Fight Aging! Newsletter, May 13th 2024
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- The Therapeutic Potential of Transdifferentiation
- Innate Immune cGAS/STING Signaling is Both Necessary and Pathological
- To Treat Alzheimer's Disease, Target the Treatment of Aging
- Antiretroviral Drug Use Associated with Lower Risk of Alzheimer's Disease
- Promising Initial Results From a Phase II Trial of VEGF Gene Therapy
- Reviewing Present Biomarkers of Aging
- Towards Superior Engineered T Cells
- In Neurodegenerative Disease, More Neurons Return to the Cell Cycle
- In Search of Natural Senolytics to Substitute for Dasatinib
- Cancer-Like Proliferation of Smooth Muscle Cells in Atherosclerosis
- Microglia Become Progressively More Dysfunctional with Age
- Towards a Small Molecule Therapy to Promote Remyelination
- Upregulation of Cyclophilin A as a Potential Path to Improve Aged Hematopoietic Stem Cell Function
- A Mismatch Between Central versus Peripheral Circadian Regulation in Aging
- State of Physical Fitness is a Reliable Predictor of Age-Related Mortality
The Therapeutic Potential of Transdifferentiation
https://www.fightaging.org/archives/2024/05/the-therapeutic-potential-of-transdifferentiation/
Transdifferentiation is the use of various techniques to convert a somatic cell of one type directly into a somatic cell of another type. This is an alternative to first using Yamanaka factors to dedifferentiate somatic cells into induced pluripotent stem cells, then guiding differentiation into the desired final somatic cell type. For both differentiation from pluripotency to somatic cell and transdifferentiation between somatic cells, a suitable recipe of factors and altered gene expression must be discovered for any given destination. A few of these protocols are now well known, but the vast majority have yet to be robustly established, or even attempted at all.
In today's open access paper, researchers refer to transdifferentiation as direct reprogramming, not to be confused with the various forms of reprogramming via Yamanaka factors, either to produce induced pluripotent stem cells, or to restore youthful epigenetic patterns via what is known as partial reprogramming or epigenetic reprogramming. Transdifferentiation offers the potential to treat aspects of aging and age-related disease that involve the loss of small, specific cell populations, such as dopaminergenic neurons or sensory hair cells. These critical populations are surrounded by other, more numerous, less critical cells, which might be targets for transdifferentiation given a sufficiently selective therapy. Proof of concept in these and a few other cases has been achieved in animal studies, and it remains to be seen as to how rapidly this can advance to the clinic.
Next-generation direct reprogramming
While the concept that mature cell states are stable holds the key for homeostasis of an organism, the long-held believe was that this state cannot ever be reversed. This fallacy has gradually broken down. Now, the Yamanaka factors are now widely used not only for reprogramming but also for partial reprogramming that leads to rejuvenation of tissues. Yet another kind of reprogramming was emerging from the basic science field, now dubbed direct reprogramming, or transdifferentiation (we use the terms interchangeably from here on). During transdifferentiation a differentiated cell changes its fate to another, more desired differentiated cell type, without entering a pluripotent stage. The first identified transcription factor capable of directly reprogramming fibroblasts to skeletal muscles was MyoD. Many other lineage-specific transcription factors capable of transdifferentiating a target cell have since been identified.
Whether induced or endogenous process, in general, pioneer factors (PF) act as the first responders in direct reprogramming by binding and opening closed chromatin. It is not clear if each transdifferentiation lineage is regulated by a specific pioneer factor, or if a universal PF for transdifferentiation (capable of initiating multitude of direct lineage reversions) is still to be identified. Transdifferentiation studies have unveiled the opportunities and offer applications in regenerative therapies, such as cell replacement therapy or immunotherapy. The key question, and the topic of this review is to identify new, feasible methods to induce specific, high efficiency and targeted transdifferentiation.
These next-generation transdifferentiation approaches will come with better efficiency and plausibly with potential to treat diseases like Alzheimer's disease, muscle injury, diabetes, or myocardial infarction, resulting in elimination of the unsurmountable treatment issues at the moment (for example, finding a right donor or graft rejections). These novel approaches will enhance the efficacy and safety of direct reprogramming, allowing the ultimate decoding of the process towards plausibly resulting in 21st century personalized regenerative medicine.
Innate Immune cGAS/STING Signaling is Both Necessary and Pathological
https://www.fightaging.org/archives/2024/05/innate-immune-cgas-sting-signaling-is-both-necessary-and-pathological/
Chronic, unresolved inflammation is a feature of aging. When the immune system is constantly active in this way, the consequent altered cell behavior throughout the body becomes disruptive to tissue and organ function, harmful to the individual. Chronic inflammation accelerates the onset and progression of all of the common fatal age-related conditions. This unwanted inflammatory signaling arises from many different roots, including the growing presence of senescent cells, but also the interaction of innate immune sensors with other forms of age-related dysfunction. For example, damage-associated molecular patterns such as mislocalized fragments of mitochondrial DNA leaking from dysfunctional mitochondria into the cell cytosol can trigger cGAS/STING signaling. This mechanism evolved to detect the presence of bacterial DNA, and unfortunately runs awry with age.
The challenge inherent in dampening age-related chronic inflammation is that, so far, it appears to use exactly the same pathways that are involved in the normal, necessary, short-term inflammatory response to injury, pathogens, potentially cancerous cells, and so forth. All of the approaches developed to date to suppress the overactivity of an immune system also suppress necessary functions, and that produces unpleasant long-term consequences. This is well established via the use of immunosuppressant drugs in patients with autoimmune disease. There was some hope that targeting aspects of cGAS/STING function would prove to be a better option, but as researchers note in today's open access paper, an operating cGAS/STING pathway appears to be necessary for long-term health.
STING promotes homeostatic maintenance of tissues and confers longevity with aging
Local immune processes within aging tissues are a significant driver of aging associated dysfunction, but tissue-autonomous pathways and cell types that modulate these responses remain poorly characterized. The cytosolic DNA sensing pathway, acting through cyclic GMP-AMP synthase (cGAS) and Stimulator of Interferon Genes (STING), is broadly expressed in tissues, and is poised to regulate local type I interferon (IFN-I)-dependent and independent inflammatory processes within tissues. Recent studies suggest that the cGAS/STING pathway may drive pathology in various in vitro and in vivo models of accelerated aging.
To date, however, the role of the cGAS/STING pathway in physiological aging processes, in the absence of genetic drivers, has remained unexplored. This remains a relevant gap, as STING is ubiquitously expressed, implicated in multitudinous disorders, and loss of function polymorphisms of STING are highly prevalent in the human population (an incidence of more than 50%). Here we reveal that, during physiological aging, STING-deficiency leads to a significant shortening of murine lifespan, increased pro-inflammatory serum cytokines and tissue infiltrates, as well as salient changes in histological composition and organization.
We note that aging hearts, livers, and kidneys express distinct subsets of inflammatory, interferon-stimulated gene (ISG), and senescence genes, collectively comprising an immune fingerprint for each tissue. These distinctive patterns are largely imprinted by tissue-specific stromal and myeloid cells. Using cellular interaction network analyses, immunofluorescence, and histopathology data, we show that these immune fingerprints shape the tissue architecture and the landscape of cell-cell interactions in aging tissues. These age-associated immune fingerprints are grossly dysregulated with STING-deficiency, with key genes that define aging STING-sufficient tissues greatly diminished in the absence of STING. This altered homeostasis in aging STING-deficient tissues is associated with a cross-tissue loss of homeostatic tissue-resident macrophage (TRM) populations in these tissues. Ex vivo analyses reveal that basal STING- signaling limits the susceptibility of TRMs to death-inducing stimuli and determines their in situ localization in tissue niches, thereby promoting tissue homeostasis.
Collectively, these data upend the paradigm that cGAS/STING signaling is primarily pathological in aging and instead indicate that basal STING signaling sustains tissue function and supports organismal longevity. Critically, our study urges caution in the indiscriminate targeting of these pathways, which may result in unpredictable and pathological consequences for health during aging.
To Treat Alzheimer's Disease, Target the Treatment of Aging
https://www.fightaging.org/archives/2024/05/to-treat-alzheimers-disease-target-the-treatment-of-aging/
One of the important points made by advocates for the treatment of aging is that one cannot distinguish between aging and age-related disease. They are one and the same. There is no magical state of "healthy aging" in which one doesn't suffer eventual disease. A decline of function in aging that does not rise to the level required to call it a disease is the subclinical stage of that disease; all the same damage has taken place under the hood, just less of it. Conversely, an age-related disease is just another facet of aging, a collection of damage and consequences of damage that becomes sizable enough to reach the definition of disease. Whether or not any specific age-related dysfunction is called a disease is just a matter of whether the degree of dysfunction is on one side or another of an arbitrary line drawn in the sand.
The authors of today's open access paper take this point and then build on it to suggest that the most robust age-slowing approaches demonstrated in animal models should be tested more rigorously in patients with common, hard-to-treat conditions such as Alzheimer's disease. The approaches with the best data include calorie restriction and all of the calorie restriction mimetic interventions that seek to replicate some part of the sweeping cellular reaction to a reduced intake of calories. Interestingly, this hasn't been well tested in Alzheimer's patients. Perhaps it should be, even given that the research community expects effects on aging to be lower in long-lived species than in short-lived species. While calorie restriction extends mouse life span by as much as 40%, it certainly doesn't do that well in humans. The actual number has yet to be established, but it would be surprising to see that the effect of long-term calorie restriction or equivalent intermittent fasting in humans is larger than a few years of additional life span.
Aging as a target for the prevention and treatment of Alzheimer's disease
Alzheimer's disease (AD), the most common etiology of dementia in older adults, is projected to double in prevalence over the next few decades. Current treatments for AD manage symptoms or slow progressive decline, but are accompanied by significant inconvenience, risk, and cost. Thus, a better understanding of the risk factors and pathophysiology of AD is needed to develop novel prevention and treatment strategies.
While a mayfly has a lifespan of one day, an elephant's lifespan may exceed 100 years. Clearly, lifespan and aging are biological traits regulated by genetics and molecular signaling pathways - that may be exploited as a therapeutic target. Aging, however, is not recognized as a disease by the U.S. Food and Drug Administration. Thus, there are no FDA-approved treatments specifically for aging. Aging, however, is the most important risk factor for multiple diseases, including dementia and AD. As molecular mechanisms regulating aging are coming to light and signaling pathways uncovered, novel therapeutic targets present an alternative approach: instead of targeting one disease at a time - leading to the inconvenience, cost, and risk of polypharmacy - targeting aging directly may prevent or slow multiple age-related diseases. CR may be a promising preventive or therapeutic option for individuals at risk for AD or already within the AD spectrum. However, current data are limited and human studies are scarce. Additional preclinical and human studies are now warranted to discover the pathways regulated by CR and to identify pharmacophores that mimic the beneficial effects of CR.
Hypotheses linking CR and weight loss to alterations in biomarkers of aging and AD may suggest novel treatment targets and strategies-and not just for AD. Newly discovered therapies may be safe and effective for prevention and/or as an adjunct to FDA-approved treatments for individuals in the AD spectrum. Prevention and treatment strategies targeting aging may be safer and more effective than the currently available treatments targeting more downstream pathways. While several studies are in progress (listed above), more are needed. In the meantime, AD trials should consider including biomarkers of aging and aging studies should include AD biomarkers.
Antiretroviral Drug Use Associated with Lower Risk of Alzheimer's Disease
https://www.fightaging.org/archives/2024/05/antiretroviral-drug-use-associated-with-lower-risk-of-alzheimers-disease/
Transposable elements in the genome are the remnants of ancient viral infections, capable of hijacking cellular machinery to copy themselves haphazardly across the genome, causing damage to existing genes. They can further provoke inflammation and cell dysfunction via the presence of the viral machinery that these transposable element sequences code for; innate immune mechanisms in cells have evolved to detect such apparently foreign molecules. Transposable elements are effectively suppressed in youth, but with age this suppression breaks down. It has been suggested that activation of transposable elements is an important contributing factor in age-related conditions, particularly in neurodegenerative conditions such as Alzheimer's disease.
As today's open access paper notes, one way to obtain evidence for this proposition is to look at the long term outcome of antiretroviral drug use. These drugs are used to treat patients and animals infected with retroviruses, most prominently HIV, but also a number of others. In additional to suppressing infectious retroviruses, antiretroviral drugs also suppress the activity of transposable elements. After thirty years of a strong focus on treating AIDS, there is now a sizable patient population in later life, at the point at which transposable elements would be expected to become active.
Nucleoside Reverse Transcriptase Inhibitor Exposure Is Associated with Lower Alzheimer's Disease Risk: A Retrospective Cohort Proof-of-Concept Study
Alzheimer's disease (AD) is the most common form of dementia, affecting an estimated 6.5 million Americans including more than 10% of Americans over 65 years of age. There are no therapies that demonstrably stop the disease despite hundreds of clinical trials. The recent identification of reverse transcriptase (RT)-mediated somatic gene recombination (SGR) in the human brain, which becomes dysregulated in sporadic AD, implicates FDA-approved reverse transcriptase inhibitors (RTIs) as potential therapeutics for AD.
Multiple FDA-approved RTIs, the first of which was approved in 1987, are currently used to treat human immunodeficiency virus (HIV) and hepatitis B. RTIs can be orthosteric (bind to the active site) nucleoside RTIs (NRTIs) or allosteric non-NRTIs (NNRTIs), and together with integrase inhibitors and protease inhibitors (PIs), represent the components of combined antiretroviral therapy (cART). Because of effective cART, tens of thousands of people with HIV have lived to older ages but are now at risk for AD, providing an opportunity to retrospectively examine the incidence of AD by assessing medical claims databases.
This retrospective, proof-of-concept study evaluated the incidence of AD in people with HIV with or without exposure to NRTIs using de-identified medical claims data. Eligible participants were aged ≥60 years, without pre-existing AD diagnoses, and pursued medical services in the United States from October 2015 to September 2016. Cohorts 1 (N = 46,218) and 2 (N = 32,923) had HIV. Cohort 1 had prescription claims for at least one NRTI within the exposure period; Cohort 2 did not. Cohort 3 (N = 150,819) had medical claims for the common cold without evidence of HIV or antiretroviral therapy.
We identified a statistically significant positive association between NRTI exposure and decreased risk for sporadic AD in patients with HIV and ≥60 years of age. Age-adjusted and sex-adjusted hazard ratio (HR) showed a significantly decreased risk for AD in Cohort 1 compared with Cohorts 2 (HR 0.88) and 3 (HR 0.84). Post-marketing surveillance of NRTIs has shown acceptable safety data sufficient to allow NRTIs to be prescribed, as a class, continuously since 1987, and tens of thousands of patients ≥60 years of age are currently taking these medications, providing support that these agents will be well tolerated in aged patients. The data presented here support controlled clinical trials using NRTIs on patients with mild cognitive impairment (MCI), pre-symptomatic familial AD, Down syndrome, and sporadic AD, along with asymptomatic APOE4 carriers.
Promising Initial Results From a Phase II Trial of VEGF Gene Therapy
https://www.fightaging.org/archives/2024/05/promising-initial-results-from-a-phase-ii-trial-of-vegf-gene-therapy/
Intravenous, high-dose AAV gene therapy to upregulate VEGF has been shown to extend life in mice. This is perhaps a demonstration of the importance of loss of capillary density in tissue as a result of age-related disruption to angiogenesis, the multi-step process by which new blood vessels branch from existing vessels. Upregulation of VEGF is one of the possible approaches to restoring maintenance of capillary networks via improved angiogenesis, as VEGF is one of the important signal molecules involved in this process.
A similar AAV gene therapy is being assessed in clinical trials for the treatment of coronary artery disease, the progressive blockage of blood flow to heart tissue by atherosclerotic plaque. Preliminary results were recently announced for the EXACT phase II trial. The idea here is to incrementally improve blood flow by encouraging the body to produce alternative paths. The therapy is locally delivered to heart tissue, and thus uses a much lower dose than would be needed for intravenous injection for delivery to much of the body. Nonetheless, the principle is much the same. One could argue that all older individuals would likely benefit from some form of VEGF upregulation delivered to much of the body.
Gene therapy treatment increasing body's signal for new blood vessel growth shows promise
Final 12-month data from the EXACT trial demonstrates safety and efficacy results for a vascular endothelial growth factor (VEGF) gene therapy treatment for patients who have advanced coronary artery disease (CAD). CAD, also known as coronary heart disease or ischemic heart disease, affects about 20.5 million U.S. adults - making it the most common type of heart disease in the United States. Often, the first sign of CAD is a heart attack, triggered by a rupture of plaque accumulated in the arteries supplying blood to the heart. Over time, plaque narrows these arteries, blood flow diminishes, leading to angina - a condition characterized by chest pain due to insufficient oxygen-rich blood supply to the heart muscle. In patients with the most severe form, angina can be disabling, and additional medications, procedures or surgery may not be effective. There is a need for therapies for such a serious condition.
The EXACT trial assesses the safety and preliminary efficacy of the gene therapy XC001 in patients with "no option" refractory angina (NORA). The gene vector is designed to more effectively and safely increase the body's own signal for new blood vessel growth. Effectiveness was measured primarily by exercise capacity, degree of impairment of blood flow to the heart, and angina frequency and severity. Among the 32 patients with NORA, the gene therapy XC001 appeared safe with no serious adverse effects due to the drug. Surgical delivery was generally well-tolerated. Early benefits of XC001 are promising in relation to improvements in exercise duration, decreased symptoms, and improved blood flow in patients' hearts.
Total exercise duration increased from a mean of 359.9 seconds at baseline to 448.2 at three months, 449.2 at six months, and 477.6 at 12 months. Total myocardial perfusion deficit on positron emission tomography imaging decreased by 10.2% at three months, 14.3% at six months, and 10.2% at 12 months - demonstrating a reduction in impaired blood flood. The time to onset of ST depression during exercise tolerance testing increased by 105.2 at three months, 113.6 at six months, and 103.1 seconds at 12 months. Angina frequency decreased by -7.7 at three months, -6.6 at six months, and -8.8 episodes at 12 months. Angina class improved in 81% of participants at six months.
Reviewing Present Biomarkers of Aging
https://www.fightaging.org/archives/2024/05/reviewing-present-biomarkers-of-aging-2/
Here find an open access review of the present landscape of biomarkers of aging, both single measures and composite measures of various sorts, such as the aging clocks developed over the past fifteen years. The development of a good, consensus measure of biological age would accelerate efforts to treat aging as a medical condition, as assessing the ability of various classes of treatment to slow or reverse aging is at present a slow and expensive process - the only proven approach is a life span study. Unfortunately, all present approaches to the assessment of biological age have their challenges. The accumulation of large amounts of data for analysis proceeds in parallel with the development of better aging clocks that seek to address the known issues.
One major barrier to longevity research is evaluating the impact of interventions that improve human health and longevity because they are complex processes that occur over long time scales. Instead, measurable phenotypic traits or proxies of longevity, termed longevity biomarkers, may be used to assess the effectiveness of longevity interventions, or prognosticate clinical outcomes. Longevity biomarkers are critical tools for predicting lifespan and susceptibility to age-related diseases, but there exist a dizzying array of options, with at times contradictory readouts, and other key weaknesses.
Strengths of longevity biomarkers include providing insight into an individual's biological age, as opposed to chronological age, which is pivotal in evaluating targeted interventions that address aging and age-related conditions. However, most longevity biomarkers also exhibit notable weaknesses, such as a lack of specificity and lack of standardization across different studies and applications. These weaknesses underscore the need for more research to enhance their accuracy and reliability in long-term longitudinal studies.
In the present review, we discuss key strengths and weaknesses of popular clinical biomarkers used to predict morbidity and mortality associated with advanced age, identify existing bottlenecks, and integrate the field consensus on further directions for robust lifespan and healthspan estimation.
Towards Superior Engineered T Cells
https://www.fightaging.org/archives/2024/05/towards-superior-engineered-t-cells/
Both cancer and aging impair the activity of T cells of the adaptive immune system, forcing these cells into exhaustion and senescence. The state of exhaustion is incompletely understood, but appears as an issue in immunotherapies making use of engineered T cells, as well as in the natural population of the aged body. Since researchers are already altering the T cells used in cancer therapies, why not alter them further to make them more able to resist the effects of aging cancer on T cell populations in the body? This is an interesting and plausible goal, but one that requires a greater understanding of T cell exhaustion than presently exists.
Cellular immunotherapy is revolutionizing oncology by harnessing T cells' unique ability to specifically target and potentially cure metastatic cancer, a feat not achievable with traditional treatments. Living T cells have proven they can eradicate even the most stubborn metastatic cells. However, challenges persist, as these therapies sometimes fail when T cells do not endure, often succumbing to exhaustion or senescence. This issue is being addressed by researchers who are exploring methods to enhance T cell resilience and functionality.
Evolution has shaped T cells to occasionally dampen their function in chronic viral infections to prevent autoimmunity and mitigate potential harm from an overly aggressive immune response. For example, the immune system's complete elimination of a hepatitis virus could cause significant liver damage. Chronic activation can also drive T cells toward senescence and exhaustion, weakening the immune response to cancer. To address these challenges, researchers have developed checkpoint inhibitors and engineered T cells to create synthetic T cells that can reverse or bypass these evolutionary constraints with great success in some indications.
Researchers have developed a synthetic T cell state they call TIF (T cells with an immortal-like and functional state). TIF cells are the product of disrupting the BCOR and ZC3H12A genes, a result that is surprising because these genes are typically expressed at low levels in T cells and lack dynamic regulation. This approach is aimed at addressing the traditional trade-off in T cell therapies between longevity and potency, offering cells that not only persist longer but also retain robust anti-tumor capabilities. TIF cells demonstrate enhanced survival and can enter a reversible dormant state, like memory cells, providing long-term immunity. Without BCOR, and in combination with ZC3H12A deficiency, genes that are usually repressed might become active, enhancing both stemness- and cytotoxicity-associated genes. This could potentially remove brakes on the T cell stemness and cytotoxic programs, enhancing therapeutic efficacy.
In Neurodegenerative Disease, More Neurons Return to the Cell Cycle
https://www.fightaging.org/archives/2024/05/in-neurodegenerative-disease-more-neurons-return-to-the-cell-cycle/
Researchers have found evidence of cellular senescence in neurons in the aging brain. How do neurons become senescent, given that they are post-mitotic, non-dividing cells? Cellular senescence is state primarily associated with excessive cell division, in which a cell reaches the Hayflick limit, though cells can become senescent in response to damage or toxicity. Here, researchers provide evidence to show that in the aging brain, and particularly in the context of neurodegenerative conditions, ever more neurons re-enter the cell cycle, which inevitably leads to senescence. This is an interesting line of research, adding another argument for the use of senolytic drugs to treat neurodegenerative conditions.
Increasing evidence indicates that terminally differentiated neurons in the brain may recommit to a cell cycle-like process during neuronal aging and under disease conditions. Because of the rare existence and random localization of these cells in the brain, their molecular profiles and disease-specific heterogeneities remain unclear. Through a bioinformatics approach that allows integrated analyses of multiple single-nucleus transcriptome datasets from human brain samples, these rare cell populations were identified and selected for further characterization.
Our analyses indicated that these cell cycle-related events occur predominantly in excitatory neurons and that cellular senescence is likely their immediate terminal fate. Quantitatively, the number of cell cycle re-engaging and senescent neurons decreased during the normal brain aging process, but in the context of late-onset Alzheimer's disease (AD), these cells accumulate instead. Transcriptomic profiling of these cells suggested that disease-specific differences were predominantly tied to the early stage of the senescence process, revealing that these cells presented more proinflammatory, metabolically deregulated, and pathology-associated signatures in disease-affected brains. Similarly, these general features of cell cycle re-engaging neurons were also observed in a subpopulation of dopaminergic neurons identified in the Parkinson's disease (PD)-Lewy body dementia (LBD) model.
An extended analysis conducted in a mouse model of brain aging further validated the ability of this bioinformatics approach to determine the robust relationship between the cell cycle and senescence processes in neurons in this cross-species setting.
In Search of Natural Senolytics to Substitute for Dasatinib
https://www.fightaging.org/archives/2024/05/in-search-of-natural-senolytics-to-substitute-for-dasatinib/
Dasatinib and quercetin used in combination clears a fraction of lingering senescent cells in aging mice, producing a sizable degree of rejuvenation, and reversal of aspects of many different age-related conditions. In humans, clinical trials are underway at a sedate pace. Dasatinib is a chemotherapeutic small molecule, while quercetin is a plant extract flavonol. Here, researchers discuss their search for plant extract alternatives that mimic the effects of dasatinib, in the hopes of producing a less regulated alternative to the use of a small molecule drug, thereby lowering the barrier to entry somewhat. Size of effect is important, however, and it is yet to be demonstrated that any of their proposed alternatives can replicate the degree to which dasatinib impacts senescent cells.
The major risk factor for chronic disease is chronological age, and age-related chronic diseases account for the majority of deaths worldwide. Targeting senescent cells that accumulate in disease-related tissues presents a strategy to reduce disease burden and to increase healthspan. The senolytic combination of the tyrosine-kinase inhibitor dasatinib and the flavonol quercetin is frequently used in clinical trials aiming to eliminate senescent cells.
Here, our goal was to computationally identify natural senotherapeutic repurposing candidates that may substitute dasatinib based on their similarity in gene expression effects. The natural senolytic piperlongumine (a compound found in long pepper), and the natural senomorphics parthenolide, phloretin, and curcumin (found in various edible plants) were identified as potential substitutes of dasatinib. The gene expression changes underlying the repositioning highlight apoptosis-related genes and pathways. The four compounds, and in particular the top-runner piperlongumine, may be combined with quercetin to obtain natural formulas emulating the dasatinib+quercetin formula.
Cancer-Like Proliferation of Smooth Muscle Cells in Atherosclerosis
https://www.fightaging.org/archives/2024/05/cancer-like-proliferation-of-smooth-muscle-cells-in-atherosclerosis/
As an atherosclerotic plaque grows into a hotspot of inflammation and cell dysfunction in a blood vessel wall, it starts to draw in the nearby vascular smooth muscle cells that wrap the outside of the vessel. As researchers here note, these smooth muscle cells are altered by the plaque environment in ways that are analogous to the behavior of cancerous cells. They change, multiply, and accelerate the growth of a fatty plaque that will eventually rupture to cause a stroke or heart attack by blocking a downstream blood vessel.
Atherosclerosis is the major cause of heart attacks and stroke around the world and occurs when fat deposits build up inside the arteries. Atherosclerosis can be reduced with a healthy diet or drugs called statins that slow or reverse the buildup of deposits. Previous studies had found that smooth muscle cells metamorphose into different types of cells inside these atherosclerotic plaques and multiply to make up most cells within the plaques. Yet until now, few studies had examined the cancer-like properties of the cells and if these changes contributed to atherosclerosis. To learn more, researchers closely tracked the development of transformed smooth muscle cells in mice with atherosclerosis and sampled plaques of people with atherosclerosis. They found striking parallels between changes in the smooth muscle cells and tumor cells, including hyperproliferation, resistance to cell death, and invasiveness.
DNA damage, another hallmark of cancer, accumulated in the mouse and human smooth muscle cells and appears to accelerate atherosclerosis, the researchers found. The researchers could further accelerate atherosclerosis in mice by introducing a genetic mutation that increased DNA damage within the smooth muscle cells. Vascular tissue from healthy mice and people had no signs of smooth muscle cells with the DNA damage found in atherosclerotic plaques. "The cells stay inside existing plaques, which makes us think that they behave mostly like benign tumor cells, but more work needs to be done in humans and animal models to address this hypothesis." If atherosclerosis is driven by cancer-like cells, anticancer therapies may be a potential new way to treat or prevent the disease.
Microglia Become Progressively More Dysfunctional with Age
https://www.fightaging.org/archives/2024/05/microglia-become-progressively-more-dysfunctional-with-age/
Microglia are innate immune cells resident in the brain, analogous to macrophages elsewhere in the body, but with the addition of a portfolio of duties relating to the maintenance of neural function. With age ever more microglia become overly inflammatory, contributing to disruptive, unresolved inflammatory signaling, and abandoning their tissue maintenance tasks. This is thought to be an important contribution to neurodegenerative conditions and loss of cognitive function more generally. Researchers here report that the adoption of an inflammatory state is a progressive dysfunction for individual microglia, not just a matter of how many microglia have switched over to undertake inflammatory behavior.
Numerous studies have indicated that aged microglia are inflamed, have reduced phagocytic capacity, and have decreased motility. Microglia exhibit several hallmarks of aging that potentially contribute to their age-related dysfunction, such as shortened telomeres, altered intercellular communication, molecular alterations, and a loss of proteostasis. Furthermore, many recent studies have started to reveal the molecular changes that define microglial aging. Single cell RNA-Seq (scRNA-Seq) analyses indicate that microglia isolated from the entire brain lose homeostasis and activate inflammatory transcriptional profiles with age. Data rich studies have also revealed partial overlaps between aging microglia and those from disease models, including Alzheimer's disease.
Studies using aged plasma administration and heterochronic blood exchange demonstrate that microglia aging is in part driven by the aged systemic environment. However, the genesis of age-related dystrophic microglial phenotypes has not been extensively investigated. So, we set out to characterize the progression of age-related hippocampal microglial dysfunction, aiming to uncover intermediate states that could be intrinsic to the aging process. To do so, we undertook complementary cellular and molecular analyses of microglia across the adult lifespan and in heterochronic parabiosis - an experimental model of aging in which the circulatory systems of young adult and aged animals are joined.
In this study, we report that microglia in the adult mouse hippocampus, a brain region responsible for learning and memory and susceptible to age-related cognitive decline, advance through intermediate states that drive inflammatory activation during aging. We utilize scRNA-Seq across the adult lifespan to identify intermediate transcriptional states of microglial aging that emerge following exposure to an aged systemic environment. Functionally, we tested the role of these intermediate states using in vitro microglia approaches and an in vivo temporally controlled adult microglia-specific Tgfb1 conditional genetic knockout mouse model to demonstrate that intermediates represent checkpoints in the progression of microglia from homeostasis to inflammatory activation, with functional implications for hippocampal-dependent cognitive decline.
Towards a Small Molecule Therapy to Promote Remyelination
https://www.fightaging.org/archives/2024/05/towards-a-small-molecule-therapy-to-promote-remyelination/
Researchers here report on their efforts to interfere in a mechanism causing loss of the myelin that sheathes nerves. The driving goal is to produce a therapy for the severe demyelinating disease of multiple sclerosis rather than to reverse the lesser degree of myelin loss that occurs for everyone in later life. The animal evidence suggests that it may also prove to be useful in the general population of older individuals, however, which is promising. Loss of myelin is thought to contribute to some fraction of age-related loss of cognitive function, and so reversing that loss is an important goal.
Oligodendrocytes (OLs) are responsible for producing myelin sheaths that wrap around cable-like parts of nerve cells called axons, much like the plastic insulation around a wire. When the protective myelin gets damaged, be it by disease or the wear and tear of age, nerve signaling gets disrupted. Depending on where the damaged nerves lead, the disruptions can affect movement, vision, thinking and so on.
Analysis of stored autopsy tissues revealed that OLs within multiple sclerosis (MS) lesions lacked an activating histone mark called H3K27ac, while expressing high levels of two other repressive histone marks H3K27me3 and H3K9me3 associated with silencing gene activity. The research team scoured a library of hundreds of small molecules known to target enzymes that could modify gene expression and influence the silenced OLs. The team determined that the compound ESI1 (epigenetic-silencing-inhibitor-1) was nearly five times more powerful than any other compounds they considered.
The compound tripled the levels of the desired H3K27ac histone mark in OLs while sharply reducing levels of the two repressive histone marks. In both aging mice and mice mimicking MS, the ESI1 treatment prompted myelin sheath production and improved lost neurological function. Testing included tracking gene activation, measuring the microscopic new myelin sheaths surrounding axons, and observing that treated mice were quicker at navigating a water maze.
Upregulation of Cyclophilin A as a Potential Path to Improve Aged Hematopoietic Stem Cell Function
https://www.fightaging.org/archives/2024/05/upregulation-of-cyclophilin-a-as-a-potential-path-to-improve-aged-hematopoietic-stem-cell-function/
Researchers here report on the importance of molecular chaperones, and cyclophilin A in particular, to the function of hematopoietic stem cells. These cells generate red blood cells and immune cells, and thus age-related changes in hematopoietic function have important consequences for health. The immune system runs awry with age, and altered hematopoiesis is one of the contributing factors. If, as researchers here suggest, upregulation of cyclophilin A can improve hematopoietic stem cell function, then using this as a basis for therapy may produce health benefits in older individuals.
Hematopoietic stem cells (HSCs) are remarkably long-lived. HSCs typically remain dormant within the bone marrow, yet they possess the ability to activate and replenish blood cells continuously, maintaining a relatively youthful profile throughout the life of an organism. A driving force of cellular aging is the accumulation of proteins that have reached the end of their useful life. With age, proteins tend to misfold, aggregate, and accumulate inside the cell, which leads to toxic stress that can disrupt cell function. Cells that frequently engage in cell division, like progenitor cells, can dispose of protein aggregates through dilution. On the other hand, long-lived HSCs, which do not divide often, face the problem of the accumulation of misfolded proteins and subsequent toxic stress. Nevertheless, HSCs remain impervious to aging. How do they do it?
Previous studies have shown that mammalian cells express hundreds of molecular chaperones, proteins that preserve or change the three-dimensional conformation of existing proteins. Cyclophilins, one of the most abundant chaperones, have been implicated in the aging process. However, how they affect cellular proteins has not previously been studied. Working with mice, the researchers first characterized the protein content of HSCs and discovered that cyclophilin A is a prevalent chaperone. Further experiments showed that the expression of cyclophilin A was significantly decreased in aged HSCs, and genetically eliminating cyclophilin A accelerated natural aging in the stem cell compartment. In contrast, reintroducing cyclophilin A into aged HSCs enhanced their function. Together, these findings support cyclophilin A as a key factor in the longevity of HSCs.
A Mismatch Between Central versus Peripheral Circadian Regulation in Aging
https://www.fightaging.org/archives/2024/05/a-mismatch-between-central-versus-peripheral-circadian-regulation-in-aging/
Researchers here present an interesting view of age-related circadian dysfunction, focusing on mismatched regulation between the central circadian clock and somewhat independent peripheral clocks. The regulation of circadian rhythm in tissues results from the activities of these complex systems of multiple parts - and like all complex systems they begin to exhibit dysfunction with advancing age. The novel aspect of this research is the concept of multiple mismatched circadian regulators as a cause of further dysfunction in tissues.
Discovered in the 1970s, circadian clocks are essential for the regulation of biological time in most cells in the human body. These internal mechanisms adjust biological processes to a 24-hour cycle, allowing the synchronisation of cellular functions with daily variations in the environment. Circadian rhythms, which are coordinated by a central clock in the brain that communicates with clocks in different peripheral tissues, influence many functions, from our sleep patterns to our ability to metabolise food.
A study on the communication between the brain and muscle confirmed that the coordination between the central and peripheral clocks is crucial for maintaining daily muscle function and preventing the premature ageing of this tissue. Restoration of the circadian rhythm reduces the loss of muscle mass and strength, thereby improving deteriorated motor functions in experimental mouse models.
The results of the study have also demonstrated that time-restricted feeding (TRF), which involves eating only in the active phase of the day, can partially replace the central clock and enhance the autonomy of the muscle clock. More relevant still is that this restoration of the circadian rhythm through TRF can mitigate muscle loss, the deterioration of metabolic and motor functions, and the loss of muscle strength in aged mice.
"It is fascinating to see how synchronisation between the brain and peripheral circadian clocks plays a critical role in skin and muscle health, while peripheral clocks alone are autonomous in carrying out the most basic tissue functions. Our study reveals that minimal interaction between only two tissue clocks (one central and the other peripheral) is needed to maintain optimal functioning of tissues like muscles and skin and to avoid their deterioration and ageing. Now, the next step is to identify the signalling factors involved in this interaction, with potential therapeutic applications in mind."
State of Physical Fitness is a Reliable Predictor of Age-Related Mortality
https://www.fightaging.org/archives/2024/05/state-of-physical-fitness-is-a-reliable-predictor-of-age-related-mortality/
Being more physically fit at a given age reliably correlates with a lower future mortality risk. While human epidemiological data can only provide correlations, animal studies can and do provide evidence for physical fitness and exercise to modestly slow aspects of aging and reduce age-related mortality. In general, maintaining physical fitness into later life appears to be a good idea, based on the evidence.
Cardiorespiratory fitness (CRF) is a physical trait that reflects the integrated function of numerous bodily systems to deliver and use oxygen to support muscle activity during sustained, rhythmic, whole-body, large muscle physical activity. CRF can be objectively measured using direct (usually by maximal exercise testing with concomitant gas exchange analysis) or indirect (exercise predicted equations) methods with a variety of maximal or submaximal protocols.
Low CRF is considered a strong chronic disease risk factor that is not routinely assessed in clinical practice. Evidence suggests that the inclusion of CRF as a clinical vital sign would enhance patient management by improving the classification of those at high risk of adverse outcomes. The evidence supporting CRF as an important risk factor has accumulated since the 1980s through large cohort studies that investigated the prospective risk of all-cause mortality and cardiovascular events associated with CRF. Research has linked CRF to the incidence of some cancers, type 2 diabetes, metabolic syndrome, stroke, and depression. Higher CRF may even improve the prognosis in those with chronic conditions such as cancer, peripheral artery disease, heart failure, and chronic kidney disease.
The objective of this study was to conduct an overview of systematic reviews with meta-analyses from cohort studies that investigated relationships between CRF and prospective health-related outcomes among adults. We identified 26 systematic reviews with meta-analysis representing over 20.9 million observations from 199 unique cohort studies. CRF had the largest risk reduction for all-cause mortality when comparing high versus low CRF (hazard ratio, HR=0.47). A dose-response relationship for every 1-metabolic equivalent of task (MET) higher level of CRF was associated with a 11%-17% reduction in all-cause mortality (HR=0.89). The certainty of the evidence across all studies ranged from very low-to-moderate according to Grading of Recommendations, Assessment, Development and Evaluations.