to allow improvement in tissue function. Significant dilution requires the introduction of new albumin, and there is presently some question over how much of the benefits result from the dilution of circulating factors versus delivery of albumin which is typically sourced from blood donations from (on average) younger individuals, and is thus less damaged. Researchers here report on the effects of repeated plasma dilution treatments in three human patients, showing an improvement in circulating protein levels known to change with age, some inflammation-linked, some more generally associated with processes of aging. It is an interesting addition to present understanding, and suggests the need for clinical trials of plasma dilution: it is a cheap intervention, and thus even modest benefit makes it worth the effort.

For people, plasma dilution is known as plasmapheresis or therapeutic plasma exchange (TPE); it replaces a patient's plasma with saline and purified albumin. The blood cells are returned to the patient so that while the cell profile does not change, the circulating blood proteins are diluted, including cytokines, autoreactive antibodies or toxins, and such pathogenic determinants of specific disorders. Although its full therapeutic benefits are still being discovered, TPE is one of the treatments for autoimmune and neurological diseases. Here, we followed the effects of a miniaturized TPE in mice and of pilot studies of TPE with 3 human patients by studying the longitudinal effects of rounds of TPE on hallmarks of systemic aging. The results demonstrate significant and lasting rejuvenation of both humoral and cellular blood compartments in people who underwent repeated plasmapheresis. The rejuvenative changes are not limited to a reduction of inflammaging but encompass diminished circulatory protein markers of neurodegeneration and cancer, as well as reduced senescence, lower DNA damage, and improved myeloid/lymphoid homeostasis.

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