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- More on NNMT Inhibitors as a Basis for Treating Sarcopenia
- Mining Cardiovascular and Metabolic Disease Treatments for Ways to Modestly Slow Aging
- Why is Low Blood Cholesterol Associated with Increased Late Life Mortality?
- A Deep Dive into the Mechanisms of Aortic Calcification, in Search of Points of Intervention
- IL-11 Inhibition Extends Life Span in Mice by up to 25%
- Proteomic Aging Clocks for Specific Organs
- A Novel Approach to Rapid Screening of Age-Slowing Small Molecules
- A Mechanism for Developmental Programming to Contribute to Degenerative Aging
- Towards Small Molecule Drugs that can Induce Trained Immunity
- Arguing for Senolytics to Prevent or Slow Development of Macular Degeneration
- Nrf2 as a Point of Intervention for Cellular Stress Responses
- A Possible Basis for Treating Lupus
- GPRC5A Inhibition as a Strategy to Enhance Bone Formation in Osteoporosis
- Low Dose Antifibrotic Drugs Slow Ovarian Aging in Mice
- Effects of Long-Term Nicotinamide Mononucleotide Supplementation on Mouse Life Span
More on NNMT Inhibitors as a Basis for Treating Sarcopenia
https://www.fightagi...ing-sarcopenia/
Sarcopenia is the name given to the characteristic, progressive loss of muscle mass and strength that takes place with aging, eventually giving rise to frailty. Many different contributing mechanisms are thought to play a role in this process: lower protein intake; dysfunction in processing of dietary protein; dysfunction in the neuromuscular junctions connecting the nervous system to muscle fibers and consequent loss of signaling needed to maintain muscle tissue; loss of muscle stem cell activity and thus a reduced supply of new muscle cells; and so forth. As is usually the case, it is a work in progress to firmly connect the observed cell and tissue changes of sarcopenia to the low-level causes of aging, forms of damage such as mitochondrial dysfunction and the accumulation of senescent cells. It is also challenging to understand which of the mechanisms contributing to sarcopenia are most important, and therefore a priority for the development of therapies.
A few years ago researchers demonstrated that inhibiting NNMT in aging mice produced increased muscle mass and strength. This appears to work because NNMT is involved in the age-related loss of function and induction of cellular senescence in muscle stem cells. In today's open access paper, the same researchers report further on their work to develop small molecule NNMT inhibitors as a potential treatment for sarcopenia. In particular they note that NNMT inhibition is additive to the effects of resistance exercise on muscle, which is a promising development.
Nicotinamide N-methyltransferase inhibition mimics and boosts exercise-mediated improvements in muscle function in aged mice
Human hallmarks of sarcopenia include muscle weakness and a blunted response to exercise. Nicotinamide N-methyltransferase inhibitors (NNMTis) increase strength and promote the regenerative capacity of aged muscle, thus offering a promising treatment for sarcopenia. Since human hallmarks of sarcopenia are recapitulated in aged (24-month-old) mice, we treated mice from 22 to 24 months of age with NNMTi, intensive exercise, or a combination of both, and compared skeletal muscle adaptations, including grip strength, longitudinal running capacity, plantarflexor peak torque, fatigue, and muscle mass, fiber type, cross-sectional area, and intramyocellular lipid (IMCL) content. Exhaustive proteome and metabolome analyses were completed to identify the molecular mechanisms underlying the measured changes in skeletal muscle pathophysiology.
Remarkably, NNMTi-treated aged sedentary mice showed ~ 40% greater grip strength than sedentary controls, while aged exercised mice only showed a 20% increase relative to controls. Importantly, the grip strength improvements resulting from NNMTi treatment and exercise were additive, with NNMTi-treated exercised mice developing a 60% increase in grip strength relative to sedentary controls. NNMTi treatment also promoted quantifiable improvements in IMCL content and, in combination with exercise, significantly increased gastrocnemius fiber cross-sectional area. Detailed skeletal muscle proteome and metabolome analyses revealed unique molecular mechanisms associated with NNMTi treatment and distinct molecular mechanisms and cellular processes arising from a combination of NNMTi and exercise relative to those given a single intervention.
These studies suggest that NNMTi-based drugs, either alone or combined with exercise, will be beneficial in treating sarcopenia and a wide range of age-related myopathies.
Mining Cardiovascular and Metabolic Disease Treatments for Ways to Modestly Slow Aging
https://www.fightagi...tly-slow-aging/
There is a trend towards examining drugs that treat cardiovascular and metabolic disease in search of modest effects on aging. This is most obvious in the attempted repurposing of antidiabetic drugs such as metformin, acarbose, and canagliflozin, but this also extends to lipid-lowering drugs such as atorvastatin. Now that SGLT2 inhibitors are popular as weight loss drugs for the control of obesity, rather than just antidiabetics, that portfolio is also under consideration. One might consider that a possible common thread here is manipulation of lipid metabolism to reduce localized excesses of free cholesterol and other lipids that become toxic when present in too large an amount. One might also argue that reduction in blood glucose is also a common thread, but it is worth noting that statins can increase this measure.
The effect on life span in mice resulting from treatment by some these drugs (e.g. arcabose and canagliflozin) is smaller than that produced by mTOR inhibitors such as rapamycin, but large enough to think that there is something real going on under the hood. That said, others such as metformin come with a panoply of very poor animal data and questionable human data for effects on aging, despite their popularity. It may be that these drugs only help in the context of a sedentary, overweight population and are of little use to physically fit individuals. It may also be that effects on aging in long-lived species such as our own are too small to spend much time on - certainly one can already argue that to be the case for calorie restriction mimetics, which as a class have a larger effect on life span in mice than antidiabetics.
Repurposing effect of cardiovascular-metabolic drug to increase lifespan: a systematic review of animal studies and current clinical trial progress
Cardiovascular and metabolic drugs are frequently repurposed due to their diverse molecular mechanism in many diseases. With various molecular mechanisms found in the aging process, cardiometabolic drugs possess the potential to delay aging. For instance, aspirin and statins are potentially beneficial for cancer, or the pleiotropic effect of metformin in cancer, cardiovascular disease, and dementia in diabetic patients. Of note, aspirin and metformin could extend the lifespan of rodents. Our systematic review primarily focused on animal studies, with additional consideration given to clinical trials and their protocols.
Dramatic growth in the variety of longevity medicines that are being identified from animal studies is not always successfully translated to clinical applications. Aspirin treatment failed to prevent mortality and morbidity in healthy older adult people and potentially increased the hemorrhagic risk in those people. In parallel, metformin could not prolong the lifespan in drosophila and rather increased the mortality in female mice. Moreover, the clinical trials of metformin, such as MILES (Metformin In Longevity Study), showed the enhancement of longevity-related gene expressions, but the valid molecular mechanisms by which metformin facilitates this activity remain unknown.
Analysis of 49 animal trials and 10 clinical trial registries show that various cardiovascular and metabolic drugs have the potential to target lifespan. Metformin, acarbose, and aspirin are the three most studied drugs in animal trials. Aspirin and acarbose are the promising ones, whereas metformin exhibits various results. In clinical trial registries, metformin, omega-3 fatty acid, acarbose, and atorvastatin are currently cardiometabolic drugs that are repurposed to target aging. Published clinical trial results show great potential for omega-3 and metformin in healthspan.
Why is Low Blood Cholesterol Associated with Increased Late Life Mortality?
https://www.fightagi...life-mortality/
The conventional wisdom propagated by physicians and cardiovascular researchers is that it is good to reduce cholesterol in the bloodstream attached to low-density lipoprotein (LDL) particles. The lower the better. This is cholesterol transported outwards from its creation in the liver for use elsewhere in the body. When sustained over decades, higher LDL-cholesterol increases the pace of development of fatty atherosclerotic plaques in blood vessel walls, the cause of eventual heart attack and stroke. Human mutants with abnormally low LDL-cholesterol levels exhibit as much as a 50% reduction in risk of death due to rupture of a plaque and resulting heart attack or stroke.
Interestingly, however, low levels of total cholesterol in the bloodstream are associated with increased late life mortality. A measure of total cholesterol counts the cholesterol attached to all forms of transport particle - so not just LDL-cholesterol leaving the liver (along with VLDL and IDL cholesterol-bearing particles) but also the high-density lipoprotein (HDL) cholesterol that is carried back to the liver. It remains unclear as to exactly why low total cholesterol is associated with increased mortality, though there is no shortage of hypotheses.
One of those hypotheses is that low total cholesterol is a side-effect of a poor diet. Another is that forms of chronic age-related dysfunction independently produce both low total cholesterol and increased mortality. In today's open access paper, researchers analyze epidemiological data to suggest that the mortality effects of low total cholesterol are not associated with diet, though the database they are working from cannot provide much further insight into mechanisms. On a related note, it is entirely unclear as to whether pharmacological approaches such as PCKS9 inhibitors that can produce very low LDL-cholesterol will also trigger increased mortality in late life, the 80s and beyond, significantly older than the patients typically included in clinical trials for heart disease. These drugs are too new for meaningful amounts of long-term data to exist.
Association between total cholesterol and all-cause mortality in oldest old: a national longitudinal study
The present findings showed that a lower total cholesterol (TC) level was associated with elevated all-cause mortality risk in a population of oldest-old adults (aged ≥85 years). When TC level was used as a continuous variable, the mortality risk increased by 12% with each 1 mmol/L reduction in TC. This is consistent with findings from several previous studies, which demonstrated that a low TC level was a risk factor for all-cause mortality in older people. This could be explained by the increased risk of non-cardiovascular mortality (e.g., from cancers and infections). After identifying this inverse association, we further explored the lower limit of TC and found a continuous increment of all-cause mortality risks when TC levels fell below 3.40 mmol/L. This indicates that a TC level lower than 3.40 mmol/L is associated with higher mortality risk among oldest-old adults. To our knowledge, this is the first study to clarify the lower TC cutoff point in this population, and it has been suggested that lower TC levels are associated with frailty and chronic disease in seniors, which further increases mortality risk.
Some researchers suggest that higher TC levels are associated with better nutritional and chronic health status in the oldest old population; thus, individuals with elevated TC levels are more likely to live longer. In the present study, we attempted to exclude the potential effect of dietary or physiological factors by including these variables in the model. In our study, self-reported diabetes, heart disease, and stroke were not significantly associated with all-cause mortality, and thus not included as covariates in the final multivariable models. The predictive value of traditional risk factors for mortality may diminish in the oldest old compared to younger populations, as supported by some previous studies.
As for dietary factors, fresh fruit consumption and fish consumption were protective factors in the multivariable model, whereas daily consumption of eggs and sugar were risk factors for all-cause mortality, which is consistent with previous findings. Adjustment for dietary behaviors and chronic health conditions did not alter the protective effect of TC on all-cause mortality, indicating that the association between TC and all-cause mortality is independent of nutritional status.
Although the biological pathways that link TC to mortality are poorly understood, several mechanisms may explain this inverse association. For example, blood lipids, which are an important component of cell membranes, may affect cell electrophysiology by modulating the distribution and function of some ion channels. Low TC levels may contribute to the pathogenesis of some common diseases in older people, such as atrial fibrillation. Another potential mechanism is that TC may regulate inflammatory markers such as C-reactive protein and attenuate the biological response to inflammation. Therefore, individuals with low TC levels may be more vulnerable to physiological disorders because of enhanced inflammation.
A Deep Dive into the Mechanisms of Aortic Calcification, in Search of Points of Intervention
https://www.fightagi...f-intervention/
Calcification of blood vessels and structures in the heart is a widespread issue in later life. Cells in the cardiovascular system become altered by the changing signal environment and molecular damage of aging, and adopt behaviors normally associated with the osteoblast cells responsible for building bone. These errant cells deposit calcium into the extracellular matrix structure, stiffening the normally elastic blood vessel and heart tissues and ultimately degrading their function. Prominent contributing factors are thought to include the chronic inflammation of aging and presence of senescent cells in cardiovascular tissues.
There is presently little that can be done about calcification. The progression can be slowed somewhat by good lifestyle choices, as is the case for cardiovascular disease in general, but only EDTA chelation therapy has shown any effectiveness in reducing established calcification - and this isn't a great therapy in the grand scheme of things, only offering modest gains. New approaches are needed. In today's open access paper, researchers dive into the biochemistry of calcification, in search of points of intervention that might more aggressively prevent it from occurring.
Osteopontin stabilization and collagen containment slows amorphous calcium phosphate transformation during human aortic valve leaflet calcification
There is mounting unmet need to discover new clinical therapies for the prevention and treatment of calcification in the human circulatory system. This process of cardiovascular calcification is a significant factor in the more than 18 million lives claimed globally each year by heart disease. Stenosis of vasculature associated with blood flow restriction and heart valve calcification is a common health disorder in people of all ages, genders, and ethnic backgrounds, is associated with other comorbidities, and is the most prevalent form of heart disease in patients 65 and older. Yet beyond invasive valve implants, there are no viable alternative drug therapies or clinical treatment options available.
The evolutionary success of invertebrate and vertebrate organisms through geological time has relied on their ability to harness the precipitation of thermodynamically unstable amorphous calcium phosphate (ACP) before it spontaneously transforms into crystalline hydroxyapatite (HAP). While ACP calcification is fundamental to an organism's ability to precipitate essential hard parts such as bone and teeth, the capacity of ACP to morphologically shape-shift and atomically rearrange also results in various soft tissue pathologies.
Previous research on aortic valve calcification has primarily focused on cellular and molecular pathophysiology processes, including extracellular matrix biochemistry and biomechanics, but has not specifically targeted the etiological processes recorded by the calcification deposits themselves. This is because standard microscopy techniques for pathological screening include stains that dissolve ACP and/or transform ACP to HAP in tissue sections, while x-ray diffraction cannot resolve the short-range ordering of ACP. Since 1975, several comprehensive reviews refer to four basic research studies that have identified ACP as the primary agent of aortic valve and arterial calcification by combining electron diffraction, standard microscopy, and microprobe analyses with optical microscopy on unstained histological cryosections. Now, a half century later, rigorous examination specifically targeting the role of ACP in cardiovascular calcification remains to be completed.
Here, we use transdisciplinary geology, biology, and medicine approaches prove that leaflet calcification is driven by amorphous calcium phosphate (ACP), ACP at the threshold of transformation toward hydroxyapatite (HAP), and cholesterol biomineralization. A paragenetic sequence of events is observed that includes: (1) original formation of unaltered leaflet tissues: (2) individual and coalescing 100's nm- to 1 μm-scale ACP spherules and cholesterol crystals biomineralizing collagen fibers and smooth muscle cell myofilaments; (3) osteopontin coatings that stabilize ACP and collagen containment of nodules preventing exposure to the solution chemistry and water content of pumping blood, which combine to slow transformation to HAP; (4) mm-scale nodule growth via ACP spherule coalescence, diagenetic incorporation of altered collagen and aggregation with other ACP nodules; and (5) leaflet diastole and systole flexure causing nodules to twist, fold their encasing collagen fibers and increase stiffness. These in vivo mechanisms combine to slow leaflet calcification and establish previously unexplored hypotheses for testing novel drug therapies and clinical interventions.
IL-11 Inhibition Extends Life Span in Mice by up to 25%
https://www.fightagi...ce-by-up-to-25/
Chronic, unresolved inflammatory signaling is a feature of aging. It arises from multiple contributing mechanisms, such as the accumulation of senescent cells and the innate immune reaction to mislocalized mitochondrial DNA. The worse the state of accumulated molecular damage, the worse the constant inflammatory response. Ultimately, all of this damage will need to be repaired, but if there are ways to inhibit this maladaptive inflammation without suppressing the entire immune system, then this should improve late life health and life span. Chronic inflammation is highly disruptive to tissue structure and function, and is major contributing component of all of the common fatal age-related conditions.
In today's open access paper, researchers report on the discovery that IL-11 is more important to the chronic inflammation of aging than previously thought. IL-11 is an immune signaling molecule, an inflammatory cytokine. Like most cytokines IL-11 has been shown to influence many fundamental cellular mechanisms and activities. The researchers show that inhibition of IL-11 signaling can extend life in mice by as much as 25%. Few approaches have been shown to robustly increase life span in mice by more than 20%, and now IL-11 inhibition adds to that small selection of interventions. As reported, IL-11 inhibition may work through essentially the same pathways as mTOR inhibition. The degree of life extension is similar to that achieved via mTOR inhibitors such as rapamycin.
Inhibition of IL-11 signalling extends mammalian healthspan and lifespan
The major signalling mechanisms that regulate lifespan across species include ERK, STK11 (also known as LKB1), AMPK, mTORC1, and IGF1-insulin modules. These pathways are collectively perturbed in old age to activate hallmarks of ageing, which include mitochondrial dysfunction, inflammation, and cellular senescence. In aged organisms, the AMPK-mTORC1 axis is uniquely important for metabolic health, with notable effects in adipose tissue, and therapeutic inhibition of mTOR extends lifespan in mice.
The importance of chronic sterile inflammation for ageing pathologies is increasingly recognized and inflammation itself is a central hallmark of ageing. In simplified terms, ageing is associated with a dysfunctional adaptive immune system that is characterized by immunosenescence and thymic involution along with inappropriate activation of innate immune genes such as IL-6, The pro-inflammatory signalling factors NF-κB and JAK-STAT3 are specifically implicated in ageing and JAK inhibitors can alleviate age-related dysfunction.
We proposed that IL-11, a pro-inflammatory and pro-fibrotic member of the IL-6 family, may promote age-associated pathologies and reduce lifespan. This premise was founded on studies showing that IL-11 can activate ERK-mTORC1 and/or JAK-STAT3, the observation that IL-11 is upregulated in older people, and the fact that IL-11 is increasingly recognized to have a role in senescence, a hallmark of ageing. Here, using a range of genetic and pharmacological approaches, we tested the hypothesis that IL-11 signalling has a negative effect on healthspan and lifespan in mice.
Deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity, and frailty in old age. Administration of anti-IL-11 antibodies to 75-week-old mice for 25 weeks improves metabolism and muscle function, and reduces ageing biomarkers and frailty across sexes. In lifespan studies, genetic deletion of Il11 extended the lives of mice of both sexes, by 24.9% on average. Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5% and of female mice by 25%.
Together, these results demonstrate a role for the pro-inflammatory factor IL-11 in mammalian healthspan and lifespan. We suggest that anti-IL-11 therapy, which is currently in early-stage clinical trials for fibrotic lung disease, may provide a translational opportunity to determine the effects of IL-11 inhibition on ageing pathologies in older people.
Proteomic Aging Clocks for Specific Organs
https://www.fightagi...pecific-organs/
Aging clocks can be constructed from any sufficiently large collection of biological data using machine learning techniques. Here, researchers report on the production of aging clocks for specific organs from the circulating proteome assessed in blood samples. New clocks are published constantly; it remains to be seen as to which of these many clocks will become adopted and used more broadly. The primary challenge remains to develop an understanding of how the specific age-related changes that make up a given clock relate to the underlying causes of aging. It is difficult to rely upon a clock to speed up the development of interventions to slow or reverse aging without this knowledge. Just because a clock works fairly well in normally aged individuals doesn't mean that it will accurately reflect all of the contributions to degenerative aging. The clock may be insensitive or overly sensitive to any one specific contribution that is the target of therapy, and thus results will be misleading.
Recent studies show that human organs age at different rates similar to what has been reported in animals, which suggests a need for organ-specific measures of biological age. Previously developed organ age estimates include those developed from clinical metrics of organ function (glomerular filtration rate, blood pressure, etc), clinical blood chemistry, brain MRI scans, immune cell DNA methylation profiles, and the levels of organ-specific proteins in blood plasma. Many questions regarding the reproducibility and utility of organ age estimates remain. For example, it is unclear the extent to which organ age estimates are stable across cohorts and longitudinal sampling, are sensitive to organ-specific diseases and modifiable lifestyle choices, and whether they predict mortality independent of each other and established aging biomarkers. Furthermore, it is unclear which organs are key to longevity in humans.
Organ-derived plasma protein signatures derived from aptamer protein arrays track organ-specific aging, disease, and mortality in humans, but the robustness and clinical utility of these models and their biological underpinnings remain unknown. Here, we estimate biological age of 11 organs from 44,526 individuals in the UK Biobank using an antibody-based proteomics platform to model disease and mortality risk. Organ age estimates are associated with future onset of heart failure (heart age HR=1.83), chronic obstructive pulmonary disease (lung age HR=1.39), type II diabetes (kidney age HR=1.58), and Alzheimer's disease (brain age HR=1.81) and sensitive to lifestyle factors such as smoking and exercise, hormone replacement therapy, or supplements.
Remarkably, the accrual of aged organs progressively increases mortality risk while a youthful brain and immune system are uniquely associated with disease-free longevity. These findings support the use of plasma proteins for monitoring organ health and the efficacy of drugs targeting organ aging disease.
A Novel Approach to Rapid Screening of Age-Slowing Small Molecules
https://www.fightagi...mall-molecules/
Many groups are working on ways to lower the cost and improve the outcomes of screening for small molecules that slow the pace of aging. Sadly, unbiased screening is great way to produce calorie restriction mimetics and other interventions with a low probability of producing sizable effects on aging in long-lived mammals. The calorie restriction response is so sweeping, so entwined with fundamental cellular biochemistry, that there are many, many ways to induce some fraction of its benefits by altering expression of specific genes or interactions of specific proteins. Nonetheless, screening is the way in which much of the biotech research and development community does its work. The future of the longevity industry will likely involve a great many drug candidates that modestly slow aging, less effective than the actual practice of calorie restriction, at least until more researchers and companies find success in developing repair therapies that actually reverse aspects of aging.
Restraining or slowing ageing hallmarks at the cellular level have been proposed as a route to increased organismal lifespan and healthspan. Consequently, there is great interest in anti-ageing drug discovery. However, this currently requires laborious and lengthy longevity analysis. Here, we present a novel screening readout for the expedited discovery of compounds that restrain ageing of cell populations in vitro and enable extension of in vivo lifespan.
We monitored DNA methylation changes accompanying long-term passaging of adult primary human cells in culture. This enabled us to develop, test, and validate the CellPopAge Clock, an epigenetic clock with underlying algorithm, unique among existing epigenetic clocks for its design to detect anti-ageing compounds in vitro. Additionally, we measured markers of senescence and performed longevity experiments in vivo in Drosophila, to further validate our approach to discover novel anti-ageing compounds.
We find that the CellPopAge Clock can detect decelerated passage-based ageing of human primary cells treated with rapamycin or trametinib, well-established longevity drugs. We then utilise the CellPopAge Clock as a screening tool for the identification of compounds which decelerate ageing of cell populations, uncovering novel anti-ageing drugs, torin2 and dactolisib (BEZ-235). We demonstrate that delayed epigenetic ageing in human primary cells treated with anti-ageing compounds is accompanied by a reduction in senescence and ageing biomarkers. Finally, we extend our screening platform in vivo by taking advantage of a specially formulated holidic medium for increased drug bioavailability in Drosophila. We show that the novel anti-ageing drugs, torin2 and dactolisib (BEZ-235), increase longevity in vivo.
A Mechanism for Developmental Programming to Contribute to Degenerative Aging
https://www.fightagi...nerative-aging/
The consensus view of the evolution of aging is that it is a consequence of selection pressure for reproductive fitness operating more strongly in early life. This allows for the selection of cellular biochemistry that works well in youth but malfunctions in later life. The more specific and less widely held hyperfunction or quasi-programmed view of aging envisages degenerative aging as a consequence of the continued activity of developmental programs. It is interesting to here see researchers proposing a specific hyperfunction-like mechanism for dysfunction in aging, linking reactivation of developmental gene expression regulation to aging.
A mechanistic connection between aging and development is largely unexplored. Through profiling age-related chromatin and transcriptional changes across 22 murine cell types, analyzed alongside previous mouse and human organismal maturation datasets, we uncovered a transcription factor binding site (TFBS) signature common to both processes. Early-life candidate cis-regulatory elements (cCREs), progressively losing accessibility during maturation and aging, are enriched for cell-type identity TFBSs. Conversely, cCREs gaining accessibility throughout life have a lower abundance of cell identity TFBSs but elevated activator protein 1 (AP-1) levels.
We implicate transcription factor (TF) redistribution toward these AP-1 TFBS-rich cCREs, in synergy with mild downregulation of cell identity TFs, as driving early-life cCRE accessibility loss and altering developmental and metabolic gene expression. Such remodeling can be triggered by elevating AP-1 or depleting repressive H3K27me3. We propose that AP-1-linked chromatin opening drives organismal maturation by disrupting cell identity TFBS-rich cCREs, thereby reprogramming transcriptome and cell function, a mechanism hijacked in aging through ongoing chromatin opening.
Towards Small Molecule Drugs that can Induce Trained Immunity
https://www.fightagi...ained-immunity/
Trained immunity is a phenomenon whereby some forms of vaccination can produce a broad improvement in defenses against pathogens, perhaps via a lasting suppression of the chronic inflammation generated by the innate immune system in old age. The innate immune system reacts in a maladaptive way to some of the forms of damage characteristic of aging, such as mislocalization of fragments of mitochondrial DNA. The mechanisms by which trained immunity produces a reduction in this maladaptive reaction are not well understood, but nonetheless, researchers here report on progress towards identifying small molecule inducers of trained immunity. Given a good side-effect profile and low cost, such small molecule drugs could be broadly beneficial.
Trained immunity is characterized by epigenetic and metabolic reprogramming in response to specific stimuli. This rewiring can result in increased cytokine and effector responses to pathogenic challenges, providing nonspecific protection against disease. It may also improve immune responses to established immunotherapeutics and vaccines. Despite its promise for next-generation therapeutic design, most current understanding and experimentation is conducted with complex and heterogeneous biologically derived molecules, such as β-glucan or the Bacillus Calmette-Guérin (BCG) vaccine. This limited collection of training compounds also limits the study of the genes most involved in training responses as each molecule has both training and nontraining effects.
Small molecules with tunable pharmacokinetics and delivery modalities would both assist in the study of trained immunity and its future applications. To identify small molecule inducers of trained immunity, we screened a library of 2,000 drugs and drug-like compounds. Identification of well-defined compounds can improve our understanding of innate immune memory and broaden the scope of its clinical applications. We identified over two dozen small molecules in several chemical classes that induce a training phenotype in the absence of initial immune activation - a current limitation of reported inducers of training. A surprising result was the identification of glucocorticoids, traditionally considered immunosuppressive, providing an unprecedented link between glucocorticoids and trained innate immunity. We chose seven of these top candidates to characterize and establish training activity in vivo. In this work, we expand the number of compounds known to induce trained immunity, creating alternative avenues for studying and applying innate immune training.
Arguing for Senolytics to Prevent or Slow Development of Macular Degeneration
https://www.fightagi...r-degeneration/
In this short commentary on omics analysis of the aging retina, researchers make the point that the evidence suggests the use of senolytic therapies to prevent or slow the development of age-related macular degeneration. This condition is associated with an increased burden of senescent cells in the retina and nearby tissues. When present over the long term, the mix of signals secreted by senescent cells induce inflammation, maladaptive tissue remodeling, and other problematic changes in the behavior of other cells.
Senescent retinal pigment epithelium (RPE) was linked to the onset of age-related macular degeneration (AMD), with senolytic agents assessed as potential treatments for AMD. A fact that has been seldom considered among the plethora of processes that are affected and, in turn, effected by cellular senescence (an adaptive cell response to stressors effected by an inflammatory secretome) is that of intercellular communication. In the case of the RPE, its functional and anatomical ties to the choroid are as much, if not more so, functionally relevant as those with the neuroretina.
A study applying a combined approach using bulk RNAseq, scRNAseq, and microarray RPE transcriptomics was able to draw substantial inferential data pertaining to intercellular communication between the RPE and the choroid. Intercellular communications between RPE cells and stromal elements involved in aging and senescence pertained notably to VEGF, BMP- and tenascin-mediated pathways, i.e., these pathways scored higher when mediating interactions between senescent cell populations. Consistently, AMD-derived patient samples scored higher overall in terms of senescence, and bulk RNAseq data showed a positive correlation in score increase with age.
These findings potentially support employing anti-aging therapies such as senolytic pharmacologic compounds to prevent or ameliorate progression to AMD, as well as underscore the necessity of more rigorous investigation into the interplay of senescence and cell-to-cell communication.
Nrf2 as a Point of Intervention for Cellular Stress Responses
https://www.fightagi...ress-responses/
Upregulation of various forms of cellular stress response has been shown to modestly slow aging in a variety of short-lived laboratory species. Allowing cells to better maintain a healthy state in response to stresses such as heat or low nutrient availability reduces the pace at which age-related damage accumulates to cause dysfunction. This improvement in stress responses is a portion of the calorie restriction response, and thus unlikely to produce effects on life span that are as large in longer-lived species. Nonetheless, it is the subject of a great deal of research. Scientists here discuss the role of Nrf2 in the mechanisms by which some supplements and dietary compounds can provoke greater levels of cellular stress responses. Nrf2, and mechanisms regulating the amount of Nrf2 present in cells, are possible targets for approaches designed to enhance cellular stress responses to a greater degree than is possible via supplement-like strategies.
The cellular stress response is regulated at the transcriptional, translational, and post-translational levels by a family of heat shock transcription factors (HSFs) that are expressed and maintained in an inactive state under non-stress conditions. HSFs, essential for all organisms to survive to acute or chronic stress, are also important for normal development and lifespan-enhancing pathways, and the repertoire of HSF targets has thus expanded well beyond the heat shock genes.
Post-translational regulation of HSFs is emerging to integrate the metabolic state of the cell with stress biology, whereby controlling fundamental aspects of the health of the proteome and aging. In addition to this, the KEAP1/Nrf2/ARE pathway is the basis of the cellular defense. Induction of this pathway has been shown to be protective against various stress conditions. On the other side, under conditions of Nrf2 deficiency with failure to upregulate this pathway, increased sensitization and accelerated disease pathogenesis have been demonstrated.
Transcription factor Nrf2, under basal conditions, is continuously targeted for ubiquitination and proteasomal degradation by KEAP1, a protein acting as a repressor. It is well defined now that many inducers of the Nrf2 pathway chemically modify specific cysteine residues within KEAP1, leading to the loss of its ability to target Nrf2 for degradation. Subsequently, Nrf2 levels accumulate and hence activate transcription of NRF2-dependent genes which encode a large network of cytoprotective proteins, including those that are involved in the metabolism and transport of a wide array of endobiotics and xenobiotics, proteins that have antioxidant functions, as well as those that participate in the synthesis, utilization, and regeneration of glutathione and NAD(P).
Several phytochemicals act through the activation of transcription factor Nrf2. Under basal conditions, these protective systems do not operate at maximum capacity but can be induced to higher activity levels by redox-active compounds, such as hormetic nutrients, thus reducing the risks of developing malignancies and multiple chronic diseases.
A Possible Basis for Treating Lupus
https://www.fightagi...treating-lupus/
Autoimmune disorders are a major challenge for modern medicine; in most cases, there is little that can be done but suppress the immune system, a strategy that has serious side-effects. The fundamental causes of these conditions are poorly understood, and researchers lack good points of intervention to reprogram an aberrant immune system. The immune system is clearly very complex, and capable of malfunctions in countless different, equally complex ways. Given that, it is always good to see the research community making inroads towards the effective treatment of an autoimmune condition, and here systemic lupus erythematosus is the target. Interestingly, lupus presents quite differently depending on age of onset; late-onset lupus that emerges in old age exhibits both less severe symptoms and greater mortality than the condition in younger individuals.
The autoimmune disease systemic lupus erythematosus - known as lupus - affects more than 1.5 million people in the US. It can result in life-threatening damage to multiple organs including the kidneys, brain, and heart. The causes of this disease have long been unclear. Existing treatments often fail to control the disease and have unintended side effects of reducing the immune system's ability to fight infections. But now researchers have discovered a molecular defect that promotes the pathologic immune response in lupus and show that reversing this defect may potentially reverse the disease.
The scientists report a new pathway that drives disease in lupus. There are disease-associated changes in multiple molecules in the blood of patients with lupus. Ultimately, these changes lead to insufficient activation of a pathway controlled by the aryl hydrocarbon receptor (AHR), which regulates cells' response to environmental pollutants, bacteria, or metabolites, a substance created when the body breaks down food, drugs, chemicals or its own tissue. Insufficient activation of AHR results in too many immune cells that promote the production of disease-causing autoantibodies.
To show this discovery can be leveraged for treatments, the investigators returned the AHR-activating molecules to blood samples from lupus patients. This seemed to reprogram these lupus-causing cells into a type of cell that may promote wound healing from the damage caused by this autoimmune disease. "We found that if we either activate the AHR pathway with small molecule activators or limit the pathologically excessive interferon in the blood, we can reduce the number of these disease-causing cells. If these effects are durable, this may be a potential cure."
GPRC5A Inhibition as a Strategy to Enhance Bone Formation in Osteoporosis
https://www.fightagi...n-osteoporosis/
Osteoporosis, the progressive age-related loss of bone mineral density, occurs due to an imbalance between the activities of osteoblast cells that build bone and osteoclast cells that break down bone. Both cell populations are constantly active, and thus balance must be maintained. Regulation of this balance is complicated, unfortunately, and the downstream effects of existing bone-promoting therapies are not fully understood. Researchers here investigate the mechanisms of a parathyroid hormone based treatment for osteoporosis, and find that GPRC5A expression suppresses the activity of osteoblasts. Thus inhibition of GPRC5A is a potential therapeutic target for future therapies aimed at enhancing bone deposition.
Induction of parathyroid hormone (PTH) signaling using the PTH-derived peptide - teriparatide, has demonstrated strong bone-promoting effects in patients with osteoporosis. These effects are mediated by osteogenesis, the process of bone formation involving the differentiation and maturation of bone-forming cells called osteoblasts. However, PTH induction is also associated with the differentiation of macrophages into osteoclasts, which are specialized cells responsible for bone resorption. Although, bone remodeling by osteoblasts and osteoclasts is crucial for maintaining skeletal health, PTH-induced osteoclast differentiation can decrease treatment efficacy in patients with osteoporosis. However, precise molecular mechanisms underlying the dual action of PTH signaling in bone remodeling are not well understood.
Researchers conducted a series of experiments to identify druggable target genes downstream of PTH signaling in osteoblasts. The researchers treated cultured mouse osteoblast cells and mice with teriparatide. They then assessed gene expression changes induced by PTH in both the cultured cells and bone cells isolated from the femurs of the treated animals, using advanced RNA-sequencing analysis. Among several upregulated genes, they identified a novel PTH-induced gene - 'Gprc5a', encoding an orphan G protein-coupled receptor, which has been previously explored as a therapeutic target. However, its precise role in osteoblast differentiation had not been fully understood.
The researchers examined the effect of Gprc5a downregulation on osteoblast proliferation and differentiation. Notably, while PTH induction alone did not affect cell proliferation, Gprc5a knockdown resulted in an increase in the expression of cell-cycle-related genes and osteoblast differentiation markers. These findings suggest that Gprc5a suppresses osteoblast proliferation and differentiation. Diving deeper into the molecular mechanisms underlying the effects of Gprc5a, in PTH-induced osteogenesis, the researchers identified Activin receptor-like kinase 3 (ALK3), a bone morphogenetic protein (BMP) signaling pathway receptor, as an interacting partner of Gprc5a. Overexpression of Gprc5a led to suppression of BMP signaling.
Overall, these findings reveal that Gprc5a, a novel inducible target gene of PTH, negatively regulates osteoblast proliferation and differentiation by partially suppressing BMP signaling. Gprc5a can thus, be pursued as a novel therapeutic target while devising treatments against osteoporosis.
Low Dose Antifibrotic Drugs Slow Ovarian Aging in Mice
https://www.fightagi...-aging-in-mice/
As in a number of other organs, fibrosis is a feature of the aging and loss of function of the ovaries. Fibrosis is the inappropriate deposition of excess collagen to the extracellular matrix, creating scar-like structures that are disruptive to normal tissue function. Here, researchers show that delivery of low dose antifibrotic drugs in mice can slow this aspect of ovarian aging and lead to improved function and extended reproductive longevity.
The female reproductive system is one of the first to age in humans, resulting in infertility and endocrine disruptions. The aging ovary assumes a fibro-inflammatory milieu which negatively impacts gamete quantity and quality as well as ovulation. Here we tested whether the systemic delivery of anti-inflammatory (Etanercept) or anti-fibrotic (Pirfenidone) drugs attenuates ovarian aging in mice. We first evaluated the ability of these drugs to decrease the expression of fibro-inflammatory genes in primary ovarian stromal cells. Whereas Etanercept did not block Tnf expression in ovarian stromal cells, Pirfenidone significantly reduced Col1a1 expression.
We then tested Pirfenidone in vivo where the drug was delivered systemically via mini-osmotic pumps for 6-weeks. Pirfenidone mitigated the age-dependent increase in ovarian fibrosis without impacting overall health parameters. Ovarian function was improved in Pirfenidone-treated mice as evidenced by increased follicle and corpora lutea number, AMH levels, and improved estrous cyclicity. Transcriptomic analysis revealed that Pirfenidone treatment resulted in an upregulation of reproductive function-related genes at 8.5 months and a downregulation of inflammatory genes at 12 months of age. These findings demonstrate that reducing the fibroinflammatory ovarian microenvironment improves ovarian function, thereby supporting modulating the ovarian environment as a therapeutic avenue to extend reproductive longevity.
Effects of Long-Term Nicotinamide Mononucleotide Supplementation on Mouse Life Span
https://www.fightagi...ouse-life-span/
There is a continued interest in the use of vitamin B3 derivatives as a strategy to increase levels of nicotinamide adenine dinucleotide (NAD) in mitochondria and thus improve function. These compounds include niacin, nicotinamide riboside, and nicotinamide mononucleotide, among others. NAD levels decline with age and this is thought to contribute to loss of mitochondrial function in aged tissues. That said, the human clinical data for these approaches as treatments for a variety of conditions isn't so great, taken as a whole. Further, these pharmacological approaches are not as effective as exercise when it comes to ability to increase NAD levels. Here, researchers add to the mouse evidence for restoration of a more youthful amount of NAD in cells to contribute to health.
Nicotinamide adenine dinucleotide (NAD) is essential for many enzymatic reactions, including those involved in energy metabolism, DNA repair, and the activity of sirtuins, a family of defensive deacylases. During aging, levels of NAD+ can decrease by up to 50% in some tissues, the repletion of which provides a range of health benefits in both mice and humans. Whether or not the NAD+ precursor nicotinamide mononucleotide (NMN) extends lifespan in mammals is not known. Here we investigate the effect of long-term administration of NMN on the health, cancer burden, frailty and lifespan of male and female mice.
Without increasing tumor counts or severity in any tissue, NMN treatment of males and females increased activity, maintained more youthful gene expression patterns, and reduced overall frailty. Reduced frailty with NMN treatment was associated with increases in levels of Anerotruncus colihominis, a gut bacterium associated with lower inflammation in mice and increased longevity in humans. NMN slowed the accumulation of adipose tissue later in life and improved metabolic health in male but not female mice, while in females but not males, NMN increased median lifespan by 8.5%, possible due to sex-specific effects of NMN on NAD+ metabolism.
Together, this data shows that chronic NMN treatment delays frailty, alters the microbiome, improves male metabolic health, and increases female mouse lifespan, without increasing cancer burden. These results highlight the potential of NAD+ boosters for treating age-related conditions and the importance of using both sexes for interventional lifespan studies.
View the full article at FightAging
