Fight Aging! Newsletter, November 6th 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/
Longevity Industry Consulting Services
Reason, the founder of Fight Aging! and Repair Biotechnologies, offers strategic consulting services to investors, entrepreneurs, and others interested in the longevity industry and its complexities. To find out more: https://www.fightaging.org/services/
- Glial Cell Mitochondrial Stress Can Indirectly Signal to the Whole Organism
- Towards Clearance of Senescent Cells to Improve Heart Regeneration
- Small Molecule Induction of Stem Cell Behavior Applied to Tendon Aging
- Accelerated Epigenetic Age and Cardiovascular Risk Factors
- Views on Senolytic Drugs from the Pharmaceutical and Healthcare Industries
- Gingivitis Bacteria Causes Harms in the Heart, Impairing Already Poor Recovery from Heart Attack
- Varieties of Buffalofish as Negligibly Senescent Species
- Engineered Gut Bacteria as a Form of Therapy
- Reviewing the Role of Insulin in Aging
- Senescent Schwann Cells Impair Nerve Regeneration in Older Individuals
- Towards Senolytic Immunotherapies that Use Cytotoxic T Cells
- Anabolic Resistance in Sarcopenia
- Inflammatory Microglia Disrupt the Cholinergic Systems of the Aging Brain
- Evidence for Menopause in Wild Chimpanzees
- Epigenetic Reprogramming as a Treatment for Alzheimer's Disease
Glial Cell Mitochondrial Stress Can Indirectly Signal to the Whole Organism
https://www.fightaging.org/archives/2023/10/glial-cell-mitochondrial-stress-can-indirectly-signal-to-the-whole-organism/
Glia of various sorts are supporting cells in the brain, assisting the function of neurons. Dysfunction and stress in glial cells is nonetheless important. A growing body of evidence suggests that cellular senescence in astrocytes and microglia contribute to age-related neurodegenerative conditions, for example. Further, stress of various forms in these cells may be provoking both inflammation and altered signaling throughout the brain and body. Overly active, pro-inflammatory astrocytes and microglia are implicated in neurodegeneration, even when these cells are not senescent. It isn't clear as to how much of this is a reaction to damage in the environment, such as the presence of protein aggregates, versus harmful changes that are intrinsic to cells, such as altered epigenetics and mitochondrial dysfunction.
In today's open access paper, researchers report on a study of the way in which mitochondrial stress in glial cells can result in signaling to provoke compensatory responses throughout the organism. The study involved nematode worms, a much simpler organism than mammals, but one might expect much of this process to be similar in humans nonetheless. It suggests that novel ways to induce greater cell maintenance in the whole body might start by manipulating astrocytes and microglia. So far, little headway has been made in producing therapies to meaningfully slow aging by boosting cell stress responses. The research community has so far collectively failed to much improve on the effects of exercise in this regard. Is this a limitation of this class of therapy, or do greater gains lie in the future? Time will tell.
Glial-derived mitochondrial signals affect neuronal proteostasis and aging
Historically, much scientific work interrogating the homeostatic roles of the nervous system focused on neurons. While it is clear that glia, the other main cell type of the nervous system, can serve many roles in neuronal development and function, these roles are normally associated with support roles, including regulating cell number, neuronal migration, axon specification and growth, synapse formation and pruning, ion homeostasis, and synaptic plasticity and providing metabolic support for neurons. However, in recent years, it has become increasingly clear that glial health can affect aging and progression of neurodegenerative diseases, like Alzheimer's disease (AD).
For example, expression of apolipoprotein E4 (ApoE4), one of the strongest risk factors for AD, specifically in astrocytes resulted in increased neuronal tau aggregation. Moreover, hyperactivation of the unfolded protein response of the endoplasmic reticulum (UPRER), which drives ER stress resilience, solely in astrocyte-like glial cells resulted in a significant life-span extension in Caenorhabditis elegans. While these studies show the importance of glial function in organismal health, what they lacked is an active function of glia in promoting these beneficial effects.
To uncover an active role for glia in stress signaling and longevity, we aimed to determine whether glial cells can sense mitochondrial stress and initiate an organism-wide response to promote mitochondrial stress resilience and longevity. We used multiple genetic methods to activate the mitochondrial unfolded protein response (UPRMT) in nonneuronal cells, including cell-type-specific application of mitochondrial stress and direct activation of the UPRMT in the absence of stress.
We found that, regardless of method, activation of UPRMT in a small subset of glial cells, the cephalic sheath glia, provided robust organismal benefits, including prolonged life span and increased resistance to oxidative stress. Perhaps most unique in this model is that UPRMT activation in cephalic sheath glia promotes neuronal health by alleviating protein aggregation in neurons of a Huntington's disease (HD) model. Cephalic sheath glia directly communicate with neurons through the release of small clear vesicles (SCVs) and relay the coordination to the periphery via downstream neuronal mechanisms. This glia to neuron signal results in induction of the UPRMT in distal tissues, through a cell nonautonomous mechanism, which is dependent on the canonical UPRMT pathway, yet unexpectedly distinct from paradigms where UPRMT is directly activated in neurons.
Collectively, these results reveal a previously unknown function for cephalic sheath glia in sensing mitochondrial stress, which initiates a signal to promote protein homeostasis in neurons and ultimately prolongs longevity. Therefore, glial cells serve as one of the upstream mediators of mitochondrial stress and its coordination across the entire organism.
Towards Clearance of Senescent Cells to Improve Heart Regeneration
https://www.fightaging.org/archives/2023/10/towards-clearance-of-senescent-cells-to-improve-heart-regeneration/
Senescent cells accumulate with age in tissues throughout the body. Cells enter a senescent state constantly throughout life, largely the result of cells reaching the Hayflick limit on replication, but also due to stress, injury, and damage. A senescent cell ceases replication and instead produces a potent mix of pro-growth, pro-inflammatory signals. The primary purpose of senescence in an adult is to signal to the immune system that a cell needs to be removed, and potentially that the surrounding region of tissue requires further attention, such as in the case of an injury or toxic environment that is damaging other cells. Unfortunately, the immune system becomes progressively incapable with advancing age, and clearance of senescent cells falters and slows. The burden of senescent cells grows, and their signaling turns from helpful to harmful when sustained constantly, disrupting tissue structure and function.
The heart is one of the least regenerative organs, and also one of the most vital. What limited capacity for regeneration that it does have is diminished with age, in part because of a growing burden of senescent cells. Thus among the many potential uses for senolytic therapies capable of selectively clearing senescent cells from tissues, we might consider treatment to improve outcomes following heart attack, or in a more preventative sense to reverse the harmful remodeling of heart muscle that occurs in response to hypertension, changes in the systemic environment, and narrowed blood vessels.
Targeting Cell Senescence to Improve Cardiac Regeneration
Aging impairs the heart's ability to repair and regenerate. As people age, their cardiac stem cells, i.e. cardiac progenitor cells (CPCs), become senescent, upregulating key markers of senescence, such as p16Ink4a and senescence-associated β-galactosidase, and markers of DNA damage, such phosphorylated histone 2AX. Senescent CPCs also possess critically short telomeres and a senescence-associated secretory phenotype (SASP). Indeed, by the time a person is 75 years old, approximately 50% of their CPCs are senescent. Cardiac progenitor cells from older patients are dysfunctional, showing impaired growth, clonogenicity, and cardiomyogenic differentiation potential. When senescent human CPCs were transplanted into a myocardial-infarcted mouse heart, there was decreased cardiac regeneration and cardiac function compared with when non-senescent CPCs were transplanted.
Next, the effects of senolytics and global senescent cell removal on the aged heart were determined. In this experiment, 24- to 32-month-old wild-type mice were randomly assigned to vehicle or senolytic dasatinib and quercetin (D+Q) treatment, administered in 4 cycles at 3 consecutive days per cycle, with the cycles occurring 12 days apart. P16Ink4a messenger RNA expression decreased in the heart following D+Q treatment in older mice. Morphometric analysis of heart sections showed that D+Q-treated mice had decreased fibrosis and hypertrophy and that senolytic treatment had induced compensatory cardiomyocyte renewal and replacement. An increased number of smaller ventricular 5-ethynyl-2ʹ-deoxyuridine-positive or Ki-67-positive cardiomyocytes were found, suggesting that these mice had cardiomyocytes that were immature and newly formed compared with vehicle-treated mice, which exhibited only rare, small 5-ethynyl-2ʹ-deoxyuridine-positive or Ki-67-positive cardiomyocytes but a greater proportion of hypertrophied myocytes. Finally, D+Q treatment rejuvenated the heart's regenerative potential, activating and increasing the number of CPCs.
The present findings support targeting senescence using senolytics to prevent, delay, and treat multiple age-related heart disorders as well as the toxic and senescence-inducing effects of cancer chemotherapy on the heart. Clinical trials on senolytics are already underway. The Translational Geroscience Network in the United States is conducting 15 clinical studies on senolytics for age-related conditions. They have developed assays for measuring biomarkers in the blood and tissues that can be used to test the efficacy of senolytics in the proposed trials and to identify people who are most likely to benefit from senolytic therapy. Research into understanding how senolytics act on the human heart, in clearing senescent cells, or whether they have any off-target side effects is greatly needed.
Small Molecule Induction of Stem Cell Behavior Applied to Tendon Aging
https://www.fightaging.org/archives/2023/11/small-molecule-induction-of-stem-cell-behavior-applied-to-tendon-aging/
While reprogramming usually refers to the production of pluripotent stem cells from somatic cells, is is becoming more broadly used to describe a range of manipulations in which the characteristics of cells in aged tissues are rejuvenated in some way. For example, finding small molecule drug candidates that can restore the potency of aging stem cell populations is the topic of today's open access paper. Since the regulation of adult stem cell and progenitor cell state is complex, there are likely many ways in which it can be manipulated, and those ways probably differ by stem cell type.
Researchers here describe the production of a system for evaluation of stem cell state and discovery of new small molecules to alter that state. They applied this system to aging tendon stem cells, and came up with a drug candidate that restores the regenerative capacity of tendons in old animals. One can make the case for this to be a form of reprogramming because of the way in which tendon stem cells lose their stemness with age; in other stem cell populations, loss of capacity with age may occur for different reasons, such as greater quiescence, or reduced population size, and different solutions will be needed.
Prim-O-glucosylcimifugin ameliorates aging-impaired endogenous tendon regeneration by rejuvenating senescent tendon stem/progenitor cells
Like most tissue regenerative processes, the regenerative capacity of tendons decreases with aging or even fails and is often accompanied by stem cell exhaustion and cellular senescence. The regenerative capacity of adult tendons depends on the status of stem/progenitor cells (TSPCs), which can activate and expand to form new tendon collagen fibers or self-renew to restore the TSPC pool in response to tissue damage. At later stages in life, TSPCs present a marked impairment of stemness and regenerative capacity, resulting in inefficient tendon self-repair. In previous research, we found that the difference in TSPC stemness between the neonatal and adult stages influenced multiple biological functions of TSPCs and the adult tendon regenerative process.
In this context, a reasonable stemness-modulating method is a prospective strategy for remedying aged TSPCs. Traditionally, the dampened stemness can only be reversed by inducing Yamanaka factors genetically. However, an efficient strategy to identify stemness-promoting small molecules is currently lacking. In recent years, deep learning approaches have been widely applied in target-based drug design and for the development of various therapeutic strategies. However, these methods cannot be used when the target is unknown; for instance, with regard to stemness promotion, only four transcription factors are known. In this study, we employed the newly developed system, DLEPS, which is an efficacy prediction system using transcriptional profiles with deep learning, to identify potential drugs to stimulate stemness.
In our study, we found that the top-ranked candidate compound prim-O-glucosylcimifugin (POG) could efficiently inhibit TSPC senescence and promote their tenogenic differentiation potential in an in vitro serial passaging cell senescence model. We also found that the top-ranked POG potently rejuvenated the proliferation and tenogenic potential of TSPCs from both aged rats and middle-aged humans by maintaining stemness and suppressing senescence.
Generally, the results from multiple senescent cell models provide solid and convincing evidence that POG is indeed a potent antisenescent drug for TSPCs. Moreover, the systemic administration of POG and the local delivery of POG encapsulated in nanoparticles were found to promote aged tendon self-repair in small-sized, partial transection tendon injuries. The combination of POG administration and the transplantation of scaffolds significantly enhanced the aged endogenous regenerative capacity in large-sized, full-cut tendon window defects in aged rats. These findings provide multiple alternative strategies for endogenous tendon repair and regeneration in aging according to different injury conditions.
Accelerated Epigenetic Age and Cardiovascular Risk Factors
https://www.fightaging.org/archives/2023/11/accelerated-epigenetic-age-and-cardiovascular-risk-factors/
Epigenetic patterns determine the behavior of a cell, and change constantly in response to cell state and the surrounding tissue environment. Epigenetic state can be used to measure biological age, the epigenetic clock. When an epigenetic clock indicates an age older than chronological age, that is referred to as epigenetic age acceleration. While the clocks are not fully understood in detail, it is thought that the specific epigenetic changes measured are reflective of the burden of cell and tissue damage and dysfunction that causes aging. This acceleration has been shown to correlate with risk and status of a number of age-related conditions.
In today's open access paper, researchers compare epigenetic age acceleration with cardiovascular risk factors. Their point of view is that epigenetic aging, and specifically increased DNA methylation, is a cause rather than a consequence of dysfunction. The work on epigenetic reprogramming of the past few years is supportive of this view that epigenetic change produces significant downstream consequences in aging: reprogramming the epigenetics of old cells does appear to produce some degree of rejuvenation in cells, tissues, and animals. It may be quite close to the root causes of aging, if the work showing it to be a direct consequence of DNA double strand break repair continues to hold up. This is not supportive of the idea that increased DNA methylation is generally a bad thing, however, or that blanket reductions in DNA methylation will be a good basis for therapy.
Accelerated DNA methylation age plays a role in the impact of cardiovascular risk factors on the human heart
DNA methylation (DNAm) age acceleration (AgeAccel) and cardiac age by 12-lead advanced electrocardiography (A-ECG) are promising biomarkers of biological and cardiac aging, respectively. We aimed to explore the relationships between DNAm age and A-ECG heart age and to understand the extent to which DNAm AgeAccel relates to cardiovascular (CV) risk factors in a British birth cohort from 1946.
We studied four DNAm ages (AgeHannum, AgeHorvath, PhenoAge, and GrimAge) and their corresponding AgeAccel. Outcomes were the results from two publicly available ECG-based cardiac age scores: a Bayesian A-ECG-based heart age score and a deep neural network (DNN) ECG-based heart age score. DNAm AgeAccel was also studied relative to results from two logistic regression-based A-ECG disease scores, one for left ventricular (LV) systolic dysfunction (LVSD), and one for LV electrical remodeling (LVER). Generalized linear models were used to explore the extent to which any associations between biological cardiometabolic risk factors (body mass index, hypertension, diabetes, high cholesterol, previous cardiovascular disease [CVD], and any CV risk factor) and the ECG-based outcomes are mediated by DNAm AgeAccel.
By the age of 60, participants with accelerated DNA methylation appear to have older, weaker, and more electrically impaired hearts. We show that the harmful effects of CV risk factors on cardiac age and health, appear to be partially mediated by DNAm AgeAccelPheno and AgeAccelGrim. This highlights the need to further investigate the potential cardioprotective effects of selective DNA methyltransferases modulators.
Views on Senolytic Drugs from the Pharmaceutical and Healthcare Industries
https://www.fightaging.org/archives/2023/11/views-on-senolytic-drugs-from-the-pharmaceutical-and-healthcare-industries/
Senescent cells accumulate with age, most likely largely due to the growing incapacity of the aging immune system, slowing the pace of removal of senescent cells to the point at which their numbers grow. Senescent cells cause significant harm via their pro-growth, pro-inflammatory signaling, disrupting tissue structure and function. Senolytic drugs can selectively destroy senescent cells, largely by attacking mechanisms that provide resistance to the programmed cell death process of apoptosis, but a range of other approaches are under development. First generation senolytics have performed impressively in mouse models of a great many age-related conditions, rapidly reversing pathology and markers of age, and extending healthy life span. This makes their further development and availability in the clinic a matter of great interest.
Today's paper summarizes views on the development of senolytic drugs from a small panel of healthcare and pharmaceutical industry experts. The specific focus is the treatment of vascular disorders of aging, but the views are broadly applicable to the application of senolytic therapies to any age-related condition. I think the most interesting of their points of agreement is that there is a near complete lack of awareness of senolytics in the world at large. Many more clinical trials should be underway using the low cost senolytic combination of dasatinib and quercetin in terms of proving that it can work and finding useful human dosing strategies. It is entirely possible that most common age-related conditions don't have to be as severe as they are for the patients suffering them, but at the present pace it'll be years yet before any useful body of data emerges for that presently available senolytic therapy.
Exploring the perspectives of pharmaceutical experts and healthcare practitioners on senolytic drugs for vascular aging-related disorder: a qualitative study
The field of targeting cellular senescence with drug candidates to address age-related comorbidities has witnessed a notable surge of interest and research and development. This study aimed to gather valuable insights from pharmaceutical experts and healthcare practitioners regarding the potential and challenges of translating senolytic drugs for treatment of vascular aging-related disorders. This study employed a qualitative approach by conducting in-depth interviews with healthcare practitioners and pharmaceutical experts. Participants were selected through purposeful sampling. Thematic analysis was used to identify themes from the interview transcripts. A total of six individuals were interviewed, with three being pharmaceutical experts and the remaining three healthcare practitioners.
Health providers and pharmaceutical experts viewed that there are certain challenges and considerations associated with measuring outcomes and assessing the effects of senolytic therapies. One of the primary issues is that measurable outcomes may not be immediate. Senescent cell clearance and subsequent tissue regeneration may take time to manifest noticeable effects. More importantly, to date there are no tools such as imaging probes or biomarkers that can measure the clearance of senescent cells from tissue. The lack of such simple tools not only hamper the identification of senolytic drugs which are truly specific for senescent cells but also for monitoring therapeutic efficacy.
Results from completed trials of dasatinib and quercetin using intermittent dosing (i.e., consecutive treatment for 2-3 days with 2-week resting period) appears to be tolerable, with mild to modest adverse effects. Hence, it is crucial to establish the safety profile and dosing regimen of new senolytic drugs to harness the beneficial effects whilst minimizing risks. From the healthcare practitioners' perspective, it is crucial to ensure that the new senolytic therapy does not interact with other medications, particularly for elderly individuals who are already managing multiple conditions and taking numerous medications. While drug interaction profiles may be available for repurposed drugs, it may not the case for newly developed senolytics. To this end, potential drug-drug interactions, particularly with medications taken by the elderly individuals for their comorbidities have yet to be examined in preclinical and clinical studies and warrant future investigations. In this regard, pharmaceutical experts of this study pointed out the importance of addressing both the selectivity and specificity of senolytics. Improving senolytics selectivity for senescent cells while sparring healthy non-senescent cells is crucial to minimize potential side effects.
The pharmaceutical sector demonstrates a positive inclination towards the commercialization of new senolytic drugs, albeit with concerns around safety and efficacy. Besides sharing the same outcome-related concerns as with the pharmaceutical experts, healthcare practitioners anticipated a lack of awareness among the general public regarding the concept of targeting cellular senescence to delay vascular aging-related disorders, and this knowledge gap extends to healthcare practitioner themselves as well.
Gingivitis Bacteria Causes Harms in the Heart, Impairing Already Poor Recovery from Heart Attack
https://www.fightaging.org/archives/2023/10/gingivitis-bacteria-causes-harms-in-the-heart-impairing-already-poor-recovery-from-heart-attack/
Inflammatory periodontal disease is caused by a specific bacterial species. The bacteria can use damaged gums to enter the bloodstream. It is thought that its ability to provoke inflammation can then contribute to cardiovascular disease and dementia, though the size of the effect is up for debate. Along these lines, researchers here show that periodontal bacteria can worsen the consequences of a heart attack, impairing the already limited ability of the heart to regenerate and restore function following injury.
Heart attacks occur when blood flow in the coronary arteries is blocked, resulting in an inadequate supply of nutrients and oxygen to the heart muscle, and ultimately death of cardiac myocytes. To prevent this, cardiac myocytes use a process known as autophagy to dispose of damaged cellular components, keeping them from causing cardiac dysfunction. Previous studies have shown that the periodontal pathogen Porphyromonas gingivalis, which has been detected at the site of occlusion in myocardial infarction, can exacerbate post-infarction myocardial fragility. However, the mechanisms underlying this effect remained unknown.
To investigate this, researchers created a version of P. gingivalis that does not express gingipain, its most potent virulence factor, which an earlier study showed can inhibit cells from undergoing programmed cell death in response to injury. They then used this bacterium to infect cardiac myocytes or mice. "The results were very clear. The viability of cells infected with the mutant bacterium lacking gingipain was much higher than that of cells infected with the wild-type bacterium. In addition, the effects of myocardial infarction were significantly more severe in mice infected with wild-type P. gingivalis than in those infected with the mutant P. gingivalis lacking gingipain."
More detailed investigation of this effect showed that gingipain interferes with fusion of two cell components known as autophagosomes and lysosomes, a process that is crucial to autophagy. In mice, this resulted in an increase in the size of cardiac myocytes and accumulation of proteins that would normally be cleared out of the cells to protect the cardiac muscle. "Our findings suggest that infection with P. gingivalis producing gingipain results in excessive autophagosome accumulation, which can lead to cellular dysfunction, cell death, and ultimately cardiac rupture."
Varieties of Buffalofish as Negligibly Senescent Species
https://www.fightaging.org/archives/2023/10/varieties-of-buffalofish-as-negligibly-senescent-species/
A number of vertebrate species exhibit negligible senescence, meaning little to no functional degeneration over the course of their lives. Usually they also exhibit very long life spans for their size, and in comparison to near relative species that do exhibit evident aging. Researchers study these species in order to (a) identify important mechanisms of degenerative aging as targets for further research, as well as to (b) potentially find adjustments to cellular biochemistry that might stop a given mechanism from contributing to aging in our species. The first goal is much more feasible in the near term; it remains to be seen as to whether the second is even plausible to engineer in our lifetimes. A necessary first step in this field of research is to identify which vertebrate species are in fact negligibly senescent. Less is known about life spans and life histories in the wild than one might think, and so one should expect the research community to continue to identify new examples as time goes on.
During the 1910s three buffalofish species (Catostomidae: Ictiobus cyprinellus, I. bubalus, I. niger) were reared in ponds along the Mississippi River. Individuals of these buffalofishes were transported to locations across the United States to support or establish commercial fisheries, including Roosevelt Lake, Arizona in 1918. During the 1930s-1960s a commercial fishery existed on Roosevelt Lake, ending by 1970. Scarce information exists on Arizona buffalofishes since.
From 2018 to 2023 we studied buffalofishes from nearby Apache Lake (adjacent and downstream of Roosevelt Lake) in collaboration with anglers. Here we show that more than 90% of buffalofishes captured from Apache Lake are more than 80 years old and that some of the original buffalofishes from the Arizona stocking in 1918 are likely still alive. Using unique markings on old-age buffalofishes, we demonstrate how individuals are identified and inform dozens of recaptures. With a sample size of only 23 individuals across the three species of buffalofishes at Apache Lake, we found direct evidence of centenarian longevity for black buffalo (108 years), bigmouth buffalo (105 years), and smallmouth buffalo (101 years).
We now know all species of USA Ictiobus can live more than 100 years, making it the only genus of animal besides marine rockfishes (Sebastes) for which three or more species have been shown to live more than 100 years. Our citizen-science collaboration has revealed remarkable longevity for freshwater fishes and has fundamentally redefined our understanding of the genus Ictiobus itself.
Engineered Gut Bacteria as a Form of Therapy
https://www.fightaging.org/archives/2023/10/engineered-gut-bacteria-as-a-form-of-therapy/
The gut microbiome appears important to health, as judged by the changes in relative population sizes between species that take place across the course of aging, and the ability of reversing those changes to improve health and extend life in old animals. If the near future is restoration of a more youthful balance of microbial populations in the aged gut microbiome, to produce more beneficial metabolites and reduce inflammation, then the next step after that is to start engineering gut microbes to produce even greater effects. The example here produces poor, sex-specific effects in rats, but it is one example of a thousand different possibilities, many of which will turn out to be far more impressive.
Engineered gut microbiota represents a new frontier in medicine, in part serving as a vehicle for the delivery of therapeutic biologics to treat a range of host conditions. The gut microbiota plays a significant role in blood pressure regulation; thus, manipulation of gut microbiota is a promising avenue for hypertension treatment. In this study, we tested the potential of Lactobacillus paracasei, genetically engineered to produce and deliver human angiotensin converting enzyme 2 (Lacto-hACE2), to regulate blood pressure in a rat model of hypertension with genetic ablation of endogenous Ace2 (Ace2-/- and Ace2-/y).
Our findings reveal a sex-specific reduction in blood pressure in female (Ace2-/-) but not male (Ace2-/y) rats following colonization with the Lacto-hACE2. This beneficial effect of lowering blood pressure was aligned with a specific reduction in colonic angiotensin II, but not renal angiotensin II, suggesting the importance of colonic Ace2 in the regulation of blood pressure. We conclude that this approach of targeting the colon with engineered bacteria for delivery of ACE2 represents a promising new paradigm in the development of antihypertensive therapeutics.
Reviewing the Role of Insulin in Aging
https://www.fightaging.org/archives/2023/10/reviewing-the-role-of-insulin-in-aging/
The relationship between insulin metabolism and aging is one of the most studied areas of the field, with decades of researchers putting in time to deepen the understanding of the web of interactions surrounding insulin. Yet this has failed to lead to any practical outcome when it comes to slowing or reversing aging. Researchers now have an incrementally better idea as to why obesity, metabolic syndrome, and type 2 diabetes shorten life and worsen health, but that was well understood to be the case well prior to the advent of modern biotechnology.
Experimental studies in animal models of aging such as nematodes, fruit flies, or mice have observed that decreased levels of insulin or insulin signaling promotes longevity. In humans, hyperinsulinemia and concomitant insulin resistance are associated with an elevated risk of age-related diseases suggestive of a shortened healthspan. Age-related disorders include neurodegenerative diseases, hypertension, cardiovascular disease, and type 2 diabetes. High ambient insulin concentrations promote increased lipogenesis and fat storage, heightened protein synthesis, and accumulation of non-functional polypeptides due to limited turnover capacity. Moreover, there is impaired autophagy activity, and less endothelial NO synthase activity. These changes are associated with mitochondrial dysfunction and oxidative stress.
The cellular stress induced by anabolic activity of insulin initiates an adaptive response aiming at maintaining homeostasis, characterized by activation of the transcription factor Nrf2, of AMP activated kinase, and an unfolded protein response. This protective response is more potent in the long-lived human species than in short-lived models of aging research resulting in a stronger pro-aging impact of insulin in nematodes and fruit flies. In humans, resistance to insulin-induced cell stress decreases with age, because of an increase of insulin and insulin resistance levels but less Nrf2 activation. These detrimental changes might be contained by adopting a lifestyle that promotes low insulin/insulin resistance levels and enhances an adaptive response to cellular stress, as observed with dietary restriction or exercise.
Senescent Schwann Cells Impair Nerve Regeneration in Older Individuals
https://www.fightaging.org/archives/2023/11/senescent-schwann-cells-impair-nerve-regeneration-in-older-individuals/
Senescent cells of many types accumulate in tissues throughout the body with age due to an imbalance between the pace of creation and pace of destruction, the immune system progressively losing its ability to destroy these senescent cells in a timely manner. Senescent cells cease to replicate and secrete a potent mix of pro-inflammatory signals, harmful to surrounding tissue when sustained over the long term. Here, researchers note one of the many specific ways in which senescent cells can impair function; this one example is multiplied a thousand times across locations, tissue types, and cell types throughout the aging body.
Following peripheral nerve injury, successful axonal growth and functional recovery require Schwann cell (SC) reprogramming into a reparative phenotype, a process dependent upon c-Jun transcription factor activation. Unfortunately, axonal regeneration is greatly impaired in aged organisms and following chronic denervation, which can lead to poor clinical outcomes. While diminished c-Jun expression in SCs has been associated with regenerative failure, it is unclear whether the inability to maintain a repair state is associated with the transition into an axonal growth inhibition phenotype.
We here find that reparative SCs transition into a senescent phenotype, characterized by diminished c-Jun expression and secretion of inhibitory factors for axonal regeneration in aging and chronic denervation. In both conditions, the elimination of senescent SCs by systemic senolytic drug treatment or genetic targeting improved nerve regeneration and functional recovery, increased c-Jun expression and decreased nerve inflammation. This work provides the first characterization of senescent SCs and their influence on axonal regeneration in aging and chronic denervation, opening new avenues for enhancing regeneration and functional recovery after peripheral nerve injuries.
Towards Senolytic Immunotherapies that Use Cytotoxic T Cells
https://www.fightaging.org/archives/2023/11/towards-senolytic-immunotherapies-that-use-cytotoxic-t-cells/
As researchers here point out, cytotoxic T cells can in principle attack and destroy lingering senescent cells in aged tissues. That they don't do enough of this in old age is clear, but that they are capable of it at all opens the door to finding ways to encourage greater activity. Deciduous Therapeutics runs a development program focused on encouraging a different set of immune cells to kill senescent cells, while engineered T cells equipped with chimeric antigen receptors have been tested in animal models for their ability to kill senescent cells. It is likely that other groups will try a variety of senolytic immunotherapy approaches in the years ahead.
With their continuous production of the senescence-associated secretory phenotype (SASP), senescent cells (SnCs) hinder tissue renewal and accelerate pathological deterioration, thus damaging the development and maintenance of functional ability, which is the major concern of healthy aging. The immune system primarily takes the responsibility of identifying and recycling irregular cells, thus ensuring an endogenous approach to achieve healthy aging. However, the immunosurveillance function gradually loses its balance with cellular and microenvironmental changes in the aging process, indulging the irreversible aging process. Hence, the restoration and mobilization of immunosurveillance could be an entry point to boost healthy aging.
Cytotoxic T lymphocytes (CTLs), as an important part of the immune system, mainly include CD4+ CTLs, CD8+ CTLs, and artificially modified cytotoxic chimeric antigen receptor T cells (CAR T cells). CTLs bind with antigen-presenting target cells, releasing perforin and granzyme which induce the death of target cells. Studies have suggested the well-established role of CTLs in eliminating cancer cells selectively. Could this theory be applied to the elimination of SnCs effectively? p21, a classical marker of cellular senescence, was found to induce CXCL14 and other immune-modulatory factors expression in hepatocytes. These immune modulatory factors further boosted M1 macrophage differentiation and the recruitment of CTLs to p21-expressing hepatocytes, strongly suggesting that CTLs may contribute to the immune clearance of SnCs
Immunosurveillance on aging is a complex yet poorly understood natural process. Revealing attempts have been made to identify prominent senescent hallmarks that activate CTLs. Furthermore, the demonstration of how SnCs are eliminated by CTLs in natural processes offers potential interference approaches. The exploratory application of immune checkpoint blockade and CAR T cells provides strategies to prevent SnCs from escaping immunosurveillance. With the discovery of new aging hallmarks and successful mobilization of CTLs, future senolysis may contribute to healthy aging and prevent aging-related diseases.
Anabolic Resistance in Sarcopenia
https://www.fightaging.org/archives/2023/11/anabolic-resistance-in-sarcopenia/
Anabolic resistance is a description of a state, not a starting point for a therapy. Anabolism is the metabolism of growth and repair, and in a state of anabolic resistance cells become less responsive to the signaling environment that normally encourages growth and repair. If the goal is therapies, then why this anabolic resistance occurs becomes the question. Muscles lose mass and strength with age, leading to the condition called sarcopenia. This, obviously, must involve anabolic resistance, and here researchers discuss what is known of this view of the sarcopenia of old age.
The development of sarcopenia in the elderly is associated with many potential factors and/or processes that impair the renovation and maintenance of skeletal muscle mass and strength as ageing progresses. Among them, a defect by skeletal muscle to respond to anabolic stimuli is to be considered. Common anabolic stimuli/signals in skeletal muscle are hormones (insulin, growth hormones, IGF-1, androgens, and β-agonists such epinephrine), substrates (amino acids such as protein precursors on top, but also glucose and fat, as source of energy), metabolites (such as β-agonists and HMB), various biochemical/intracellular mediators), physical exercise, neurogenic and immune-modulating factors, etc. Each of them may exhibit a reduced effect upon skeletal muscle in ageing.
In this article, we overview the role of anabolic signals on muscle metabolism, as well as currently available evidence of resistance, at the skeletal muscle level, to anabolic factors, from both in vitro and in vivo studies. Some indications on how to augment the effects of anabolic signals on skeletal muscle are provided.
Inflammatory Microglia Disrupt the Cholinergic Systems of the Aging Brain
https://www.fightaging.org/archives/2023/11/inflammatory-microglia-disrupt-the-cholinergic-systems-of-the-aging-brain/
Cholinergic neurons are important in many functions in the brain. It is becoming apparent that chronic inflammation in brain tissue is an important contributing cause in the decline of cholinergic systems of brain function. Microglia, innate immune cells of the brain, are one of the cell populations responsible for sustaining harmful inflammation. These cells become active and inflammatory in ever increasing numbers in the aging brain, a maladaptive reaction to growing levels of metabolic waste and pro-inflammatory signaling outside cells, alongside age-related dysfunction inside cells.
This study assessed the effect of normal aging and neuroinflammation on the medial septal Iba-1+ microglia population and the consequential effect on the choline acetyl transferase (ChAT)+ cholinergic cell population. Chronic IL-6 expression in the mouse brain significantly increased the reactive Iba-1+ microglia and decreased the ChAT+ cholinergic cell number in the medial septum and this tendency exacerbated with aging. We also showed that aging and chronic IL-6 expression reorientated the septal microglia morphology towards a more reactive and de-ramified pro-inflammatory phenotype.
These findings further reflected upon the septal cholinergic cell population displaying a neurodegenerative phenotype. The resultant direct effect of neuroinflammation and aging on the septal cholinergic population mirrored upon the hippocampal pyramidal cell dendritic spine density. Overall, these findings demonstrate a potential detrimental effect of chronic microglia activation on the medial septum, which can exacerbate throughout aging, leading to cholinergic dysfunction that could in turn disrupt hippocampal pyramidal cell network regulation.
Evidence for Menopause in Wild Chimpanzees
https://www.fightaging.org/archives/2023/11/evidence-for-menopause-in-wild-chimpanzees/
Few mammalian species exhibit menopause. It is thought that humans evolved into this state of post-reproductive old age in part because older individuals can help to enhance the reproductive fitness of their direct offspring. This view is known as the "grandmother hypothesis". The same behavior is observed in orcas, one of the few other mammals to exhibit menopause. Researchers here provide evidence for chimpanzees to undergo menopause, which is a strike against the grandmother hypothesis, as chimpanzee elders do not assist their offspring in this way.
A team of researchers studying the Ngogo community of wild chimpanzees in western Uganda's Kibale National Park for two decades has published a report showing that females in this population can experience menopause and postreproductive survival. Prior to the study these traits had only been found among mammals in a few species of toothed whales, and among primates only in humans. These new demographic and physiological data can help researchers better understand why menopause and post-fertile survival occur in nature, and how it evolved in the human species.
The grandmother hypothesis has been used to explain the existence of human postmenopausal survival, proposes that females in their postreproductive years may be able to pass on more of their genes by helping to raise the birth rates of their own children or by caring directly for grandchildren, thereby increasing grandchildren's odds of survival. And indeed, several studies of human grandmothers have found these positive effects. But chimpanzees have very different living arrangements than humans. Older female chimpanzees typically do not live near their daughters or provide care for grandchildren, yet females at Ngogo often live past their childbearing years.
While substantial postreproductive life spans have not previously been observed in other long-term studies of wild chimpanzees, they have sometimes been seen in chimpanzees and other primates in captivity, who receive good nutrition and medical care. This raises the possibility that the postreproductive life spans of female Ngogo chimpanzees may be a temporary response to unusually favorable ecological conditions, as this population enjoys a stable and abundant food supply and low levels of predation. Another possibility, however, is that postreproductive life spans are actually an evolved, species-typical trait in chimpanzees but have not been observed in other chimpanzee populations because of the recent negative impacts of humans.
Epigenetic Reprogramming as a Treatment for Alzheimer's Disease
https://www.fightaging.org/archives/2023/11/epigenetic-reprogramming-as-a-treatment-for-alzheimers-disease/
This review paper lumps together thoughts on the prospects for both epigenetic reprogramming and upregulation of autophagy as approaches to the treatment of Alzheimer's disease, the former a much more recent development in the research community, and the latter a long-running goal that has seen less concrete progress than desired. The long, slow path to any sort of success in the development of Alzheimer's therapies based on clearance of amyloid-β has led to considerable pressure to try other other avenues, but despite numerous trials and development programs, few of those have made much progress towards the clinic as of yet.
Age remains the largest risk factor in the development of neurodegenerative diseases such as Alzheimer's disease (AD). Numerous cellular hallmarks of aging contribute to the advancement of the pathologies associated with neurodegenerative disease. Not all cellular hallmarks of aging are independent and several fall into the broader category of cellular rejuvenation, which captures returning cells to a more youthful, improved functional state. Cellular rejuvenation is quickly becoming a hot topic in the development of novel therapeutic modalities for a range of diseases. Therapeutic approaches that utilize cellular rejuvenation technologies are rapidly advancing and will represent the next phase of AD therapeutics.
This review focuses on two important processes, epigenetic reprogramming, and chaperone-mediated autophagy (CMA) that play a critical role in aging and in neurodegenerative diseases and the potential therapeutic approaches (gene therapy, small molecule) towards targeting these mechanisms. In aging and in AD, epigenetic changes on DNA (e.g., hypermethylation on CpG islands) lead to alterations in gene expression. Partial epigenetic reprogramming utilizes transcription factors to remove the epigenetic marks and to rejuvenate cells to a more youthful state. During aging and in neurodegenerative disorders, CMA becomes impaired resulting in a buildup of proteins known to be associated with neurodegenerative pathologies. The protein buildups lead to aggregates that preclude proteostasis leading to cell toxicity. Small-molecule CMA activators restore proteostasis and limit toxicity enabling cellular rejuvenation.