Fight Aging! Newsletter, October 23rd 2023
Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter, please visit: https://www.fightaging.org/newsletter/
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- More Evidence for Impaired Hearing to Contribute to Cognitive Decline
- Lifestyle Produces a Much Greater Contribution to Human Life Expectancy than a Genetic Risk Score
- Towards Inhibition of α-Synuclein Aggregation
- Combining CAR-T Therapy with Tumor-Seeking Bacteria
- Worldwide Trends in Healthy versus Unhealthy Remaining Life Expectancy at 60
- Imaging of Chromatin Structure as a Basis for an Aging Clock
- Calorie Restriction Improves Pancreatic Function in Aging Mammals
- Aspects of Iron Metabolism Correlate with Epigenetic Age Acceleration
- Reviewing the Aging of the Ovaries
- A Microbial Metabolite can Harm Dopaminergenic Neurons
- The AgingReG Database of Regulatory Relationships in Aging
- Mitochondrial DNA Mislocalization is an Important Driver of the Senescence-Associated Secretory Phenotype
- In Search of Target Mechanisms to Enhance Aggrephagy
- Modest Calorie Restriction Improves Muscle Quality in Humans
- Reviewing the Potential of Extracellular Vesicles to Treat Degenerative Bone Conditions
More Evidence for Impaired Hearing to Contribute to Cognitive Decline
https://www.fightaging.org/archives/2023/10/more-evidence-for-impaired-hearing-to-contribute-to-cognitive-decline/
There is some debate over the mechanisms involved in the bidirectional relationship between hearing loss and cognitive decline in aging. While both must, logically, arise from the same underlying causes of aging, the increased burden of a variety of forms of cell and tissue damage that produce many different forms of dysfunction, it appears that (a) loss of function in the brain can itself contribute to hearing loss, while (b) hearing loss can in and of itself accelerate the pace of cognitive decline.
Thanks to the existence of electromechanical means of improving hearing, meaning hearing aids, cochlear implants, and the like, there is a growing body of evidence to show that people with these devices suffer a slower pace of cognitive decline than those without, at a given level of age-related hearing loss. This is a strong argument for portions of the brain to require the exercise of processing sound in order to better resist decline. "Use it or lose it" isn't just for muscles, and this isn't the only line of evidence to suggest that a well exercised mind will lose functional capacity more slowly in later life. Similar effects are observed for blindness and cognitive decline, for example, implying that the exercise of processing of visual information helps to resist loss of brain function.
Interestingly, the study noted in today's open access paper suggests that the effect of maintained processing of audio information only goes so far. It only helps for a few years. More is needed if we are to be the masters of our own destiny when it comes to the aging of the brain. Rejuvenation therapies must directly address the underlying mechanisms of cell and tissue damage, and the research community must aim at greater goals than a mere slowing of aging.
Longitudinal trajectories of memory among middle-aged and older people with hearing loss: the influence of cochlear implant use on cognitive functioning
Cochlear implants (CI) are the gold standard intervention for severe to profound hearing loss, a known modifiable risk factor for dementia. However, it remains unknown whether CI use might prevent the age-related cognitive decline. Recent studies are encouraging but are limited, mainly by short follow-up periods and, for ethical reasons, lack of appropriate control groups. Further, as age-related cognitive decline is multifaceted and not linear, other statistical approaches have to be evaluated.
Immediate and delayed recall as measures of cognitive function were assessed in 75 newly implanted CI users (mean age 65.41 years ± 9.19) for up to 5 years (mean 4.5 ± 0.5) of CI use and compared to 8,077 subjects of the same age range from two longitudinal cohort studies, the Health and Retirement Study (HRS) and the English Longitudinal Study of Aging (ELSA). Linear and quadratic changes in cognitive trajectories were analyzed in detail using mixed growth models, considering possible confounders.
For CI users, the linear time slope showed a significant improvement in the specific domains (recall and delayed recall) over time. The quadratic time slope clearly indicated that the predicted change after CI provision followed an inverted U-shape with a predicted decline 2 years after CI provision. In the hearing-impaired group, a significant decline over time was found, with steeper declines early on and the tendency to flatten out in the follow-up. In conclusion, cochlear implant use seems to boost cognitive trajectories in the first years after implantation. However, long-term prevention of dementia seems to need far more than restoration of hearing loss.
Lifestyle Produces a Much Greater Contribution to Human Life Expectancy than a Genetic Risk Score
https://www.fightaging.org/archives/2023/10/lifestyle-produces-a-much-greater-contribution-to-human-life-expectancy-than-a-genetic-risk-score/
Since the advent of very large databases of combined human genetic and epidemiological information, the evidence has increasingly leaned to support only a modest effect of genetic variation on human life span variation. Setting aside small populations with rare mutations, lifestyle has a much greater effect on life expectancy than one's genes. Even cases of familial longevity might largely result from transmission of culture, and thus lifestyle choices, rather than transmission of genetic variants.
Today's open access paper reports on data in which both genetic risk and lifestyle risk can be assessed. It is worth noting that the genetic risk is here limited to a consideration of only a few genes, but equally only a small number of genetic variants have been shown to robustly correlate with human life span. The thing to take away from the results is the degree to which the effects of a healthy lifestyle on life expectancy are similar for the high genetic risk and low genetic risk cohorts. In other words, the high genetic risk as assessed here isn't doing all that much to life expectancy when compared to the consequences of lifestyle choices.
Healthy lifestyle in late-life, longevity genes, and life expectancy among older adults: a 20-year, population-based, prospective cohort study
Lifestyle and longevity genes have different and important roles in the human lifespan; however, the association between a healthy lifestyle in late-life and life expectancy mediated by genetic risk is yet to be elucidated. We aimed to investigate the associations of healthy lifestyle in late-life and genetic risk with life expectancy among older adults.
A weighted healthy lifestyle score was constructed from the following variables: current non-smoking, non-harmful alcohol consumption, regular physical activity, and a healthy diet. Participants were recruited from the Chinese Longitudinal Healthy Longevity Survey, a prospective community-based cohort study that took place between 1998 and 2018. Eligible participants were aged 65 years and older with available information on lifestyle factors at baseline, and then were categorised into unhealthy (bottom tertile of the weighted healthy lifestyle score), intermediate (middle tertile), and healthy (top tertile) lifestyle groups. A genetic risk score was constructed based on 11 lifespan loci among 9,633 participants, divided by the median and classified into low and high genetic risk groups. Stratified Cox proportional hazard regression was used to estimate the interaction between genetic and lifestyle factors on all-cause mortality risk.
36,164 adults aged 65 years and older were recruited, among whom a total of 27 ,462 deaths were documented during a median follow-up of 3.12 years and included in the lifestyle association analysis. Compared with the unhealthy lifestyle category, participants in the healthy lifestyle group had a lower all-cause mortality risk (hazard ratio 0.56). The highest mortality risk was observed in individuals in the high genetic risk and unhealthy lifestyle group (hazard ratio 1.80). The absolute risk reduction was greater for participants in the high genetic risk group. A healthy lifestyle was associated with a gain of 3.84 years at the age of 65 years in the low genetic risk group, and 4.35 years in the high genetic risk group.
A healthy lifestyle, even in late-life, was associated with lower mortality risk and longer life expectancy among Chinese older adults, highlighting the importance of a healthy lifestyle in extending the lifespan, especially for individuals with high genetic risk.
Towards Inhibition of α-Synuclein Aggregation
https://www.fightaging.org/archives/2023/10/towards-inhibition-of-%ce%b1-synuclein-aggregation/
A small number of the thousands of different proteins in the body are capable of misfolding in ways that encourage other molecules of the same protein to misfold in the same way. These misfolded proteins spread, multiply, and form solid aggregates. The surrounding halo of altered biochemistry that attends these aggregates is harmful to cells, leading to dysfunction, inflammation, and even cell death. Many neurodegenerative conditions involve protein aggregation, of amyloid-β, α-synuclein, and tau, among others. Aggregation of misfolded transthyretin, meanwhile, contributes to cardiovascular disease and other conditions.
The dominant therapeutic approach for most of the protein aggregates in the brain is clearance via immunotherapy. For transthyretin, the research and development community has focused on use of small molecules that inhibit the misfolding and aggregation process, allowing cellular quality control mechanisms to catch up with the task of degrading aggregates. This inhibition approach could be applied to other protein aggregates as well, as illustrated by today's research materials focused on α-synuclein.
"Anti-tangle" molecule could aid search for new dementia treatments
Alpha-synuclein, a protein found in brain cells, is commonly associated with neurodegenerative diseases such as Parkinson's, a debilitating neurological disorder that affects millions worldwide. In healthy individuals, alpha-synuclein interacts with cell membranes where it plays a role in how brain cells (neurons) communicate with each other, but as a person ages, the 3D shape of the protein can malform, or "misfold", causing it to start sticking together to form toxic clumps in the brain. Over time these clumps continue to stack, forming fibres that can interfere with the protein's normal role, eventually killing brain cells, contributing to the development of Parkinson's and related dementia diseases.
A team of scientists took a protein fragment, or peptide, from one end of the alpha-synuclein protein strand and mixed it with samples of the full-length alpha-synuclein protein. They found that the fragment prevented misfolding in vitro, by stabilising its normal structure to prevent it from tangling, forming clumps and disrupting the cell membrane. This research opens up new avenues for therapeutic development, potentially in the future leading to drugs that can target and disrupt alpha-synuclein misfolding, ultimately preventing or slowing down the progression of diseases like Parkinson's.
An N-terminal alpha-synuclein fragment binds lipid vesicles to modulate lipid-induced aggregation
Misfolding and aggregation of alpha-synuclein (αS) into toxic conformations is involved in numerous neurodegenerative diseases. In Parkinson's disease (PD), this occurs within dopaminergic neurons, causing cell death and disease symptoms. During αS aggregation, many protein-protein interactions (PPIs) form over broad and flat protein surfaces, limiting potential for small-molecule intervention. Peptides, however, harbor great therapeutic promise since they can selectively engage with and modulate the large surface areas involved yet are small enough to function as druggable agents if suitably structured.
Here, we explore the first 25 residues of αS (αS1-25) as a template for peptide-based αS aggregation antagonists. We report that αS1-25 inhibits lipid-induced αS aggregation in a dose-dependent manner. αS1-25 functions by binding to lipids to prevent αS binding, with both αS and peptide requiring lipid for inhibition to occur. These findings present a potential mechanistic route for the treatment or prevention of PD.
Combining CAR-T Therapy with Tumor-Seeking Bacteria
https://www.fightaging.org/archives/2023/10/combining-car-t-therapy-with-tumor-seeking-bacteria/
T cells engineered to express a chimeric antigen receptor (CAR) aggressively attack other cells bearing surface markers that match that receptor. This approach is expensive, as it requires engineering cells taken from a patient, and developing CARs specific to each cancer subtype, but has so far proven effective against a number of forms of cancer. Not all cancers are consistent in markers expressed by cancer cells, however, and many cancers exhibit rapid evolution of tumor cell characteristics - only a marginal slowing of progress is achieved when much of the cancer can quickly become immune to a therapeutic approach.
In today's research materials, scientist report on an interesting and novel way to make CAR-T therapies both more effective and logistically efficient. The researchers used engineered, tumor-seeking bacteria to introduce consistency into the markers found on cancerous cells, allowing engineered immune cells to more efficiently destroy tumor tissue. Targeting different cancers then becomes a matter of picking the right bacterial species to engineer, most of which are quite capable of seeking out many different types of cancer, as well as adapting to the evolution of a tumor, rather than having to develop new CARs.
Engineered Bacteria Paint Targets on Tumors for Cancer-killing T Cells to See
For several years, researchers have been successfully using chimeric antigen receptor (CAR) T cells to target specific antigens found on blood cells as a cure for patients with leukemia and lymphoma. But solid tumors, like breast and colon cancers, have proven to be more difficult to home in on. Solid tumors contain a mix of cells that display different antigens on their surface - often shared with healthy cells in the body. Thus, identifying a consistent and safe target has impeded the success of most CAR-T cell therapy for solid tumors at the first phase of development.
Researchers have now engineered tumor-colonizing bacteria (probiotics) to produce synthetic targets in tumors that direct CAR-T cells to destroy the newly highlighted cancer cells. "Traditional CAR-T therapies have relied on targeting natural tumor antigens. This is the first example of pairing engineered T cells with engineered bacteria to deliver synthetic antigens safely, systemically, and effectively to solid tumors. This could have a significant impact on the treatment of many cancers."
This probiotic-guided CAR-T cell (ProCAR) platform is the first time that scientists have not only successfully combined engineered probiotics with CAR-T cells, but have also demonstrated the first evidence of CARs responding to synthetic antigens produced directly within the tumor. "Combining the advantages of tumor-homing bacteria and CAR-T cells provides a new strategy for tumor recognition, and this builds the foundation for engineered communities of living therapies. We chose to bridge the individual limitations of these two cell therapies by combining the best features of each - using bacteria to place the targets, and T cells to destroy the malignant cells."
Probiotic-guided CAR-T cells for solid tumor targeting
A major challenge facing tumor-antigen targeting therapies such as chimeric antigen receptor (CAR)-T cells is the identification of suitable targets that are specifically and uniformly expressed on heterogeneous solid tumors. By contrast, certain species of bacteria selectively colonize immune-privileged tumor cores and can be engineered as antigen-independent platforms for therapeutic delivery.
To bridge these approaches, we developed a platform of probiotic-guided CAR-T cells (ProCARs), in which tumor-colonizing probiotics release synthetic targets that label tumor tissue for CAR-mediated lysis in situ. This system demonstrated CAR-T cell activation and antigen-agnostic cell lysis that was safe and effective in multiple xenograft and syngeneic models of human and mouse cancers. We further engineered multifunctional probiotics that co-release chemokines to enhance CAR-T cell recruitment and therapeutic response.
Worldwide Trends in Healthy versus Unhealthy Remaining Life Expectancy at 60
https://www.fightaging.org/archives/2023/10/worldwide-trends-in-healthy-versus-unhealthy-remaining-life-expectancy-at-60/
Human life expectancy has been trending upwards, slowly, for a very long time. Life expectancy at birth is influenced by a great many factors that have little to do with aging, and so is much less interesting than, say, life expectancy at 60. At present, that number increases by one year with every passing decade. This has been the case in an environment in which essentially nothing was being done to deliberately target underlying mechanisms of aging. The trend is an incidental side-effect of, most likely, (a) better life-long control over the burden of infectious disease, and (b) general improvements in the ability to treat age-related conditions without addressing their deeper causes, the mechanisms of aging.
The outcome of a modest slowing of aging across the life span coupled with better medicines for age-related diseases that fail to target mechanisms of aging is the situation that we find ourselves in, in which all three of (a) time spent in health, (b) time spent in ill health, and (c) overall life span are increasing over time. Near all of the furor over the burden of healthcare spending in overly centralized medical systems derives from the increase in time spent in ill health. It is expensive and difficult to keep someone going when the therapies to hand do not address the actual causes of ill health, meaning the specific forms of cell and tissue damage that cause aging.
All of this will change dramatically with the advent of rejuvenation therapies that deliberately target that underlying cell and tissue damage. The point of the exercise is to both greatly extend time spent in health and make it possible to take people in late-life disease states and fix their issues, restoring them to health. This won't happen overnight, it will be an incremental progression of ever better partial successes that add up over time, but it will happen.
Long-term Trends in Healthy and Unhealthy Life Expectancy Among Adults Aged 60 - A Global Perspective, 1990-2019
Although life expectancy has been a crucial health population metric, distinguishing between "healthy" and "unhealthy" years lived gains heightened significance, particularly in the face of medical advancements that prolong life. Despite extensive research on life expectancy and healthy life expectancy (HALE), a noticeable gap prevails in concurrent investigations of healthy and unhealthy life expectancies in the older demographic.
Using data derived from the Global Burden of Disease Study 2019 (GBD 2019), our research provides an in-depth analysis of global trends in these three metrics from 1990 to 2019 for older adults. For the study, Life Expectancy at age 60 (LE-60), constructed based on age-specific mortality rates from all locations and estimations years across all populations by sex, and the HALE at age 60 (HALE-60) were employed to assess "healthy" years. Proportion of Years in Ill Health at age 60 (PYIH-60), meaning (LE-60 - HALE-60) / LE-60, has been used to calculate the "unhealthy" years proportion in life expectancy.
The study yields several critical observations. First, the disparity between global life expectancy, which has been on a steady rise, and HALE, suggests a prolonged period of morbidity or disability for older adults. This emphasizes the need for health systems to shift focus from extending life to prioritizing quality of the extended years. Unlike unhealthy life expectancy, augmenting the health life expectancy of a population results in higher per capita output levels and improved labor productivity. This also allows for the reduction of social and medical security costs for older adults. Future research assessing the impact of specific.
Attention must also be paid to regional variations. The swift increase in life expectancy in regions like South Asia and East Asia may be attributed to economic growth, enhancements in healthcare infrastructure, and successful public health interventions. Yet, the concurrent enlargement of unhealthy life expectancy in certain regions underlines the urgency for interventions targeted at addressing health challenges unique to specific regions. The significant increase in China's life expectancy warrants special attention. This progress may be attributed to the country's strategic health reforms, economic growth, and public health initiatives. However, the rise in PYIH-60 among older adults in China indicates an area of concern, suggesting potential areas for targeted healthcare interventions and policy implementation.
The correlation between HALE-60 and various sociodemographic and health system indicators illuminates the interaction between social determinants and health outcomes. The observed positive relationship, showing that an increase in sociodemographic index (SDI), universal health coverage (UHC), healthcare access and quality index (HAQ), and healthcare expenditure leads to an improvement in HALE-60, suggests that comprehensive socio-economic development paired with accessible, high-quality healthcare yields measurable benefits for the aging population.
Imaging of Chromatin Structure as a Basis for an Aging Clock
https://www.fightaging.org/archives/2023/10/imaging-of-chromatin-structure-as-a-basis-for-an-aging-clock/
Researchers here report a novel approach to building an aging clock, a system that can usefully measure biological age, the growing burden of damage and dysfunction. Epigenetic data, usually the status of DNA methylation at various sites on the genome, has been used to construct aging clocks in the past. Epigenetic changes of all sorts alter gene expression by altering the structure of chromatin, folded DNA in the cell nucleus, determining which regions and genes are exposed to transcriptional machinery. Thus why not directly assess changes in the structure of chromatin via microscopy imaging approaches? Researchers have now tried that, and it seems to work.
Biomarkers of biological age that predict the risk of disease and expected lifespan better than chronological age are key to efficient and cost-effective healthcare. Several years ago, we pioneered microscopic imaging of epigenetic landscapes rooted in the analysis of chromatin topography in single cells. We employed immunolabeling with antibodies specific for histone modifications (e.g. acetylation and methylation marks) and automated microscopy to capture cell-specific patterns using image texture analysis, resulting in multiparametric signatures of cellular states. Here, we took advantage of this technique to develop an image-based chromatin and epigenetic age (ImAge), a fundamentally different approach to studying aging compared to DNA methylation clocks.
We observed the emergence of intrinsic trajectories of ImAge using dimensionality reduction without regression on chronological age. ImAge was correlated with chronological age in all tissues and organs examined and was consistent with the expected acceleration and/or deceleration of biological age in chronologically identical mice treated with chemotherapy or following a caloric restriction regimen, respectively. ImAge from chronologically identical mice inversely correlated with their locomotor activity (greater activity for younger ImAge), consistent with the essential role of locomotion as an aging biomarker. Finally, we demonstrated that ImAge is reduced upon partial reprogramming in vivo following transient expression of OSKM in the liver and skeletal muscles of old mice and validated the power of ImAge to assess the heterogeneity of reprogramming.
We propose that ImAge represents the first-in-class individual-level biomarker of aging and rejuvenation with single-cell resolution.
Calorie Restriction Improves Pancreatic Function in Aging Mammals
https://www.fightaging.org/archives/2023/10/calorie-restriction-improves-pancreatic-function-in-aging-mammals/
Beta cells in the pancreas produce insulin and are essential to the regulation of glucose metabolism. Dysfunction in this cell population causes diabetes, whether the origin is autoimmune destruction of beta cells (type 1 diabetes) or senescence of beta cells brought on by obesity (type 2 diabetes). Aging also impairs beta cell function through some of the same mechanisms, such as cellular senescence and constant, unresolved inflammatory signaling. The practice of calorie restriction slows aging, albeit to a greater degree in short-lived species than in long-lived species, and so it is not surprising to see that calorie restriction attenuates this aspect of degenerative aging.
Caloric restriction (CR) extends organismal lifespan and health span by improving glucose homeostasis mechanisms. How CR affects organellar structure and function of pancreatic beta cells over the lifetime of the animal remains unknown. Here, we used single nucleus transcriptomics to show that CR increases the expression of genes for beta cell identity, protein processing, and organelle homeostasis. Gene regulatory network analysis link this transcriptional phenotype to transcription factors involved in beta cell identity (Mafa) and homeostasis (Atf6). Imaging metabolomics further demonstrates that CR beta cells are more energetically competent.
In fact, high-resolution light and electron microscopy indicates that CR reduces beta cell mitophagy and increases mitochondria mass, increasing mitochondrial ATP generation. Finally, we show that long-term CR delays the onset of beta cell aging and senescence to promote longevity by reducing beta cell turnover. Therefore, CR could be a feasible approach to preserve compromised beta cells during aging and diabetes.
Aspects of Iron Metabolism Correlate with Epigenetic Age Acceleration
https://www.fightaging.org/archives/2023/10/aspects-of-iron-metabolism-correlate-with-epigenetic-age-acceleration/
The consensus on iron is that higher levels become an issue in the context of aging, contributing to a number of issues such as raised oxidative stress and creation of the metabolic waste known as lipofuscin. Researchers here provide evidence for increased iron levels to correlate with epigenetic age acceleration, a measure of biological age. This is an expected result, given all of the other data on the possible role of dysfunctional iron metabolism in degenerative aging.
Iron is one of the most essential transition metals in the human body. The balance of iron metabolism, also known as iron homeostasis, is strictly regulated due to its crucial role in erythropoiesis, oxidative phosphorylation, and redox reaction. Evidence has connected altered iron homeostasis with biological aging. For example, epidemiological research reported that over 10% of both men and women aged 65 years or older were anemic in the US, in which iron deficiency made up approximately 20% of all anemia cases. Chronic inflammation of the elder people might also contribute to the alteration of serum iron biomarkers, causing iron deficiency and impaired iron mobilization. On the other hand, cellular iron accumulation in older individuals was observed. Serum level of ferritin, which reflected the storage of iron, was reported to be increasing with age and negatively associated with telomere length. Iron overload in cell induced the accumulation of lipofuscin, which was considered one of the hallmarks of aging and could be cytotoxic.
Epigenetic clocks based on DNA methylation status and chronological age and health-related outcomes were built to discover the impact of both genetic and environmental factors on human aging. Epigenetic age acceleration (EAA) was used to describe individuals with greater epigenetic-clock-estimated age than their true chronological age, indicating worse health outcome. Although iron homeostasis is connected with aging, no research regarding the relationship between epigenetic clocks or EAA and iron homeostasis has been conducted.
Utilizing outcomes from genome-wide association studies (GWAS), Mendelian randomization (MR) has been widely used in discovering causality between exposure factors and outcomes. Researchers have conducted a GWAS of four epigenetic clocks, and subsequent MR analysis identified several risk factors of EAAs. In this study, we conducted a two-sample MR analyses with summarized GWAS data mentioned above to investigate the causal relationship between iron homeostasis and EAAs. Each standard deviation (SD) increase in genetically predicted serum iron was associated with increased GrimAge acceleration (GrimAA), HannumAge acceleration (HannumAA), and Intrinsic epigenetic age acceleration (IEAA). Similar results were also observed in transferrin saturation. Transferrin carries and transports most of the serum iron to organs and tissues.
In conclusion, the results of the present investigation unveiled the causality of iron overload on acceleration of epigenetic clocks. Researches are warranted to illuminate the underlying mechanisms and formulate strategies for potential interventions.
Reviewing the Aging of the Ovaries
https://www.fightaging.org/archives/2023/10/reviewing-the-aging-of-the-ovaries/
The ovaries, like the thymus, undergo a form of degenerative aging that occurs somewhat in advance of the aging of other parts of the body. It leads to the phenomenon of menopause and subsequent consequences to health and function, which, interestingly, is a feature of aging that is shared with only a few other mammalian species. That makes the ovaries and their surrounding tissues an interesting target for the development of ways to slow or reverse loss of function. Maintained ovarian function may prove to modestly slow aging in older women; it is a reasonable hypothesis and goal to pursue given what is known of the interaction of ovarian aging with other aspects of aging in humans.
Ovarian reserve is essential for fertility and influences healthy aging in women. Advanced maternal age correlates with the progressive loss of both the quantity and quality of oocytes. The molecular mechanisms and various contributing factors underlying ovarian aging have been uncovered.
In this review, we highlight some of critical factors that impact oocyte quantity and quality during aging. Germ cell and follicle reserve at birth determines reproductive lifespan and timing the menopause in female mammals. Accelerated diminishing ovarian reserve leads to premature ovarian aging or insufficiency. Poor oocyte quality with increasing age could result from chromosomal cohesion deterioration and misaligned chromosomes, telomere shortening, DNA damage and associated genetic mutations, oxidative stress, mitochondrial dysfunction, and epigenetic alteration.
We also discuss the intervention strategies to delay ovarian aging. Both the efficacy of senotherapies by antioxidants against reproductive aging and mitochondrial therapy are discussed. Functional oocytes and ovarioids could be rejuvenated from pluripotent stem cells or somatic cells. We propose directions for future interventions. As couples increasingly begin delaying parenthood in life worldwide, understanding the molecular mechanisms during female reproductive aging and potential intervention strategies could benefit women in making earlier choices about their reproductive health.
A Microbial Metabolite can Harm Dopaminergenic Neurons
https://www.fightaging.org/archives/2023/10/a-microbial-metabolite-can-harm-dopaminergenic-neurons/
The standard view of Parkinson's disease is that misfolding of α-synuclein occurs in the gut or brain, and then spreads in a prion-like manner to cause widespread dysfunction and cell death throughout the brain. The most vulnerable cells are dopaminergic neurons, and their destruction causes the most evident symptoms of the disease. Some people have a greater risk of Parkinson's disease than others. The most studied vulnerabilities are genetic variants that appear to make dopaminergic neurons even more vulnerable to stress. Environmental factors may also attack this population of neurons: here, researchers note that a soil bacteria sometimes found in the gut microbiome can produce a metabolite that is toxic to dopaminergic neurons.
The causes of nigrostriatal cell death in idiopathic Parkinson's disease are unknown, but exposure to toxic chemicals may play some role. We followed up here on suggestions that bacterial secondary metabolites might be selectively cytotoxic to dopaminergic neurons. Extracts from Streptomyces venezuelae were found to kill human dopaminergic neurons in vitro. Utilizing this model system as a bioassay, we identified a bacterial metabolite known as aerugine and confirmed this finding by chemical re-synthesis.
This compound was previously shown to be a product of a wide-spread biosynthetic cluster also found in the human microbiome and in several pathogens. Aerugine triggered half-maximal dopaminergic neurotoxicity at 3-4 µM. It was less toxic for other neurons (10-20 µM), and non-toxic (at <100 µM) for common human cell lines. Neurotoxicity was completely prevented by several iron chelators, by distinct anti-oxidants and by a caspase inhibitor.
In the Caenorhabditis elegans model organism, general survival was not affected by aerugine concentrations up to 100 µM. When transgenic worms, expressing green fluorescent protein only in their dopamine neurons, were exposed to aerugine, specific neurodegeneration was observed. The toxicant also exerted functional dopaminergic toxicity in nematodes as determined by the "basal slowing response" assay.
Thus, our research has unveiled a bacterial metabolite with a remarkably selective toxicity toward human dopaminergic neurons in vitro and for the dopaminergic nervous system of Caenorhabditis elegans in vivo. These findings suggest that microbe-derived environmental chemicals should be further investigated for their role in the pathogenesis of Parkinson's disease.
The AgingReG Database of Regulatory Relationships in Aging
https://www.fightaging.org/archives/2023/10/the-agingreg-database-of-regulatory-relationships-in-aging/
The scientific community seeks a complete understanding of the progression of degenerative aging, at the fine-grained level of environmental influences on specific molecular machinery in the cell, by cell type, by cell status, and then how all of those mechanisms interact with one another as they change. It is a vast project, and may well be largely irrelevant to the task of building a first generation of rejuvenation therapies based on what we presently know of the forms of damage and dysfunction that accumulate in cells and tissues with age. If damage can be periodically repaired, then it isn't so important to know what that damage does in fine detail when it is left to accumulate.
Aging and cellular senescence are characterized by a progressive loss of physiological integrity, which could be triggered by aging factors such as physiological, pathological and external factors. Numerous studies have shown that gene regulatory events play crucial roles in aging, increasing the need for a comprehensive repository of regulatory relationships during aging. Here, we established a manually curated database of aging factors (AgingReG), focusing on the regulatory relationships during aging with experimental evidence in humans. By curating thousands of published items in the literature, 2157 aging factor entries (1345 aging gene entries, 804 external factor entries and eight aging-related pathway entries) and related regulatory information were manually curated.
The regulatory relationships were classified into four types according to their functions: (i) upregulation, which indicates that aging factors upregulate the expression of target genes during aging; (ii) downregulation, which indicates that aging factors downregulate the expression of target genes during aging; (iii) activation, which indicates that aging factors influence the activity of target genes during aging and (iv) inhibition, which indicates that aging factors inhibit the activation of target molecule activity, leading to declined or lost target activity. AgingReG involves 651 upregulating pairs, 632 downregulating pairs, 330 activation-regulating pairs and 34 inhibition-regulating pairs, covering 195 disease types and more than 800 kinds of cells and tissues from 1784 published literature studies. AgingReG provides a user-friendly interface to query, browse and visualize detailed information about the regulatory relationships during aging. We believe that AgingReG will serve as a valuable resource database in the field of aging research.
Mitochondrial DNA Mislocalization is an Important Driver of the Senescence-Associated Secretory Phenotype
https://www.fightaging.org/archives/2023/10/mitochondrial-dna-mislocalization-is-an-important-driver-of-the-senescence-associated-secretory-phenotype/
The presence of lingering senescent cells characteristic of aged tissues is harmful due to the pro-inflammatory signaling produced by these cells, the senescence-associated secretory phenotype (SASP). Researchers here show that mitochondrial stress leading to mislocalization of mitochondrial DNA and a consequent inflammatory response is important in the generation of the SASP. Mammalian cells have evolved an innate immune response to the presence of foreign DNA, but mitochondrial DNA is sufficiently bacteria-like that it can trigger this response. Thus the mitochondrial stress and dysfunction that takes place in aged tissues can provoke some fraction of the chronic inflammation of aging. This process appears to be particularly pronounced in senescent cells.
Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP). Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated.
Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS-STING pathway, a major regulator of the SASP.
We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.
In Search of Target Mechanisms to Enhance Aggrephagy
https://www.fightaging.org/archives/2023/10/in-search-of-target-mechanisms-to-enhance-aggrephagy/
Aggrephagy is a comparatively poorly understood cell maintenance mechanism that targets aggregated proteins, distinct from the ubiquitin-proteasome system that disposes of misfolded or otherwise problematic proteins. Alterations to protein structure break the proper function of the protein, and damaged machinery causes problems to a cell. Protein aggregation is a feature of neurodegenerative conditions, and scientists are in search of ways to encourage cells to more rapidly and efficiently remove these aggregates before they accumulate to pathological levels.
The ubiquitin-proteasome system (UPS) and autophagy are the two primary cellular pathways of misfolded or damaged protein degradation that maintain cellular proteostasis. When the proteasome is dysfunctional, cells compensate for impaired protein clearance by activating aggrephagy, a type of selective autophagy, to eliminate ubiquitinated protein aggregates; however, the molecular mechanisms by which impaired proteasome function can activate aggrephagy remain poorly understood.
Here, we demonstrate that activation of aggrephagy is transcriptionally induced by the transcription factor NRF1 in response to proteasome dysfunction. Although NRF1 has been previously shown to induce the expression of proteasome genes after proteasome inhibition (i.e., the proteasome bounce-back response), our genome-wide transcriptome analyses identified autophagy-related p62 and GABARAPL1 as genes directly targeted by NRF1. Intriguingly, NRF1 was also found to be indispensable for the formation of p62-positive puncta and their colocalization with ULK1 and TBK1, which play roles in p62 activation via phosphorylation. Consistently, NRF1 knockdown substantially reduced the phosphorylation rate of p62.
Finally, NRF1 selectively upregulated the expression of GABARAPL1, an ATG8 family gene, to induce the clearance of ubiquitinated proteins. Our findings highlight the discovery of an activation mechanism underlying NRF1-mediated aggrephagy through gene regulation when proteasome activity is impaired.
Modest Calorie Restriction Improves Muscle Quality in Humans
https://www.fightaging.org/archives/2023/10/modest-calorie-restriction-improves-muscle-quality-in-humans/
The practice of calorie restriction is known to improve health in many ways. Researchers continue to perform analyses on the samples taken from the human CALERIE study that was conducted some years ago, in which comparatively mild calorie restriction produced worthwhile results in the study participants. Here, researchers note improvements in markers of muscle quality, as one might expect given the animal studies of calorie restriction in which similar improvements were observed in skeletal muscle.
The lifespan extension induced by 40% caloric restriction (CR) in rodents is accompanied by postponement of disease, preservation of function, and increased stress resistance. Whether CR elicits the same physiological and molecular responses in humans remains mostly unexplored. In the CALERIE study, 12% CR for 2 years in healthy humans induced minor losses of muscle mass (leg lean mass) without changes of muscle strength, but mechanisms for muscle quality preservation remained unclear.
We performed high-depth RNA-Seq (387-618 million paired reads) on human vastus lateralis muscle biopsies collected from the CALERIE participants at baseline, 12- and 24-month follow-up from the 90 CALERIE participants randomized to CR and "ad libitum" control. Using linear mixed effect model, we identified protein-coding genes and splicing variants whose expression was significantly changed in the CR group compared to controls, including genes related to proteostasis, circadian rhythm regulation, DNA repair, mitochondrial biogenesis, mRNA processing/splicing, FOXO3 metabolism, apoptosis, and inflammation.
Changes in some of these biological pathways mediated part of the positive effect of CR on muscle quality. Differentially expressed splicing variants were associated with change in pathways shown to be affected by CR in model organisms. Two years of sustained CR in humans positively affected skeletal muscle quality, and impacted gene expression and splicing profiles of biological pathways affected by CR in model organisms, suggesting that attainable levels of CR in a lifestyle intervention can benefit muscle health in humans.
Reviewing the Potential of Extracellular Vesicles to Treat Degenerative Bone Conditions
https://www.fightaging.org/archives/2023/10/reviewing-the-potential-of-extracellular-vesicles-to-treat-degenerative-bone-conditions/
First generation stem cell therapies, in which cells near entirely die following transplantation, cause benefits via changes in native cell behavior resulting from the signaling produced by the transplanted cells. Much of cell signaling is carried in extracellular vesicles, membrane-bound packages of various molecules. The types, contents, and circumstances of creation of extracellular vesicles are not fully understood, a work in progress. Harvesting these vesicles from specific cell types known to be beneficial when transplanted is a way to circumvent this lack of knowledge in the near term.
Degenerative bone disorders, encompassing conditions such as intervertebral disc degeneration (IVDD), osteoarthritis (OA), and osteoporosis (OP), exert a profound impact on the well-being of individuals. In recent years, the landscape of regenerative medicine has been transformed by the emergence of stem cell-derived extracellular vesicles (EVs) therapies, presenting a promising approach for improving degenerative bone disorders.
These diminutive yet potent membrane-enclosed vesicles, released by stem cells, have emerged as the effective factors responsible for the regenerative outcomes witnessed in stem cell therapies. With their bioactive cargo, these EVs derived from stem cells release a complex of regenerative signals, directing a coordinated interaction within the complicated microenvironment of deteriorating bone. This captivating phenomenon has captured the attention of both researchers and clinicians, as stem cell-derived EVs show their remarkable potential in reshaping the landscape of regenerative medicine.
By harnessing the inherent regenerative attributes of stem cells and utilizing the distinctive cargo encapsulated within their secreted EVs, researchers, and clinicians aspire to surmount the constraints frequently linked to conventional therapeutic modalities. In contrast to conventional methods primarily centered on symptom management, this pioneering strategy aims to exploit the innate healing potential of the human body. In this extensive review, we perform an intriguing exploration to investigate the captivating domain of therapies involving EVs derived from stem cells, with a particular emphasis on their prospective applications in revitalizing degenerated bone tissues.