Fight Aging! Newsletter, January 15th 2024 – Fight Aging!
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A Direct Link Between Genomic Instability and Inflammation in Senescent Cells
https://www.fightaging.org/archives/2024/01/a-direct-link-between-genomic-instability-and-inflammation-in-senescent-cells/
Aging is characterized by constant sterile inflammation, a state that is disruptive to tissue structure and function. A number of forms of molecular damage have been shown via various mechanisms to provoke this inflammation. Mitochondrial dysfunction, for example causes mitochondrial DNA to mislocalize to the cytoplasm, where it triggers an innate immune response that evolved to recognize the presence of bacterial DNA. Mitochondria are the evolved descendants of ancient symbiotic bacteria, and their remnant DNA is close enough to bacterial genomes for this to occur.
In today’s open access paper, researchers discuss a different direct link between mutational damage to the genome and inflammation. It nonetheless also involves mitochondria and triggering of the cGAS-STING pathway that recognizes mislocalized DNA fragments. The authors of the paper consider this mechanism in the context of senescent cells, which actively generate inflammatory signaling. Senescent cells are also characterized by DNA damage, and undergo a significant amount of that damage in the process of becoming senescent. Research into the mechanisms driving senescent cell inflammatory signaling may lead to ways to suppress this damaging contribution to the inflammation of aging.
A mitochondria-regulated p53-CCF circuit integrates genome integrity with inflammation
Genomic instability and inflammation are distinct hallmarks of aging, but the connection between them is poorly understood. Understanding their interrelationship will help unravel new mechanisms and therapeutic targets of aging and age-associated diseases. Here we report a novel mechanism directly linking genomic instability and inflammation in senescent cells, through a mitochondria-regulated molecular circuit that connects the p53 tumor suppressor and cytoplasmic chromatin fragments (CCF), a driver of inflammation through the cGAS-STING pathway.
Activation or inactivation of p53 by genetic and pharmacologic approaches showed that p53 suppresses CCF accumulation and the downstream inflammatory senescence-associated secretory phenotype (SASP), independent of its effects on cell cycle arrest. p53 activation suppressed CCF formation by promoting DNA repair, reflected in maintenance of genomic integrity, particularly in subtelomeric regions, as shown by single cell genome resequencing. Activation of p53 by pharmacological inhibition of MDM2 in old mice decreased features of SASP in liver, indicating a senomorphic role in vivo. Remarkably, mitochondria in senescent cells suppressed p53 activity by promoting CCF formation and thereby restricting ATM-dependent nuclear DNA damage signaling.
This data provides evidence for a mitochondria-regulated p53-CCF circuit in senescent cells that controls DNA repair, genome integrity and inflammatory SASP, and is a potential target for senomorphic healthy aging interventions.
Chronological Age is Not a Good Component of Patient Risk Assessment
https://www.fightaging.org/archives/2024/01/chronological-age-is-not-a-good-component-of-patient-risk-assessment/
Chronological age is embedded in a great many standardized, widely-used protocols for patient risk assessment. Age-related diseases are, after all, age-related, and this use of chronological age has long seemed a reasonable choice. That said, we are now moving into an era in which novel means of measuring biological age are under development, such as epigenetic clocks.
Biological age is the burden of damage and dysfunction resulting from the causative processes of aging. Obviously, this should better reflect the odds of suffering age-related disease. While biological age correlates with chronological age, there is a great deal of room for differences between the two in any given individual. This development has also highlighted the point that a number of established functional measures, such as grip strength and other components of frailty assessment, particularly when these measures are combined together, might also be considered crude assessments of biological age.
This new knowledge regarding the measurement of age and processes of aging is making chronological age appear an ever worse choice for patient risk assessment. Different people age at meaningfully different rates. Today that occurs largely as the result of the combination of lifestyle choice, exposure to persistent pathogens, and the presence of environmental stressors such as particulate air pollution. In the decades ahead it will occur largely due to the use of interventions to repair and reverse causative processes of aging, progressively decoupling aging from the chronological passage of time.
Personalizing Cardiovascular Disease Risk Assessment: Is it Time to Forget About Chronologic Age?
It is commonly said that “age is just a number,” and chronologic age, calculated as the time elapsed from birth, has been the primary way to define an individual’s age. However, this method fails to account for the complex and diverse processes of aging. Indeed, a person’s genetics along with their diet, lifestyle, and cumulative exposure to risk factors leads to significant heterogeneity in biologic age for persons of the same chronologic age. This creates a problem for cardiovascular risk calculators such as the Pooled Cohort Equation (PCE), because chronologic age is the most heavily weighted variable. Nearly all adults younger than 40 years have a low 10-year predicted risk of atherosclerotic cardiovascular disease (ASCVD), while most men older than 60 and women older than 65 years of age have at least an intermediate 10-year ASCVD risk from 7.5% to 20%, regardless of their traditional risk factor burden.
The shortcomings of chronologic age have led to an increased recognition that other measures are needed to better classify an individual’s biologic age and ASCVD risk. Genetic biomarkers of DNA methylation and telomere length have been linked to acceleration of the aging processes, but the cost of testing and expertise needed for interpretation of the results limit their widespread use in clinical practice. Interestingly, even a subjective estimation of an individual’s perceived age provides significant insight into their biologic age and survival. More direct quantification of arterial or vascular aging with the use of coronary artery calcium (CAC) scoring or noninvasive markers of arterial stiffness such as pulse-wave velocity (PWV) also better classify biologic age, which in turn improves ASCVD risk stratification relative to models that rely on chronologic age and may provide a more accurate and personalized estimate of ASCVD risk.
Compared with measuring systolic and diastolic blood pressure, measuring PWV provides distinct information on vascular health that is specifically related to vascular compliance and distensibility and is an early marker of poor vascular health, even before the development of hypertension. PWV is also strongly associated with cardiovascular outcomes and improves risk prediction beyond traditional cardiovascular risk factors, with a 30% increased risk for cardiovascular disease (CVD) for every 1 standard deviation higher PWV. As such, PWV is one simple method to improve the measurement of biologic age.
NRF1 is Neuroprotective via Proteasomal Function
https://www.fightaging.org/archives/2024/01/nrf1-is-neuroprotective-via-proteasomal-function/
Cells maintain themselves against damage and stress via a range of maintenance processes. These include autophagy, in which proteins and structures are transported to the lysosome to be broken down by enzymes, and the ubiquitin-proteasome system, in which specific proteins are dismantled in the proteasome, among others. It is well demonstrated that upregulation of these processes improves resistance to cell stress, and can also improve long-term health, reducing risk of age-related disease and slowing progression of those conditions. Upregulation of autophagy, for example, is a feature of many interventions that modestly slow the progression of degenerative aging. Some approaches to improve proteasomal function have also been shown to slow aging and extend life in short-lived species. Thus a broad range of research is focused on increasing the efficiency or effectiveness of these processes.
In today’s open access paper, researchers discuss upregulation of NRF1, also known as NFE2L1, as a way to improve proteasomal function. The specific focus is neurodegeneration rather than aging more generally, but it is still the case that greater resistance to the consequences of cell stress can preserve function in the face of many distinct and complex damaging processes. While the research community expends a great deal of time and effort on the question of how to improve the operation of systems of cell maintenance, it remains the case that few well developed therapies have shown any improvement over exercise in this respect. Large gains seem elusive, particularly as effect sizes appear to diminish with increased species life span. This perhaps suggests that many of the possible optimizations are already operating in long-lived species.
NFE2L1/Nrf1 serves as a potential therapeutical target for neurodegenerative diseases
Nuclear factor-erythroid 2 (NFE2)-related factor 1 (Nrf1, encoded by NFE2L1) acts as a transcription factor involved in multiple essential life processes, e.g., redox signaling, cellular metabolism, and proteasomal regulation. Of note, NFE2L1 binds to the promoter regions of its target genes through the antioxidant response elements (AREs), crucially to drive transactivation of those stress-responsive and cytoprotective genes, which are also present in the promoters of genes encoding proteasomal subunits. Further studies revealed that NFE2L1 regulates multiple antioxidant genes, such as HMOX1, SOD1, or GCLC; it has also been verified as a master regulator of the ubiquitin-proteasome system (UPS) by controlling the transcriptional expression of almost all proteasome subunits and relevant co-factors.
Multiple neuroprotective interventions, as aforementioned, rely mainly on increasing NFE2L1 activity in neurons, which enhances the cell survival ability to defend against various stressors. NFE2L1 is essential for the proper functioning of proteasomes, and its lack results in an aberrant accumulation of ubiquitinated proteins through the nervous system. Notably, the knockout of the NFE2L1 gene in animal models brings about a severe pathology that resembles human neurodegenerative diseases. In the postmortem analyses, reduced NFE2L1 levels were found in the substantia nigra region of patients with Parkinson’s disease and in the hippocampus of patients with Alzheimer’s disease. This presents a strong case of NFE2L1 deficiency involved in the pathogenesis of neurodegenerative diseases.
Therefore, it is plausible that NFE2L1 has significant potential in translational medicine to serve as a therapeutic target for these neurodegenerative diseases. Nevertheless, since NFE2L1 is widely expressed throughout a given organism’s whole body, a neuron-specific activation of this transcription factor would be more beneficial to minimize off-target effects.
Amyloid-β Inhibits Synaptic Proteasomal Function in Alzheimer’s Disease
https://www.fightaging.org/archives/2024/01/amyloid-%ce%b2-inhibits-synaptic-proteasomal-function-in-alzheimers-disease/
Cells contain many proteasomes, one portion of a broad array of repair and quality control mechanisms. The proteasome is a hollow, capped cylindrical structure made of many component proteins. It admits entry only to proteins that have been decorated with the addition of a ubiquitin molecule. Once inside the proteasome’s central chamber, the ubiquinated protein is disassembled into short peptides suitable for reuse in the synthesis of other proteins. This ubiquitin-proteasome system is necessary to prevent the buildup of damaged, misfolded, unfolded, or otherwise unwanted proteins.
It has been noted that proteasomal function is impaired in Alzheimer’s disease patients, and that inhibition of proteasomal function, such as by downregulating expression of specific proteasomal component proteins, produces symptoms akin to those of neurodegenerative conditions. In today’s open access paper, researchers further explore this topic, showing that the amyloid-β associated with Alzheimer’s disease is capable of inhibiting proteasomal function in the synapses that link neurons in the brain. This points to the merits of both clearance of amyloid-β and also the development of ways to augment proteasomal function, such as by increased expression of some of its component proteins.
Synaptic proteasome is inhibited in Alzheimer’s disease models and associates with memory impairment in mice
The proteasome plays key roles in synaptic plasticity and memory by regulating protein turnover, quality control, and elimination of oxidized/misfolded proteins. Here, we investigate proteasome function and localization at synapses in Alzheimer’s disease (AD) post-mortem brain tissue and in experimental models.
We found a marked increase in ubiquitinylated proteins in post-mortem human AD hippocampi compared to controls. Using several experimental models, we show that amyloid-β oligomers (AβOs) inhibit synaptic proteasome activity and trigger a reduction in synaptic proteasome content. We further show proteasome inhibition specifically in hippocampal synaptic fractions derived from Alzheimer’s model mice.
Reduced synaptic proteasome activity instigated by AβOs is corrected by treatment with rolipram, a phosphodiesterase-4 inhibitor, in mice. Results further show that dynein inhibition blocks AβO-induced reduction in dendritic proteasome content in hippocampal neurons. Finally, proteasome inhibition induces AD-like pathological features, including reactive oxygen species and dendritic spine loss in hippocampal neurons, inhibition of hippocampal mRNA translation, and memory impairment in mice. Results suggest that proteasome inhibition may contribute to synaptic and memory deficits in AD.
Continued Assessment of the Fasting Mimicking Diet as an Adjuvant Cancer Therapy
https://www.fightaging.org/archives/2024/01/continued-assessment-of-the-fasting-mimicking-diet-as-an-adjuvant-cancer-therapy/
The fasting mimicking diet resulted from efforts to understand how nutrient sensing systems in cells respond to a lower calorie intake. The question of interest was this: at what level of calorie intake do the benefits of fasting start to emerge, and at what level of calorie intake are most of the benefits present? Does one actually have to reduce calorie intake to zero to obtain all of the benefits? As it turns out, no. Low calorie intake, on the order of 600-750 calories per day, is almost as good as fasting when sustained for week or so.
On the basis of these results, a specific fasting mimicking medical diet was then commercialized and put through the FDA process as an adjuvant treatment for cancer patients, where it continues to show benefits in human trials. This is the usual consequence of the excessive costs of medical regulation, in that the only way for a cheap therapy to be used is to first turn it into a patented, expensive therapy, but it served to bring funding into a part of the field that usually lacks the incentives to attract investment. For the rest of us, it is easy enough to use the fasting mimicking approach to improve health and metabolism without the expensive, regulated diet. It is simply a set of targets for calorie and micronutrient intake over a period of time, and leads to sustained improvements in measures of metabolism.
Fasting-Mimicking Diet Inhibits Autophagy and Synergizes with Chemotherapy to Promote T-Cell-Dependent Leukemia-Free Survival
Fasting mimicking diets (FMDs) have the potential to enhance the efficacy of a wide variety of cancer treatments, weakening cancer cells by a process we termed differential stress sensitization (DSS) while strengthening normal cells by a response termed differential stress resistance (DSR). The effects of fasting/FMD in inducing DSS in both in vitro and in vivo models were previously shown to be mediated, in part, by the reduction of circulating IGF-1 and glucose levels. In a mouse leukemia model, fasting alone reversed the progression of both B cell and T cell acute lymphoblastic leukemia (ALL) but did not affect acute myeloid leukemia (AML).
Here we show that cycles of FMD induce significant anti-leukemia efficacy and cancer-free survival when combined with vincristine, in part by activating T-cell-dependent anti-cancer effects. Fasting/FMD alone causes a trend for increasing autophagy, but when fasting/FMD is combined with vincristine, a significant and consistent downregulation of autophagy markers is observed. This role of autophagy in the FMD/VC-dependent toxicity to ALL cells is confirmed by the effect of the combination of vincristine with the autophagy inhibitor chloroquine, which also promotes p53 modulation, apoptosis, and cancer-free survival in agreement with the established role of p53 in mediating cell death in AML and in solid malignancies.
Fasting/FMD and other dietary restrictions have also been tested clinically in a number of clinical trials. In a prospective, nonrandomized, controlled trial of 40 patients, the potential benefits of caloric restriction were shown (The Improving Diet and Exercise in ALL (IDEAL)) in the efficacy of chemotherapy in patients newly diagnosed with B-ALL. This intervention resulted in a low minimal residual disease risk, high-circulating adiponectin and low insulin resistance. In a randomized controlled study of 131 patients with HER2-negative early-stage breast cancer, FMD cycles significantly enhanced the effects of neoadjuvant chemotherapy on the radiological and pathological tumor response. A short-term fasting-mimicking diet was also well tolerated during chemotherapy in patients with ovarian cancers and appeared to improve quality of life and fatigue. In conclusion, FMD cycles have high potential to be effective in increasing the toxicity of a range of therapies against ALL and other blood cancers and should be tested in randomized clinical trials, especially in combination with immunotherapy and low toxicity cancer therapies.
In summary, we present a new strategy for improving leukemia treatment by combining FMD with chemotherapy to promote the killing of ALL cells in part by an immune-dependent mechanism. Fasting/FMD has been shown to reduce chemotherapy-associated toxicity in pre-clinical and clinical studies and thus represents a safe and potentially effective treatment adjunct for leukemia patients which should be tested clinically.
HKDC1 and TFEB in Maintenance of Mitophagy and Lysosomal Function
https://www.fightaging.org/archives/2024/01/hkdc1-and-tfeb-in-maintenance-of-mitophagy-and-lysosomal-function/
Researchers here report that HKDC1 is important in the autophagic processes that remove worn and damaged mitochondria, sending them to be recycled in the lysosome. Mitochondrial function declines with age, and this is thought to result in large part due to this decline in mitophagy, the name given to mitochondria-specific autophagy. Finding novel targets for therapies that might enhance mitophagy is a popular topic, despite the comparatively poor results obtained to date. Few of the existing approaches are better than exercise. Much more is needed if the objective is to significantly slow aging.
Mitochondria power the cell and lysosomes keep the cell tidy. Although damage to these two organelles has been linked to aging, cellular senescence, and many diseases, the regulation and maintenance of these organelles has remained poorly understood. There was evidence that a protein called TFEB is involved in maintaining the function of both organelles, but no targets of this protein were known. By comparing all the genes of the cell that are active under particular conditions, and by using a method called chromatin immunoprecipitation, which can identify the DNA targets of proteins, researchers have shown that the gene encoding HKDC1 is a direct target of TFEB, and that HKDC1 becomes upregulated under conditions of mitochondrial or lysosomal stress.
One way that mitochondria are protected from damage is through the process of “mitophagy”, the controlled removal of damaged mitochondria. There are various mitophagy pathways, and the most well-characterized of these depends on proteins called PINK1 and Parkin. “We observed that HKDC1 co-localizes with a protein called TOM20, which is located in the outer membrane of the mitochondria. Through our experiments, we found that HKDC1, and its interaction with TOM20, are critical for PINK1/Parkin-dependent mitophagy.”
“HKDC1 is localized to the mitochondria, right? Well, this turns out to also be critical for the process of lysosomal repair. Lysosomes and mitochondria contact each other via proteins called VDACs. Specifically, HKDC1 is responsible for interacting with the VDACs; this protein is essential for mitochondria-lysosome contact, and thus, lysosomal repair.” These two diverse functions of HKDC1, with key roles in both the lysosome and the mitochondria, help to prevent cellular senescence by simultaneously maintaining the stability of these two organelles.
The Hallmarks of Aging in the Context of Sarcopenia
https://www.fightaging.org/archives/2024/01/the-hallmarks-of-aging-in-the-context-of-sarcopenia/
Researchers have implicated numerous mechanisms in the age-related loss of muscle mass and strength leading to the condition known as sarcopenia. While not everyone arrives at a diagnosis of sarcopenia, everyone is subject to the progressive deterioration of muscle tissue. One of the challenges facing attempts to understand age-related disease in detail is that the noteworthy mechanisms of aging form a complex, interacting web of cause and consequence. It is next to impossible to determine which mechanisms are more or less important from observation alone. So while one can mount a good argument for sarcopenia to be driven by reduced stem cell activity, proving that would require interventions that do not at present exist. One is further left struggling to explain how exactly that loss of stem cell function takes place: which of the mechanisms of aging are most important in driving it?
Ageing is a complex biological process associated with increased morbidity and mortality. Nine classic, interdependent hallmarks of ageing have been proposed involving genetic and biochemical pathways that collectively influence ageing trajectories and susceptibility to pathology in humans. Ageing skeletal muscle undergoes profound morphological and physiological changes associated with loss of strength, mass, and function, a condition known as sarcopenia. The aetiology of sarcopenia is complex and whilst research in this area is growing rapidly, there is a relative paucity of human studies, particularly in older women.
Here, we evaluate how the nine classic hallmarks of ageing: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication contribute to skeletal muscle ageing and the pathophysiology of sarcopenia. We also highlight five novel hallmarks of particular significance to skeletal muscle ageing: inflammation, neural dysfunction, extracellular matrix (ECM) dysfunction, reduced vascular perfusion, and ionic dyshomeostasis, and discuss how the classic and novel hallmarks are interconnected. Their clinical relevance and translational potential are also considered.
We conclude that there is strong evidence for epigenetic alteration, mitochondrial dysfunction, neural dysfunction, and moderate evidence for inflammation, deregulated nutrient sensing, immunoaging, ECM dysfunction, and reduced vascular perfusion as hallmarks for skeletal muscle ageing, with their relevance for sarcopenia evolving.
Visualizing Clearance of Cerebrospinal Fluid via the Glymphatic System
https://www.fightaging.org/archives/2024/01/visualizing-clearance-of-cerebrospinal-fluid-via-the-glymphatic-system/
Evidence strongly suggests that failing drainage of cerebrospinal fluid contributes to neurodegeneration, as the flow of fluid from the brain into the body carries metabolic waste with it. This metabolic waste, such as misfolded amyloid-β, becomes more prone to accumulate given the reduced drainage that occurs in later life, and this accumulation contributes to the onset and progression of neurodegenerative conditions. One of the pathways for drainage is the comparatively recently discovered glymphatic system. Here, researchers discuss a way to measure the flow of cerebrospinal fluid through the glymphatic system. Putting numbers to the problem of reduced drainage is an important step on the way to doing something about it.
Glymphatic clearance dysfunction may play an important role in a variety of neurodegenerative diseases and the progression of ageing. However, in vivo imaging of the glymphatic system is challenging. In this study, we describe an MRI method based on chemical exchange saturation transfer (CEST) of the Angiopep-2 probe to visualize the clearance function of the glymphatic system.
We injected rats with Angiopep-2 via the tail vein and performed in vivo MRI at 7 T to track differences in Angiopep-2 signal changes; we then applied the same principles in a bilateral deep cervical lymph node ligation rat model and in ageing rats. We demonstrated the feasibility of Angiopep-2 CEST for visualizing the clearance function of the glymphatic system. Finally, a pathological assessment was performed. Within the model group, the deep cervical lymph node ligation group and the ageing group showed higher CEST signal than the control group. We conclude that this new MRI method can visualize clearance in the glymphatic system.
The Longevity-Associated Gene INDY as a Target for Treatment of Osteoporosis
https://www.fightaging.org/archives/2024/01/the-longevity-associated-gene-indy-as-a-target-for-treatment-of-osteoporosis/
INDY is a well-studied longevity-associated gene. Reduced INDY expression extends life in a number of short-lived laboratory species. Here, researchers argue that INDY inhibition could form the basis for osteoporosis treatments. Osteoporosis is the condition resulting from age-related loss of bone density. Bone is constantly remodeled by osteoblasts that build bone extracellular matrix and osteoclasts that destroy it. With advancing age, the activity of osteoclasts steadily outpaces the activity of osteoblasts. This occurs for a variety of reasons, and much of the research into osteoporosis is conducted in search of ways to restore the balance in some way.
Reduced expression of the plasma membrane citrate transporter SLC13A5, also known as INDY, has been linked to increased longevity and mitigated age-related cardiovascular and metabolic diseases. Citrate, a vital component of the tricarboxylic acid cycle, constitutes 1-5% of bone weight, binding to mineral apatite surfaces. Our previous research highlighted osteoblasts’ specialized metabolic pathway facilitated by SLC13A5 regulating citrate uptake, production, and deposition within bones. Disrupting this pathway impairs bone mineralization in young mice.
New Mendelian randomization analysis using UK Biobank data indicated that SNPs linked to reduced SLC13A5 function lowered osteoporosis risk. Comparative studies of young (10 weeks) and middle-aged (52 weeks) osteocalcin-cre-driven osteoblast-specific Slc13a5 knockout mice (Slc13a5cKO) showed a sexual dimorphism: while middle-aged females exhibited improved elasticity, middle-aged males demonstrated enhanced bone strength due to reduced SLC13A5 function. These findings suggest reduced SLC13A5 function could attenuate age-related bone fragility, advocating for SLC13A5 inhibition as a potential osteoporosis treatment.
Another Large Study of Hearing Aid Use Shows Deafness Increases Dementia Risk
https://www.fightaging.org/archives/2024/01/another-large-study-of-hearing-aid-use-shows-deafness-increases-dementia-risk/
You might compare the research noted here with another similar study published a year ago. In both cases, data on hearing aid use in large patient populations is used to demonstrate that hearing loss contributes to the onset and progression of dementia. This data doesn’t favor any specific theory regarding the mechanism, such as atrophy of brain structures resulting from disuse versus some form of maladaptive compensatory activity in the brain. Greater understanding of the mechanisms involved will require further research.
Hearing loss has been suggested as a risk factor for dementia, but there is still a need for high-quality research to better understand the association between these two conditions and the underlying causal mechanisms and treatment benefits using larger cohorts and detailed data. This population-based cohort study was conducted in Southern Denmark between January 2003 and December 2017 and included all residents 50 years and older. We excluded all persons with dementia before baseline as well as those who did not live in the region 5 years before baseline, with incomplete address history, or who had missing covariate information.
The study population comprised 573,088 persons (298,006 women [52%]; mean [SD] age, 60.8 [11.3] years) with 23,023 cases of dementia and mean (SD) follow-up of 8.6 (4.3) years. Having a hearing loss was associated with an increased risk of dementia, with an adjusted hazard ratio (HR) of 1.07 compared with having no hearing loss. Severe hearing loss in the better and worse ear was associated with a higher dementia risk, with an HR of 1.20 and 1.13, respectively, compared with having no hearing loss in the corresponding ear. Compared with people without hearing loss, the risk of dementia was higher among people with hearing loss who were not using hearing aids than those who had hearing loss and were using hearing aids, with HRs of 1.20 and 1.06, respectively.
The results of this cohort study suggest that hearing loss was associated with increased dementia risk, especially among people not using hearing aids, suggesting that hearing aids might prevent or delay the onset and progression of dementia. The risk estimates were lower than in previous studies, highlighting the need for more high-quality longitudinal studies.
Natural Killer Cell Numbers Increase with Age
https://www.fightaging.org/archives/2024/01/natural-killer-cell-numbers-increase-with-age/
The immune system ages in ways that are harmful to tissue function and health, becoming both less effective and overly inflammatory. Not all of the observed changes in immune cell activities and immune cell population sizes are harmful, however. Some are compensatory, even though this compensation isn’t enough to stop the overall decline. With that in mind, researchers here report on an analysis of the size of immune cell populations in old individuals, including centenarians. They find that natural killer cells increase in number with age, which they characterize as an adaptation to the aged environment.
The immune system of semi-centenarians and super-centenarians (i.e., the oldest centenarians) is believed to have peculiar characteristics that enable them to reach extreme longevity in a relatively healthy state. Therefore, in previous papers, we investigated, through flow cytometry, variations in the percentages of the main subsets of αβ T cells and γδ T cells in a Sicilian cohort of 28 women and 26 men (age range 19-110 years), including 11 long-living individuals (older than 90 years) and 8 oldest centenarians. These investigations suggested that some observed immunophenotypic changes may contribute to the extreme longevity of the oldest centenarians.
In the present study, to further characterize the immunophenotype of the oldest centenarians, we examined the percentages of Natural Killer (NK) cells identified as CD3-CD56+CD16+ in the previously described Sicilian cohort. We found a highly significant increase in NK cell percentages with age. When stratified by gender, this significant increase with age was maintained in both sexes, with higher significance observed in males.
Our findings on NK cells, together with the previously obtained results, discussed in the context of the literature, suggest that these changes are not unfavourable for centenarians, including the oldest ones, supporting the hypothesis that immune aging should be considered as a differential adaptation rather than a general immune alteration. These adapted immune mechanisms allow the oldest centenarians to successfully adapt to a history of insults and achieve remarkable longevity.
Stress Temporarily Increases Epigenetic Age
https://www.fightaging.org/archives/2024/01/stress-temporarily-increases-epigenetic-age/
Physiological and other forms of stress are known to affect the immune system. Epigenetic age measured from a blood sample is an assessment of immune cells, not the organism as a whole. One might expect any sort of stress put on the immune system to alter measures of epigenetic age conducted on blood samples, but quite different results might emerge from an assessment of epigenetic age conducted on tissue biopsies.
This study used DNA methylation (DNAm)-based aging clocks to measure changes in biological age in response to diverse forms of stress. The researchers began with a laboratory experiment known to produce aged physiology in young mice or restore youthful physiology to old mice by surgically joining young, 3-month-old mice with older, 20-month-old mice, which allowed them to share their blood. At the molecular level, they found that the biological age of the young mice increased when measured with most aging clocks. Once the young mice were separated from the old mice and therefore were no longer experiencing the older mouse physiology, their biological age returned to youthful levels. This finding suggested that biological age is malleable and potentially reversible, and these changes are reported by DNAm aging clocks.
Next, the researchers examined blood samples from people who had recently experienced stressful situations, including surgery (emergency versus elective), pregnancy, or severe COVID-19. Analysis of blood samples from patients who underwent emergency surgery showed their biological age increased the morning after surgery and returned to pre-surgery levels four to seven days later. Elective surgeries, on the other hand, had less impact on biological age, which the authors attribute to pre-operative regimens known to aide recovery. Pregnancy in both mice and humans led to increased biological age at delivery, which reverted to lower biological age following delivery and recovery.
Hypertension Pressure Turns Vascular Smooth Muscle Cells into Foam Cells
https://www.fightaging.org/archives/2024/01/hypertension-pressure-turns-vascular-smooth-muscle-cells-into-foam-cells/
The raised blood pressure of hypertension correlates with the development of atherosclerosis, a condition characterized by cholesterol-rich lesions that grow in blood vessel walls. Researchers have proposed mechanisms by which hypertension can cause cell dysfunction, such as by indirectly increasing circulating immune cell numbers, cells that are then drawn into the plaque and killed by it, increasing its mass. More directly, increased pressure on arterial walls causes them to become less permeable to cholesterol carried in the bloodstream, encouraging deposits to form in the inner blood vessel wall. As another potential mechanism, researchers here identify a way in which increased pressure can induced pathological dysfunction in the vascular smooth muscle cells that become involved in atherosclerosis.
Arterial vascular smooth muscle cells (VSMCs) play a central role in the onset and progression of atherosclerosis. Upon exposure to pathological stimuli, they can take on alternative phenotypes that, among others, have been described as macrophage like, or foam cells. VSMC foam cells make up more than 50% of all arterial foam cells and have been suggested to retain an even higher proportion of the cell stored lipid droplets, further leading to apoptosis, secondary necrosis, and an inflammatory response. However, the mechanism of VSMC foam cell formation is still unclear.
Here, it is identified that mechanical stimulation through hypertensive pressure alone is sufficient for the phenotypic switch. Hyperspectral stimulated Raman scattering imaging demonstrates rapid lipid droplet formation and changes to lipid metabolism and changes are confirmed in ABCA1, KLF4, LDLR, and CD68 expression, cell proliferation, and migration. Further, a mechanosignaling route is identified involving Piezo1, phospholipid, and arachidonic acid signaling, as well as epigenetic regulation, whereby CUT&Tag epigenomic analysis confirms changes in the cells (lipid) metabolism and atherosclerotic pathways.
Overall, the results show for the first time that VSMC foam cell formation can be triggered by mechanical stimulation alone, suggesting modulation of mechanosignaling can be harnessed as potential therapeutic strategy.
Effects of LDLR Variants on Longevity via Lowered Cardiovascular Disease
https://www.fightaging.org/archives/2024/01/effects-of-ldlr-variants-on-longevity-via-lowered-cardiovascular-disease/
The development of atherosclerosis leading to stroke or heart attack is the primary cause of human mortality, accounting for ~26% of deaths worldwide. It also contributes meaningfully to as much as another 15% of deaths through narrowing of blood vessels, heart failure, and so forth. It is well known that lowered LDL-cholesterol in the bloodstream, when maintained over a lifetime, pushes back the tipping point at which atherosclerotic lesions form. So genetic variants that affect LDL-cholesterol levels tend to also affect longevity to some degree, as demonstrated in this study. Unfortunately, therapies that lower LDL-cholesterol levels have nowhere near the same effect size, as (a) these treatments are not maintained over the full lifespan, and (b) lowering LDL-cholesterol has little effect on established atherosclerotic plaque in most patients.
It remains controversial whether the long-term use of statins or newer nonstatin drugs has a positive effect on human longevity. Therefore, this study aimed to investigate the genetic associations between different lipid-lowering therapeutic gene targets and human longevity. Two-sample Mendelian randomization analyses were conducted. The exposures comprised genetic variants that proxy nine drug target genes mimicking lipid-lowering effects (LDLR, HMGCR, PCSK9, NPC1L1, APOB, CETP, LPL, APOC3, and ANGPTL3). Two large-scale genome-wide association study (GWAS) summary datasets of human lifespan, including up to 500,193 European individuals, were used as outcomes.
Genetically proxied LDLR variants, which mimic the effects of lowering low-density lipoprotein cholesterol (LDL-C), were associated with extended lifespan. This association was replicated in the validation set and was further confirmed in the eQTL summary data of blood and liver tissues. Mediation analysis revealed that the genetic mimicry of LDLR enhancement extended lifespan by reducing the risk of major coronary heart disease, accounting for 22.8% of the mediation effect. The genetically proxied CETP and APOC3 inhibitions also showed causal effects on increased life expectancy in both outcome datasets. The lipid-lowering variants of HMGCR, PCKS9, LPL, and APOB were associated with longer lifespans but did not causally increase extreme longevity. No statistical evidence was detected to support an association between NPC1L1 and lifespan.
This study suggests that LDLR is a promising genetic target for human longevity. Lipid-related gene targets, such as PCSK9, CETP, and APOC3, might potentially regulate human lifespan, thus offering promising prospects for developing newer nonstatin therapies.
Reviewing the Prospects for Dentin Regeneration
https://www.fightaging.org/archives/2024/01/reviewing-the-prospects-for-dentin-regeneration/
The regrowth of teeth – and the components of teeth, such as dental pulp, dentin, and enamel, that do not naturally exhibit sufficient regenerative capacity to address damage – has been a goal for researchers for some years now. Inroads have been made, but the research community is still some years from being able to sufficiently control the regrowth of entire teeth to produce more than technology demonstrations. Meanwhile, perhaps more meaningful advances have been made towards provoking the regeneration of damaged teeth in situ, finding ways to program cells in and around teeth into more regenerative modes of behavior.
Dentin is a complex mineralized tissue primarily composed of hydroxyapatite crystals, collagen fibers, and a fluid-filled tubular structure that extends from the pulp to the dentino-enamel or dentino-cementum junctions. Dentin is formed by highly specialized cells called odontoblasts, which secrete an extracellular matrix comprising collagen fibers and non-collagen proteins that serve as a scaffold for subsequent mineralization. Odontoblasts deposit dentin throughout the life of a tooth, albeit at a slower rate after early dentinogenesis, contributing to the thickening of dentin and potentially aiding in response of the tooth to external insults.
As a consequence of dentinal injury or decay, tertiary dentinogenesis of two different natures occur to protect and maintain dental pulp integrity. When secretory activities of quiescent odontoblasts are re-activated, reactionary dentin that is structurally and functionally similar to physiologic dentin is formed. On the other hand, newly differentiated odontoblast-like cells form pathologic reparative dentin, which is often less organized and more akin to bone-like tissue rather than dentin at the histological level. Likewise, physiologic dentin regeneration and pathologic dentin repair are two distinct processes aimed at restoring dentin functionality following damage, and re-establish a protective barrier for the pulp, alleviate sensitivity, and prevent further loss.
Physiologic dentin regeneration, in particular, seeks to recreate dentin that closely mimics its original, healthy state. This includes the reconstruction of dentinal tubules that integrate seamlessly with remaining dentin, the restoration of dentin-pulp complex, and the engagement of cellular and molecular pathways that govern dentinogenesis. The unique structure and function of true dentin, characterized by its distinctive tubular architecture housing odontoblasts and nerve endings, not only confers mechanical resilience to the tooth but plays a crucial role in the tooth’s immune and sensitivity responses. A number of biological molecules that can direct the odontoblastic differentiation of dental pulp cells have been studied, most of which are part of key signaling pathways regulating dentinogenesis during tooth development. These include TGF-β, BMP, and Wnt/β-catenin signaling known to orchestrate the complex processes of cell differentiation, matrix deposition, and mineralization. The use of bioactive molecules in dentin regeneration has emerged as a promising approach, leveraging the biological cues to promote natural tissue regeneration.
