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Alternative Polyadenylation in Nematode Aging and Longevity
https://www.fightaging.org/archives/2024/07/alternative-polyadenylation-in-nematode-aging-and-longevity/
Polyadenylation occurs during the creation of messenger RNA (mRNA). It is one part of the complex processes of transcription of the DNA sequence for a gene and assembly of the resulting RNA molecule. In the polyadenylation process, a tail of repeated adenine bases – called the poly(A) tail – is appended to the mRNA molecule. This protects the mRNA from degradation once it has left the nucleus, and also helps in other ways with the process of translation, in which the mRNA molecule is used as a blueprint by a ribosome to assemble protein molecules from amino acids. Changes in the length of the mRNA tail will affect levels of protein production, and thus the behavior of cells.
In today’s open access paper, researchers report on their efforts to discover novel age-related changes in the nematode worm species Caenorhabditis elegans via extensive single cell sequencing of the transcriptome. This led them to uncover differences in the polyadenylation process (a) over the course of aging, and (b) between short-lived and long-lived nematode lineages. This age-related change in polyadenylation acts to reduce the pace of production of many proteins, which likely has many complex downstream effects, while longer-lived nematodes are somewhat resistant to this change in polyadenylation. Can this be dysfunction be rescued by a comparatively simple set of changes? Perhaps, as polyadenylation is regulated by a proteins that might be upregulated or downregulated, but it is likely a lengthy road from here to that sort of intervention.
Aging atlas reveals cell-type-specific effects of pro-longevity strategies
Although multiple pro-longevity strategies have been discovered in multicellular organisms ranging from Caenorhabditis elegans to mice, whether and how these strategies slow aging of different tissues in distinct manners are yet to be determined. In recent years, single-cell and single-nucleus RNA sequencing (scRNA-seq and snRNA-seq) have proven to be effective ways to systemically profile transcriptomes at single-cell resolution and have facilitated the discovery of cell-type-specific transcriptomic signatures in different tissues.
In this study, we used snRNA-seq transcriptomic profiling of different somatic cell and germ cell types to build an adult cell atlas. Using snRNA-seq data from wild-type (WT) adults at different ages, we generated tissue-specific transcriptomic aging clocks as well as germ cell differentiation trajectory maps to assess how aging affects the function of different cell types. We also revealed age-associated, tissue-specific transcriptomic changes associated with three different pro-longevity mechanisms. Furthermore, we profiled pre-mRNA alternative polyadenylation (APA) at the genome level in different cell types at different ages and systemically discovered APA events with tissue-specific patterns and how age-associated APA changes in different tissues are attenuated by those pro-longevity mechanisms.
APA plays a crucial role in the control of mRNA metabolism, gene regulation and protein diversification51. Our study provides, to our knowledge, the first systematic profiling of APA changes at the whole transcriptome level. Interestingly, APA events exhibit tissue-specific distribution, undergo significant changes during aging and can be differentially regulated by different pro-longevity mechanisms. We discovered that, during aging, all cell types shift their APA preference toward the distal site, and this shifted preference is suppressed in the long-lived strains. Previous studies revealed that the usage of the distal APA site is inversely correlated with the level of core polyadenylation factors.
Additionally, the increased usage of distal APA sites may lead to longer 3′ UTRs, which are associated with mRNA instability. Based on our findings, we speculate that, with aging, the level of core polyadenylation factors may decrease and the length of 3′ UTRs may increase, potentially resulting in declines in translational efficiency. Thus, suppressing the distal APA usage in the long-lived strains may help improve protein outputs, contributing to their longevity effects.
Positive Functions of Possibly Senescent p16-Expressing Immune Cells in Disease Tolerance
https://www.fightaging.org/archives/2024/07/positive-functions-of-possibly-senescent-p16-expressing-immune-cells-in-disease-tolerance/
It has been a question for some time as to whether immune cells expressing p16 and β-galactosidase, markers of cellular senescence, are in fact all or even majority senescent. Macrophages, for example, can certainly express these proteins without entering a senescent state. Some assays of cellular senescence and associations with disease published in past years are thus likely reflective of both (a) the burden of senescence, but also (b) other responses to aging or processes of aging taking place in immune cell populations, particularly those resident in tissues.
With that in mind, today’s open access paper is an interesting exploration of what exactly it is that these maybe-senescent p16 and β-galactosidase expressing immune cells might be doing in the aged body. The authors draw in the concept of disease tolerance, which might be thought of as covering all of the ways in which cells might act, individually or in collaboration, to reduce the impact of infectious disease without killing the pathogens involved. It is not what one might think of the immune system being involved in, but nonetheless, that may be an evolved role for p16 and β-galactosidase expressing immune cells.
Does this mean that it is a bad idea to clear a large fraction of the p16-expressing or β-galactosidase-expressing cells in the body? Probably not, provided one restricts clearance to a short period of time, and avoids doing it while the patient is infected or injured. It has always been known that senescent cells do have useful roles when present for the short-term, including wound healing, suppression of potentially cancerous cells, and so forth. The problem in aging is that there are too many lingering senescent cells, to the point at which any benefit is buried by the downside of constant pro-inflammatory signaling. Getting rid of the excess in a short period of time should allow the useful processes to pick up again.
p16High immune cell – controlled disease tolerance as a broad defense and healthspan extending strategy
Substantial experimental evidence suggests that the accumulation of senescent cells is an important factor in age-related tissue deterioration as it is associated with the production of different molecules capable of restructuring the extracellular matrix, modifying the behavior of neighboring cells and systemically affecting the activity of the immune system. Despite these deleterious functions of senescent cells in the aging process, accumulating evidence supports cellular heterogeneity among p16High cells with some mediating important homeostatic functions that have been identified during embryonic development as well as in adult skin, liver and lung. This suggests that depending on the context, p16High senescent cells could be either beneficial or detrimental. What defines either group remains however largely unknown.
The development of different genetic mouse models is now facilitating the further identification and characterization of p16High cells in vivo. Among the different p16High subtypes, cells of the immune system, including T cells and macrophages, have been identified and further analysis revealed that some express additional markers of senescence such as enhanced senescence-associated β-galactosidase (SA-β-gal) activity and DNA damage. Furthermore, the frequency of such cells increases significantly in animals during natural and accelerated aging, which may highlights their potential importance. On the other hand, a modest or even transient activation of p16, as well as excessive lysosomal activity (and thus higher SA-β-gal activity) in phagocytic cells such as macrophages has been observed under different conditions. Whether such activation indeed reflects classical pathways of senescence activation is unclear.
In our current study, we used a genetic mouse model to trace cells with high expression of p16 in vivo. We found that the p16High program was activated during aging not only in long-lived macrophages and T cells, but in all the immune subsets analyzed. Our detailed analysis of T cells and tissue-resident macrophages as well as the use of a genetic model for selective ablation of p16High cells, allowed us to determine that p16High immune cells play an important regulatory functions in vivo. These functions were further critical for animal survival after severe inflammation and tissue damage. While the ability of an organism to overcome infectious diseases has traditionally been linked to killing invading pathogens, evidence indicates that, apart from restricting pathogen loads, organismal survival is coupled to an additional yet poorly understood mechanism called disease tolerance. Here we argue that induction of p16High immune cells is a key mechanism in establishing disease tolerance.
Cellular Reprogramming via Gene Therapy Improves Memory Function in Old Rats
https://www.fightaging.org/archives/2024/07/cellular-reprogramming-via-gene-therapy-improves-memory-function-in-old-rats/
A number of groups have demonstrated that selectively exposing aged rodent tissues to expression of the Yamanaka factors – OCT4, SOX2, KLF4, and MYC (collectively OSKM) – can induce restoration of more youthful epigenetic patterns and gene expression, accompanied by restoration of tissue function. The Yamanaka factors were first explored as a way to replicate the process by which adult germline cells become embryonic stem cells at the outset of embryogenesis, leading to the now well established capacity to produce what are known as induced pluripotent stem cells from somatic cell samples. Importantly, this process doesn’t just lead over time to a radical alteration of cell fate, but also quite rapidly rejuvenates epigenetic regulation of gene expression.
As noted in today’s open access paper, one can’t just apply Yamanaka factors globally to obtain a good outcome. Some tissues react poorly. Thus researchers have focused initially on a few use cases in which it seems likely that there is a path to therapies at the end of the day, many of which are focused on neural tissue. That said, the work here involves direct injection of gene therapy vectors to specific areas of the brain, and thus is at the very least a lengthy delivery technology research and development program away from adoption. The primary challenge in the development of gene therapy is how to obtain selective delivery to specific areas of the body when direct injection is infeasible, expensive, or risky. There is no clear path ahead at this time for many of the relatively small and deeply internal tissues.
Cognitive rejuvenation in old rats by hippocampal OSKM gene therapy
At the molecular level, gene expression studies in aging rodents have documented significant changes in hippocampal genes related to cholesterol synthesis, inflammation, transcription factors, neurogenesis, and synaptic plasticity. In the hippocampus of female rats, 210 genes have been reported to be differentially expressed in aged individuals compared to their young counterparts, with the majority being downregulated.
Yamanaka genes, along with other pluripotency genes, possess high therapeutic potential for treating the aged central nervous system affected by various neurodegenerative diseases. Recent results revealed that the Yamanaka genes display a dual behavior when expressed continuously in vivo, being regenerative when delivered via viral vectors but highly toxic when expressed in transgenic mice. Thus, it has been reported that delivery of the OSK genes by intravitreally injecting a regulatable adeno-associated viral vector type 2 (AAV2) expressing the polycistron OSK can reverse vision deficits in an experimental model of glaucoma in mice as well as in 11 months old mice showing age-related vison impairment. Fifteen months of continuous expression of the OSK genes in retinal ganglion cells (RGCs) induced neither pathological changes nor proliferation of RGCs. Young- and middle-aged mice injected intravenously with OSK-AAV2 for 15 months did not exhibit any adverse side effects. In contrast, DOX-induced expression of OSK genes in mice transgenic for OSK resulted in rapid weight loss and death, likely due to severe dysplasia in the digestive system.
Administering an adenovector to the hypothalamus of young female rats, which carries both the OSKM transcription factors and the green fluorescent protein (GFP) marker, has not only significantly decelerated the pace of reproductive aging but also tripled the fertility rates in 9-month-old females compared to those receiving a placebo vector. Notably, at 9 months of age, female rats are approaching the age of ovulatory cessation, which typically occurs at around 10 months. Inspired by the pioneering results achieved by a team employing OSK gene therapy in the retina of mice, we decided to conduct a medium-term 39-day OSKM gene therapy trial in another brain region: the hippocampus of aged rats. The main goal was to restore learning and spatial memory performance in this animal model. For comparison, we used control groups of similarly aged rats injected with a placebo adenovector.
The Barnes maze test, used to assess cognitive performance, demonstrated enhanced cognitive abilities in old rats treated with OSKM compared to old control animals. In the treated old rats, there was a noticeable trend towards improved spatial memory relative to the old controls. Further, OSKM gene expression did not lead to any pathological alterations within the 39 days. Analysis of DNA methylation following OSKM treatment yielded three insights. First, epigenetic clocks for rats suggested a marginally significant epigenetic rejuvenation. Second, chromatin state analysis revealed that OSKM treatment rejuvenated the methylome of the hippocampus. Third, an epigenome-wide association analysis indicated that OSKM expression in the hippocampus of old rats partially reversed the age-related increase in methylation.
Moving the STING Gene from Long-Lived Bats into Short-Lived Mice, Reducing Age-Related Inflammation
https://www.fightaging.org/archives/2024/08/moving-the-sting-gene-from-long-lived-bats-into-short-lived-mice-reducing-age-related-inflammation/
It has taken some time for researchers involved in the study of the comparative biology of aging between species to start moving genes from long-lived species into short-lived species. This is now underway to some degree, however. One research group reported on the results of moving a naked mole-rat cancer resistance gene into mice not so long ago. In today’s open access paper, a different set of researchers report on the results of moving the STING gene from a long-lived bat species into very much shorter-lived mice. STING is involved in innate immune sensing of pathogens and damage. Pathways involving STING are maladaptively triggered in later life, contributing to a rising level of chronic inflammation. That chronic inflammation is disruptive to tissue structure and function, contributing to age-related disease.
Bats are notoriously resilient to the consequences of viral infection, making them able to act as reservoirs of viral pathogens that can be spread to other species while apparently causing little to no harm to the bats themselves. It is thought that the mechanisms granting this form of resilience may also confer resistance to the inflammation that occurs in other mammals due to maladaptive innate immune reactions to forms of molecular damage characteristic of aging. The pathways for pathogen-driven and aging-drive inflammatory signaling are known to overlap, and STING is particularly implicated.
Myotis bat STING attenuates aging-related inflammation in female mice
Bats are also recognized as natural reservoir hosts for diverse highly pathogenic viruses, some of which have precipitated large-scale infectious diseases in humans, such as SARS-related coronaviruses and Ebola virus. Bats are also noted for their unparalleled longevity among mammals relative to their size, with those within the genus Myotis exhibiting the greatest longevity, living up to 40 years. However, the mechanisms underlying these unique characteristics, particularly their roles as viral reservoir hosts and long-lived animals, remain inadequately understood.
In recent years, research efforts have predominantly centered on unraveling the coexistence of bats and viruses. Our work, along with that of other researchers, has revealed that bats maintain a constitutively expressed interferon system, with a simultaneous dampening of stimulator of interferon gene (STING) expression and inflammatory response. These characteristics may enable early inhibition of viral replication or moderate the immune response upon viral infection. Notably, a low-level, overactive inflammatory response is also a hallmark of human aging, attributed to the senescence-associated secretory phenotype (SASP), which largely depends on the DNA-cGAS-STING pathway.
We previously identified a universal replacement of the serine 358 residue (a critical activation residue) in STING in bats, leading to attenuated downstream interferon responses and antiviral activity. In recent years, extensive research has explored the role of STING in the human aging process. Studies have shown that the cGAS-STING pathway acts as a driver of the senescence-associated secretory phenotype (SASP) in humans, and inhibiting cGAS-STING signaling may be a potential strategy for impeding neurodegenerative processes in old age. Consequently, we hypothesized that the uniquely dampened character of STING in bats may contribute to their relatively extended healthspan. In this study, we established a Myotis davidii bat STING (MdSTING)-knock-in mouse model and conducted a comprehensive comparative analysis of aging-related genotypes with wild-type (WT) mice over a 3-year period.
Blood transcriptomic analysis indicated a reduction in aging-related inflammation in female MdSTING mice, as evidenced by significantly lower levels of pro-inflammatory cytokines and chemokines, immunopathology, and neutrophil recruitment in aged female MdSTING mice compared to aged wild-type mice in vivo. These results indicated that MdSTING knock-in attenuates the aging-related inflammatory response and may also improve the healthspan in mice in a sex-dependent manner. Although the underlying mechanism awaits further study, this research has critical implications for bat longevity research, potentially contributing to our comprehension of healthy aging in humans.
Walk Faster, Age More Slowly
https://www.fightaging.org/archives/2024/08/walk-faster-age-more-slowly/
Walking speed is one of the long-standing simple biomarkers of aging, predating modern medicine. Measures of physical capacity correlate with the onset of frailty and increased risk of mortality. People become weaker and walk more slowly as they lose fitness and strength with the progression of aging. With the ongoing development of new measures of biological age, including epigenetic clocks and combinations of simple measures such as phenotypic age, researchers have some interest in comparing the new with the old.
In today’s open access paper, researcher use the technique of Mendelian randomization to try to derive some indication of causation regarding walking speed and degenerative aging. They conclude that the data is supportive of a causal relationship between a faster walking pace and slower pace of aging. This fits well with current thought on the merits of mild physical activity on long-term health and mortality. The use of accelerometers in epidemiological studies has shown that even a modest level of activity in later life correlates with significant improvements versus being sedentary.
Effects of walking on epigenetic age acceleration: a Mendelian randomization study
Walking stands as the most prevalent physical activity in the daily lives of individuals and is closely associated with physical functioning and the aging process. Nonetheless, the precise cause-and-effect connection between walking and aging remains unexplored. The epigenetic clock emerges as the most promising biological indicator of aging, capable of mirroring the biological age of the human body and facilitating an investigation into the association between walking and aging. Our primary objective is to investigate the causal impact of walking with epigenetic age acceleration (EAA).
This represents the inaugural large-scale two-sample Mendelian randomization (MR) study uncovering the causal link between walking and epigenetic aging. Our results illuminate a consistent and significant causal association, indicating that increased walking speed correlates with the deceleration of epigenetic aging. Essentially, brisk walking appears to exert a beneficial influence on slowing down the aging process. Notably, this causal relationship persists uniformly across all four classical epigenetic clocks.
In contrast, alternate facets of walking, including walking duration and frequency over the past four weeks, did not exhibit resilient causality concerning accelerated epigenetic aging. Additionally, a comparative analysis using sedentary behavior revealed that leisurely sedentary behavior induced GrimAge EAA. While no conclusive causal link was identified in the analysis of sedentary behavior on the remaining three epigenetic clocks, the heightened correlation of GrimAge with behavioral lifestyle suggests a potential association between sedentary behavior and accelerated aging.
The Challenges of Finding a Drug to Treat Sarcopenia
https://www.fightaging.org/archives/2024/07/the-challenges-of-finding-a-drug-to-treat-sarcopenia/
The characteristic loss of muscle mass and strength that occurs with age leads to sarcopenia and frailty. While a few companies are targeting this age-related muscle loss via development of small molecule drugs, the recent history of this part of the field is not encouraging. None of the attempted approaches have yet improved on exercise. That may well be due to a failure to specifically target underlying mechanisms that drive degenerative aging, projects instead relying on the sort of adjustments to metabolism that are discussed in the paper referenced here, but only time will tell.
A healthy lifespan relies on independent living, in which active skeletal muscle is a critical element. The cost of not recognizing and acting earlier on unhealthy or aging muscle could be detrimental, since muscular weakness is inversely associated with all-cause mortality. Sarcopenia is characterized by a decline in skeletal muscle mass and strength and is associated with aging. Exercise is the only effective therapy to delay sarcopenia development and improve muscle health in older adults. Although numerous interventions have been proposed to reduce sarcopenia, none has yet succeeded in clinical trials. This review evaluates the biological gap between recent clinical trials targeting sarcopenia and the preclinical studies on which they are based, and suggests an alternative approach to bridge the discrepancy.
The use of hormone replacement and myostatin-based therapies in clinical trials – aimed at promoting muscle hypertrophy – has not resulted in notable advancements in muscle strength or functional performance. The decline in sex hormones that occurs with aging is closely tied to the development of sarcopenia. However, the potential adverse effects of sex hormone replacement therapy outweigh its modest advantages in mitigating muscle aging. There is no conclusive association between circulating myostatin level and muscle aging, and myostatin-based therapy does not affect muscle aging.
While effective in promoting muscle growth, hypertrophic signaling compromises muscle protein quality control, exacerbating age-related muscle dysfunction. An alternative intervention to refine mechanistic target of rapamycin (mTOR) functions is proposed to benefit muscle health in the elderly. Both hormone replacement and myostatin-based therapies stimulate muscle growth by activating mTORC1, which controls growth by responding to nutrient availability and should be active only when nutrients are present. Yet chronic activation of mTORC1 in skeletal muscle accelerates sarcopenia development in mice. The crucial question is whether the interventions focused on increasing muscle size through mTORC1 will truly be beneficial in addressing muscle aging in humans, given that mTORC1 insensitivity is frequently seen in aged individuals
Meta-Analysis Suggests a Declining Trend in Dementia Incidence
https://www.fightaging.org/archives/2024/07/meta-analysis-suggests-a-declining-trend-in-dementia-incidence/
Researchers here conduct a meta-analysis of systemic reviews of dementia incidence over time. The results indicate that the risk of dementia is decreasing. The authors suggest that the reduction in the prevalence of smoking in recent decades is a major factor. That in turn tends to reinforce the consensus on the relationship between cardiovascular disease and neurodegenerative disease, that declining cardiovascular health strongly influences the risk of dementia.
Some cohort studies have reported a decline in dementia prevalence and incidence over time, although these findings have not been consistent across studies. We reviewed evidence on changes in dementia prevalence and incidence over time using published population-based cohort studies that had used consistent methods with each wave and aimed to quantify associated changes in risk factors over time using population attributable fractions (PAFs).
We identified 1,925 records in our initial search, of which five eligible systematic reviews were identified. Within these systematic reviews, we identified 71 potentially eligible primary papers, of which 27 were included in our analysis. 13 (48%) of 27 primary papers reported change in prevalence of dementia, ten (37%) reported change in incidence of dementia, and four (15%) reported change in both incidence and prevalence of dementia. Studies reporting change in dementia incidence over time in Europe (n=5) and the USA (n=5) consistently reported a declining incidence in dementia. One study from Japan reported an increase in dementia prevalence and incidence and a stable incidence was reported in another study.
Overall, across studies, the PAFs for less education or smoking, or both, generally declined over time, whereas PAFs for obesity, hypertension, and diabetes generally increased. The decrease in PAFs for less education and smoking was associated with a decline in the incidence of dementia in the Framingham study (Framingham, MA, USA, 1997-2013), the only study with sufficient data to allow analysis.
Considering the Gut Microbiome’s Influence on Astrocytes in the Aging Brain
https://www.fightaging.org/archives/2024/07/considering-the-gut-microbiomes-influence-on-astrocytes-in-the-aging-brain/
The influence of the gut microbiome on the long-term trajectory of health is a popular topic these days. Tools for assessing the microbial composition of the gut microbiome are accurate and cost little, and variance in the relative sizes of microbial populations between individuals and across a life span are increasingly correlated with effects on health, disease, and the pace of aging. Of particular interest are the ways in which the gut microbiome may be affecting the operation of the brain, such as via the generation of harmful inflammatory signaling, or the production of metabolites such as butyrate that can influence neurogenesis. Here, researchers focus specifically on connections between the gut microbiome and the supporting astrocyte cells of the brain, known to become dysfunction with age.
As the most abundant type of glial cells, astrocytes perform significant functions in neural activity regulation, synapse formation, neural metabolism, and blood-brain barrier (BBB) integrity and, therefore, maintain the normal physiological functions of the central nervous system (CNS). With continuous advancements in research, the roles of astrocytes in aging and neurodegenerative diseases (NDs) have started to receive scientific attention. There is a loss of morphological structure in star-shaped astrocytes with brain aging that can lead to a decline in their functionality, such as reduced astrocytic synaptic coverage, fewer aquaporin 4 (AQP4) channels expressed in astroglial end-feet followed by decreased lymphatic clearance, compromised BBB integrity, inadequate clearance of glutamate and potassium ions, and impaired energy metabolism. Additionally, with advancing age, and in the context of NDs, reactive astrocytes and aged astrocytes gradually accumulate, triggering neuroinflammation and having detrimental impacts on the tissue microenvironment, and ultimately leading to age-related cognitive decline.
Over the past decade, the roles of the intestinal microbiota in regulating the gut-brain axis and its involvement in the pathophysiology of brain aging have become increasingly emphasized. A previous study has shown that the gut microbiota is an important upstream factor in astrocyte activation, which is closely associated with neuroinflammation and neurodegeneration. Thus, a deeper comprehension of the roles and mechanisms of the gut microbiota-astrocyte axis in age-related cognitive decline is becoming ever more necessary and meaningful. This review aims to elucidate and summarize the unique changes to gut microbiomes seen during the process of aging, alterations in the shape and function of astrocytes within the aging brain, and potential mechanisms, such as the vagus nerve, immune responses, the circadian rhythm, and microbial metabolites, by which gut microbiomes influence cognitive function by impacting CNS astrocyte activity. In this way, we aim to provide new insights into therapeutic avenues for age-related cognitive decline.
Neural Epigenetic Aging as a Driver of Cognitive Decline
https://www.fightaging.org/archives/2024/07/neural-epigenetic-aging-as-a-driver-of-cognitive-decline/
Ever-shifting epigenetic marks on the genome determine its structure in the cell nucleus, and thus which portions of the genome are accessible to the machinery of gene expression, and thus which proteins are produced at a given time. This epigenetic regulation of gene expression changes in characteristic ways with age, and many of those alterations are clearly maladaptive. Hence the present interest in epigenetic reprogramming, in which researchers adapt some of the processes that take place during embryonic development in order to restore a youthful epigenetic state to adult cells. It is very much a work in progress, but early results in animal studies are promising.
Neurons undergo pronounced alterations in morphology and function throughout the lifespan, and these have been related to disturbed neuronal signaling and impaired information processing in the aged brain. The function of different neuron types in multiple brain areas is affected by aging, with the hippocampus and prefrontal cortex – both brain regions with key roles in memory storage and cognitive flexibility – being particularly compromised.
Since neurons are post-mitotic and mostly generated during early development, they represent one of the oldest cell types in the body. Therefore, to preserve their function throughout life, neurons are dependent on the long-term maintenance of molecular programs that define their neuronal identity and enable activity-induced plasticity in response to environmental cues. Yet, multiple studies have reported impairments in neuron-specific gene expression programs in the aging brain, including alterations in transcription, RNA processing, and protein levels, which have been linked to neuronal dysfunction. The long-term maintenance of neuronal gene expression programs critically depends on the epigenetic machinery, and accumulating evidence suggests impairments of epigenetic regulation as cell-intrinsic drivers of aging in neurons.
Intriguingly, recent studies suggest that neuronal epigenetic aging can be slowed down or reversed by rejuvenating interventions that are known to counteract age-related impairments in brain function, thus opening the field for therapeutic anti-aging strategies. Interventions shown to be effective include changes to lifestyle (such as exercise, environmental enrichment, and caloric restriction), the transfer of young blood factors or cellular reprogramming, among others. The malleability of the neuronal epigenome during aging suggests that it can be targeted to prevent epigenetic aging or even restore a youthful epigenetic state in aged neurons.
Towards a Genetically Engineered Gut Microbiome
https://www.fightaging.org/archives/2024/07/towards-a-genetically-engineered-gut-microbiome/
The gut microbiome influences long-term health. The balance of microbial populations shifts with age to become more harmful, certainly more inflammatory. While it is possible to produce sizable benefits to health via rejuvenation of the aged gut microbiome with simple approaches, such as fecal microbiota transplantation using a young donor, the future will clearly involve more of the application of biotechnology to the problem. If one can produce lasting change in the composition of the gut microbiome by delivering microbes in sufficient quantity, then why not deliver engineered versions of existing gut microbes that are altered to produce less inflammatory signaling or more beneficial metabolites?
Microbiome research is now demonstrating a growing number of bacterial strains and genes that affect our health. Although CRISPR-derived tools have shown great success in editing disease-driving genes in human cells, we currently lack the tools to achieve comparable success for bacterial targets in situ. Here we engineer a phage-derived particle to deliver a base editor and modify Escherichia coli colonizing the mouse gut. Editing of a β-lactamase gene in a model E. coli strain resulted in a median editing efficiency of 93% of the target bacterial population with a single dose. Edited bacteria were stably maintained in the mouse gut for at least 42 days following treatment.
This was achieved using a non-replicative DNA vector, preventing maintenance and dissemination of the payload. We then leveraged this approach to edit several genes of therapeutic relevance in E. coli and Klebsiella pneumoniae strains in vitro and demonstrate in situ editing of a gene involved in the production of curli in a pathogenic E. coli strain. Our work demonstrates the feasibility of modifying bacteria directly in the gut, offering a new avenue to investigate the function of bacterial genes and opening the door to the design of new microbiome-targeted therapies.
A Study of Rapamycin in the Context of Ovarian Aging
https://www.fightaging.org/archives/2024/07/a-study-of-rapamycin-in-the-context-of-ovarian-aging/
Rapamycin is arguably the best of the calorie restriction mimetic drugs so far tested in mice. It slows aging robustly in animal studies, and has been used in humans at much higher doses than the anti-aging dose (around 5mg once per week) for decades. Still, there is a lack of human trials conducted for the purposes of slowing aspects of aging. More trial data than the little that presently exists would increase the number of physicians willing to prescribe off-label for anti-aging purposes. The specific focus of the trial doesn’t much matter so long as the researchers measure enough data to assemble biomarkers of aging and general health. So, for example, one might look at a recently launched study of gum disease in older patients, and the study noted here that is focused on ovarian aging. Both have the potential to produce data relevant to the general question of aging. There are a few more such studies beside these, either planned or in the early stages.
Research into repurposing the immunosuppressant rapamycin has been hailed a “paradigm shift” in how menopause is studied. The Validating Benefits of Rapamycin for Reproductive Aging Treatment (Vibrant) study is designed to measure whether the drug can slow ovaries ageing, thereby delaying menopause, extending fertility and reducing the risk of age-related diseases. The study, which will eventually include more than 1,000 women, now has 34 participants aged up to 35, with more women joining every day.
Early results suggested it was realistic to hope the drug could decrease ovary ageing by 20% without women experiencing any of the 44 side-effects rapamycin can have, which range from mild nausea and headaches to high blood pressure and infections. In fact, participants in the randomised, placebo-controlled study had self-reported improvements in their health, memory, energy levels and in the quality of their skin and hair: health improvements consistent with other studies into rapamycin.
Ovaries release eggs continuously: women lose about 50 every month, with just one reaching ovulation. A small, weekly dose of rapamycin slows ovaries down, so they release only 15 eggs a month. Because rapamycin is a cheap, generic drug already widely used, once the evidence is established, progress will be fast. “The very features of the drug that make it so promising and give it such great potential for having a quick and major impact for women are, ironically, the very factors that make it hard to find funders for the study. That’s why this hasn’t been done before: it’s an expensive study and a lot of women will benefit from it – but there’s no motivation for pharmaceutical companies to invest because there’s no possibility of making money from an off-patent drug.”
A clinical trial of rapamycin in humans has also been considered impossible because it would take decades to detect any longevity effects. Ovaries, however, age so quickly that change can be measured over six months. The level of rapamycin used is small: women are given 5mg a week for three months compared with the 13mg a day that transplant patients can be prescribed for years.
Reinforcing the Point that Moderate Alcohol Use Does Not Add to Life Expectancy
https://www.fightaging.org/archives/2024/08/reinforcing-the-point-that-moderate-alcohol-use-does-not-add-to-life-expectancy/
It is now understood that the past studies indicating that low levels of alcohol use were protective and modestly extended life were flawed. This has been the case for a few years now; the research noted here is just hammering home that point in a more robust way. The fundamental problem is that people can stop drinking for health reasons, and thus the cohort of abstainers tends to contain more sick individuals with a higher mortality risk than is the case for the moderate intake cohort. Problems of this nature, simple in hindsight but essentially ignored for years, bedevil many areas of epidemiological study. There were very similar issues in studies indicating a protective effect for being moderately overweight in later life, for example.
Studies linking moderate drinking to health benefits suffer from fundamental design flaws. The major issue: Those studies have generally focused on older adults and failed to account for people’s lifetime drinking habits. So moderate drinkers were compared with “abstainer” and “occasional drinker” groups that included some older adults who had quit or cut down on drinking because they’d developed any number of health conditions. That makes people who continue to drink look much healthier by comparison. And in this case, he noted, looks are deceiving.
For the analysis, researchers identified 107 published studies that followed people over time and looked at the relationship between drinking habits and longevity. When the researchers combined all the data, it looked like light to moderate drinkers (that is, those who drank between one drink per week and two per day) had a 14% lower risk of dying during the study period compared with abstainers.
Things changed, however, when the investigators did a deeper dive. There were a handful of “higher quality” studies that included people who were relatively young at the outset (younger than 55, on average) and that made sure former and occasional drinkers were not considered “abstainers.” In those studies, moderate drinking was not linked to a longer life. Instead, it was the “lower quality” studies (older participants, no distinction between former drinkers and lifelong abstainers) that did link moderate drinking to greater longevity.
Reviewing the Development of Urolithin A as an Age-Slowing Intervention
https://www.fightaging.org/archives/2024/08/reviewing-the-development-of-urolithin-a-as-an-age-slowing-intervention/
Of the supplement compounds that have been shown to in some way improve mitochondrial function, urolithin A is probably the least well understood when it comes to how exactly it works. This is interesting, as a range of academic and industry groups are presently working on it or derivatives of it. A reasonable view of this class of approach to mitochondrial dysfunction in aging, which also includes MitoQ and vitamin B3 derivatives like nicotinamide riboside, is that the interventions likely produce much of their effect by improving the operation of the mitochondrial quality control processes of mitophagy. They may achieve this quite indirectly, as mitophagy is complex and appears strongly affected by changes in mitochondrial dynamics and function. Impaired mitophagy leading to damaged mitochondria and impaired mitochondrial function is a feature of aging. The primary objection to a focus on supplements to improve mitochondrial function is that, so far, exercise produces better results.
Urolithin A (UA) is a gut metabolite derived from ellagic acid. This systematic review assesses the potential geroprotective effect of UA in humans. In five studies including 250 healthy individuals, UA (10-1000 mg/day) for a duration ranging from 28 days to 4 months, showed a dose-dependent anti-inflammatory effect and upregulated some mitochondrial genes, markers of autophagy, and fatty acid oxidation. It did not affect mitochondrial maximal adenosine triphosphate production, biogenesis, dynamics, or gut microbiota composition. UA increased muscle strength and endurance, however, had no effect on anthropometrics, cardiovascular outcomes, and physical function.
There is very limited evidence on the effect of UA in human aging. UA showed some improvement in mitochondrial activity and autophagy. It decreased inflammatory markers and increased muscle strength and endurance. Taken together, current evidence does not support the beneficial effects of UA on physical function in healthy individuals. However, this conclusion should be considered in light of several limitations: small sample sizes, short intervention durations, and a wide participant age range (45-85 years), which includes both middle-aged and older individuals who may not be ideal candidates for geroprotection.
Features of the Gut Microbiome Correlating with Osteoporosis Risk
https://www.fightaging.org/archives/2024/08/features-of-the-gut-microbiome-correlating-with-osteoporosis-risk/
The composition of the gut microbiome both changes with age and appears influential on the trajectory of aging. A microbiome with more inflammatory microbes and fewer beneficial microbes is harmful over the long term. Now that researchers can cheaply and accurately measure the relative abundance of microbial species present in the gut, they can ask questions about how exactly specific microbes are slowing or accelerating the onset and progression of specific age-related conditions. Here is an example of this sort of work applied to osteoporosis, the loss of bone density that occurs with age.
Osteoporosis (OP) constitutes a notable public health concern that significantly impacts the skeletal health of the global aging population. Its prevalence is steadily escalating, yet the intricacies of its diagnosis and treatment remain challenging. Recent investigations have illuminated a profound interlink between gut microbiota (GM) and bone metabolism, thereby opening new avenues for probing the causal relationship between GM and OP.
Employing Mendelian randomization (MR) as the investigative tool, this study delves into the causal rapport between 211 varieties of GM and OP. The data are culled from genome-wide association studies (GWAS) conducted by the MiBioGen consortium, in tandem with OP genetic data gleaned from the UK Biobank, BioBank Japan Project, and the FinnGen database.
The discernment emerged that the genus Coprococcus3 is inversely associated with OP, potentially serving as a deterrent against its onset. Additionally, 21 other gut microbial species exhibited a positive correlation with OP, potentially accentuating its proclivity and progression. Subsequent to rigorous scrutiny via heterogeneity and sensitivity analyses, these findings corroborate the causal nexus between GM and OP. Facilitated by MR, this study successfully elucidates the causal underpinning binding GM and OP, thereby endowing invaluable insights for deeper exploration into the pivotal role of GM in the pathogenesis of OP.
Reviewing Mitochondrial Dysfunction in Aging
https://www.fightaging.org/archives/2024/08/reviewing-mitochondrial-dysfunction-in-aging/
Every cell contains hundreds of mitochondria, actively generating adenosine triphosphate (ATP), a chemical energy store molecule used to power cell processes. Mitochondria are descended from symbiotic bacteria and retain many bacterial features, such as a circular genome, the mitochondrial DNA, and the ability to replicate and fuse together. Nonetheless, they have become cell components and are recycled by the quality control mechanism of mitophagy when damaged. In aged tissues, mitochondria become altered in size, activity, and ability to produce ATP for reasons that may have as much to do with epigenetic changes in the cell nucleus as they do with damage to mitochondrial DNA. It is thought that this mitochondrial dysfunction is an important contributing cause of degenerative aging.
Mitochondria are unique double-membrane organelles that came into existence due to the engulfment of alpha-proteobacterium by a eukaryotic progenitor cell in an endosymbiosis process, demonstrating evolutionary importance in the advancement of eukaryotic life. Mitochondria, apart from the nucleus, comprises its genome, metabolome, transcriptome, and proteome. Mitochondria have been considered a cellular powerhouse, responsible for approximately 95% of cellular ATP production. They are responsible for significantly contributing to the maintenance of cellular homeostasis by contributing to metabolic processes such as the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS).
Apart from regulating cellular energetics, mitochondria also play an essential role in intracellular calcium signaling, thermogenesis, apoptosis, generation of reactive oxygen species (ROS), and regulation of oxidative stress response. Any defect or deficit in mitochondrial number and function might be responsible for cellular damage. Mitochondrial dysfunction has been reported to be associated with aging and almost all chronic aging-associated diseases through reduced ATP production, alteration in the regulation of apoptosis, increased ROS production, and defective calcium signaling.
Accumulation of mutations in mitochondrial DNA (mtDNA) is the primary cause of mitochondrial anomalies, further contributing to aging and associated diseases. Here, we provide a detailed description of mitochondrial dysfunction, its implications in the aging process, the onset of aging-associated diseases, and potential therapeutic interventions that target mitochondrial dysfunction to develop an effective strategy for treating age-related diseases.
