Fight Aging!

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Contents

• Poor Oral Health Correlates with Increased Mortality Risk in Older People
• Speculating on Involvement of SIRT1 and SIRT3 in the Aging of the Heart
• Exercise and Epigenetics in Neurodegeneration
• Metformin Remains a Poor Choice in the Treatment of Aging
• Fecal Microbiota Transplant as a Treatment for Neurodegenerative Conditions
• Lower Fracture Incidence in a Population of Nonagenarians
• Building a Therapy for Aging Based on SIRT6 Upregulation
• Most Small Molecules that Influence Life Span in Model Organisms Also Influence Expression of Extracellular Matrix Genes
• Engineering Chimeric Antigen Receptor T Cells to Activate Only When Ultrasound Energy is Applied
• miR-455 is Protective in Osteoarthritis
• Is Impaired Mitophagy or Increased Oxidative Stress the First Cause in Mitochondrial Aging?
• A Short Tour of the Senescence-Associated Secretory Phenotype
• Long Term Calorie Restriction in Rats Slows Muscle Fiber Atrophy with Aging
• Dysregulated Feedback Between Smooth Muscle and Extracellular Matrix as a Cause of Vascular Stiffening
• Immunoporosis: the Role of Immune Cells in Osteoporosis

Poor Oral Health Correlates with Increased Mortality Risk in Older People
https://www.fightaging.org/archives/2021/08/poor-oral-health-correlates-with-increased-mortality-risk-in-older-people/

It is suggested that inflammation in the gums spreads to cause inflammation in the heart and brain, raising the risk of cardiovascular disease and dementia. There is a good deal of evidence for this spread of inflammation to exist, the question is whether or not it contributes to age-related disease to a significant degree in comparison to other mechanisms present in the aging body. Epidemiological data such as that reported in today's open access paper shows meaningful correlations between poor oral health and raised risk of mortality, but it is only a matter of correlation. It might also be compared with other studies, such as an analysis that suggested only a small effect on risk of dementia due to gum disease.

Another possibility, when looking at large effect sizes such as those observed in the study below, is that people with poor oral health have poor oral health because they make bad lifestyle choices and fail to adequately maintain their health in a more general sense. Choose to live an unhealthy life and the gums will be far from the only part of the body to suffer as a consequence. As a further alternative, consider that those people with the worst burden of age-related damage, dysfunction, and chronic inflammation may well suffer worse oral health as one of the many outcomes. There, a raised mortality risk and a raised risk of gum disease stem from the same root causes.

Oral health and all-cause, cardiovascular disease, and respiratory mortality in older people in the UK and USA

Aging is characterized by an accumulation of chronic diseases and conditions, including poor oral health, which can influence quality of life and health. Oral health problems, including tooth loss, periodontal disease, and dry mouth, accumulate throughout adult life and worsen with increasing age3. Poor dental health is associated with high levels of inflammation, poor diet quality, and conditions such as disability, diabetes, and increased risk of cardiovascular disease (CVD) and pneumonia.

Furthermore, studies have suggested that poor oral health is associated with higher risk of mortality, including major causes of death such as CVD and respiratory diseases or infections. Tooth loss and periodontal disease have been reported to be associated with increased risks of all-cause, CVD, and respiratory mortality in community-dwelling middle-aged and older people. Furthermore, poor self-rated oral health was found to be associated with increased risk of all-cause mortality in a population of middle-aged and older adults.

We used cohort data from the British Regional Health Study (BRHS) (N = 2147, 71-92 years), and the US Health, Aging, and Body Composition (HABC) Study (N = 3075, 71-80 years). Follow-up was 9 years (BRHS) and 15 years (HABC Study). Oral health comprised tooth loss, periodontal disease, dry mouth, and self-rated oral health. Cox regression was performed for all-cause mortality, competing risks for CVD mortality, and accelerated failure time models for respiratory mortality.

In the BRHS, tooth loss was associated with all-cause mortality (hazard ratio = 1.59). In the HABC Study, tooth loss, dry mouth, and having ≥ 3 oral problems were associated with all-cause mortality; periodontal disease was associated with increased CVD mortality (subdistribution hazard ratio = 1.49); tooth loss, and accumulation of oral problems were associated with high respiratory mortality (time ratio = 0.73). Findings suggest that poor oral health is associated with mortality.

Speculating on Involvement of SIRT1 and SIRT3 in the Aging of the Heart
https://www.fightaging.org/archives/2021/08/speculating-on-involvement-of-sirt1-and-sirt3-in-the-aging-of-the-heart/

In today's research materials, scientists demonstrate that the combination of reduced SIRT1 and SIRT3 causes weakness in heart muscle via disruption of mitochondrial function. Mitochondria are the power plants of the cell, a herd of hundreds of bacteria-like organelles that are responsible for producing the chemical energy store molecule adenosine triphosphate (ATP) to power cellular operations. Impairment of mitochondrial function thus results in impaired cell function, a characteristic change observed in old tissues. Mitochondrial dynamics, the balance of fusion and fission of mitochondria, shift with age in ways that impair the processes of mitophagy that are responsible for removing damaged mitochondria. This leads to impaired function as damaged mitochondrial accumulate. A number of lines of evidence suggest that improved mitophagy can help restore mitochondrial function in old individuals.

Of note, the research here only shows that (a) depletion of SIRT1 and SIRT3 in young individuals causes harm, (b) the resulting changes in cells have some similarities to those seen in aging, and (c) that SIRT1 and SIRT3 are depleted in old individuals. This does not prove that boosting SIRT1 and SIRT3 in old individuals will help restore lost function, but it makes the case to fund that experiment. Of note, upregulation of SIRT1 on its own was the focus of considerable effort some years back, with entirely lackluster results when it came to health and life span. SIRT1 just does not seem to be an important part of the mechanisms linking metabolism to aging. One has to make a solid case in order to convince people to revisit that failure.

Age-related decline in two sirtuin enzymes alters mitochondrial dynamics, weakens cardiac contractions

Mitochondria produce the energy needed to drive nearly all processes in living cells. Cardiac muscle cells contain more mitochondria than any other cells, because the heart needs large amounts of energy to constantly pump blood throughout the body. Stable mitochondrial dynamics maintain a healthy balance between the constant division (fission) and merging (fusion) of mitochondria and help ensure the quality of these specialized structures known as the "powerhouse" of the cell.

Reperfusion, a common treatment following acute heart attack, restores blood flow (and thus oxygen) to a region of the heart damaged by a blood clot blocking the coronary artery. Paradoxically, in some patients this necessary revascularization procedure triggers further injury to heart muscle tissue surrounding the initial heart attack site. No effective therapies currently exist to prevent reperfusion injury.

To help analyze the response of cardiac mitochondria to ischemia-reperfusion stress, researchers deleted SIRT1 or SIRT3 in cardiac muscle cells of mouse hearts, and examined the mitochondrial response to ischemic stress by restricted blood flow. The researchers found that the mitochondria in mouse hearts lacking cardiomyocyte SIRT3 were more vulnerable to reperfusion stress than the mouse hearts with SIRT3 intact. The cardiac mitochondrial dynamics (including shape, size, and structure of mitochondria) in these knockout mice physiologically resembled that of aged wildtype (normal) mice retaining cardiac SIRT3.

Furthermore, the young mice with SIRT1 or SIRT3 removed had measurably weaker cardiomyocyte contractions and exhibited aging-like heart dysfunction when ischemia-reperfusion stress was introduced. In essence, without SIRT1/SIRT3 the hearts of these otherwise healthy young mice looked and behaved like old hearts.

Alterations in mitochondrial dynamics with age-related Sirtuin1/Sirtuin3 deficiency impair cardiomyocyte contractility

Sirtuin1 (SIRT1) and Sirtuin3 (SIRT3) protects cardiac function against ischemia/reperfusion (I/R) injury. Mitochondria are critical in response to myocardial I/R injury as disturbance of mitochondrial dynamics contributes to cardiac dysfunction. It is hypothesized that SIRT1 and SIRT3 are critical components to maintaining mitochondria homeostasis, especially mitochondrial dynamics, to exert cardioprotective actions under I/R stress. The results demonstrated that deficiency of SIRT1 and SIRT3 in aged (24-26 months) mice hearts led to the exacerbated cardiac dysfunction in terms of cardiac systolic dysfunction, cardiomyocytes contractile defection, and abnormal cardiomyocyte calcium flux during I/R stress. Moreover, the deletion of SIRT1 or SIRT3 in young (4-6 months) mice hearts impair cardiomyocyte contractility and shows aging-like cardiac dysfunction upon I/R stress, indicating the crucial role of SIRT1 and SIRT3 in protecting myocardial contractility from I/R injury.

Exercise and Epigenetics in Neurodegeneration
https://www.fightaging.org/archives/2021/09/exercise-and-epigenetics-in-neurodegeneration/

It is indisputably the case that regular exercise and maintenance of physical fitness into later life lowers the incidence and slows the progression of neurodegenerative disease. One can write any number of reviews akin to today's open access paper, walking through the evidence for cellular pathways involved in neurodegeneration to be beneficially influenced by physical activity, as well as the epidemiological data linking fitness and exercise with a reduced burden of neurodegeneration in the broader population. There is a great deal of evidence, even even we restrict ourselves to only those studies published in the past twenty years or so.

The focus in today's paper is the effects of exercise on epigenetic regulation via DNA methylation. The nuclear genome is methylated at numerous distinct CpG sites, an ever-changing pattern of decorations that shift the structure of the genome in ways that enable or disable expression of specific genes. DNA methylation status is maintained by a complex array of machinery and feedback loops that react to the circumstances a cell finds itself in. Since aging occurs for the same underlying reasons in all of us, the pattern of methylation status changes in characteristic ways with age. This has allowed the production of epigenetic clocks to measure the burden of biological aging, constructed via machine learning approaches.

It is interesting to note that, as the authors of this paper point out, there are any number of specific instances one can point to in which physical activity has been shown to alter DNA methylation machinery in ways that affect neurodegenerative processes. Further, physical activity and fitness clearly reduces mortality and disease incidence, a modest slowing of aging. Yet the original Horvath epigenetic clock is insensitive to differences in physical fitness, despite performing well in many other circumstances. Later clocks such as GrimAge appear to be better in this regard, but it is certainly a concern.

This highlights the major issue with epigenetic clocks, as well as related measures of aging produced from other biological data. Given that they were produced by mining omics data in search of patterns, it is unclear as to what exactly they measure. Aging consists of numerous interacting processes, proceeding largely in parallel in any given individual. Any given clock implementation may well reflect the consequences of only some of those processes, and thus may be a bad choice if used to assess the results of any given approach to treating aging as a medical condition. The only sure way to calibrate a clock in order to validate its use for a specific scenario is the hard way: run a life span study.

Roles of physical exercise in neurodegeneration: reversal of epigenetic clock

The lack of physical exercise (PE) is a common phenomenon in modern society and has become a risk factor for many diseases, including cardiovascular diseases, metabolic dysfunctions, cancers, and neurodegenerative diseases. Appropriate exercise shapes the athletic figure and improves the body's basal metabolic rate. PE also plays a vital role in brain health, especially in preventing and alleviating the decline of cognitive function as well as the occurrence of some neurodegenerative diseases. The positive effects of regular, long-term physical activities and exercise interventions on cognition have been reported in the literature. Since only limited therapies are available for cognitive impairment, exercise may serve as a promising non-pharmaceutical treatment.

The process of brain aging, which is one of the risk factors for neurodegeneration, has been found to involve epigenetic mechanisms. Epigenetics, by definition, refers to a set of heritable mechanisms and phenomena that determine cell phenotypes without changing the genome. Epigenetic modifications such as abnormal DNA methylation (DNAm), microRNAs, and histone modifications are closely associated with damage to brain health and neurodegenerative diseases. As individuals age, the age-related changes are often linked to the fluctuating methylation levels of specific genes.

The DNAm has been proposed as a potential multi-tissue estimator of biological age and the concept of epigenetic clock (i.e., DNAm clock) has been developed with a suitable regression model to systemically measure the biological age. This tool has been extensively applied to distinguish between chronological age and biological age, as well as to estimate the corresponding health/disease status. While healthy individuals have almost identical chronological age and biological age (normal aging), patients with cancer and neurodegenerative diseases are biologically older (pathologic aging) and the offspring of centenarians are biologically younger (delayed aging). Therefore, the epigenetic clock is capable of assessing the state of aging among populations. Moreover, DNAm is associated with environmental and lifestyle factors, which have the capacity for regulating epigenetic variability in the brain. Given the effects of such factors as PE in slowing down the epigenetic age acceleration or even resetting the aging clock, the epigenetic clock has progressively become an exciting area of research.

In this review, we summarize brain-specific, disease-related mechanisms involving DNAm, through which PE reverses epigenetic changes to ameliorate neurodegeneration in aging, AD, and PD. We also integrate data from muscular-related molecule cascades in the periphery, which are directly induced by PE to affect the central nervous system (CNS). Furthermore, as a potential mediator of motor skills, DNAm can be modulated to improve the pathological symptoms of dyskinesia-related neurodegenerative diseases. The role of PE in neurodegeneration is further explored from the perspective of epigenetic-related mechanisms, and PE can be viewed as a potential rejuvenation therapy.

Metformin Remains a Poor Choice in the Treatment of Aging
https://www.fightaging.org/archives/2021/09/metformin-remains-a-poor-choice-in-the-treatment-of-aging/

Now that we find ourselves in an era in which there is growing support and funding for the treatment of aging as a medical condition, the battle ceases to be one of persuading people to take the idea seriously, and more a matter of convincing research and development concerns to focus on projects that are more likely rather than less likely to produce meaningful gains. Rejuvenation and many added years is the desired goal, not merely a gentle slowing of aging that is little better than the results of optimal exercise and diet. Unfortunately, most of the research and development community is indeed working on projects that will, at best, produce that gentle slowing of aging. A panoply of drugs and mechanisms relate to cellular stress responses, those triggered by calorie restriction and exercise, and which produce a gentle slowing of aging when triggered independently of those lifestyle choices. Far too much attention is directed towards ways to induce these stress responses, and far too little to more ambitious projects.

Metformin remains something of a poster child for these efforts. It is a very safe drug, with decades of widespread human use, and hence it was picked as the vehicle for the TAME trial, an effort to persuade the FDA to run a clinical trial with endpoints that represent aging, a blueprint for later trials. Metformin has terrible animal data, however: there is very little consistency to support a claim that it slows aging, and the most robust studies show no effect on life span. Where it does extend life in animal studies, the effect size is less than that of calorie restriction. There is a large human trial that produced a small extension of life in diabetic patients taking metformin, but there is no data for metformin to have any such effects in metabolically normal humans. Further, the effect is modest. One can do better with exercise. This is not the road to meaningful interventions in aging; it is a distraction from better paths forward.

A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan

The numerous beneficial health outcomes associated with the use of metformin to treat patients with type 2 diabetes (T2DM), together with data from pre-clinical studies in animals including the nematode, C. elegans, and mice have prompted investigations into whether metformin has therapeutic utility as an anti-aging drug that may also extend lifespan. Indeed, clinical trials, including the MILES (Metformin In Longevity Study) and TAME (Targeting Aging with Metformin), have been designed to assess the potential benefits of metformin as an anti-aging drug.

Preliminary analysis of results from MILES indicate that metformin may induce anti-aging transcriptional changes; however it remains controversial as to whether metformin is protective in those subjects free of disease. Furthermore, despite clinical use for over 60 years as an anti-diabetic drug, the cellular mechanisms by which metformin exerts its actions remain unclear. In this review, we have critically evaluated the literature that has investigated the effects of metformin on aging, healthspan, and lifespan in humans as well as other species. In preparing this review, particular attention has been placed on the strength and reproducibility of data and quality of the study protocols with respect to the pharmacokinetic and pharmacodynamic properties of metformin.

We conclude that despite data in support of anti-aging benefits, the evidence that metformin increases lifespan remains controversial. However, via its ability to reduce early mortality associated with various diseases, including diabetes, cardiovascular disease, cognitive decline, and cancer, metformin can improve healthspan thereby extending the period of life spent in good health. Based on the available evidence we conclude that the beneficial effects of metformin on aging and healthspan are primarily indirect via its effects on cellular metabolism and result from its anti-hyperglycemic action, enhancing insulin sensitivity, reduction of oxidative stress and protective effects on the endothelium and vascular function.

Fecal Microbiota Transplant as a Treatment for Neurodegenerative Conditions
https://www.fightaging.org/archives/2021/09/fecal-microbiota-transplant-as-a-treatment-for-neurodegenerative-conditions/

It is thought that an appreciable fraction of the chronic inflammation of aging is caused by changes in the gut microbiome. There is a bidirectional interaction between the immune system and the microbial populations of the intestinal tract. The immune system gardens these populations, destroying problematic microbes. Microbes secrete metabolites and other molecules that can either benefit or harm the function of the immune system, the harms caused particularly by those microbes capable of provoking a sustained inflammatory response. The immune system declines with age for a range of reasons, and reduced efficacy in immune surveillance of gut microbes allows harmful microbial populations to grow in number, in turn further degrading immune function by inducing a state of chronic inflammation.

Many of the common, ultimately fatal age-related conditions are driven by chronic inflammation and the resulting disruption of normal tissue function. This is very much the case for neurodegenerative conditions. Inflammation in the brain is a prominent feature of tauopathies such as Alzheimer's disease, for example, in which toxic aggregates of altered tau protein form and spread in parallel with the inflammation of brain tissue. Researchers have shown that removing pro-inflammatory senescent cells from the brain, using senolytic drugs, reverses pathology in animal models of tauopathy. How much of inflammation in the brain is the result of senescent cells versus the gut microbiome versus other causes? The only way to find out is to remove each potential cause individually and observe the outcome.

In the case of the gut microbiome, strategies exist to reverse age-related changes. Fecal microbiota transplantation from young individuals to old individuals is the most studied of these approaches, well proven in animal models to reset the balance of microbial populations, reduce inflammation, and improve health. It is already used in humans to tackle cases in which pathological bacteria take over the intestines, and thus, given the will and the funding, it would be a comparatively short path to deploy fecal microbiota transplantation in clinical trials involving patients with inflammatory neurodegenerative conditions.

Fecal Microbiota Transplantation: A Microbiome Modulation Technique for Alzheimer's Disease

The gut microbiota plays a key role in modulating the gut-brain axis, which is a bidirectional communication network that involves the central nervous system, the autonomic nervous system (sympathetic and parasympathetic branches), the enteric nervous system, and the hypothalamic-pituitary-adrenal axis. Recent advances have revealed that the microbiota of the human gut has numerous beneficial functions, such as immune system development, resistance to pathogens, vitamin synthesis, production of metabolites such as short-chain fatty acids (SCFAs), nutrient and drug metabolism, and maintenance of the structural integrity of the intestinal mucosal barrier.

In humans, dysbiosis and changes in gut microbiome composition have been found to contribute to inflammatory bowel disease, type 2 diabetes, metabolic syndrome, obesity, colorectal cancer, Alzheimer's disease (AD), and numerous other diseases. AD is a disastrous neurological disorder affecting 5.8 million Americans (aged 65 years or older) in 2020. AD was the sixth most common cause of death in 2017, accounting for 121,404 deaths in the United States, and the fifth most common cause of death among elderly Americans (65+ years). The sizeable economic burden of AD, as well as its growing prevalence, are leading researchers to look for preventive or disease-modifying treatments.

There are various gut microbiota modulation interventions such as diet modification, prebiotics, probiotics, synbiotics, or fecal microbiota transplantation (FMT). FMT includes the transplantation of the gut microbiota from a donor to a recipient to refurbish the intestinal microflora of the recipient. It has been proven to be a successful treatment for recurrent Clostridium difficile infections. In this review, we summarize the procedure of FMT and its application in the treatment of various neurological disorders with a special emphasis on AD.

Lower Fracture Incidence in a Population of Nonagenarians
https://www.fightaging.org/archives/2021/08/lower-fracture-incidence-in-a-population-of-nonagenarians/

People who survive to exceptional old age tend to do so because they have a lower burden of damage and dysfunction. A lesser degree of chronic inflammation maintained over time, for example, improves the long-term function of organs throughout the body. That in turn leads to a lesser degree of age-related disease and the lower mortality rate needed in order to survive to exceptional old age. Thanks to variations in lifestyle and burden of persistent infection, one can find groups with better health than average, such as the nonagenarians noted here, who collectively exhibit a significantly lower risk of fracture due to weakened bone strength. As to why they are better off, that question is left unanswered by the authors of this paper. It is interesting to note the metrics that were not different, such weight and common blood markers associated with bone health.

The goal of this study was to investigate whether various aspects of bone health among the very elderly could provide insight into the aging process in this unique population. Our study investigated the prominence of fractures, osteopenia, and osteoporosis among our study population and made comparative analyses specifically looking at metabolic values and blood indices characteristic of bone health as well as the impact of prescribed medication therapies.

Overall, we found a low rate of fractures in our group of patients over 90 years of age. The distribution of fractures found in our study correlates with the expected distribution of fractures for an elderly cohort, with the most common occurring at the spine and hip. Additionally, there was a trend toward lower incidence of fracture among the oldest individuals, as compared to the general very old population in the United States. The incidence for hip fractures in the ≥100-year-old population has been estimated to be 23.1 per 1000 individuals per year (2.3% per year), whereas our study found a fracture incidence of 1.9% per year among our population of very elderly individuals. This indicates that our population of nonagenarians may have characteristics that contributed to the preservation of bone health even into extreme old age.

In conclusion, patients over 90 years of age had an overall low prevalence of fractures and relative preservation of bone health, suggesting a preserved bone molecular profile in these individuals. Epigenetic factors and activity levels might also have favorably affected bone health. The low percentage of osteoporosis and fractures likely reduced the morbidity and mortality in this population, potentially contributing to their overall longevity.

Building a Therapy for Aging Based on SIRT6 Upregulation
https://www.fightaging.org/archives/2021/08/building-a-therapy-for-aging-based-on-sirt6-upregulation/

Genflow Biosciences is working on a gene therapy to deliver a variant SIRT6, a protein involved in DNA repair, and thus touches on many aspects of aging. Upregulation of SIRT6 modestly extends life in mice, accompanied by what looks like a better maintenance of mitochondrial function into old age. Versions of SIRT6 found in short-lived mammalian species appear to produce a worse efficiency of DNA repair than the version found in long-lived mammalian species.

The Genflow principals intend to deliver a SIRT6 gene therapy as a compensatory approach to DNA repair deficiency conditions, such as Werner syndrome, that have the appearance of accelerated aging. This is hoped to be a stepping stone to later attempts to treat aging. It remains an interesting question as to what adjustments to DNA repair efficiency can do for long term health in long-lived mammalian species such as our own. Is this yet another case, like stress response upregulation, in which modest effect sizes in mice turn into negligible effect sizes in humans? The only practical way to find out is to try.

Key to Genflow's approach is a collaboration with Vera Gorbunova - a member of the company's scientific advisory board, and well known for her research into SIRT6. "In 2019, Vera published a paper that showed, in rodents, you could have a very good correlation between lifespan and the quality of SIRT6. She found she could increase or decrease the lifespan of rodents based on the variant of SIRT6 that she was providing." This led researchers wonder whether it was possible to find a "better" SIRT6 than the one that already exists in humans. "We discovered that it was possible, thanks to the discovery of a variant of SIRT6 only found in centenarians. So we decided to create a company that will deliver this SIRT6 variant in order to prevent the accelerated aging process."

"Ten years ago, gene therapy was a bad word associated with high cost and high toxicity - a dangerous last resort therapy. Now you see progress in AAVs every week. Today we have AAVs that are almost invisible to the immune system, they are non-integrating, their cost has decreased substantially, and there are now more than 40 companies developing clinical trials with AAVs. So, it's now possible to have an ethical, patient friendly and cost-effective intervention at the genetic level."

While progeria, Werner's syndrome, and other indications are in the company's pipeline for eventual human trials, Genflow is really only thinking about targeting aging. "One of the differences between us and other longevity companies is that we are fully dedicating to longevity. Yes, we will have a trial in Werner's syndrome, but we consider that a door opener to having a true aging indication. At one point, we know that the regulatory agencies will change their mindset on this - we see an evolution - and we want to be positioned to be to take advantage of that."

Most Small Molecules that Influence Life Span in Model Organisms Also Influence Expression of Extracellular Matrix Genes
https://www.fightaging.org/archives/2021/08/most-small-molecules-that-influence-life-span-in-model-organisms-also-influence-expression-of-extracellular-matrix-genes/

An interesting observation is discussed in this open access paper, which is that most small molecule compounds that extend life in short lived species also change the expression of extracellular matrix genes. The majority of such compounds are thought to extend life by provoking some of the same stress response mechanisms as calorie restriction, heat shock, and other common stressors, resulting in improved cell maintenance and thus improved cell and tissue function. Why do they also lead to changes in cellular activity relating to the maintenance of the extracellular matrix? A detailed answer to that question may emerge at some point, but cellular metabolism and its interaction with aging are very complex, slow-moving areas of study. Manipulation of metabolism to slow aging is a part of the field in which interventions are found by screening, none are fully understood, and none have interestingly large effects in long-lived species such as our own.

A few geroprotective drugs exist that postpone age-related diseases. For instance, the anti-diabetes drug metformin reduces age-related chronic diseases and mortality from all causes. Ongoing clinical trials on geroprotective drugs or compounds include the anti-diabetic drugs metformin and acarbose; mTOR-inhibiting and immunosuppressant drug rapamycin; natural compounds resveratrol and urolithin A; and nicotinamide adenine dinucleotide precursors NR and NMN. One primary outcome measure used in the aforementioned clinical trials for metformin and acarbose is the restoration from an "old" to a "youthful" gene expression signature. Therefore, we reasoned that cross-comparing youthful expression signatures against expression profiles elicited by small molecules could identify geroprotective compounds.

A key signature of aging is the continuous decline of collagen and cell adhesion gene expression accompanied with an increase in matrix metalloproteinase expression. Gene expression ontologies of extracellular matrix (ECM) genes have been associated with healthy aging in humans. The ECM not only embeds cells and tissues but also provides instructive cues that change cellular function and identity. For instance, placing old cells into a "young" ECM rejuvenates senescent cells or stem cells and even reprograms tumor cells. Moreover, collagen homeostasis is required and sufficient for longevity in Caenorhabditis elegans. Chondroitin biosynthesis and TGFβ pathway are frequently enriched in C. elegans longevity drug screens. Collectively, these functionally implicated genes are all members of the matrisome.

To harness this observation, we used age-stratified human transcriptomes to define the age-related matreotype, which represents the matrisome gene expression pattern associated with age. Using a "youthful" matreotype, we screened in silico for geroprotective drug candidates. To validate drug candidates, we developed a novel tool using prolonged collagen expression as a non-invasive and in-vivo surrogate marker for Caenorhabditis elegans longevity. With this reporter, we were able to eliminate false-positive drug candidates and determine the appropriate dose for extending the lifespan of C. elegans. We improved drug uptake for one of our predicted compounds, genistein, and reconciled previous contradictory reports of its effects on longevity. We identified and validated new compounds, tretinoin, chondroitin sulfate, and hyaluronic acid, for their ability to restore age-related decline of collagen homeostasis and increase lifespan. Thus, our innovative drug screening approach - employing extracellular matrix homeostasis - facilitates the discovery of pharmacological interventions promoting healthy aging.

Engineering Chimeric Antigen Receptor T Cells to Activate Only When Ultrasound Energy is Applied
https://www.fightaging.org/archives/2021/08/engineering-chimeric-antigen-receptor-t-cells-to-activate-only-when-ultrasound-energy-is-applied/

Providing a patient's T cells with a receptor to match the surface characteristics of the patient's cancer cells is proving to work quite well for some types of cancer. Unfortunately the match is never perfectly specific for cancerous cells, and chimeric antigen receptor T cells (CAR-T cells) can do a lot of damage to healthy tissue in many of the desired scenarios for treatment. Researchers here report on one of a number of presently explored approaches to limit the activation of CAR-T cells to only the cancerous tissue of interest, thereby making the therapy more viable.

New work addresses a longstanding problem in the field of cancer immunotherapy: how to make chimeric antigen receptor (CAR) T-cell therapy safe and effective at treating solid tumors. CAR T-cell therapy is a promising new approach to treat cancer. It involves collecting a patient's T cells and genetically engineering them to express special receptors, called CAR, on their surface that recognize specific antigens on cancer cells. The resulting CAR T cells are then infused back into the patient to find and attack cells that have the cancer antigens on their surface.

This therapy has worked well for the treatment of some blood cancers and lymphoma, but not against solid tumors. That's because many of the target antigens on these tumors are also expressed on normal tissues and organs. This can cause toxic side effects that can kills cells - these effects are known as on-target, off-tumor toxicity. To combat this issue, the team took standard CAR T cells and re-engineered them so that they only express the CAR protein when ultrasound energy is applied. This allowed the researchers to choose where and when the genes of CAR T cells get switched on. Ultrasound can penetrate tens of centimeters beneath the skin, so this type of therapy has the potential to non-invasively treat tumors that are buried deep inside the body.

The team's approach involves injecting the re-engineered CAR T cells into tumors in mice and then placing a small ultrasound transducer on an area of the skin that's on top of the tumor to activate the CAR T cells. The transducer uses focused ultrasound beams to focus or concentrate short pulses of ultrasound energy at the tumor. This causes the tumor to heat up moderately - in this case, to a temperature of 43 degrees Celsius (109 degrees Fahrenheit) - without affecting the surrounding tissue. The CAR T cells in this study are equipped with a gene that produces the CAR protein only when exposed to heat. As a result, the CAR T cells only switch on where ultrasound is applied.

miR-455 is Protective in Osteoarthritis
https://www.fightaging.org/archives/2021/09/mir-455-is-protective-in-osteoarthritis/

MicroRNAs are involved in the regulation of gene expression, increasing or decreasing the production of proteins for specific genes, and thereby changing cell behavior. Researchers here find a microRNA that acts to reduce cartilage degeneration in osteoarthritis. Levels are reduced in human osteoarthritic cartilage, and delivering this microRNA as a therapy reduces the level of pathology in a mouse model of injury-induced osteoarthritis. The delivery of manufactured microRNA, intended to alter cell behavior in advantageous ways, is a growing area of development. There is enough industry support to encourage more basic research into this approach to manipulating cell activity. It is a step up from small molecule approaches in terms of off-target effects and size of therapeutic effect, but remains considerably more expensive.

Osteoarthritis (OA), the most common aging-related joint disease, is caused by an imbalance between extracellular matrix synthesis and degradation. Here, we discover that both strands of microRNA-455 (miR-455), -5p and -3p, are up-regulated by Sox9, an essential transcription factor for cartilage differentiation and function. Both miR-455-5p and -3p are highly expressed in human chondrocytes from normal articular cartilage and in mouse primary chondrocytes.

We generate miR-455 knockout mice, and find that cartilage degeneration mimicking OA and elevated expression of cartilage degeneration-related genes are observed at 6-months-old. Using a cell-based miRNA target screening system, we identify hypoxia-inducible factor-2α (HIF-2α), a catabolic factor for cartilage homeostasis, as a direct target of both miR-455-5p and -3p. In addition, overexpression of both miR-455-5p and -3p protect cartilage degeneration in a mouse OA model, demonstrating their potential therapeutic value. Furthermore, knockdown of HIF-2α in 6-month-old miR-455 knockout cartilage rescues the elevated expression of cartilage degeneration-related genes.

This data strongly implicates miR-455-5p and -3p in supporting articular cartilage homeostasis by targeting Hif-2α.

Is Impaired Mitophagy or Increased Oxidative Stress the First Cause in Mitochondrial Aging?
https://www.fightaging.org/archives/2021/09/is-impaired-mitophagy-or-increased-oxidative-stress-the-first-cause-in-mitochondrial-aging/

Mitochondria are vital cellular components, a herd of hundreds of these organelles in every cell working to produce the adenosine triphosphate (ATP) needed to power cellular processes. A side effect of this activity is the production of free radicals, which can increase to the point of causing oxidative stress to a cell when mitochondria are damaged. The herd is culled by the mechanisms of mitophagy, which clear out damaged mitochondria in order to maintain function. With age, mitophagy declines in efficiency, mitochondria become more damaged and dysfunctional, and oxidative stress rises. But in which direction is the arrow of causation? Evidence from the use of mitochondrially targeted antioxidants suggests that reducing oxidative stress improves mitophagy. Equally, improving mitophagy via other means, such as NAD+ upregulation, also seems to reduce oxidative stress.

Mitochondrial dysfunction is a hallmark of aging. Dysfunctional mitochondria are recognized and degraded by a selective type of macroautophagy, named mitophagy. One of the main factors contributing to aging is oxidative stress, and one of the early responses to excessive reactive oxygen species (ROS) production is the induction of mitophagy to remove damaged mitochondria. However, mitochondrial damage caused at least in part by chronic oxidative stress can accumulate, and autophagic and mitophagic pathways can become overwhelmed. The imbalance of the delicate equilibrium among mitophagy, ROS production, and mitochondrial damage can start, drive, or accelerate the aging process, either in physiological aging, or in pathological age-related conditions, such as Alzheimer's and Parkinson's diseases.

The interplay between mitophagy, ROS production, and aging is complex and far from being completely elucidated. The central role of ROS production and consequent damage to mitochondria in the aging process has been clearly established in the last 50 years, despite some objections to this theory over the past 15 years, and mitophagy is a key mechanism for mitochondrial quality and quantity control, as it limits the production of ROS, the damage to mitochondrial DNA of transmembrane potential loss, and the decrease in ATP production.

Evidence indicates that the imbalance of the delicate equilibrium among mitophagy, ROS production, and mitochondrial damage can start, drive, or accelerate the aging process, either in physiological or pathological conditions. It remains to be determined which is the prime mover of this imbalance, i.e., whether it is the mitochondrial damage caused by ROS that initiates the dysregulation of mitophagy, thus activating a vicious circle that leads to the reduced ability to remove damaged mitochondria, and further damage from ROS, or if, on the other hand, an alteration in the regulation of mitophagy constitutes one of the initial events leading to the main of the excessive production of ROS.

A Short Tour of the Senescence-Associated Secretory Phenotype
https://www.fightaging.org/archives/2021/09/a-short-tour-of-the-senescence-associated-secretory-phenotype/

Senescent cells accumulate with age, but are never more than a tiny fraction of somatic cells in most tissues, even in very late life. Senescent cells nonetheless cause considerable harm via the signals that they produce, the senescence-associated secretory phenotype (SASP). These signals provoke chronic inflammation, harmful remodeling of tissue, and dysfunctional activity in nearby cells. That comparatively few senescent cells can cause an outsized level of pathology simply by existing is why the strategy of selectively destroying senescent cells with senolytic therapies produces such impressive results in animal studies. Removing accumulated senescent cells turns back degenerative aging. A meaningful fraction of the inflammatory, disrupted state of aged tissue is actively maintained by the SASP generated by senescent cells.

A number of features of senescence have been characterized, which could be used as proper biomarkers or potential therapeutic targets. Senescent cells generally display dramatically morphological changes, increased β-galactosidase activity, stable cell cycle arrest, persistent DNA damage response, metabolic reprogramming, and significant chromatin remodeling. The secretion of senescence-associated secretory phenotype (SASP) factors change the tissue microenvironment and affect even remote tissue via paracrine mechanisms, which is believed to contribute to organ degeneration with aging.

The phenotypic manifestations of SASP are heterogeneous and induced by different internal and external stimulus including telomere attrition, DNA damage, oncogenic activation, mitochondrial dysfunction, or epigenetic alterations. The SASP factors are mainly made of different types of soluble components including pro-inflammatory cytokines, growth factors, chemokines, and extracellular matrix-degrading proteins. This particular combination of signaling factors and the proteases that degrade extracellular matrix (ECM) to facilitate signal transduction has made SASP a powerful mechanism to modulate intercellular communication. The secretion of SASP factors is considered as a major detrimental aspect of senescence because it promotes chronic inflammation, induces fibrosis, and causes stem cell exhaustion.

However, it has also been shown to favor embryonic development or wound healing, suggesting whether beneficial or detrimental effects the SASP exerts depends on the physiological and pathological context. For example, a recent study has shown that transiently exposing the primary mouse keratinocytes to SASP factors increased cell stemness and regenerative capacity in vivo, while prolonged exposure caused secondary senescence and hindered regeneration. This suggests senescence has more complicated physiological roles than currently understood.

Senescence and its secretion phenotype SASP are the most fundamental player that could systematically change physiological functions at the intercellular level and reshape the tissue microenvironment toward aging. They directly change compositions of cell population by arresting the proliferation of progenitor cells or release pro-inflammatory factors to chronically elevate basal inflammation level causing systematic inflammaging. The effects of senescence and SASP are "erosive." Once it starts, it has the potential to spread via the flowing cytokines to induce remote secondary senescence.

Elimination of senescent cells by senolytic drugs has been proven to be effective to counteract senescence in natural aging or age-related disease model. Recently, the first clinical trial of senolytic drug was conducted in human with idiopathic pulmonary fibrosis (IPF). Surprisingly, instead of rescuing lung functions, there was significant improvement in locomotor function such as walking distance or gait speed. Although it is a mystery why the drug failed to take effect in lungs where the most of senescent cells exist in IPF patients, it is still exciting to see the improvement in motor functions which proved senescence communicates at inter-tissue levels. In the future, increasing the specificities of senolytic drugs might help to better cure aging-related diseases.

Long Term Calorie Restriction in Rats Slows Muscle Fiber Atrophy with Aging
https://www.fightaging.org/archives/2021/09/long-term-calorie-restriction-in-rats-slows-muscle-fiber-atrophy-with-aging/

Muscle mass and strength declines with age, leading to sarcopenia and contributing to frailty. Many distinct mechanisms are thought to be involved, from stem cell inactivity to chronic inflammation. Most of these mechanisms are favorably impacted by the sweeping metabolic changes induced by the practice of calorie restriction. The study here adds to past evidence for calorie restriction to slow the onset of sarcopenia, yet another of the many reasons to consider it as a lifestyle choice.

Aging causes loss of skeletal muscle mass and function, which is called sarcopenia. While sarcopenia impairs the quality of life of older adults and is a major factor in long-term hospitalization, its detailed pathogenic mechanism and preventive measures remain to be identified. Caloric restriction (CR) suppresses age-related physiological and pathological changes in many species and prolongs the average and healthy life expectancy. It has recently been reported that CR suppresses the onset of sarcopenia; however, few studies have analyzed the effects of long-term CR on age-related skeletal muscle atrophy. Thus, we investigated the aging and CR effects on soleus (SOL) muscles of 9-, 24-, and 29-month-old ad libitum-fed rats (9AL, 24AL, and 29AL, respectively) and of 29-month-old CR (29CR) rats.

The total muscle cross sectional area (mCSA) of the entire SOL muscle significantly decreased in the 29AL rats, but not in the 24AL rats, compared with the 9AL rats. SOL muscle of the 29AL rats exhibited marked muscle fiber atrophy and increases in the number of muscle fibers with a central nucleus, in fibrosis, and in adipocyte infiltration. Additionally, although the decrease in the single muscle fiber cross-sectional area (fCSA) and the muscle fibers' number occurred in both slow-type and fast-type muscle fibers, the degree of atrophy was more remarkable in the fast-type fibers.

However, CR suppressed the muscle fiber atrophy observed in the 29AL rats' SOL muscle by preserving the mCSA and the number of muscle fibers that declined with aging, and by decreasing the number of muscle fibers with a central nucleus, fibrosis, and denervated muscle fibers. Overall, these results revealed that advanced aging separately reduces the number and fCSA of each muscle fiber type, but long-term CR can ameliorate this age-related sarcopenic muscle atrophy.

Dysregulated Feedback Between Smooth Muscle and Extracellular Matrix as a Cause of Vascular Stiffening
https://www.fightaging.org/archives/2021/09/dysregulated-feedback-between-smooth-muscle-and-extracellular-matrix-as-a-cause-of-vascular-stiffening/

Researchers here identify a point of intervention in the age-related dysregulation of smooth muscle cell activity and surrounding extracellular matrix structure in blood vessel walls. Blood vessels stiffen with age, which leads to hypertension and consequent pressure damage to delicate structures throughout the body. The damage caused by hypertension is an important component of aging, a significant contribution to loss of function and mortality. Loss of elastin, cross-linking of extracellular matrix molecules, and the chronic inflammation generated by senescent cells are all known to contribute to vascular stiffening. Linking together various causes and consequences of aging are the diverse mechanisms of cell signaling and regulation of cell behavior, a layer of greater complexity. That complexity makes it challenging to piece together exactly how individual discoveries relate to one another, so the work noted here stands in isolation, with further research needed in order to better understand it in the broader context.

The muscle cells in healthy blood vessels are elastic and can stretch like rubber bands, allowing high volumes of blood to pump through. When the blood vessel tissues lose their elasticity, the vessels stiffen, forcing the heart to work harder to pump blood throughout the body. While diet, exercise and medication can improve overall heart health, there are no drugs on the market to treat underlying stiffening in blood vessels.

Most research into blood vessel stiffening has focused on the material surrounding the living cells - called the extracellular matrix - as the most important contributor to this condition. However, researchers now lay out evidence that smooth muscle cells independently contribute to vascular stiffening. To study this connection, the researchers first had to cut the line of communication between cells and the surrounding matrix. They used a gene editing tool called CRISPR to breed mice lacking the gene that produces transglutaminase (TG2), an enzyme enabling this crosstalk to take place.

Compared with mice that had normal TG2 production, the researchers found that in mice with no TG2 - where the crosstalk between the matrix and vascular smooth muscle cells was uncoupled - the development of vascular stiffening was reduced by nearly 70% at age 15 months. This is old age for a mouse and, generally, the time when blood vessels stiffen. The researchers say this indicates smooth muscle cells independently contribute to vascular stiffening, and that crosstalk influences vascular aging. Researchers suspect that severe vascular stiffening, like that seen in humans of old age, could be caused by out-of-control feedback between smooth muscle cells and their surrounding matrix.

Immunoporosis: the Role of Immune Cells in Osteoporosis
https://www.fightaging.org/archives/2021/09/immunoporosis-the-role-of-immune-cells-in-osteoporosis/

Osteoporosis, the age-related loss of bone mass and strength, is a serious condition. Bone is constantly remodeled, created by osteoblasts and removed by osteoclasts. With age, the balance of these activities tips towards favoring the osteoclasts, and bone mineral density declines over time as a consequence. It is becoming clear that inflammatory signaling is an important contributing factor in this dysregulation of the normal balance. The chronic inflammation that accompanies aging, the consequence of rising numbers of senescent cells, as well as of the presence of molecular damage that provokes the immune system, can be blamed for a great deal of the burden of aging.

Osteoporosis or porous bone disorder is the result of an imbalance in an otherwise highly balanced physiological process known as 'bone remodeling'. The immune system is intricately involved in bone physiology as well as pathologies. Inflammatory diseases are often correlated with osteoporosis. Inflammatory mediators such as reactive oxygen species (ROS), and pro-inflammatory cytokines and chemokines directly or indirectly act on the bone cells and play a role in the pathogenesis of osteoporosis.

Recently, researchers have coined the term "immunoporosis" to emphasize the role of immune cells in the pathology of osteoporosis. Accumulated evidence suggests both innate and adaptive immune cells contribute to osteoporosis. However, innate cells are the major effectors of inflammation. They sense various triggers to inflammation such as pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), cellular stress, etc., thus producing pro-inflammatory mediators that play a critical role in the pathogenesis of osteoporosis.

Cells of the myeloid lineage, including macrophages, monocytes, and dendritic cells, explicitly influences the skeletal system by the action of production of pro-inflammatory cytokines and can transdifferentiate into osteoclasts. Other cells of the myeloid lineage, such as neutrophils, eosinophils, and mast cells, largely impact osteoporosis via the production of pro-inflammatory cytokines. Further, cells of the lymphoid lineage, including natural killer cells and innate lymphoid cells, share innate-like properties and play a role in osteoporosis.