Fight Aging! Newsletter, September 11th 2023
Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter, please visit: https://www.fightaging.org/newsletter/
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- Is Transfusion of Young Blood Essentially a Form of Extracellular Vesicle Therapy?
- A High Level Popular Science View of the Longevity Industry
- The Heart Has High Energy Needs, Making it Vulnerable to Age-Related Mitochondrial Dysfunction
- Towards an Improved Suppression of Maladaptive Inflammation
- DNA Damage and Consequent Inflammation in Heart Failure
- The Cost of Cardiovascular Disease
- A Discussion of Current Approaches Under Development for the Treatment of Aging
- Reviewing What is Known of the Aging of Neural Stem Cells
- Cardiolipin Oxidation in Mitochondrial Dysfunction
- PU.1 Inhibition to Reduce Microglial Inflammation in the Aging Brain
- Towards Engraftment of New Stem Cells into Damaged Lungs
- Identifying a Stem Cell Population in the Adult Thymus
- Reducing Cardiovascular Risk Factor Also Reduces Incidence of Neurodegenerative Disease
- Reviewing Nicotinamide Riboside as a Strategy to Increase NAD Levels
- Suppression of Transposable Element Activity Extends Life in Nematode Worms
Is Transfusion of Young Blood Essentially a Form of Extracellular Vesicle Therapy?
https://www.fightaging.org/archives/2023/09/is-transfusion-of-young-blood-essentially-a-form-of-extracellular-vesicle-therapy/
Are beneficial effects of transfusion of blood fractions from young individuals to old individuals observed in animal studies the result of transferring the contents of extracellular vesicles rather than any signal molecules not packaged into a vesicle? While considering this question, it is worth noting that transfusion of plasma has quite mixed outcomes in both mice and humans. It doesn't appear to be a good approach to therapy, based on the results to date.
This is unlike the robust benefits produced in old animals by heterochronic parabiosis, linking the circulatory system of an old and a young mouse. In a parabiosis study, the old mouse is getting a great deal more of everything that might be found in young blood than is the case in even repeated transfusions employed as therapy. At the same point in time potentially harmful components of old blood are being (a) diluted, and (b) passed through young kidneys, liver, and other organs that might remove them. These latter aspects of parabiosis do not occur in transfusion, and at present there is some debate as to whether there are any meaningfully beneficial factors to be found in young blood fractions.
In today's open access paper, researchers describe transfusion of serum rather plasma from young animals to old animals, and provide data to suggest that it is the contents of the extracellular vesicles in serum that mediate beneficial effects. It is worth noting that extracellular vesicles will be present in all blood fractions unless deliberately filtered out. Blood fractionation is accomplished via centrifugation, so it is possible that there is some biasing of vesicles to one fraction or another based on size. Otherwise, the same arguments might be applied to serum transfusions as to plasma transfusions; despite the existence of some studies in which benefits were shown, the data in aggregate doesn't make this appear to be a good basis for therapy.
Extracellular Vesicles in Young Serum Contribute to the Restoration of Age-Related Brain Transcriptomes and Cognition in Old Mice
The conventional wisdom is that a better understanding of the myriad roles of extracellular vesicles (EVs) in central nervous system (CNS) homeostasis is essential for developing novel therapeutics to alleviate and reverse the neurological disturbances of aging. Thus far, an increasing number of studies have revealed the complexities of EV-mediated cell-cell communications in the brain, predominantly emphasizing the role of EV released by brain cells under physiological conditions. It has been well established that EVs can cross brain barriers such as the blood-brain barrier (BBB) and brain-cerebrospinal fluid (CSF) barrier (BCsfB).
If isolated from CSF and plasma, brain EVs provide an array of options with which to learn about normal brain functions and monitor changes in the brain associated with aging or neurodegenerative pathology. Since humoral factors can enter the brain at the BBB and BCsfB, in vivo models, for example, heterochronic parabiosis (HB), heterochronic blood exchange (HBE), and infusions of small volumes of plasma or serum, have been used to uncover and better understand the role of those factors in aging and age-related diseases. Recently, using infusions of small volumes of serum, we evaluated the contribution of circulating EVs to the beneficial effect of young serum on aged muscle stem cell (MuSC) function and the skeletal muscle regenerative cascade. We demonstrated that young serum restored a youthful bioenergetic and myogenic profile to old muscle cell progeny and that this effect was dependent on circulating EVs. Yet, the full spectrum of effects of circulating young EVs on aged organs and tissues, including the brain, remains poorly understood.
In this study, we examined the effect of young serum on the cognitive performance of aged mice. We show that repeated infusions with small volumes of young serum significantly improved age-associated memory deficits and this effect was abrogated after the serum was depleted of circulating EVs. RNA-seq analysis of choroid plexus demonstrated effects on genes involved in barrier function and trans-barrier transport. Interestingly, the hippocampal transcriptome demonstrated a significant upregulation of Klotho (Kl) gene, which codes for the longevity protein Klotho, following young serum treatment. Notably this effect was abrogated after serum EV depletion, suggesting that EVs may serve as vehicles for Klotho messages from the periphery to the brain. Given the well-established role of Klotho in cognitive functioning, we performed transcriptional profiling of Klotho knockout (Klko) and Klotho heterozygous (Klhet) mice and found an association with downregulated categories such as transport, exocytosis, and lipid transport, while upregulated genes were associated with microglia.
To test if changes in transcriptomes represent transcriptomic rejuvenation, we correlated the transcriptomes of the treated mice to the most recently published chronological aging clocks, which revealed a reversal of transcriptomic aging in the choroid plexus. The results of our study indicate that further evaluation of EVs as vehicles for delivering signals from the periphery to the brain and coordinating the responses of different brain regions will open new avenues with which to expand the research and to better understand aging and rejuvenation.
A High Level Popular Science View of the Longevity Industry
https://www.fightaging.org/archives/2023/09/a-high-level-popular-science-view-of-the-longevity-industry/
The article I'll point out today is an entirely unremarkable, high level tour of the most discussed, most notable portions of the longevity industry and related research efforts. Twenty years ago, we'd all have been delighted to see the media both noticing translational aging research at all, and then actually taking seriously the prospect of treating aging as a medical condition. We've come a long way to now see summary discussions of work on the treatment of aging as business as usual, not really worth mentioning. Still, articles like this miss near all of the really interesting projects, and that is the way of high level overviews. What is most talked about today is only rarely what is most important tomorrow, or at least given a few years to see how and where the dust settles.
Articles of this sort also tend to feature people who believe that only marginal progress towards greater longevity is possible in the foreseeable future; that may or may not be true, but to even answer that question a great deal more support for clinical trials of presently available options is required. The first viable senolytic drugs have been known for going on a decade, low-cost and readily available for anyone who wants to try them. Yet there is no rush to run clinical trials that would answer whether or not they are as impressive in human aging as they are for mice, and the vast majority of older people have no idea that this option is even on the table.
Interested in living healthier longer? Longevity science explained
After age 65, most people have two or more chronic diseases. U.S. adults in their 60s and 70s take up to five different prescription medications at a time. And what helps one condition may worsen another. At about 76, the U.S. life expectancy, the adult will probably die from one of these diseases. All of these chronic conditions share a risk factor: age. It may be the process of aging itself that makes us vulnerable to these diseases, which affects our health span (how long we stay healthy) and life span (how long we live.) As we get older, we lose strength and mobility as our bodies undergo molecular changes that eventually undermine their integrity and resiliency. Scientists refer to these changes as hallmarks. These include chronic inflammation and the accumulation of senescent cells that stop multiplying because of damage or stress but don't die as they are supposed to.
Some researchers believe that through addressing aging itself, diseases related to aging can be pushed back and possibly prevented. This would mean living healthier, longer. "The important implication is that we can study the biology of aging, start to learn about it and we have a potential to intervene in that biology to have a positive impact on disease outcomes and health." The field is known by many names: longevity, geroscience, anti-aging. Regardless of the name, it's still in the early stages. Several drugs may have the ability to postpone or prevent the onset of debilitating diseases. Animal studies have demonstrated their potential, and now clinical trials are beginning to assess whether their promise holds true in humans. "I think it's certainly legitimate to ask why we haven't done that previously. And in part it's because we really haven't had the knowledge base to be able to do that."
One promising drug is rapamycin. It's an antifungal approved by the FDA as an immune suppressor to prevent organ recipients from rejecting a new organ. Rapamycin inhibits a protein called mechanistic target of rapamycin (mTOR). The protein senses nutrients and then controls cell outputs regulating many processes in the cell. Giving rapamycin to yeast, worms, flies and mice prolonged their lives, studies have shown. Scientists began exploring rapamycin's anti-aging effects in people, and studies suggest this immune-suppressing compound can actually improve immune function in older adults boosting their response to flu shots and lowering their odds of getting severely ill during cold and flu season.
As we age, immune function both declines and increases. Though the ability of our immune system to respond to pathogens declines, it can also overreact by striking in the absence of any threat. This can result in healthy tissues and organs being attacked, which can lead to chronic inflammation linked with various kinds of diseases. So, what is causing the inflammation itself? One possible culprit is senescent cells that stop dividing but don't die. They accumulate as we get older and give off inflammatory signals, which contribute to some age-related diseases.
If a drug is ever to be used as an anti-aging therapy, it'll need to be tested in healthy people who are aging naturally the way that new drugs for a certain illness are tested on people who have that disease. However, aging isn't officially defined as a disease. One clinical trial aims to prove that aging is something that can be targeted and treated. It involves metformin, long used to treat Type 2 diabetes. In a trial called Targeting Aging With Metformin (TAME), researchers will track 3,000 adults 65 to 80, who will take the drug for six years. The goal is to see if metformin can prevent or delay three age-related diseases: dementia, heart disease, and cancer. This will show if metformin can increase health span. If the trial succeeds, it may show that drugs to target aging don't need to be expensive and can be available to more people, not just the rich.
The Heart Has High Energy Needs, Making it Vulnerable to Age-Related Mitochondrial Dysfunction
https://www.fightaging.org/archives/2023/09/the-heart-has-high-energy-needs-making-it-vulnerable-to-age-related-mitochondrial-dysfunction/
Not all tissues are equal in their energy needs. The brain and more consistently active muscles, such as the heart, are at the top of the list. Energy for cell and tissue processes is provided by the chemical energy store molecule adenosine triphosphate (ATP), which is produced by mitochondria. Every cell contains hundreds of mitochondria, the descendants of ancient symbiotic bacteria now evolved to become fully integrated cell components. Mitochondria still replicate much like bacteria, each containing a small remnant circular genome. When damaged or dysfunctional, mitochondria are cleared by the complex process of mitophagy, a mitochondrially targeted form of autophagy that recognizes impaired mitochondria and ensures that they are transported to a lysosome for disassembly.
Unfortunately, mitochondria become dysfunctional with age in ways that can (a) promote inflammation, such as via escape of mitochondrial DNA into the cytoplasm where it can trigger defenses that evolved to identify bacterial DNA, and (b) reduce ATP production. Epigenetic changes affect the dynamics of mitochondrial fusion and fission in ways that impair mitophapy. Similarly, epigenetic change leads to a decline in autophagy in general with age. Worn and damaged mitochondria accumulate as a result. Further, mitochondrial DNA is less well protected and repaired than is the case for nuclear DNA. Damage to mitochondrial DNA can disrupt ATP production and in extreme cases produce broken mitochondria that can outcompete their undamaged peers, replicating to overtake a cell. All of this arguably produces the worst outcomes in tissues like the heart and brain, where the demand for ATP is the highest.
Cardiovascular aging: the mitochondrial influence
The beating heart is a highly energy-consuming organ and the cellular energy needed to sustain contraction is primarily generated by mitochondrial oxidative phosphorylation (OXPHOS). Mitochondria are also involved in supporting various metabolic processes, as well as activation of the innate immune response and cell death pathways. Thus, the heart is highly susceptible to the effects of mitochondrial dysfunction. Mitochondria have been directly implicated as underlying drivers of cardiac aging. Studies have reported that the age-related decline in cardiac function is partly attributed to dysregulation of mitochondrial function and a decline in mitochondrial quality control. The aged heart accumulates dysfunctional mitochondria that are deficient in ATP generation and become major sources of reactive oxygen species (ROS) and oxidative stress. Interestingly, various interventions or treatments that directly or indirectly target mitochondria to reduce ROS generation, promote oxidative metabolism or enhance quality control have all been demonstrated to delay cardiac aging and alleviate disease development.
Currently, effective treatments to prevent age-related cardiovascular dysfunction are lacking, but there is a strong interest in developing therapeutics that are aimed at preserving or improving mitochondrial health in cells. Many interventions that protect against cardiac aging, including caloric restriction, exercise, and nicotinamide riboside, spermidine or rapamycin treatments, are mediated at least in part through the preservation of mitochondria. Pre-clinical studies clearly suggest that directly targeting mitochondrial ROS production or enhancing repair and turnover may have promising therapeutic benefits in the aging heart. For example, administration of the mitochondria-targeted antioxidant MitoTEMPO to aged mice reduces oxidative stress and improves systolic and diastolic function, while MitoQ administration can ameliorate vascular endothelial dysfunction in aged mice. Treatment of aged mice with the mitochondrially-targeted tetrapeptide SS-31 (elamipretide) for 8 weeks leads to reduced oxidative stress in hearts with improvements in cardiac function and reversal of cardiac hypertrophy.
There is also great interest in developing small molecules that can directly activate mitophagy in cells. VL-004 is a small molecule that increases mitophagy and longevity in C.elegans via dct-1, the worm homolog of mammalian mitophagy receptors Bnip3 and BNIP3L/NIX. VL-004 failed to extend lifespan in dct-1 mutant worms, confirming that the effect on lifespan extension is dependent on mitophagy. Although these studies targeting mitophagy are promising, whether the beneficial effects are preserved in larger organisms remains to be investigated.
Due to the longer lifespan in the population, treatments that prevent late-life morbidities and increase healthspan are urgently needed. Dysfunctional mitochondrial are clearly major contributors to cardiac aging. Although rejuvenating mitochondria to reverse or prevent aging by directly targeting mitochondrial ROS or activating mitophagy seems to have anti-aging benefits, these interventions are not without risks. ROS also function as signaling molecules in cells and complete suppression of mitochondrial ROS has adverse effects on heart function. Similarly, too much activation of mitophagy can lead to excessive clearance of mitochondria. If the clearance exceeds the cells' capacity to generate new mitochondria, it can lead to a catastrophic energy deficiency. Thus, the therapeutic window of these interventions needs to be clearly defined.
Towards an Improved Suppression of Maladaptive Inflammation
https://www.fightaging.org/archives/2023/09/towards-an-improved-suppression-of-maladaptive-inflammation/
Chronic inflammation remains an important contributing process in the development of age-related dysfunction and disease, one that is presently difficult to address. This unresolved inflammation is a direct consequence of a number of different causes of aging. They include mitochondrial dysfunction leading to mislocalization of mitochondrial DNA into the cytoplasm, where it triggers responses evolved to detect bacterial infection, as well as the now well-studied burden of senescent cells found in aged tissues and the pro-inflammatory secretions that these errant cells produce.
A great many research groups and development programs are aimed at suppression of excessive inflammation. Unfortunately, near all present approaches suppress both excessive and necessary inflammation, reducing harms, but at the cost of also impairing vital immune responses to infection and cancer. Approaches to date that definitively only reduce harmful chronic inflammation while preserving the response to infection and cancer include some stem cell therapies and the clearance of senescent cells via senolytic drugs, but these are not as widely used as they might be. The more established approaches to reducing inflammation involve the blockade of specific signal molecules such as TNF or interference in the response to those signals, but these signals and their responses are involved in essential as well as unwanted inflammation.
It is hoped that an improved understanding of the complex mechanisms that regulate the inflammatory response and its resolution will lead to ways to distinguish excessive inflammation from necessary inflammation, and thus interventions that only suppress the harmful, unwanted inflammation. To that end, one can find a great deal of research similar to that summarized in today's open access review paper, digging into the regulation of inflammation in search of novel targets for anti-inflammatory treatments.
MicroRNA-7: A New Intervention Target for Inflammation and Related Diseases
MicroRNAs (miRNAs) are a class of small noncoding RNA that can regulate physiological and pathological processes through post-transcriptional regulation of gene expression. As an important member of the miRNAs family, microRNA-7 (miR-7) was first discovered in 2001 to play an important regulatory role in tissue and organ development. Studies have shown that miR-7 participates in various tissue and organ development processes, tumorigenesis, aging, and other processes by regulating different target molecules. Notably, a series of recent studies have determined that miR-7 plays a key regulatory role in the occurrence of inflammation and related diseases. In particular, miR-7 can affect the immune response of the body by influencing T cell activation, macrophage function, dendritic cell (DC) maturation, inflammatory body activation, and other mechanisms, which has important potential application value in the intervention of related diseases.
Under normal circumstances, inflammation is a physiological defense response of the body to stimulation, involving a complex and fine-tuned regulatory process that is conducive to eliminating pathogens and promoting tissue repair. It is now known that the inflammatory process is closely related to the body's innate and adaptive immune responses, involving the activation and function of innate immune cells, such as macrophages and DCs, and adaptive immune cells, such as T cells and B cells. However, if the immune response process is abnormal, the continuous development of inflammation can lead to autoimmune or inflammatory diseases, neurodegenerative diseases, and even cancer. The inflammatory response involves innate and adaptive immune response processes mediated by immune cells with the participation of histiocytes and molecules. Therefore, the regulatory mechanisms involved in the development of inflammation and related diseases are very complex. The analysis of these mechanisms is of great significance for understanding the mechanisms of related diseases and clinical treatment.
This article reviews the current regulatory role of miR-7 in inflammation and related diseases, including viral infection, autoimmune hepatitis, inflammatory bowel disease, and encephalitis. It expounds on the molecular mechanism by which miR-7 regulates the occurrence of inflammatory diseases. Finally, the existing problems and future development directions of miR-7-based intervention on inflammation and related diseases are discussed to provide new references and help strengthen the understanding of the pathogenesis of inflammation and related diseases, as well as the development of new strategies for clinical intervention.
DNA Damage and Consequent Inflammation in Heart Failure
https://www.fightaging.org/archives/2023/09/dna-damage-and-consequent-inflammation-in-heart-failure/
One of the ways in which cell damage characteristic of aging can provoke inflammation is via the mislocalization of DNA. Either nuclear DNA or mitochondrial DNA can find its way to the cytosol, where it can trigger responses evolved to detect bacterial or viral infection, or severe cell damage. This creates a cascade of downstream signaling leading to an inflammatory response. In youth these events occur comparatively rarely, and in circumstances wherein immune response and potentially even cell death are beneficial. With age, however, there is a continued mild but growing level of dysfunction and consequent sustained inflammation that is never fully resolved. Such continual inflammatory signaling is disruptive to cell and tissue function, and is thought to be an important contributing factor in degenerative aging.
In today's open access paper, researchers examine the contribution of nuclear DNA mislocalization to one specific form of heart failures://en.wikipedia.org/wiki/Heart_failure">heart failure, dilated cardiomyopathy, in which the heart becomes enlarged and weakened in response to poorly understood causes. The researchers examine human tissues with an eye to validating data obtained in animal models. The overall picture is that stress on cells in the heart leads to an excessive pace of DNA double strand breaks, which in turn enables DNA fragments to escape from the nucleus into the cytosol. There, the inflammatory reaction takes over. Sustained inflammation in turns drives the dysfunctional regulation leading enlargement and weakening of heart muscle. The degree to which this mechanism is important in humans might be determined via inhibition of specific parts of the cytosolic DNA detection mechanism, a test that might be readily carried out given funding and the will to try.
Cytosolic DNA sensing protein pathway is activated in human hearts with dilated cardiomyopathy
The genome is constantly exposed to numerous stressors, which induce DNA lesions, including double-stranded DNA breaks (DSBs). DSBs are the most dangerous, as they induce genomic instability. In response to DNA damage, the cell activates nuclear DNA damage response (DDR) and the cytosolic DNA sensing protein (CDSP) pathways, the latter upon release of the DSBs to the cytosol. The CDSP pathway activates NFκB and IRF3, which induce the expression of the pro-inflammatory genes. There is scant data on the activation of the CDSP pathway in human hearts with dilated cardiomyopathy (DCM).
To our knowledge, our study results are the first documentation of increased expression levels of the protein components of the CDSP pathway, namely CGAS, TBK1, RELB, P52, and P50 in the human heart samples from patients with heart failure due to DCM. These findings by showing the upregulation of expression of the CDSPs, including the components of the NFκB pathway, complement the previous data on the activation of the nuclear DDR pathway in human heart tissues from patients with DCM. The findings in the human heart samples, being devoid of the genetic manipulations, also give credence to the findings in the model organisms.
Collectively, the data implicate increased DSBs and activation of the DDR and CDSP pathways in the pathogenesis of the DCM and set the stage for further delineation of the pathogenic role of these pathways in human primary DCM. Given the salubrious effects of targeting the CDSP pathway in mouse models of DCM, the findings raise the prospects for targeting the activated CDSP pathways for the prevention and attenuation of the phenotype in human primary DCM. Given that cell stress, including transcriptional stress, is common to various forms of cardiovascular pathology, one may speculate that increased DSBs and activation of DDR and the CDSP pathways are pervasive and ubiquitous features of cardiovascular diseases.
The Cost of Cardiovascular Disease
https://www.fightaging.org/archives/2023/09/the-cost-of-cardiovascular-disease/
Age-related disease places a huge financial burden on individuals and their caregivers; even the need for caregivers arises only because aging produces disability. Even only considering cardiovascular disease, the largest contribution to human mortality, the costs are enormous. This is a point often made by advocates arguing for greater institutional funding of ways to treat aging. Present levels of funding for research and development of means to reduce age-related disease are very low in comparison to the massive ongoing costs that result from age-related disease. It makes little sense for this to be the case in an age of rapid progress in biotechnology, but nonetheless it is the case that vastly more funding is devoted to novel approaches in war, sports, and video games than towards improving medical technology.
Cardiovascular disease (CVD) cost the EU an estimated €282 billion in 2021, according to late breaking research presented at ESC Congress 2023. Health and long-term care accounted for €155 billion (55%) of these costs, equalling 11% of EU health expenditure. "CVD had a significant impact on the EU27 economy, costing a total of €282 billion in 2021. That's equivalent to 2% of Europe's GDP and is significantly more than the entire EU budget itself, used to fund research, agriculture, infrastructure and energy across the Union. By choosing not to invest in cardiovascular disease we are simply deferring the cost. This data forces us to ask the question: do we invest in cardiovascular health today or be forced to pay more at a later stage?"
This was the most comprehensive and up-to-date analysis of the economic costs of CVD to society in the EU since 2006. It is the first study to use Europe-wide patient registries and surveys rather than relying on assumptions and, unlike previous reports, includes the costs of long-term social care. The current analysis provides estimates of the societal economic costs of CVD for the 27 members states of the EU in 2021, including 1) health and social care; 2) informal care; and 3) productivity losses. The breakdown includes: €130 billion for healthcare (46%); €25 billion for social care (9%); €79 billion for informal care (28%); €15 billion in productivity losses due to illness/disability (5%); €32 billion in productivity losses due to premature death (12%). The total cost equated to €630 per EU citizen, ranging from €381 in Cyprus to €903 in Germany.
Healthcare included primary care, emergency care, hospital care, outpatient care and medications, while social care included long-term institutionalised care, and care at home. The main contributor was hospital care, which cost €79 billion, representing 51% of CVD-related care costs. CVD medications accounted for €31 billion (20%) of care costs, followed by residential nursing care homes at €15 billion (9%). Informal care costs included the work or leisure time, valued in monetary terms, that relatives and friends gave up to provide unpaid care. Relatives and friends provided 7.5 billion hours of unpaid care for patients with CVD, amounting to €79 billion across the EU.
A Discussion of Current Approaches Under Development for the Treatment of Aging
https://www.fightaging.org/archives/2023/09/a-discussion-of-current-approaches-under-development-for-the-treatment-of-aging/
This open access paper tours a number of the present approaches under development to the treatment of aging as a medical condition, dwelling the most on therapies targeting senescent cells, either for destruction or to suppress the harmful senescence-associated secretory phenotype. We live in an exciting time of great potential, an age of accelerating progress in the capabilities of medical biotechnology, though it remains the case that too few people realize just how close we are to the widespread use of the first practical rejuvenation therapies.
Aging poses one of the greatest challenges for modern medicine, as it is a major risk factor for chronic diseases such as cancer, cardiovascular and neurodegenerative diseases. As the global population continues to age, there is an urgent need to develop effective interventions and diagnostic tools to prevent illness and extend a healthy lifespan, thereby reducing the burden of age-related diseases on healthcare systems.
Most basic research on aging is focused on identifying mechanisms contributing to this trait. Several hallmarks/pillars of aging have been defined and summarize the main processes underlying aging. Although these definitions are still suboptimal, they provide a nice framework used by many groups in the field to define which aspects of aging their research is focused on. One approach is to target the driving mechanisms of aging, like impaired autophagy and senescence. Inactivation of the mTOR pathway by interventions such as dietary restriction or with small molecule inhibitors like rapamycin, results in autophagy de-repression and lifespan extension (in fruit flies, worms, and mice). Extensive data suggest that rapamycin and rapalogs may have positive effects on age-related conditions and possibly on human longevity.
Cellular senescence is another potentially druggable mechanism that has been much 'in focus' to try to prevent or treat many age-associated pathologies, including cardiovascular, cerebrovascular, neurodegenerative, metabolic, and malignant diseases. Accumulated senescent cells (SenC) have deleterious effects due to the induced proinflammatory microenvironment that supports chronic low-grade inflammation ('inflammaging') and possible tumor development, and accelerate other aging mechanisms which will progress concomitantly. The depletion of SenC in aged organisms, either via genetic ablation or pharmacologically with senolytics, may have therapeutic benefits by alleviating a series of age-associated comorbidities and thus improving healthspan and even lifespan, as shown in lower organisms.
By now, research and development in the biology of aging have moved to the mainstream with initiatives by large pharmaceutical companies and funds, highlighting the growing interest in geroscience and the development of interventional gerotherapeutics. On the financing side, players like Altos Labs and Hevolution have entered the field, looking to deploy massive amounts of capital to accelerate research and commercial product development. These initiatives reflect the increasing recognition of the potential commercial impact of anti-aging therapies on healthcare and society.
Reviewing What is Known of the Aging of Neural Stem Cells
https://www.fightaging.org/archives/2023/09/reviewing-what-is-known-of-the-aging-of-neural-stem-cells/
Neural stem cells produce the new neurons necessary for memory function and maintenance of brain tissue throughout adult life. This process of neurogenesis declines with age, however. Neural stem cell activity is reduced with age, in much the same way as all stem cell populations (and their niche structures) appear to become damaged and impaired as a result of the mechanisms of aging. Do we know enough about the way in which neural stem cells age in order to attempt prevention? As researchers point out here, some strategies may make the situation worse by exhausting rather than renewing stem cell pools. A few inroads are being made, however.
Extensive research in recent years has significantly advanced our knowledge of the mechanisms underlying neural stem cell (NSC) aging and age-related decline in neurogenesis, although much remains obscure. Central to this decline is an escalating impairment of the NSC pool, characterized by increased quiescence, altered lineage specification, and progressive depletion of NSCs. The mechanisms underlying NSC aging in the dentate gyrus (DG) are complex and multifactorial. Over the course of their life, NSCs accumulate several defects, including a failure to maintain a healthy proteome, metabolic alterations, DNA damage, and epigenetic drift. It is now recognized that, in addition to intrinsic mechanisms, extrinsic changes in the NSC niche and systemic environment are the primary contributors to NSC aging, and that these mechanisms are not mutually exclusive, but rather interrelated and interacting with each other.
To safeguard the NSC pool from depletion, it is vital to gain a comprehensive understanding of the cellular and molecular mechanisms regulating NSCs and their aging. The advent of innovative new techniques such as single-cell RNA sequencing and spatial transcriptomics holds immense potential for unravelling the full complexity of the mechanisms involved in the declining capacities of NSCs during aging. Other technologies, such as CRISPR-Cas or adenovirus-mediated gene transfer, enable diverse types of gene function screens, facilitating the exploration of molecular interdependencies and their impact on NSC aging. Understanding the mechanisms that control NSC functions and their aging holds potential for the identification of novel therapeutic targets to either slow the aging process or rejuvenate aged NSCs, thereby enhancing the regenerative and cognitive capacities of the aging hippocampus.
Preventively, simple interventions with few side effects, such as diet or exercise, are particularly promising. Curatively, it becomes more difficult, as the interventional activation of NSCs usually leads to premature exhaustion and accelerated depletion of the pool. However, recent findings that have been able to identify targets whose manipulation increases the self-renewal of NSCs in the aged DG without accelerating their depletion (VEGF, combination of Plagl2 with anti-Dyrk1a) give cause for optimism.
Cardiolipin Oxidation in Mitochondrial Dysfunction
https://www.fightaging.org/archives/2023/09/cardiolipin-oxidation-in-mitochondrial-dysfunction/
An interesting question is posed here by some of the researchers responsible for creating plastoquinone mitochondrially-targeted antioxidants. To what degree do mitochondrially-targeted antioxidants improve mitochondrial function and modestly slow aging by preventing cardiolipin oxidation? Past a certain level of detail, less is known of mitochondrial biochemistry than one might think. This organelle is very well studied, but it is still the case that many approaches known to improve mitochondrial function are incompletely understood, or only understood in outline. It is clear that the mitochondrial generation of reactive oxygen species is a problem that increases alongside mitochondrial dysfunction with age, but down in the depths of the interaction of many different molecules there is room for argument and opinion regarding how it all actually works in practice.
Cellular respiration is associated with at least six distinct but intertwined biological functions. (1) biosynthesis of ATP from ADP and inorganic phosphate, (2) consumption of respiratory substrates, (3) support of membrane transport, (4) conversion of respiratory energy to heat, (5) removal of oxygen to prevent oxidative damage, and (6) generation of reactive oxygen species (ROS) as signaling molecules. Here we focus on function (6), which helps the organism control its mitochondria. The ROS bursts typically occur when the mitochondrial membrane potential (MMP) becomes too high, e.g., due to mitochondrial malfunction, leading to cardiolipin (CL) oxidation.
Depending on the intensity of CL damage, specific programs for the elimination of damaged mitochondria (mitophagy), whole cells (apoptosis), or organisms (phenoptosis) can be activated. In particular, we consider those mechanisms that suppress ROS generation by enabling ATP synthesis at low MMP levels. We discuss evidence that the mild depolarization mechanism of direct ATP/ADP exchange across mammalian inner and outer mitochondrial membranes weakens with age. We review recent data showing that by protecting CL from oxidation, mitochondria-targeted antioxidants decrease lethality in response to many potentially deadly shock insults. Thus, targeting ROS- and CL-dependent pathways may prevent acute mortality and, hopefully, slow aging.
PU.1 Inhibition to Reduce Microglial Inflammation in the Aging Brain
https://www.fightaging.org/archives/2023/09/pu-1-inhibition-to-reduce-microglial-inflammation-in-the-aging-brain/
Researchers here report on a drug discovery effort targeting PU.1, a gene implicated in increased inflammation of microglia in the brain. Microglia are innate immune cells of the central nervous system. Like macrophages in the rest of the body, they react to the damage and dysfunction of aging with increased inflammatory behavior, a maladaptive response that worsens pathology. Chronic, unresolved inflammation is clearly disruptive to tissue function wherever it occurs in the body. In the brain, chronic inflammation is a well-studied feature of conditions such as Alzheimer's disease. A greater population of inflammatory microglia is characteristic of aging and neurodegenerative conditions, and the research community is increasingly interested in finding ways to address this issue.
A 2015 study implicated PU.1 as a regulator of errant microglia inflammation in a mouse model of Alzheimer's disease. Genetically knocking down PU.1 in the body is not a viable therapeutic strategy given its importance in normal healthy function. Researchers therefore screened more than 58,000 small molecules from libraries of FDA-approved drugs and novel chemicals to see if any could safely and significantly reduce key inflammation and Alzheimer's related genes regulated by by PU.1 in cell cultures. After several rounds of increasingly stringent screening, they narrowed the field down to six chemicals. A11 was by far the most potent among them.
Researchers tested the effects of A11 doses on the function of human microglia-like cells cultured from patient stem cells. When they exposed the microglia-like cells to immune molecules that typically trigger inflammation, cells dosed with A11 exhibited reduced expression and secretion of inflammatory cytokines and less of the cell body shape changes associated with microglia inflammatory responses. The cells also showed less accumulation of lipid molecules, another sign of inflammatory activation. Looking at gene expression patterns, the scientists observed that A11-treated cells exposed to inflammatory triggers behaved much like unperturbed microglia, suggesting that A11 helps prevent microglia from overreacting to inflammatory cues.
In a new paper, researchers started with experiments to further validate that PU.1 would be a therapeutically meaningful target. To do that the scientists compared gene expression in immune cells of postmortem brain samples from Alzheimer's patients and mouse models and matching non-Alzheimer's controls. The comparisons showed that Alzheimer's effects major changes in microglial gene expression and that an increase in PU.1 binding to inflammatory gene targets was a significant component of that change. Moreover, they showed that reducing PU.1 activity in a mouse model of Alzheimer's reduced inflammation and neurodegeneration, the death of neurons.
Two more lab tests aimed at understanding how A11 exerts its effects revealed that it doesn't change PU.1 levels. Instead it counteracts PU.1 activity by recruiting several proteins including MECP2, HDAC1, SIN3A and DMNT3A, known to repress expression of its targets. Essentially amid Alzheimer's disease, A11 tamps down what PU.1 amps up.
Towards Engraftment of New Stem Cells into Damaged Lungs
https://www.fightaging.org/archives/2023/09/towards-engraftment-of-new-stem-cells-into-damaged-lungs/
Perhaps the most important challenge in the field of regenerative medicine is to enable engraftment and survival of transplanted cells, allowing new cell populations to replace those made damaged or dysfunctional due to age, injury, or other causes. Despite some advances, survival of transplanted cells remains a significant challenge. Here is one example of signs of progress on this front, however. Judging by the recent past, solutions discovered by researchers are likely to continue to be tissue specific. This implies that a great deal more work lies ahead in order to build a usefully broad toolkit to allow creation and transplantation of suitable cells for all of the major tissues of interest, such as heart, lung, kidneys, liver, and so forth.
Durable reconstitution of the distal lung epithelium with pluripotent stem cell (PSC) derivatives, if realized, would represent a promising therapy for diseases that result from alveolar damage. Here, we differentiate murine PSCs into self-renewing lung epithelial progenitors able to engraft into the injured distal lung epithelium of immunocompetent, syngeneic mouse recipients. After transplantation, these progenitors mature in the distal lung, assuming the molecular phenotypes of alveolar type 2 (AT2) and type 1 (AT1) cells.
After months in vivo, donor-derived cells retain their mature phenotypes, as characterized by single-cell RNA sequencing (scRNA-seq), histologic profiling, and functional assessment that demonstrates continued capacity of the engrafted cells to proliferate and differentiate. These results indicate durable reconstitution of the distal lung's facultative progenitor and differentiated epithelial cell compartments with PSC-derived cells, thus establishing a novel model for pulmonary cell therapy that can be utilized to better understand the mechanisms and utility of engraftment.
Identifying a Stem Cell Population in the Adult Thymus
https://www.fightaging.org/archives/2023/09/identifying-a-stem-cell-population-in-the-adult-thymus/
Researchers here report on the characterization of a stem cell population in the adult thymus that gives rise to the thymic epithelial cells that allow the thymus to host the development of T cells of the adaptive immune system. This is of interest because the thymus atrophies with age, losing active thymic epithelial tissue. The supply of new T cells provided to the immune system diminishes greatly as a consequence, and this is a major contributing factor in the age-related decline of immune function. It is the case that cell therapy approaches are one of the potential ways in which an aged thymus might be regenerated, and the discovery of a stem cell population associated with this tissue can only help these efforts.
The thymus is necessary for lifelong immunological tolerance and immunity. It displays a distinctive epithelial complexity and undergoes age-dependent atrophy. Nonetheless, it also retains regenerative capacity, which, if harnessed appropriately, might permit rejuvenation of adaptive immunity. By characterizing cortical and medullary compartments in the human thymus at single-cell resolution, in this study we have defined specific epithelial populations, including those that share properties with bona fide stem cells (SCs) of lifelong regenerating epidermis.
Thymic epithelial SCs display a distinctive transcriptional profile and phenotypic traits, including pleiotropic multilineage potency, to give rise to several cell types that were not previously considered to have shared origin. Using here identified SC markers, we have defined their cortical and medullary niches and shown that, in vitro, the cells display long-term clonal expansion and self-organizing capacity. These data substantively broaden our knowledge of SC biology and set a stage for tackling thymic atrophy and related disorders.
Reducing Cardiovascular Risk Factor Also Reduces Incidence of Neurodegenerative Disease
https://www.fightaging.org/archives/2023/09/reducing-cardiovascular-risk-factor-also-reduces-incidence-of-neurodegenerative-disease/
It is well known that the aging of the vasculature contributes to the aging of the brain. The brain requires a great deal of energy to operate, and the nutrients and oxygen needed for optimal brain metabolism are supplied in the bloodstream. With age, capillary density declines, the heart becomes weaker, and blood vessels are narrowed by the development of atherosclerotic lesions. All of this combines to reduce the delivery of nutrients to the brain, and its metabolism suffers as a result. Here, researchers present additional evidence to support this view of the impact of cardiovascular aging on brain aging.
Cardiovascular disease and dementia frequently occur together in elderly people. Nevertheless, few longitudinal studies have examined how atherosclerosis and its associated risk factors affect brain health from middle age. Now, a new study provides data on this relationship; the results confirm the importance of controlling traditional cardiovascular risk factors, such as hypertension, cholesterol, diabetes, smoking, and a sedentary lifestyle, not only to preserve cardiovascular health, but also to prevent Alzheimer's disease and other dementias.
In 2021,scientists discovered that the presence of cardiovascular risk factors and subclinical (presymptomatic) atherosclerosis in the carotid arteries (the arteries that supply the brain) was associated with lower glucose metabolism in the brains of apparently healthy 50-year-old participants in the PESA-CNIC-Santander study. Glucose metabolism in the brain is considered an indicator of brain health. Glucose is the main energy source for neurons and other brain cells. The PESA-CNIC-Santander study is a prospective study that includes more than 4,000 asymptomatic middle-aged participants who have been exhaustively assessed for the presence and progression of subclinical atherosclerosis since 2010.
Researchers have continued to monitor the cerebral health of these participants over 5 years. Their research shows that individuals who maintained a high cardiovascular risk throughout this period had a more pronounced reduction in cerebral glucose metabolism, detected using imaging techniques such as positron emission tomography (PET). "In participants with a sustained high cardiovascular risk, the decline in cerebral metabolism was three times greater than in participants who maintained a low cardiovascular risk. The individuals showing this metabolic decline already show signs of neuronal injury."
Reviewing Nicotinamide Riboside as a Strategy to Increase NAD Levels
https://www.fightaging.org/archives/2023/09/reviewing-nicotinamide-riboside-as-a-strategy-to-increase-nad-levels/
The vitamin B3 derivative nicotinamide riboside is one of the more studied ways to increase nicotinamide adenine dinucleotide (NAD) levels in aged tissues. NAD is important in mitochondrial function, but for incompletely understood reasons becomes less available with advancing age. Delivering precursors to NAD synthesis such as nicotinamide riboside can help to boost NAD levels, but researchers have failed to show that the increase in NAD levels and resulting health benefits of this sort of approach are any better than those produced by regular exercise. Clinical trials of various means of increasing NAD levels have produced mixed to uninspiring results. The open access paper here is in part a review of this history, and in part a pitch for using a different, more stable form of nicotinamide riboside to improve the effect size.
Many studies have suggested that the oxidized form of nicotinamide adenine dinucleotide (NAD+) is involved in an extensive spectrum of human pathologies, including neurodegenerative disorders, cardiomyopathy, obesity, and diabetes. Further, healthy aging and longevity appear to be closely related to NAD+ and its related metabolites, including nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). As a dietary supplement, NR appears to be well tolerated, having better pharmacodynamics and greater potency. Unfortunately, NR is a reactive molecule, often unstable during its manufacturing, transport, and storage.
Recently, work related to prebiotic chemistry discovered that NR borate is considerably more stable than NR itself. However, immediately upon consumption, the borate dissociates from the NR borate and is lost in the body through dilution and binding to other species, notably carbohydrates such as fructose and glucose. The NR left behind is expected to behave pharmacologically in ways identical to NR itself. This review provides a comprehensive summary of the literature that makes the case for the consumption of NR as a dietary supplement. It then summarizes the challenges of delivering quality NR to consumers using standard synthesis, manufacture, shipping, and storage approaches. It concludes by outlining the advantages of NR borate in these processes.
Suppression of Transposable Element Activity Extends Life in Nematode Worms
https://www.fightaging.org/archives/2023/09/suppression-of-transposable-element-activity-extends-life-in-nematode-worms/
There is a growing interest in the role of transposable elements in aging. These are sections of the genome, remnants of ancient viral infections, that are capable of copying themselves when active, causing mutational damage in the process. Transposable elements are suppressed in youth, their portions of the genome folded away and hidden from transcriptional machinery, but this suppression fails with age as epigenetic markers that determine the structure of the genome change. Any mechanism that increases mutational damage in large numbers of cells might be suspected to contribute to degenerative aging, but definitive proof is always a challenge, given the difficulty of adjusting just one feature of cellular biochemistry in isolation of all other features. Nonetheless, researchers make the attempt here in nematode worms, and the results are interesting.
Mobility of transposable elements (TEs) frequently leads to insertional mutations in functional DNA regions. In the potentially immortal germline, TEs are effectively suppressed by the Piwi-piRNA pathway. However, in the genomes of ageing somatic cells lacking the effects of the pathway, TEs become increasingly mobile during the adult lifespan, and their activity is associated with genomic instability.
Whether the progressively increasing mobilization of TEs is a cause or a consequence of ageing remains a fundamental problem in biology. Here we show that in the nematode Caenorhabditis elegans, the downregulation of active TE families extends lifespan. Ectopic activation of Piwi proteins in somatic cells also promotes longevity. Furthermore, DNA N6-adenine methylation at TE stretches gradually rises with age, and this epigenetic modification elevates their transcription as the animal ages. These results indicate that TEs represent a novel genetic determinant of ageing, and that N6-adenine methylation plays a pivotal role in ageing control.