Fight Aging! Newsletter, September 4th 2023
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- The Meninges at the Border Between the Brain Immune System and the Peripheral Immune System
- A Perspective on the Coming Regulatory Shift to Approval of Drugs to Treat Aging
- Intermittent Fasting Reduces Pathology in a Mouse Model of Alzheimer's Disease
- Physical Fitness Correlates with Slower Epigenetic Aging in Newer DNA Methylation Clocks
- Release of Acetylcholine is Necessary for the Aging Brain to Compensate for a Lack of Neurogenesis
- A Senolytic Chimeric Antigen Receptor T Cell Therapy
- More Evidence for Vaccination to Reduce Alzheimer's Disease Risk
- Physical Fitness Correlates with a Lower Risk of Atrial Fibrillation and Stroke
- Quality of Diet versus Pace of Aging
- A Large Study of Immune Aging in T Cell and Natural Killer Cell Populations
- PGC-1α4 Gene Therapy Reduces Sarcopenia and Metabolic Disease in Aged Mice
- Sex Differences in Microglial Senescence in the Context of Alzheimer's Disease
- Transferring the Naked Mole Rat Hyaluronan Synthase 2 Gene Into Mice Reduces Cancer Incidence, Extends Life
- Declining Cardiovascular Mortality in Atrial Fibrillation Patients
- Adjusting Macrophages to an Anti-Inflammatory Phenotype Improves Pathology Following a Heart Attack
The Meninges at the Border Between the Brain Immune System and the Peripheral Immune System
https://www.fightaging.org/archives/2023/08/the-meninges-at-the-border-between-brain-immune-system-and-peripheral-immune-system/
While the immune system of the brain is distinct from that of the rest of the body, the central nervous system walled off by the blood-brain barrier, the inflammatory status of the brain is very much influenced by the inflammatory status of the rest of the body. Signals pass back and forth, and at the edges of the brain there are a variety of tissues in which one can find peripheral immune cells such as macrophages of the innate immune system or T cells of the adaptive immune system.
One such tissue is the meninges, the membranes that wrap the brain and spinal cord. In recent years, since the discovery of the glymphatic system that drains waste from the brain, more attention has been given to cell populations in the lymphatic vessels and vasculature of the meninges, as well as other tissues bordering the brain, such as the choroid plexus. As an example of this work, today's open access review discusses what is known of the way in which peripheral immune system involvement in the meninges may influence the inner regions of the brain.
Current views on meningeal lymphatics and immunity in aging and Alzheimer's disease
Alzheimer's disease (AD) is an aging-related form of dementia associated with the accumulation of pathological aggregates of amyloid beta and neurofibrillary tangles in the brain. These phenomena are accompanied by exacerbated inflammation and marked neuronal loss, which altogether contribute to accelerated cognitive decline. The multifactorial nature of AD, allied to our still limited knowledge of its etiology and pathophysiology, have lessened our capacity to develop effective treatments for AD patients.
Over the last few decades, genome wide association studies and biomarker development, alongside mechanistic experiments involving animal models, have identified different immune components that play key roles in the modulation of brain pathology in AD, affecting its progression and severity. As we will relay in this review, much of the recent efforts have been directed to better understanding the role of brain innate immunity, and particularly of microglia. However, and despite the lack of diversity within brain resident immune cells, the brain border tissues, especially the meninges, harbour a considerable number of different types and subtypes of adaptive and innate immune cells. Alongside microglia, which have taken the centre stage as important players in AD research, there is new and exciting evidence pointing to adaptive immune cells, namely T cells and B cells found in the brain and its meninges, as important modulators of neuroinflammation and neuronal (dys)function in AD.
Importantly, a genuine and functional lymphatic vascular network is present around the brain in the outermost meningeal layer, the dura. The meningeal lymphatics are directly connected to the peripheral lymphatic system in different mammalian species, including humans, and play a crucial role in preserving a "healthy" immune surveillance of the central nervous system, by shaping immune responses, not only locally at the meninges, but also at the level of the brain tissue. In this review, we will provide a comprehensive view on our current knowledge about the meningeal lymphatic vasculature, emphasizing its described roles in modulating central nervous system fluid and macromolecule drainage, meningeal and brain immunity, as well as glial and neuronal function in aging and in AD.
A Perspective on the Coming Regulatory Shift to Approval of Drugs to Treat Aging
https://www.fightaging.org/archives/2023/08/a-perspective-on-the-coming-regulatory-shift-to-approval-of-drugs-to-treat-aging/
At some point, regulatory bodies that oversee the development of new medicine will accept that therapies can target causative mechanisms of aging in order to slow or reverse the progression of aging, and that there are viable ways to assess new treatments that treat aging. There is growing pressure from the academic community and longevity-focused biotech industry for the ability to run clinical trials to treat aging, rather than to treat one specific age-related disease.
While inevitable, this change will take some years to come to pass, and likely require greater consensus in the research community on reasonable approaches to measure biological age. The scientific community is making good progress towards the adoption of improved epigenetic clocks as as a consensus means of measuring biological age in a natural environment, but it becomes challenging to stand by any of these clocks when any one causative mechanism of aging is slowed or reversed via therapy. The clock may over-represent or under-represent the contributions of that mechanism to degenerative aging, and there is no real way to find out without calibrating the clock against that specific therapy in lengthy animal studies.
In the meanwhile, companies developing therapies that target the mechanisms of aging choose one specific age-related condition for clinical trials and regulatory approval. They move ahead assuming that widespread off-label use will likely follow approval for any one age-related disease, providing further pressure for the regulatory edifice will shift to allow a more defined path towards treatment of aging as a medical condition in all older individuals.
Challenges in developing Geroscience trials
Multiple clinical conditions and pathophysiological processes have long been considered as inescapable and unmodifiable consequences of the aging process. However, these perceptions are changing. Over the past few decades, research focusing on the interplay between the fundamental processes of aging and the biology of co-morbidities has given rise to the concept of Geroscience, the goal of which is to develop new biologically-based therapeutic and preventive approaches that target fundamental aging processes; thus, to decrease age-related multi-morbidities as a group and improve healthspan.
The beneficial effect of using Gerotherapeutic drugs to modulate the fundamental molecular, cellular, and/or genetic mechanisms of aging has been demonstrated in animal models, and offers exciting preventive and even curative therapeutic translational opportunities in humans. However, Geroscience trials face numerous methodological challenges in their study design regarding the demonstration of clinical effectiveness successfully in humans. One critical challenge is that the usual design of therapeutic clinical trials is centered on disease-specific diagnosis and physiopathology, whereas Geroscience trials aim to target mechanisms of aging in order to delay or prevent the onset or reduce the progression of multiple age-related diseases, geriatric syndromes, and potentially alleviate or treat such conditions.
The European Medicine Agency (EMA) and the Food and Drug Agency (FDA) have high concordance (91-98%) in decisions on marketing approvals, but the arrival of gerotherapeutic drugs will challenge both agencies to define the terms of marketing approval in the context of Geroscience. Being an emergent discipline, Geroscience will challenge some of the established protocols for fast approval of new drugs and biomarkers needed to meet the challenges of an aging society. In general, FDA or EMA approve drugs for treating diseases; however, aging by itself is not currently considered as a "disease", but as the major risk factor for multiple morbidities.
Basic scientists, clinicians, and drug agency officials already interact so that the concept behind Geroscience is understood and shared. A scale for evaluating FDA-approved drugs for their Gerotherapeutic potential has been proposed. In this context, it is important to highlight that the design of the TAME (Targeting Aging with MEtformin) trial has been approved by the FDA; TAME aims to delay mortality and the onset of several age-related diseases (e.g., myocardial infarction, stroke, cancer, dementia) and conditions (e.g., major decline in mobility or cognitive function) rather than targeting a single disease. The TAME trial may serve as a proof of concept that proves to the medical agencies that aging can be a therapeutic indication in itself. This result would favor conditions for defining new marketing approval, type of approval, and approved indication for new or already approved drugs and will be incentive for pharmaceutical companies to invest in research on Geroscience.
Designing a disease-centric trial remains the only way to date to gain approval from the FDA or EMA, each of which still adheres to the "one disease, one drug" model. The regulatory constraints required for a new drug to be brought to patients and the extent to which the patients benefit from it must also be taken into consideration when designing a trial. However, targeting a single pathology in a clinical trial is not without risk either. Diagnostic criteria change over time, in particular with the emergence of biomarkers, not-withstanding that most diseases of ageing are of complex etiology, resulting from (still poorly understood) interactions between non-modifiable factors (including age, sex, and genetic predisposition) and modifiable factors, related to environmental and other exposures, lifestyle factors, etc. Moreover, it should be emphasized that some Gerotherapeutic drugs could have a very modest and difficult to demonstrate effect in organs evaluated separately, but have a clinically significant overall effect due to their action on the whole organism, and the alternative also exists that a study using a composite score might fail to capture substantial changes within just one domain if not statistically powered for that endpoint alone. A trial centered on only one function or disease is the current conventional approach but is probably not appropriate for certain molecules such as metformin, for which effects are pleiotropic, acting on multiple organs and through multiple biological mechanisms.
Intermittent Fasting Reduces Pathology in a Mouse Model of Alzheimer's Disease
https://www.fightaging.org/archives/2023/08/intermittent-fasting-reduces-pathology-in-a-mouse-model-of-alzheimers-disease/
The sizable body of work produced on calorie restriction and fasting over the last twenty years is supportive of the hypothesis that time spent hungry is an important factor determining the scale of benefits to health and longevity. The cellular response to a transient lack of nutrients involves improved cell maintenance, such as upregulation of autophagy to clear out damaged and worn molecular machinery. Looking at a level of organization above the cell, a transient state of hunger likely produces many other benefits to the way in which complex tissues and relationships between tissues function in the body. It dampens inflammatory signaling in the aging immune system, for example.
With this in mind, we expect to see many age-related conditions improved by calorie restriction, intermittent fasting, and similar interventions, such as fasting mimicking diets. In today's open access paper, researchers report that intermittent fasting without reduced calories can reduce pathology in a mouse model of Alzheimer's disease. As the researchers note, trying this out in humans is quite straightforward; it only requires funding. Unfortunately, funding for clinical trials of interventions such as intermittent fasting, in which there no profit to be made at the end of the day, is hard to come by. There is a role for philanthropy here that has yet to be fully realized.
Intermittent Fasting Improves Alzheimer's Pathology
One of the hallmarks of Alzheimer's disease is disruption to the body's circadian rhythm, the internal biological clock that regulates many of our physiological processes. Nearly 80% of people with Alzheimer's experience these issues, including difficulty sleeping and worsening cognitive function at night. However, there are no existing treatments for Alzheimer's that target this aspect of the disease.
Boosting the circadian clock is an emerging approach to improving health outcomes, and one way to accomplish this is by controlling the daily cycle of feeding and fasting. The researchers tested this strategy in a mouse model of Alzheimer's disease, feeding the mice on a time-restricted schedule where they were only allowed to eat within a six-hour window each day. For humans, this would translate to about 14 hours of fasting each day.
Compared to control mice who were provided food at all hours, mice fed on the time-restricted schedule had better memory, were less hyperactive at night, followed a more regular sleep schedule and experienced fewer disruptions during sleep. The test mice also performed better on cognitive assessments than control mice, demonstrating that the time-restricted feeding schedule was able to help mitigate the behavioral symptoms of Alzheimer's disease.
The researchers also observed improvements in the mice on a molecular level. In mice fed on a restricted schedule, the researchers found that multiple genes associated with Alzheimer's and neuroinflammation were expressed differently. They also found that the feeding schedule helped reduce the amount of amyloid protein that accumulated in the brain. Amyloid deposits are one of the most well-known features of Alzheimer's disease.
Circadian modulation by time-restricted feeding rescues brain pathology and improves memory in mouse models of Alzheimer's disease
Circadian disruptions impact nearly all people with Alzheimer's disease (AD), emphasizing both their potential role in pathology and the critical need to investigate the therapeutic potential of circadian-modulating interventions. Here, we show that time-restricted feeding (TRF) without caloric restriction improved key disease components including behavioral timing, disease pathology, hippocampal transcription, and memory in two transgenic mouse models of AD.
We found that TRF had the remarkable capability of simultaneously reducing amyloid deposition, increasing Aβ42 clearance, improving sleep and memory, and normalizing daily transcription patterns of multiple genes, including those associated with AD and neuroinflammation. Thus, our study unveils for the first time the pleiotropic nature of timed feeding on AD, which has far-reaching effects beyond metabolism, ameliorating neurodegeneration and the misalignment of circadian rhythmicity. Since TRF can substantially modify disease trajectory, this intervention has immediate translational potential, addressing the urgent demand for accessible approaches to reduce or halt AD progression.
Physical Fitness Correlates with Slower Epigenetic Aging in Newer DNA Methylation Clocks
https://www.fightaging.org/archives/2023/08/physical-fitness-correlates-with-slower-epigenetic-aging-in-newer-dna-methylation-clocks/
Epigenetic clocks that measure chronological or biological age are at present largely based on patterns of DNA methylation that change in characteristic ways over a lifetime. There are other options, such as looking at histones, but they are not as well explored. DNA methylation is the process or adding and removing methyl groups from nuclear DNA, changing its structure in ways that expose or hide gene sequences from the machinery of gene expression. These epigenetic decorations this control the production of proteins, and are continually changing in response to environmental factors and cell processes.
Since epigenetic clocks were produced via machine learning, a process of identifying patterns from raw data, it remains largely unknown as to why specific DNA methylation sites on the genome tend to become methylated or unmethylated with age. Explaining these clocks is a work in its infancy, despite their increasing use in research. One of the quirks of the early epigenetic clocks is that they proved to be insensitive to exercise and physical fitness. For example, see the results from a study of sedentary versus physically fit twin pairs. In general, we might take this as a warning that a specific epigenetic clock may well have hidden biases that make it unsuitable to assess a specific intervention to slow or reverse aging. The only way to find out in certainty would be to test the clock and therapy in long, expensive studies.
When it comes to physical fitness, which we know has a measurable, beneficial effect on health and late life mortality, and which should be reflected in a good epigenetic clock, it is reassuring to see that later DNA methylation clocks do appear to react in the right way. Unfortunately, these results have no bearing on whether or not more recent clocks will correctly assess, say, the results of clearing senescent cells, or transplanting mitochondria, or any of the other avenues to eventual human rejuvenation. Finding out will likely require years and a great deal of funding.
Associations between cardiorespiratory fitness and lifestyle-related factors with DNA methylation-based ageing clocks in older men: WASEDA'S Health Study
DNA methylation-based age estimators (DNAm ageing clocks) are currently one of the most promising biomarkers for predicting biological age. However, the relationships between cardiorespiratory fitness (CRF), measured directly by expiratory gas analysis, and DNAm ageing clocks are largely unknown. We investigated the relationships between CRF and the age-adjusted value from the residuals of the regression of DNAm ageing clock to chronological age (DNAmAgeAcceleration: DNAmAgeAccel) and attempted to determine the relative contribution of CRF to DNAmAgeAccel in the presence of other lifestyle factors.
DNA samples from 144 Japanese men aged 65-72 years were used to appraise first-generation (i.e., DNAmHorvath and DNAmHannum) and second-generation (i.e., DNAmPhenoAge, DNAmGrimAge, and DNAmFitAge) DNAm ageing clocks. Various surveys and measurements were conducted, including physical fitness, body composition, blood biochemical parameters, nutrient intake, smoking, alcohol consumption, disease status, sleep status, and chronotype.
Both oxygen uptake at ventilatory threshold (VO2/kg at VT) and peak oxygen uptake (VO2/kg at Peak) showed a significant negative correlation with GrimAgeAccel, even after adjustments for chronological age and smoking and drinking status. Notably, VO2/kg at VT and VO2/kg at Peak above the reference value were also associated with delayed GrimAgeAccel. Multiple regression analysis showed that calf circumference, serum triglyceride, carbohydrate intake, and smoking status, rather than CRF, contributed more to GrimAgeAccel and FitAgeAccel. In conclusion, although the contribution of CRF to GrimAgeAccel and FitAgeAccel is relatively low compared to lifestyle-related factors such as smoking, the results suggest that the maintenance of CRF is associated with delayed biological ageing in older men.
Release of Acetylcholine is Necessary for the Aging Brain to Compensate for a Lack of Neurogenesis
https://www.fightaging.org/archives/2023/09/release-of-acetylcholine-is-necessary-for-the-aging-brain-to-compensate-for-a-lack-of-neurogenesis/
Neurogenesis is the process by which new neurons are created by neural stem cells, thereafter maturing and integrating into existing neural circuits. This is most studied in the hippocampus, where continual change in the circuits of the brain is essential to memory. With age, the pace of neurogenesis declines, as one might expect given what is known of the progressive loss of stem cell activity in later life. This is thought to contribute to cognitive decline in general, and to loss of memory function specifically.
In today's open access paper, researchers report on a study in which they disabled neurogenesis in mice to observe the resulting loss of memory function. Along the way they found evidence for a compensatory process that operates when neurogenesis falters, but operates poorly. The process can be dramatically improved by provoking a greater secretion of stored acetylcholine. This prevents loss of memory function, despite the continued lack of neurogenesis. As the researchers point out, success in restoring memory in mice via this approach is unexpected, given that efforts to increase levels of acetylcholine, via acetylcholinesterase inhibitor drugs that block the degradation of acetylcholine, failed to produce meaningful gains in memory function. Clearly the underlying biochemistry is complex.
Baby Neurons in Adult Brains Are Needed to Maintain Memory
Researchers estimate that the brain's hippocampus - which plays a key role in memory, learning, and emotion - makes about a thousand new neurons each day throughout adulthood. "Considering that the brain contains about 100 billion neurons, it's reasonable to question whether this level of neurogenesis could have any impact on brain function. But over the life of the animal, the effects of these new cells can add up as they make connections with other neurons and other parts of the brain."
To test whether adult neurogenesis is vital to brain health over the long term, the team stopped the process in adult mice by irradiating the birthplace of new neurons or with genetic engineering. Over time, the mice produced less and less of the neurotransmitter acetylcholine in the hippocampus, leading to a profound rewiring of a brain circuit critical for memory. The mice also experienced a slow but progressive decline in working memory (temporary "sticky notes" for carrying out mental tasks). Remarkably, while neurogenesis was suppressed immediately after treatment, the memory, anatomic, and biochemical changes took five months (about a quarter of the mouse life span) to emerge.
Even though the brain circuit changed in a way that impaired memory, the circuit did form new, but dysfunctional, connections that could be recruited to improve memory."It was as if existing neurons were trying, but failing, to compensate for the loss of neurogenesis and what started out as a subtle defect in acetylcholine, and they just needed a little nudge." The researchers suspected that the remodeled circuit had sufficient reserves of acetylcholine but couldn't release it when needed. Using a drug, the researchers nudged the circuit to release more acetylcholine and completely rescued the memory deficits even in aged mice.
"The results suggest that we have to revisit old notions about the aging brain. It seems to be more plastic than we've thought." Cholinesterase inhibitors have been used to treat patients with Alzheimer's disease, with little success. "We think this drug, and many others, have failed because they're focused on one type of cell or molecule. What our findings tell us is that we probably need to address the fact that the whole memory circuit is compromised in aging and dementia."
Adult-born neurons maintain hippocampal cholinergic inputs and support working memory during aging
Adult neurogenesis is reduced during aging and impaired in disorders of stress, memory, and cognition though its normal function remains unclear. Moreover, a systems level understanding of how a small number of young hippocampal neurons could dramatically influence brain function is lacking. We examined whether adult neurogenesis can sustain hippocampal connections cumulatively across the life span. Long-term suppression of neurogenesis as occurs during stress and aging resulted in an accelerated decline in hippocampal acetylcholine signaling and a slow and progressing emergence of profound working memory deficits.
These deficits were accompanied by compensatory reorganization of cholinergic dentate gyrus inputs with increased cholinergic innervation to the ventral hippocampus and recruitment of ventrally projecting neurons by the dorsal projection. While increased cholinergic innervation was dysfunctional and corresponded to overall decreases in cholinergic levels and signaling, it could be recruited to correct the resulting memory dysfunction even in old animals. Our study demonstrates that hippocampal neurogenesis supports memory by maintaining the septohippocampal cholinergic circuit across the lifespan. It also provides a systems level explanation for the progressive nature of memory deterioration during normal and pathological aging and indicates that the brain connectome is malleable by experience.
A Senolytic Chimeric Antigen Receptor T Cell Therapy
https://www.fightaging.org/archives/2023/08/a-senolytic-chimeric-antigen-receptor-t-cell-therapy/
Chimeric antigen receptor (CAR) T cell therapies involve engineering a patient's T cells to add receptors complementary to a specific surface feature of a target cell population that one wants destroyed. This approach to therapy was pioneered in the cancer research community, and has performed well to date. Here, researchers demonstrate that it is possible to use a CAR-T approach to target senescent cells. Clearance of senescent cells in older individuals produces rejuvenation and reversal of many different age-related conditions in animal studies, and we might hope that the same will occur in humans.
Cellular senescence, characterized by stable cell cycle arrest, plays an important role in aging and age-associated pathologies. Eliminating senescent cells rejuvenates aged tissues and ameliorates age-associated diseases. Here, we identified that natural killer group 2 member D ligands (NKG2DLs) are up-regulated in senescent cells in vitro, regardless of stimuli that induced cellular senescence, and in various tissues of aged mice and nonhuman primates in vivo. Accordingly, we developed and demonstrated that chimeric antigen receptor (CAR) T cells targeting human NKG2DLs selectively and effectively diminish human cells undergoing senescence induced by oncogenic stress, replicative stress, DNA damage, or P16INK4a overexpression in vitro.
Targeting senescent cells with mouse NKG2D-CAR T cells alleviated multiple aging-associated pathologies and improved physical performance in both irradiated and aged mice. Autologous T cells armed with the human NKG2D CAR effectively delete naturally occurring senescent cells in aged nonhuman primates without any observed adverse effects. Our findings establish that NKG2D-CAR T cells could serve as potent and selective senolytic agents for aging and age-associated diseases driven by senescence.
More Evidence for Vaccination to Reduce Alzheimer's Disease Risk
https://www.fightaging.org/archives/2023/08/more-evidence-for-vaccination-to-reduce-alzheimers-disease-risk/
There is good evidence for the various forms of later life vaccination, such as for herpes zoster or influenza, to reduce the risk of later suffering Alzheimer's disease. One possibility is that people who take the time to obtain a vaccine tend to take better care of their health across the board. Another possibility is that vaccination produces a trained immunity effect that dampens age-related inflammation for a sustained period of time. It may also be the case that suffering from influenza, pneumonia, or similar infectious diseases causes sufficient additional inflammation to move the odds on suffering later neurodegenerative disease, and this is a large enough effect to show up in sizable study populations with an increased infection risk and severity for the unvaccinated. Regardless, this is an interesting area of research that is clearly connected to the growing interest in the role of chronic inflammation in the development of age-related neurodegenerative conditions.
Accumulating evidence suggests that adult vaccinations can reduce the risk of developing Alzheimer's disease (AD) and Alzheimer's disease related dementias. To compare the risk for developing AD between adults with and without prior vaccination against tetanus and diphtheria, with or without pertussis (Tdap/Td); herpes zoster (HZ); or pneumococcus, a retrospective cohort study was performed. Included patients were free of dementia during a 2-year look-back period and were ≥65 years old by the start of the 8-year follow-up period. We compared two similar cohorts identified using propensity score matching (PSM), one vaccinated and another unvaccinated, with Tdap/Td, HZ, or pneumococcal vaccines. We calculated the relative risk and absolute risk reduction for developing AD.
For the Tdap/Td vaccine, 7.2% (n = 8,370) vaccinated patients and 10.2% (n = 11,857) unvaccinated patients developed AD during follow-up; the relative risk was 0.70 and absolute risk reduction was 0.03. For the HZ vaccine, 8.1% (n = 16,106) vaccinated patients and 10.7% (n = 21,273) unvaccinated patients developed AD during follow-up; the relative risk was 0.75 and absolute risk reduction was 0.02. For the pneumococcal vaccine, 7.92% (n = 20,583) vaccinated patients and 10.9% (n = 28,558) unvaccinated patients developed AD during follow-up; the relative risk was 0.73 and absolute risk reduction was 0.02. Thus several vaccinations, including Tdap/Td, HZ, and pneumococcal, are associated with a reduced risk for developing AD.
Physical Fitness Correlates with a Lower Risk of Atrial Fibrillation and Stroke
https://www.fightaging.org/archives/2023/08/physical-fitness-correlates-with-a-lower-risk-of-atrial-fibrillation-and-stroke/
As one might expect, people who better maintain physical fitness into later life exhibit lesser degrees of age-related disease. In this case, the correlation is specifically for forms of cardiovascular disease, but researchers have reported that numerous other improvements in health can be linked to greater fitness. Animal studies can and do show causation in this relationship between fitness and age-related disease. It is reasonable to believe that the human correlations also largely reflect a causal relationship. There are a great many good reasons to make the effort to better maintain physical fitness throughout life.
A new study assessed 15,450 individuals without atrial fibrillation who were referred for a treadmill test between 2003 and 2012. The average age was 55 years and 59% were men. Fitness was assessed using the Bruce protocol, where participants are asked to walk faster and at a steeper grade in successive three-minute stages. Fitness was calculated according to the rate of energy expenditure the participants achieved, which was expressed in metabolic equivalents (METs).
Participants were followed for new-onset atrial fibrillation, stroke, myocardial infarction, and death. The researchers analysed the associations between fitness and atrial fibrillation, stroke, and major adverse cardiovascular events (MACE; a composite of stroke, myocardial infarction and death) after adjusting for factors that could influence the relationships including age, sex, cholesterol level, kidney function, prior stroke, hypertension, and medications.
During a median of 137 months, 515 participants (3.3%) developed atrial fibrillation. Each one MET increase on the treadmill test was associated with an 8% lower risk of atrial fibrillation, 12% lower risk of stroke and 14% lower risk of MACE. Participants were divided into three fitness levels according to METs achieved during the treadmill test: low (less than 8.57 METs), medium (8.57 to 10.72) and high (more than 10.72). The probability of remaining free from atrial fibrillation over a five-year period was 97.1%, 98.4%, and 98.4% in the low, medium and high fitness groups, respectively.
Quality of Diet versus Pace of Aging
https://www.fightaging.org/archives/2023/08/quality-of-diet-versus-pace-of-aging/
Given the advent of various clocks that measure biological age, one might expect that the research community will repeat and update past efforts to quantify the effects of diet, exercise, and other lifestyle factors on the long-term risk of age-related disease and mortality. The open access paper here is an example of this sort of work, focused on the impact of diet. The researchers made use of their own aging clock based on simple biomarkers, similar to Phenotypic Age, in order to determine a relationship between dietary quality and pace of aging.
In this prospective cohort study of 12,784 participants, based on a recently developed biological aging measure acquired at four-time points within an 8-year period, we identified three aging trajectories where participants in medium-degree or high-degree accelerated aging trajectory groups had higher risks of death than those in the slow aging trajectory. We then found that adopting an overall plant-based dietary pattern was associated with lower odds of being in medium-degree or high-degree accelerated aging trajectories. Plant-based dietary patterns were assessed by overall plant-based diet index (PDI), healthful PDI (hPDI), and unhealthful PDI (uPDI) Our study demonstrated a differential impact of plant-based foods on accelerated aging trajectory, i.e., a healthful plant-based diet was more beneficial to aging than an unhealthful plant-based diet. Fresh fruits, fresh vegetables, and legumes were major contributors found in our healthful plant-based diet analysis, whereas refined grain, salt-preserved vegetable, dairy products, and pluck were major contributors from unhealthful plant-based diet analysis.
We identified three latent classes of accelerated aging trajectories: slow aging, medium-degree, and high-degree accelerated aging trajectories. Participants who had higher PDI or hPDI had lower odds of being in medium-degree (odds ratio = 0.75 for PDI; odds ratio = 0.73 for hPDI) or high-degree (odds ratio = 0.63 for PDI; odds ratio = 0.62 for hPDI) accelerated aging trajectories. Participants in the highest quintile of uPDI were more likely to be in medium-degree (odds ratio = 1.72) or high-degree (odds ratio = 1.70) accelerated aging trajectories. With a mean follow-up time of 8.40 years and 803 (6.28%) participants died by the end of follow-up, we found that participants in medium-degree (hazard ratio = 1.56) or high-degree (hazard ratio = 3.72) accelerated aging trajectory groups had higher risks of death than those in the slow aging trajectory.
A Large Study of Immune Aging in T Cell and Natural Killer Cell Populations
https://www.fightaging.org/archives/2023/08/a-large-study-of-immune-aging-in-t-cell-and-natural-killer-cell-populations/
The overall population size of broad immune cell categories, such as T cells, remains remarkably consistent across a lifespan, even given a reduced supply of replacement T cells as the thymus atrophies and hematopoietic stem cell populations become dysfunctional. In an environment of limited supply, numbers are kept up in the face of continued attrition by increased replication, which leads to increased cellular senescence in immune cell populations as ever more cells hit the Hayflick limit. Another aspect of immune aging is a progressively larger shift in the relative count of different types of immune cell, such as diminished numbers of naive T cells capable of responding to novel pathogens.
Ageing is often accompanied with a decline in immune system function, resulting in immune ageing. Numerous studies have focussed on the changes in different lymphocyte subsets in diseases and immunosenescence. The change in immune phenotype is a key indication of the diseased or healthy status. However, the changes in lymphocyte number and phenotype brought about by ageing have not been comprehensively analysed. Here, we analysed T cell and natural killer (NK) cell subsets, the phenotype and cell differentiation states in 43,096 healthy Chinese individuals, aged 20-88 years, without known diseases. Thirty-six immune parameters were analysed and the reference ranges of these subsets were established in different age groups divided into 5-year intervals.
The data were subjected to random forest machine learning for immune-ageing modelling and confirmed using the neural network analysis. Our initial analysis and machine modelling prediction showed that naïve T cells decreased with ageing, whereas central memory T cells (Tcm) and effector memory T cells (Tem) increased CD28-associated T cells.
This is the largest study to investigate the correlation between age and immune cell function in a Chinese population, and provides insightful differences, suggesting that healthy adults might be considerably influenced by age and sex. The age of a person's immune system might be different from their chronological age. Our immune-ageing modelling study is one of the largest studies to provide insights into 'immune-age' rather than 'biological-age'. Through machine learning, we identified immune factors influencing the most through ageing and built a model for immune-ageing prediction.
PGC-1α4 Gene Therapy Reduces Sarcopenia and Metabolic Disease in Aged Mice
https://www.fightaging.org/archives/2023/08/pgc-1%ce%b14-gene-therapy-reduces-sarcopenia-and-metabolic-disease-in-aged-mice/
Researchers here demonstrate that aged muscle metabolism can be improved via gene therapy to deliver a short isoform of PGC-1α. Upregulating PGC-1α in muscle tissue is suggested to be a good approach to therapy based on its declining expression with age. It is interesting that the researchers focus on an isoform of the protein shown to be upregulated in exercise, in effect aiming to produce an exercise mimetic gene therapy that switches on one of the reactions to exercise and leaves it switched on indefinitely.
Sarcopenia is characterized of muscle mass loss and functional decline in elder individuals which severely affects human physical activity, metabolic homeostasis, and life quality. Physical exercise is considered effective in combating muscle atrophy and sarcopenia, yet it is not feasible to elders with limited mobility. PGC-1α4, a short isoform of PGC-1α, is strongly induced in muscle under resistance training, and promotes muscle hypertrophy. In the present study, we showed that the transcriptional levels and nuclear localization of PGC1α4 was reduced during aging, accompanied with muscle dystrophic morphology, and gene programs. We thus designed NLS-PGC1α4, a nuclear localization sequence attached to PGC1α4, and ectopically express it in myotubes to enhance PGC1α4 levels and maintain its location in nucleus.
Indeed, NLS-PGC1α4 overexpression increased muscle sizes in myotubes. In addition, by utilizing AAV-mediated NLS-PGC1α4 delivery into gastrocnemius muscle, we found that it could improve sarcopenia with grip strength, muscle weights, fiber size, and molecular phenotypes, and alleviate age-associated adiposity, insulin resistance, and hepatic steatosis, accompanied with altered gene signatures. Mechanistically, we demonstrated that NLS-PGC-1α4 improved insulin signaling and enhanced glucose uptake in skeletal muscle. Besides, via RNA-seq analysis, we identified myokines IGF1 and METRNL as potential targets of NLS-PGC-1α4 that possibly mediate the improvement of muscle and adipose tissue functionality and systemic energy metabolism in aged mice. Moreover, we found a negative correlation between PGC1α4 and age in human skeletal muscle.
Together, our results revealed that NLS-PGC1α4 overexpression improves muscle physiology and systematic energy homeostasis during aging and suggested it as a potent therapeutic strategy against sarcopenia and aging-associated metabolic diseases.
Sex Differences in Microglial Senescence in the Context of Alzheimer's Disease
https://www.fightaging.org/archives/2023/08/sex-differences-in-microglial-senescence-in-the-context-of-alzheimers-disease/
Why are two-thirds of Alzheimer's patients women? Women live longer than men, making up an ever larger share of the surviving cohort at any given age, and Alzheimer's is an age-related disease. This doesn't explain the whole of the difference, however. A dominant hypothesis is that the immune system is sufficiently different between the sexes to produce marginally greater dysfunction and neuroinflammation in women, in the same way that still incompletely understood biochemical differences lead to a greater incidence of autoimmunity in women. Researchers here produce supporting evidence for this hypothesis, showing that female Alzheimer's model mice exhibit a greater burden of cellular senescence in microglia, producing a greater level of neuroinflammation.
Microglia, the brain's principal immune cells, have been implicated in the pathogenesis of Alzheimer's disease (AD), a condition shown to affect more females than males. Although sex differences in microglial function and transcriptomic programming have been described across development and in disease models of AD, no studies have comprehensively identified the sex divergences that emerge in the aging mouse hippocampus. Further, existing models of AD generally develop pathology (amyloid plaques and tau tangles) early in life and fail to recapitulate the aged brain environment associated with late-onset AD. Here, we examined and compared transcriptomic and translatomic sex effects in young and old murine hippocampal microglia.
Hippocampal tissue from C57BL6/N and microglial NuTRAP mice of both sexes were collected at young (5-6 month-old) and old (22-25 monoth-old) ages. There were marginal sex differences identified in the young hippocampal microglia, with most differentially expressed genes (DEGs) restricted to the sex chromosomes. Both sex chromosomally and autosomally encoded sex differences emerged with aging. These sex DEGs identified at old age were primarily female-biased and enriched in senescent and disease-associated microglial signatures. Pathway analyses identified upstream regulators induced to a greater extent in females than in males, including inflammatory mediators IFNG, TNF, and IL1B, as well as AD-risk genes TREM2 and APP.
This data suggests that female microglia adopt disease-associated and senescent phenotypes in the aging mouse hippocampus, even in the absence of disease pathology, to a greater extent than males. This sexually divergent microglial phenotype may explain the difference in susceptibility and disease progression in the case of AD pathology. Future studies will need to explore sex differences in microglial heterogeneity in response to AD pathology and determine how sex-specific regulators (i.e., sex chromosomal or hormonal) elicit these sex effects.
Transferring the Naked Mole Rat Hyaluronan Synthase 2 Gene Into Mice Reduces Cancer Incidence, Extends Life
https://www.fightaging.org/archives/2023/08/transferring-the-naked-mole-rat-hyaluronan-synthase-2-gene-into-mice-reduces-cancer-incidence-extends-life/
Naked mole rats live far longer than similarly sized mammals, and are near immune to cancer. One of the mechanisms of cancer resistance involves the production of a different form of high molecular weight hyaluronan, and much more of it, improving the anti-cancer mechanism of contact inhibition. In addition, other mechanisms derived from changes in hyaluronan may affect life span through improved cellular function, but this is less well explored. Researchers here take the naked mole-rat version of the gene for high molecular weight hyoluronan, hyaluronan synthase 2, and put it into mice. The result is less cancer, improved metabolism, and longer lives.
Naked mole rats are mouse-sized rodents that have exceptional longevity for rodents of their size; they can live up to 41 years, nearly ten times as long as similar-size rodents. Unlike many other species, naked mole rats do not often contract diseases - including neurodegeneration, cardiovascular disease, arthritis, and cancer - as they age. Researchers previously discovered that high molecular weight hyaluronic acid (HMW-HA) is one mechanism responsible for naked mole rats' unusual resistance to cancer. Compared to mice and humans, naked mole rats have about ten times more HMW-HA in their bodies. When the researchers removed HMW-HA from naked mole rat cells, the cells were more likely to form tumors.
The team genetically modified a mouse model to produce the naked mole rat version of the hyaluronan synthase 2 gene, which is the gene responsible for making a protein that produces HMW-HA. While all mammals have the hyaluronan synthase 2 gene, the naked mole rat version seems to be enhanced to drive stronger gene expression. The researchers found that the mice that had the naked mole rat version of the gene had better protection against both spontaneous tumors and chemically induced skin cancer. The mice also had improved overall health and lived longer compared to regular mice. As the mice with the naked mole rat version of the gene aged, they had less inflammation in different parts of their bodies - inflammation being a hallmark of aging - and maintained a healthier gut. While more research is needed on exactly why HMW-HA has such beneficial effects, the researchers believe it is due to HMW-HA's ability to directly regulate the immune system.
Declining Cardiovascular Mortality in Atrial Fibrillation Patients
https://www.fightaging.org/archives/2023/09/declining-cardiovascular-mortality-in-atrial-fibrillation-patients/
A downward trend in cardiovascular mortality has prevailed for some time now, and we might take the data here as an example of ways in which improved options for detection and treatment produce results in specific portions of the patient population. Also worthy of note is the point that these older patients have many issues, and while slowing the pace of cardiovascular decline with age should have beneficial effects throughout the body, reduced cardiovascular mortality due to improved treatment that specifically focuses on cardiovascular disease allows other age-related conditions to claim a greater proportion of the population.
The research examined data from electronic health records of 72,412 patients from a representative sample of the UK population, who had been diagnosed with atrial fibrillation (AF) between 2001 and 2017. The team assessed the health outcomes in patients in the first year after their AF diagnosis, and analysed changes in cause-specific mortality and hospitalisation over time and by sex, age, socioeconomic status, and diagnostic care setting. The average patient was aged 75.6. Some 48.2% of patients were women, and 61.8% had three or more comorbidities. Over the study period, coexisting health concerns became more common, with almost 70% of newly diagnosed AF patients also having at least three comorbidities. Mortality rates at one year post diagnosis were investigated, as well as the number of hospital admissions with an overnight stay within 1 year of diagnosis.
Over the study period, 20% of patients died from any cause within a year of being diagnosed with AF - but this declined over time. However the researchers found that deaths due to cardiovascular and cerebrovascular events (strokes) more than halved over the study period. Cardiovascular deaths declined from 7.3% in 2001/02 to 3% in 2016/2017, while cerebrovascular deaths declined from 2.6% to 1.1%. The researchers say that the lower rates of cardiovascular deaths among AF patients in the study may be partly explained by improvements in strategies to prevent heart disease, and by changes in clinical practice that could lead to people being diagnosed earlier.
By contrast, there was an increase in mortality rates from mental and neurological disorders, from 2.5% in 2001/02 to 10.1% in 2016/17. Of these deaths, 87.2% were caused by dementia, Alzheimer's disease, and Parkinson's disease. The research team say that while this could be partly due to greater awareness of dementia, it also strengthens the evidence that the relationship between AF and dementia is a pressing research priority.
Adjusting Macrophages to an Anti-Inflammatory Phenotype Improves Pathology Following a Heart Attack
https://www.fightaging.org/archives/2023/09/adjusting-macrophages-to-an-anti-inflammatory-phenotype-improves-pathology-following-a-heart-attack/
Macrophages of the innate immune system can adopt a variety of behavior packages in response to circumstances. The most commonly studied are M1 (aggressive and inflammatory) versus M2 (anti-inflammatory and regenerative), as these capture two of the most interesting aspects of these immune cells. Macrophages hunt and destroy pathogens and rogue cells in their M1 form, but also participate in tissue maintenance and repair in their M2 form. A sizable number of research and development programs are based on ways to persuade M1 macrophages in injured tissues to switch into the M2 phenotype, resulting in improved regeneration and reduced harmful inflammation. Here, researchers show that their approach to this switching of phenotype can improve outcomes in a rat model of heart attack.
The modulation of inflammatory responses plays an important role in the pathobiology of cardiac failure. In a natural healing process, the ingestion of apoptotic cells and their apoptotic bodies by macrophages in a focal lesion result in resolution of inflammation and regeneration. However, therapeutic strategies to enhance this natural healing process using apoptotic cell-derived biomaterials have not yet been established.
In this study, apoptotic bodies-mimetic nanovesicles derived from apoptotic fibroblasts (ApoNVs) conjugated with dextran and ischemic cardiac homing peptide (CHP) (ApoNV-DCs) for ischemia-reperfusion (IR)-injured heart treatment are developed. Intravenously injected ApoNV-DCs actively targeted the ischemic myocardium via conjugation with CHP, and are selectively phagocytosed by macrophages in an infarcted myocardium via conjugation with dextran. ApoNV-DCs polarized macrophages from the M1 to M2 phenotype, resulting in the attenuation of inflammation.
Four weeks after injection, ApoNV-DCs attenuated cardiac remodeling, preserved blood vessels, and prevented cardiac function exacerbation in IR-injured hearts. Taken together, the findings may open a new avenue for immunomodulation using targeted delivery of anti-inflammatory nanovesicles that can be universally applied for various inflammatory diseases.