Fight Aging!

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Contents

• Senolytic Treatment Minimizes the Contribution of Excess Fat Tissue to Insulin Resistance in Mice
• Results from a Trial of the Senolytic Fisetin in a Single Individual with Autoimmunity
• Leucadia Therapeutics: Towards the Prevention of Alzheimer's Disease
• Adult Disruption of Growth Hormone Receptor in Mice Produces Improved Health and Longevity
• A Fasting Mimicking Diet Improves Anti-Cancer Immune Function
• Tongue Exercise Does Not Help with the Age-Related Decline of Tongue Muscle Function in Rats
• Oral Bacteria and Age-Related Airway Inflammation
• Heart Rate Variability, Aging, and Cardiovascular Fitness
• The Lack of Funding for Chronic Kidney Disease Research is Not an Outlier
• The Continued Quest for Pluripotent Adult Stem Cells
• Microglia as Mediators of the Link Between Psychological Stress and Cognitive Aging
• D-Glyceric Acid Supplementation Improves Mitochondrial Function and Reduces Inflammation in Old People
• Reviewing α-Synuclein Aggregation in Parkinson's Disease
• α-synuclein Harms Microglial Function in the Progression of Parkinson's Disease
• The Longevity Gene Cisd2 Improves Liver Function in Aged Mice

Senolytic Treatment Minimizes the Contribution of Excess Fat Tissue to Insulin Resistance in Mice
https://www.fightaging.org/archives/2021/11/senolytic-treatment-minimizes-the-contribution-of-excess-fat-tissue-to-insulin-resistance-in-mice/

Senescent cells accumulate with age throughout the body, and contribute directly to the onset and progression of a wide range of age-related conditions. While never present in large numbers in comparison to normal somatic cells, senescent cells are metabolically active, secreting signals that provoke chronic inflammation, altered cell behavior, and numerous forms of tissue dysfunction. Senolytic therapies selectively target senescent cells for destruction, most by forcing these errant cells into the programmed cell death process of apoptosis. Senescent cells are primed to self-destruct, and suppressing anti-apoptosis mechanisms for a time can push them over the edge while leaving normal cells largely unaffected.

In recent years, researchers have shown that many of the detrimental effects of excess visceral fat tissue are mediated by the presence of senescent cells in that fat tissue. This isn't just age-related: excess visceral fat generates senescent cells even in youth, but it does become worse with age. Thus eliminating senescent cells on a periodic basis via the use of senolytic therapies may allow for some decoupling of excess visceral fat from poor health and accelerated aging. One of the more prominent consequences of gaining too much fat tissue is the onset of type 2 diabetes, a condition that can be reversed even at a comparatively late stage by low-calorie diets leading to weight loss. Senescent cells appear to play an important role here, causing the death and dysfunction of islet cells in the pancreas, cells that are necessary for the correct function of insulin metabolism.

Researchers here demonstrate that eliminating senescent cells in fat tissue causes a sizable improvement in the manifestations of type 2 diabetes in mice. This isn't the first time that results of this sort have been produced by the scientific community, and the data here can be added to that from similar studies conducted in last few years. Since most of these studies used the readily available senolytic treatment of dasatinib and quercetin, presently in human trials for other conditions, it is perhaps surprising to see little movement towards off-label use in humans, given the considerable size of the diabetic patient community.

Deleting Dysfunctional Cells Alleviates Diabetes

The cells in your body are constantly renewing themselves, with older cells aging and dying as new ones are being born. But sometimes that process goes awry. Occasionally damaged cells linger. Called senescent cells, they hang around, acting as a bad influence on other cells nearby. Their bad influence changes how the neighboring cells handle sugars or proteins and so causes metabolic problems. Type 2 diabetes is the most common metabolic disease in the US. Most people with diabetes have insulin resistance, which is associated with obesity, lack of exercise, and poor diet. But it also has a lot to do with senescent cells in people's body fat, according to new findings. And clearing away those senescent cells seems to stop diabetic behavior in obese mice.

Alleviating the negative effects of fat on metabolism was a dramatic result, the researchers said. If a therapy worked that well in humans, it would be a game-changing treatment for diabetes. Researchers tested the efficacy of a combination of experimental drugs, dasatinib and quercetin. Dasatinib and quercetin had already been shown to extend lifespan and good health in aged mice. In this study, they found these drugs can kill senescent cells from cultures of human fat tissue. The tissue was donated by individuals with obesity who were known to have metabolic troubles. Without treatment, the human fat tissues induced metabolic problems in immune-deficient mice. After treatment with dasatinib and quercetin, the harmful effects of the fat tissue were almost eliminated.

Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity

Insulin resistance is a pathological state often associated with obesity, representing a major risk factor for type 2 diabetes. Limited mechanism-based strategies exist to alleviate insulin resistance. Here, using single-cell transcriptomics, we identify a small, critically important, but previously unexamined cell population, p21Cip1 highly expressing (p21high) cells, which accumulate in adipose tissue with obesity. By leveraging a p21-Cre mouse model, we demonstrate that intermittent clearance of p21high cells can both prevent and alleviate insulin resistance in obese mice.

Exclusive inactivation of the NF-κB pathway within p21high cells, without killing them, attenuates insulin resistance. Moreover, fat transplantation experiments establish that p21high cells within fat are sufficient to cause insulin resistance in vivo. Importantly, a senolytic cocktail, dasatinib plus quercetin, eliminates p21high cells in human fat ex vivo and mitigates insulin resistance following xenotransplantation into immunodeficient mice. Our findings lay the foundation for pursuing the targeting of p21high cells as a new therapy to alleviate insulin resistance.

Results from a Trial of the Senolytic Fisetin in a Single Individual with Autoimmunity
https://www.fightaging.org/archives/2021/11/results-from-a-trial-of-the-senolytic-fisetin-in-a-single-individual-with-autoimmunity/

Today's materials from the Intraclear Biologics team may be of interest to those following the development of senolytic therapies. Since the Mayo Clinic has yet to publish results from their clinical trials of fisetin as a senolytic therapy, and may not do so for a few years yet, it is good to see even preliminary data from other sources. Senolytic therapies selectively destroy senescent cells, though only one approach (the combination of dasatinib and quercetin) has been definitely shown to destroy significant numbers of senescent cells in humans. Data has yet to be published on whether fisetin performs as well in humans as it does in mice.

The Intraclear Biologics data is an example of the Mayo Clinic's senolytic dose of fisetin applied to a single younger patient with autoimmunity - in effect a well-conducted self-experiment. The age of the patient, mid-thirties, is far too young to have any meaningful age-related accumulation of senescent cells. But various lines of work from recent years suggest that many autoimmune conditions are at least in part driven by the presence of senescent cells, a bidirectional dysfunctional relationship between the immune system and senescent cells in the tissue under attack. Type 1 diabetes, for example, and perhaps rheumatoid arthritis. Unfortunately, no assessment of senescent cell burden was carried out in this study, so it is possible that other mechanisms are involved in the lowered inflammation and other benefits experienced by the patient. Still, the results point the way to larger studies that include more comprehensive assessments.

Preliminary results of trials of Fisetin in a person with autoimmune thyroiditis

Since senescent cells also arise in the immune system, being one of the causes of autoimmune diseases, there is a hypothesis that the destruction of senescent cells will help in the prevention and treatment of many autoimmune diseases. It is important that the mechanisms of cell senescence and the effects of their destruction by senolytics are similar in mice and humans. For example, it has been shown that the combination of dasatinib (a relatively aggressive chemotherapeutic) and quercetin (a flavonoid) works in humans as well as in mice when it comes to destruction of senescent cells.

Some drugs that have established senolytic effects are available for purchase just now. However, they are usually used in much lower dosages than is required for the senolytic effect. Such substances include the readily available and cheap bioactive flavonoid fisetin. Mice experiments show that fisetin is about as effective against senescent cells as the dasatinib + quercetin combination. The advantage of fisetin, which is a plant substance, is its safety compared to many other drugs that have shown a senolytic effect.

There are currently three trials of fisetin as a senolytic in humans. They are conducted in Mayo Clinic (USA), where a special treatment protocol was developed. Mayo Protocol consists of taking 20 mg/kg of fisetin orally for two days in a row, after which a person takes the second course after a month or two months. Because of the availability and safety of fisetin, we decided to conduct our own trial of this drug in a person with autoimmune thyroiditis. It is noteworthy that, unlike most tests, we focus not on chronic inflammation, but on immune function.

In accordance with animal experiments, the inflammatory factors C reactive protein and rheumatoid factor decreased. Antibodies to thyroglobulin did not change, which means the autoimmune response does not decrease. TSH returned to normal value, which allowed the patient to reduce the dose of hormone therapy.

Leucadia Therapeutics: Towards the Prevention of Alzheimer's Disease
https://www.fightaging.org/archives/2021/12/leucadia-therapeutics-towards-the-prevention-of-alzheimers-disease/

The Leucadia Therapeutics principals and staff are working towards the prevention of Alzheimer's disease. Unlike most other initiatives in the space, their work is based on a novel understanding of the way in which reduced drainage of cerebrospinal fluid gives rise to Alzheimer's disease and potentially other neurodegenerative conditions. These conditions are characterized by rising levels of protein aggregates and other forms of molecular waste in the brain. This leads to toxicity to neurons, as well as to chronic inflammation due to the reactions of immune cells and other cells in brain tissue.

Cerebrospinal fluid drainage from the brain into the body is one of the ways in which these forms of waste are removed from the brain, keeping levels more manageable. As drainage falters due to age-related changes to the tissues involved, ever more molecular waste is trapped in the brain. Alzheimer's disease is one of the results. Leucadia researchers have in recent years used ferrets to show that surgically blocking cerebrospinal fluid drainage paths provokes early increases in protein aggregation, and then consequent neurodegeneration and cognitive decline.

Leucadia is one of the many stories in the anti-aging research and development community that in some way involves the Methuselah Foundation. Early work at Leucadia was funded by the foundation, and it was a conversation with Dave Gobel of the Methuselah Foundation at a scientific conference that convinced Doug Ethell, the Leucadia founder, to take his work out of academia and start down the road to human clinical trials. The company will in the next few years implant valve devices into patients to restore a measured flow of cerebrospinal fluid through the most important drainage pathway, and hopefully thereby definitely proof that Alzheimer's disease can be indefinitely postponed via this approach.

Scientists Develop AI Algorithms To Analyze Enormous Datasets In Alzheimer's Research

For the past 25 years, Alzheimer's disease researchers have viewed plaques and tangles pathology as the cause of Alzheimer's, which has led to an unbroken string of failed clinical trials. In 2014, neuroscientist Doug Ethell published a new hypothesis about the trigger for Alzheimer's and related dementias. In 2015, he founded Leucadia Therapeutics to develop a therapy based on his hypothesis. Leucadia's research has shown that plaques and tangles are effects of a more serious underlying condition that triggers the formation of those pathological features.

The cribriform plate is a porous bony structure located in the roof of the nasal cavity. The plate contains two deep pockets called fossa and many holes called olfactory foramina. Olfactory nerves that transmit the sense of smell pass through these holes. The cribriform plate is an outflow route the brain uses to clear out waste in cerebrospinal fluid (CSF). About half a liter of CSF is produced by the brain each day, but only about 1/20 of it drains through the cribriform plate. However, that small amount of CSF is responsible for clearing brain regions that are critical for making new memories and orienting us in the world. As humans age, the cribriform plate becomes ossified and less porous. The small holes close up and restrict the flow of cerebrospinal fluid. As less and less of this fluid is drained out of the brain, waste and toxins accumulate in the upstream brain regions responsible for memory. These waste-products form a slough (an area of dead tissue) where plaques form and neurons form tangles - two key hallmarks of Alzheimer's disease. Ethell's research indicates that Alzheimer's disease pathology result from reductions in cerebrospinal fluid drainage across the cribriform plate.

Leucadia Therapeutics is preparing for a clinical trial in 2022 that will use an implantable device to restore CSF drainage across the cribriform plate. With increasing life-expectancy, Dr. Ethell believes his device will become as common as a pacemaker. This well-founded approach should reverse early mild cognitive impairment and prevent Alzheimer's disease from occurring at all.

Adult Disruption of Growth Hormone Receptor in Mice Produces Improved Health and Longevity
https://www.fightaging.org/archives/2021/12/adult-disruption-of-growth-hormone-receptor-in-mice-produces-improved-health-and-longevity/

Genetic engineering of mouse lineages to produce life-long disruption of growth hormone metabolism, either growth hormone itself or growth hormone receptor, extends life. Animals are smaller, more challenged in maintaining body temperature, have more fat tissue, yet enhanced insulin sensitivity, and exhibit as much as a 70% longer life span. The present record for engineered mouse longevity has been held since 2003 by growth hormone receptor knockout (GHRKO) mice. That this record still stands in 2021 might be taken as a sign that the research and development community are not yet trying hard enough to produce therapies capable of meaningful rejuvenation and extension of healthy life span.

It is an interesting question as to how much of the longevity of GHRKO and similar mice results from the disruption of growth hormone metabolism during development. To pick just one example, a smaller body size can produce a broad range of effects, such as lowered risk of cancer. In today's open access paper, researchers report on their use of an inducible gene knockout mouse lineage to remove growth hormone receptor expression at six months of age, roughly equivalent to a mid-30s human. The mice thus had a normal development, allowing for a better assessment of growth hormone metabolism as a target for therapies intended to slow the progression of aging.

I am not that optimistic that meaningful therapies will result from this line of work. Changes in metabolism that operate for short periods of time have smaller effects than those that operate for longer periods of time. Further, the usual approach of small molecule treatments that interfere in growth hormone metabolism will likely do so only partially, not producing the full effect of a gene knockout. Further, alterations to growth hormone metabolism have much smaller effects on aging in long-lived mammals than is the case for short-lived mammals. The human Laron syndrome population has loss of function mutations in growth hormone receptor, and they do not appear to live significantly longer than the rest of us.

Growth hormone receptor gene disruption in mature-adult mice improves male insulin sensitivity and extends female lifespan

Several mouse lines with germline growth hormone (GH) axis disruptions have shown extensions in lifespan. As a result, it has been proposed that targeted inhibition of the GH axis could be a promising pharmacological intervention to extend healthy aging. Notably, except for the GHRKO mice, the aforementioned mouse lines have reduced action of at least one additional hormone such as prolactin, thyroid-stimulating hormone, or GHRH, that may contribute to their extended longevity phenotype. Therefore, the GHRKO mouse line was established as a model to study the specific effects of reduced GH action in vivo.

Importantly, due to their exceptional longevity, the GHRKO mice hold the Methuselah mouse prize for the world's longest-lived laboratory mouse with a lifespan a week short of 5 years of age. The GHRKO mice also exhibit improved healthspan, showing improved cognition and insulin sensitivity, resistance to diabetes, reduced neoplasia, and decreased markers of aging such as adipose tissue (AT) senescence and mTORC1 signaling in liver, kidney, heart, and muscle.

Our laboratory recently reported that some of the benefits of congenital GH deficiency, such as enhanced insulin sensitivity and extended lifespan in females could be achieved if GHR is disrupted during puberty at 1.5 months of age. In light of such promising results, the present study sought to answer if it is possible to attenuate GH action further in life and attain the benefits obtained in mice with congenital GHR ablation. Clinically relevant interventions to extend healthy lifespan should be given at an adult age. Therefore, here, we disrupted the GHR at 6 months of age in mice.

In the present study, we tested how adult-onset reductions in GH action affect health and lifespan, using a mouse line of inducible ablation of the GHR starting at 6 months of age (6mGHRKO). These mice exhibited GH resistance (reduced IGF-1 and elevated GH serum levels), increased body adiposity, reduced lean mass, and minimal effects on body length. Importantly, 6mGHRKO males have enhanced insulin sensitivity and reduced neoplasms while females exhibited increased median and maximal lifespan. Furthermore, fasting glucose and oxidative damage was reduced in females compared to males irrespective of Ghr deletion. Overall, disrupted GH action in adult mice resulted in sexual dimorphic effects suggesting that GH reduction at older ages may have gerotherapeutic effects.

A Fasting Mimicking Diet Improves Anti-Cancer Immune Function
https://www.fightaging.org/archives/2021/12/a-fasting-mimicking-diet-improves-anti-cancer-immune-function/

The fasting mimicking diet is, in essence, a clever strategy to pull in significant funding for the rigorous study of the use of forms of calorie restriction as a therapy. A fasting mimicking diet involves taking in just few enough calories to trigger most of the benefits of fasting. There must exist a dividing line in calorie intake at which nutrient sensor mechanisms determine that the body is in a state of fasting. Early research into fasting mimicking found that dividing line to be somewhere in the vicinity of 500 to 750 calories daily, but later studies use lower calorie levels. Another important point of calibration is to determine how long a fast must continue in order to produce the optimal, lasting benefits to metabolism. At this point, standard fasting mimicking is a five day exercise, with significant changes to the immune system occurring after the third day.

The real trick here, when it comes to enlisting the support of large entities in the world of regulation and medical development, is that while there is no good way to monetize the practice of fasting, there are very definitely ways to monetize a specific diet. An entire industry is focused on medical diets and the regulation thereof. Thus a specific fasting mimicking diet was created, patented, and fed into the regulatory approval process - and in the process pulled in funding and interest for this line of research and development. For those of us with little interest in these machinations, it is worth noting that the specifics of the diet are unimportant. Any sensible dietary composition that hits the calorie targets and duration should have the desired outcome.

In recent years, the primary focus for clinical trials of fasting mimicking has been its use in the treatment of cancer. It has long been known, as a matter of common wisdom in the medical community, that cancer patients tend do better as a result of forms of calorie restriction. Cancer is unfettered growth, and lowered calorie intake works against that growth in many different ways. Now much more robust data is emerging; today's research materials are an example of the results of that ongoing work.

Fasting-Mimicking Diet Is Safe, May Modulate Metabolism and Boost Antitumor Immunity in Cancer Patients

A diet involving short-term, severe calorie restriction was safe, feasible, and resulted in a decrease of blood glucose and growth factor concentration, reduction in peripheral blood immunosuppressive cells, and enhanced intratumor T-cell infiltration in cancer patients receiving standard-of-care therapy, according to the results of a clinical trial. Researchers enrolled 101 patients in the study with various tumor types treated with different standard anticancer therapies.

The researchers administered a fasting mimicking diet (FMD) regimen to the study participants that consisted of a five-day, low-carbohydrate, low-protein, plant-derived diet, which provided up to 600 Kcal on day 1 and up to 300 Kcal on days 2, 3, 4, and 5, for a total amount of up to 1,800 Kcal in five days. The cycle was repeated every three or four weeks for up to a maximum of eight consecutive cycles. Calorie restriction was followed by a refeeding period of 16 to 23 days, during which patients were not subjected to specific dietary restrictions but were recommended to adhere to international guidelines for a healthy diet and lifestyle.

In 99 evaluable patients, the FMD regimen reduced the median plasma glucose concentration by 18.6 percent, serum insulin by 50.7 percent, and serum IGF-1 by 30.3 percent, with these modifications remaining stable over the course of eight consecutive cycles. In an analysis conducted on 38 patients at the end of a five-day FMD cycle, the researchers found a significant decrease of circulating immunosuppressive myeloid subpopulations and an increase of activated CD8+ T cells. Both of these effects occurred independently of concomitant antitumor therapies and were also observed in a small group of healthy volunteers.

To investigate the effects of the FMD diet on intratumor immunity, researchers performed an interim analysis of another ongoing trial testing a five-day FMD cycle seven to 10 days before surgery in early-stage breast cancer and melanoma patients. Specifically, they evaluated the tumor-infiltrating immune cells and transcriptomic immune profiles in 22 breast cancer patients for whom enough tumor tissue had been collected before and after the FMD. This analysis revealed a significant increase in tumor-infiltrating CD8+ T cells and other changes, indicating a functional switch toward an antitumor immune microenvironment following FMD.

Fasting-mimicking diet is safe and reshapes metabolism and antitumor immunity in cancer patients

In tumor-bearing mice, cyclic fasting or fasting-mimicking diets (FMDs) enhance the activity of antineoplastic treatments by modulating systemic metabolism and boosting antitumor immunity. Here we conducted a clinical trial to investigate the safety and biological effects of cyclic, five-day FMD in combination with standard antitumor therapies. In 101 patients, the FMD was safe, feasible, and resulted in a consistent decrease of blood glucose and growth factor concentration, thus recapitulating metabolic changes that mediate fasting/FMD anticancer effects in preclinical experiments.

Integrated transcriptomic and deep-phenotyping analyses revealed that FMD profoundly reshapes anticancer immunity by inducing the contraction of peripheral blood immunosuppressive myeloid and regulatory T-cell compartments, paralleled by enhanced intratumor T-helper 1/cytotoxic responses and an enrichment of interferon-gamma and other immune signatures associated with better clinical outcomes in cancer patients. Our findings lay the foundations for phase II/III clinical trials aimed at investigating FMD antitumor efficacy in combination with standard antineoplastic treatments.

Tongue Exercise Does Not Help with the Age-Related Decline of Tongue Muscle Function in Rats
https://www.fightaging.org/archives/2021/11/tongue-exercise-does-not-help-with-the-age-related-decline-of-tongue-muscle-function-in-rats/

Exercise in the form of strength training creates such broad changes in metabolism and produces such diverse benefits to health that it is interesting to see a specific example in which it doesn't help at all. That is possibly a path to better understanding which of the results of exercise are important, versus which are not, when it comes to functional improvement of specific tissues in later life. Many of the benefit of exercise are likely secondary effects produced by changes in skeletal muscle metabolism and myokine signaling on other parts of the body. Those effects will be largely absent in a study such as this, where only one small set of muscles are trained.

Exercise-based treatment approaches for dysphagia may improve swallow function in part by inducing adaptive changes to muscles involved in swallowing. We have previously shown that both aging and progressive resistance tongue exercise, in a rat model, can induce biological changes in the genioglossus (GG); a muscle that elevates and protrudes the tongue. However, the impacts of progressive resistance tongue exercise on the retrusive muscles (styloglossus, SG; hyoglossus, HG) of the tongue are unknown. The purpose of this study was to examine the impact of a progressive resistance tongue exercise regimen on the retrusive tongue musculature in the context of aging. Given that aging alters retrusive tongue muscles to more slowly contracting fiber types, we hypothesized that these biological changes may be mitigated by tongue exercise.

Hyoglossus (HG) and styloglossus (SG) muscles of male rats were assayed in age groups of young (9 months old, n = 24), middle-aged (24 months old, n = 23), and old (32 months old, n = 26), after receiving an 8-week period of either progressive resistance protrusive tongue exercise, or sham exercise conditions. Following exercise, HG and SG tongue muscle contractile properties were assessed in vivo. HG and SG muscles were then isolated and assayed to determine myosin heavy chain isoform (MyHC) composition.

Both retrusive tongue muscle contractile properties and MyHC profiles of the HG and SG muscles were significantly impacted by age, but were not significantly impacted by tongue exercise. Old rats had significantly longer retrusive tongue contraction times and longer decay times than young rats. Additionally, HG and SG muscles showed significant MyHC profile changes with age, in that old groups had slower MyHC profiles as compared to young groups. However, the exercise condition did not induce significant effects in any of the biological outcome measures.

Oral Bacteria and Age-Related Airway Inflammation
https://www.fightaging.org/archives/2021/11/oral-bacteria-and-age-related-airway-inflammation/

Researchers have in the past proposed links between oral bacteria and chronic inflammation, particularly in the heart and brain, proposing that bacterial toxins and bacteria themselves enter the bloodstream via damaged gums. This undoubtedly happens, but supporting data is mixed when it comes to the question of whether or not this has a meaningful effect size in comparison to other inflammatory mechanisms and contributions to age-related disease. Here, a different route for bacteria is proposed: passage into the airways and lungs, a possibly explanation as why gum disease and respiratory mortality are correlated in older patients.

The global population is aging, and elderly people have a higher incidence of lower airway diseases owing to decline in swallowing function, airway ciliary motility, and overall immunity associated with aging. Furthermore, lower airway diseases in the elderly tend to have a high mortality rate. Their prevention is important for extending healthy life expectancy and improving the quality of life of each individual.

In recent years, the relationship between chronic periodontitis and oral bacteria, especially the periodontopathic ones, and respiratory diseases (e.g., pneumonia, chronic obstructive pulmonary disease, and influenza) has become clear. In addition, the association of several periodontal pathogens with the onset and aggravation of coronavirus disease 2019 (COVID-19) is also being reported. The oral cavity is the entry point for bacteria and viruses to enter the body, and it is also the entrance to the lower airway, including the bronchi and lungs, in which inflammation occurs during lower airway diseases. Therefore, if aspiration of oral bacteria has an adverse effect on lower airway diseases, it is not difficult to imagine such an effect.

In support of these findings, oral health management has shown to reduce deaths from pneumonia and prevent influenza in nursing homes and inpatient wards. This has led to clinical and multidisciplinary cooperation between physicians and dentists, among others. However, to date, the mechanisms by which chronic periodontitis and oral bacteria contribute to lower airway diseases have not been well understood. Clarifying these mechanisms will lead to a theoretical basis for answering the question, "Why is oral health management effective in preventing lower airway diseases?"

Heart Rate Variability, Aging, and Cardiovascular Fitness
https://www.fightaging.org/archives/2021/11/heart-rate-variability-aging-and-cardiovascular-fitness/

Heart rate variability is an increasingly popular measure of cardiovascular health. Heart rate variability is known to decline with age, but to what degree is this a reflection of processes of cardiovascular aging versus the loss of physical fitness that is a feature of old age in our present, overly sedentary societies? This remains an open question, and an important one, given the range of evidence for exercise programs, and thus increased physical fitness, to be as effective as many medical interventions when it comes to improving cardiovascular health and reducing mortality in later life. Yes, aging causes an inevitable decline in physical condition, but living a sedentary lifestyle certainly speeds up that process.

Fluctuation analysis in intervals between heartbeats provides important indices related to autonomic modulation of heart rate variability (HRV). These indices are considered predictors of morbidity and mortality as they are frequently altered in patients with chronic degenerative diseases, especially in those with cardiovascular and metabolic diseases. Similarly, a reduction in HRV is common with aging. In all cases, cardiovascular fitness is often reduced to below the predicted values.

In turn, increases in cardiovascular fitness through regular physical exercise, especially aerobic exercise, represent an important therapeutic tool capable of promoting positive adjustments in cardiac autonomic modulation. These adjustments are characterized by reduced sympathetic modulatory influence and/or increased vagal modulatory influence on the heart, increasing the HRV. Therefore, several methodological tools have been used to assess the degree of impairment of autonomic modulation and the therapeutic effects of physical exercise.

In summary, there is a close relationship between cardiovascular fitness and HRV. This relationship was more evident in patients with cardiovascular and metabolic diseases and in aging, especially in those whose cardiovascular fitness and HRV were below the predicted values for age and sex. The challenge is to develop techniques and interpretation of increasingly accurate data, as well as standardizing the application of these techniques.

The Lack of Funding for Chronic Kidney Disease Research is Not an Outlier
https://www.fightaging.org/archives/2021/11/the-lack-of-funding-for-chronic-kidney-disease-research-is-not-an-outlier/

In this commentary, scientists note the paucity of funding for chronic kidney disease research, given the widespread suffering and death caused by this presently incurable condition. This and many other areas of medicine are seen as solved problems by the powers that be simply because there is some form of treatment, even palliative treatment, in widespread use. That the treatment does little and many people die doesn't appear to motivate those who could fund progress. There is no sense of urgency and little sense of need. We might make the same comments in the case of atherosclerosis, a condition many consider to be adequately treated and under control, due to the existence of statins and similar drugs that lower LDL cholesterol in the bloodstream, despite the fact that these treatments only somewhat reduce mortality, and that atherosclerosis still kills 27% of our species at the present time. We could indeed make much the same argument for many other primarily age-related conditions.

The uptake of the current concept of chronic kidney disease (CKD) by the public, physicians and health authorities is low. Physicians still mix up CKD with chronic kidney insufficiency or kidney failure. In a recent manuscript, only 23% of participants in a cohort of persons with CKD had been diagnosed by their physicians as having CKD while 29% has a diagnosis of cancer and 82% had a diagnosis of hypertension. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%.

A prevalent view is that for those in whom kidneys fail, the problem is "solved" by dialysis or kidney transplantation. However, the main burden of CKD is accelerated aging and all-cause and cardiovascular premature death. CKD is the most prevalent risk factor for lethal COVID-19 and the factor that most increases the risk of death in COVID-19, after old age. Moreover, men and women undergoing KRT still have an annual mortality which is 10-100-fold higher than similar age peers, and life expectancy is shortened by around 40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth global cause of death by 2040 and the second cause of death in Spain before the end of the century, a time when 1 in 4 Spaniards will have CKD.

However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded CIBER network research structure in Spain. Leading Spanish kidney researchers aim to prevent the dire predictions for the global 2040 burden of CKD from becoming true. However, only the highest level of research funding through the CIBER will allow to adequately address the issue before it is too late.

The Continued Quest for Pluripotent Adult Stem Cells
https://www.fightaging.org/archives/2021/12/the-continued-quest-for-pluripotent-adult-stem-cells/

Does the adult mammalian body contain naturally pluripotent stem cells, capable for forming any other cell type, given the right stimuli? Over the past twenty years various groups have argued that it does, but none of those scientists have produced evidence that is both compelling and easily replicated. If they had, the entire research community would have quickly jumped onto that bandwagon, just as they did after the discovery of reprogramming as a way to produce induced pluripotent stem cells. Patient-specific pluripotent cells are a highly desirable item, and a cost-effect source would enable many applications in regenerative medicine and tissue engineering. Given this history, I think it appropriate to treat the material here with a healthy degree of skepticism.

A certain cell type can be isolated from different organs in the adult body (i.e., adipose tissue, heart, skin, bone marrow, or skeletal muscle) that can differentiate into ectoderm, mesoderm, and endoderm, providing significant support for the existence of a certain type of small, ubiquitously distributed, universal, vascular-associated, pluripotent stem cell in the adult body (vaPS cells). These vaPS cells fundamentally differ from embryonic stem cells and induced pluripotent stem cells in that the latter possess the necessary genetic guidance that makes them intrinsically pluripotent. In contrast, vaPS cells do not have this intrinsic genetic guidance. Nevertheless, they are able to differentiate into somatic cells of all three lineages under guidance of the microenvironment they are located in, independent from the original tissue or organ that they are derived from.

These vaPS cells are of high relevance for clinical application because they are contained in unmodified, autologous, adipose-derived regenerative cells (UA-ADRCs). The latter can be obtained from and re-applied to the same patient at the point of care, without the need for further processing, manipulation, and culturing. These findings as well as various clinical examples presented in this paper demonstrate the potential of UA-ADRCs for enabling an entirely new generation of medicine for the benefit of patients and healthcare systems.

As with any medical innovation, the scientific and medical community interested in these novel therapies needs to develop sound clinical evidence to further show safety and efficacy of cell-based therapies. Our understanding of the mechanism of actions and potential benefit of stem cell therapy has increased enormously over the past decade and we hope that there is now enough data to convince others to embark on scientifically designed clinical studies that will provide the necessary objective evidence.

Microglia as Mediators of the Link Between Psychological Stress and Cognitive Aging
https://www.fightaging.org/archives/2021/12/microglia-as-mediators-of-the-link-between-psychological-stress-and-cognitive-aging/

Psychological stress appears to modestly accelerate some measures of aging, though most of the evidence for this correlation comes from animal studies. Evidence points to chronic inflammation, and the immune system in general, as an important factor in this correlation. Separately, chronic inflammation in brain tissue is known to be important in neurodegenerative conditions, and the behavior of innate immune cells known as microglia are of late receiving increased attention in this context. Researchers here join the dots to discuss whether microglia may be a primary link between stress and accelerated aging.

The relationship between the central nervous system (CNS) and microglia is lifelong. Microglia originate in the embryonic yolk sac during development and populate the CNS before the blood-brain barrier forms. In the CNS, they constitute a self-renewing population. Although they represent up to 10% of all brain cells, we are only beginning to understand how much brain homeostasis relies on their physiological functions. Often compared to a double-edged sword, microglia hold the potential to exert neuroprotective roles that can also exacerbate neurodegeneration once compromised.

Microglia can promote synaptic growth in addition to eliminating synapses that are less active. Synaptic loss, which is considered one of the best pathological correlates of cognitive decline, is a distinctive feature of major depressive disorder (MDD) and cognitive aging. Long-term psychological stress accelerates cellular aging and predisposes to various diseases, including MDD, and cognitive decline. Among the underlying mechanisms, stress-induced neuroinflammation alters microglial interactions with the surrounding parenchymal cells and exacerbates oxidative burden and cellular damage, hence inducing changes in microglia and neurons typical of cognitive aging.

Focusing on microglial interactions with neurons and their synapses, this review discusses the disrupted communication between these cells, notably involving fractalkine signaling and the triggering receptor expressed on myeloid cells (TREM). Overall, chronic stress emerges as a key player in cellular aging by altering the microglial sensome, notably via fractalkine signaling deficiency. To study cellular aging, novel positron emission tomography radiotracers for TREM and the purinergic family of receptors show interest for human study.

D-Glyceric Acid Supplementation Improves Mitochondrial Function and Reduces Inflammation in Old People
https://www.fightaging.org/archives/2021/12/d-glyceric-acid-supplementation-improves-mitochondrial-function-and-reduces-inflammation-in-old-people/

This open access paper reports on a small study of D-glyceric acid supplementation in older adults. A few weeks of supplementation produced modest gains in mitochondrial function and reductions in measures of inflammation. As is usually the case, it is worth comparing this with the effects of regular exercise, which remains somewhat better at improving mitochondrial function and reducing inflammation in comparison to most of the other available approaches to manipulation of mitochondrial metabolism.

D-glyceric acid (DGA) is a natural organic acid present in very small amounts in vertebrates and plants. Nevertheless, there are only a few scientific studies on this small metabolite. Due to its small size and low, varying, concentrations even the measurement of exact DGA concentration from fluids, and tissues at physiological levels is somewhat challenging. The aim of the present study was to find out direct and indirect indications of the activation of mitochondrial metabolism by the use of DGA.

The main target in the present study with 27 healthy 50-60-year-old human volunteers was to find out whether an "acute" 4-days and a longer 21-days exogenous DGA regimen caused moderate activation of the mitochondrial energy metabolism. The results revealed the following statistically significant findings: 1) plasma concentrations of metabolites related to aerobic energy production, especially lactate, were strongly reduced, 2) systemic inflammation was lowered both in 4- and 21-days, 3) mitochondria-related mRNA expressions in circulating immune cells were noticeably modulated at Day 4, 4) cellular membrane integrity seemed to be sharply enhanced, and 5) cellular NADH/NAD+ ratio was upregulated.

Mitochondrial metabolism was clearly upregulated at the whole-body level in both 4 and 21 days. At the same time, the effect of DGA was very well tolerated. Based on received solid results, the DGA regimen may alleviate acute and chronic energy metabolic challenges in main organs like the liver, central nervous system, and skeletal muscles. Enhanced membrane integrity combined with lower systemic inflammation and activated metabolic flows by the DGA regimen may be beneficial especially for the aging population.

Reviewing α-Synuclein Aggregation in Parkinson's Disease
https://www.fightaging.org/archives/2021/12/reviewing-%ce%b1-synuclein-aggregation-in-parkinsons-disease/

Like other neurodegenerative conditions, Parkinson's disease is accompanied by the growing presence of a protein aggregate in the brain. The α-synuclein associated with Parkinson's disease is one of the few proteins in the body that can misfold in ways that encourage other molecules of the same protein to also misfold, this dysfunction spreading through tissue over time, creating solid protein aggregates that are toxic to cells or provoke inflammatory reactions in brain tissue. Targeting these aggregates is at present an active area of research, albeit not as far advanced towards the clinic as is the case for targeting the different forms of protein aggregates found in Alzheimer's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder that falls under the category of synucleinopathy. PD is characterized by distinct aging-independent loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) region and the decrease in dopamine levels. Possibly, PD leads to the loss of terminal ends of striatum, which occurs before the neuronal loss in SNpc and; it seems to be more significant in disease pathogenesis. About 95% of PD cases are sporadic with no genetic linkage. Mostly, PD has its mean age of onset at 55 years with increased incidences with aging.

The most pathological hallmark of PD is Lewy bodies (LB). Lewy bodies are intraneuronal inclusions that contain immunoreactive alpha-synuclein aggregates which may also contain various neurofilament proteins as well as proteins involved in proteolysis such as ubiquitin. Predominantly, the cell death is caused by disruption of nuclear membrane integrity and release of alpha synuclein aggregation promoting nuclear factors like histones. Alpha synuclein may spread to other cells by direct or indirect means once aggregation starts. When compared with unaffected normal individuals, around 50-70% of neurons are lost in this region, at the time of death in patients with PD. Some studies suggest that LBs are the cell's defensive mechanism to prevent intracellular protein aggregate accumulation, while other studies suggest LBs to have a pathogenic role in PD.

Presently, there are no effective therapeutics contrived for PD. A prudent way to effectively alleviate PD would be to target one of its crucial causatives, alpha-synuclein. Recently, various therapeutic strategies have been formulated, to encumber alpha-synuclein's toxic effect. One such strategy would be to control transmission by blocking alpha-synuclein receptors. LAG3-directed antibodies were reported to substantially regulate aberrant alpha-synuclein induced toxicity. Concurrently, silencing alpha-synuclein expression in mouse and rat brain models through shRNA and siRNA was also reported. Further, the oligomer regulator Anle138b was able to hinder the synthesis and accumulation of alpha-synuclein oligomers. Additionally, numerous small molecule-based inhibitors have been elucidated to impede alpha-synuclein aggregation.

α-synuclein Harms Microglial Function in the Progression of Parkinson's Disease
https://www.fightaging.org/archives/2021/12/%ce%b1-synuclein-harms-microglial-function-in-the-progression-of-parkinsons-disease/

Researchers here note that the presence of α-synuclein protein aggregates, a characteristic feature of Parkinson's disease, contributes to the dysfunction of microglia. Microglia are innate immune cells of the brain, responsible not just for attacking pathogens and clearing debris, but also involved in maintaining the synaptic connections between neurons. Increasing attention is placed upon the age-related dysfunction of microglia as an important contribution to the progression of neurodegenerative diseases such as Parkinson's. Chronic inflammation in brain tissue is a feature of neurodegeneration, and much of that may be caused or amplified by changes that take place in the microglial population in response to the age-damaged tissue environment.

Parkinson's disease (PD) is an age-related neurodegenerative disorder, affecting about 2% of the population over 60. Pathologically, it is characterized by dopamine (DA) neuron losses and α-synuclein (α-Syn)-abundant Lewy body or neurites formation in the substantia nigra (SN). Additionally, microglia activation, along with excessive generation of inflammatory cytokines, is reported in the brains of PD patients and animal models.

α-Syn misfolding and aggregation are linked to PD pathology. Under pathological conditions, this synaptic protein can be released from neurons, propagating and spreading in the nervous system via cell autonomous and non-autonomous machinery. The natural state (monomer vs. tetramer) and the structure of neuron-released α-Syn is controversial. But it is well demonstrated that extracellular α-Syn activates microglia and inflammatory response, contributing to PD progression.

In this study, we reported an impairment of microglial autophagy caused by extracellular α-Syn via toll-like receptor 4 (Tlr4) and downstream p38 and Akt-mTOR signaling pathways and provided the evidence that conditional knockout of microglial autophagy-related gene 5 (Atg5) in mice enhanced the neuroinflammation and DA neuron losses in the midbrain and exacerbated the locomotor deficits in a viral-based α-Syn overexpression mouse model.

In sum, our findings demonstrate that α-Syn disrupts microglial autophagy initiation via Tlr4-dependent p38 and Akt-mTOR signaling and reveal that microglial autophagy impairment contributes to neuroinflammation and other PD pathogenesis. Therefore, the pharmacologic and genetic strategies that aim to modulate autophagy activity in the brain may become a potential venue for PD therapy.

The Longevity Gene Cisd2 Improves Liver Function in Aged Mice
https://www.fightaging.org/archives/2021/12/the-longevity-gene-cisd2-improves-liver-function-in-aged-mice/

Cisd2 is one of the few genes shown to regulate life span in both directions in animal models; less of it shortens life span, while overexpression extends life. Researches here focus on the effects of cisd2 on liver function in mice, showing that maintaining high levels of cisd2 expression into old age beneficially impacts a number of processes implicated in degenerative aging and liver disease. This isn't the only organ in which cisd2 expression has measurable effects; other groups have studied cisd2 in the heart, for example.

The liver plays a pivotal role in mammalian aging. However, the mechanisms underlying liver aging remain unclear. Cisd2 is a pro-longevity gene in mice. Cisd2 mediates lifespan and healthspan via regulation of calcium homeostasis and mitochondrial functioning. Intriguingly, the protein level of Cisd2 is significantly decreased by about 50% in the livers of old male mice. This down-regulation of Cisd2 may result in the aging liver exhibiting non-alcoholic fatty liver disease (NAFLD) phenotype. Here, we use Cisd2 transgenic mice to investigate whether maintaining Cisd2 protein at a persistently high level is able to slow down liver aging.

Our study identifies four major discoveries. Firstly, that Cisd2 expression attenuates age-related dysregulation of lipid metabolism and other pathological abnormalities. Secondly, revealed by RNA sequencing analysis, the livers of old male mice undergo extensive transcriptomic alterations, and these are associated with steatosis, hepatitis, fibrosis, and xenobiotic detoxification. Intriguingly, a youthful transcriptomic profile, like that of young 3-month-old mice, was found in old Cisd2 transgenic male mice at 26 months old. Thirdly, Cisd2 suppresses the age-associated dysregulation of various transcription regulators (Nrf2, IL-6, and Hnf4a), which keeps the transcriptional network in a normal pattern. Finally, a high level of Cisd2 protein protects the liver from oxidative stress, and this is associated with a reduction in mitochondrial DNA deletions.

These findings demonstrate that Cisd2 is a promising target for the development of therapeutic agents that, by bringing about an effective enhancement of Cisd2 expression, will slow down liver aging.