Fight Aging! Newsletter, July 8th 2024

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Small Molecule Upregulation of TERT Expression Improves Function in Aged Mice

Increased telomerase expression achieved via gene therapy is well demonstrated to improve health and extend life span in mice. The end of every chromosome is capped with telomeres, repeated sequences of DNA that act as part of a system to limit cell replication, the Hayflick limit. A little of the length of a telomere is lost with each replication, and a cell becomes senescent or enters programmed cell death when telomeres become too short. The cells of the body are divided between the vast majority of somatic cells that are limited in this way, and the tiny minority of privileged stem cells that are capable of using telomerase to extend their telomeres, and thus replicate indefinitely. The role of stem cells is to produce new somatic cells to replace those lost to the Hayflick limit. This complicated system most likely evolved because it keeps the risk arising from cancerous mutations and other pathological forms of cell damage to a low enough level for a species to compete effectively.

When looking at telomere length in cell populations, the average is some reflection of pace of somatic cell division versus the pace at which stem cells deliver replacement somatic cells with long telomeres. With advancing age, stem cell function declines, and thus average telomere length decreases. This correlation isn't very strong, and only shows up in large data sets; there isn't much predictive power to measuring an individual's average telomere length in isolation. Nonetheless, forcing greater telomerase expression is beneficial in mice, improving tissue function across the board. Will this be true in larger mammals such as humans, species with quite different telomere dynamics? Mice express more telomerase more widely in their cell populations than is the case in primates, so that remains an open question.

This complicated business of telomere length is just one of the ways in which telomerase influences cell and tissue function, as today's research materials make clear. Telomerase expression declines with age, and when restored to youthful levels it initiates a broad cascade of changes in gene expression and improvements in cell function. Unlike past research, the scientists here made use of a newly discovered small molecule that can increase telomerase expression. Long-term use improves outcomes in aged mice in similar ways to one-time telomerase gene therapy, though the effect size will likely be smaller once enough work has been conducted to robustly calibrate the results. This is usually the case when moving from gene therapies to small molecule therapies that target the same mechanisms. Given that mice express telomerase to at least some degree most of their cells, while humans do not, one might wonder whether a small molecule approach to increase expression that works well in mice will be anywhere near as useful in our species - it may not work at all in somatic cells that do not express telomerase. The researchers tested in human cell lines, but these cell lines are by definition immortalized, expressing telomerase to maintain lengthy telomeres.

Activating molecular target reverses multiple hallmarks of aging

Researchers have identified a small molecule compound that restores physiological levels of telomerase reverse transcriptase (TERT), which normally is repressed with the onset of aging. Maintenance of TERT levels in aged lab models reduced cellular senescence and tissue inflammation, spurred new neuron formation with improved memory, and enhanced neuromuscular function, which increased strength and coordination. "Epigenetic repression of TERT plays a major role in the cellular decline seen at the onset of aging by regulating genes involved in learning, memory, muscle performance and inflammation. By pharmacologically restoring youthful TERT levels, we reprogrammed expression of those genes, resulting in improved cognition and muscle performance while eliminating hallmarks linked to many age-related diseases."

A high-throughput screen of over 650,000 compounds identified a small-molecule TERT activating compound (TAC) that epigenetically de-represses the TERT gene and restores physiological expression present in young cells. In preclinical models equivalent to adults over age 75, TAC treatment for six months led to new neuron formation in the hippocampus (memory center) and improved performance in cognitive tests. Additionally, there was an increase in genes involved in learning, memory, and synaptic biology, consistent with TERT's ability to interact with and control the activity of transcription factor complexes regulating diverse genes. TAC treatment also significantly reduced inflammaging - an age-related increase in inflammatory markers linked with multiple diseases - in both blood and tissue samples and also eliminated senescent cells by repressing the p16 gene, a key senescence factor. TAC improved neuromuscular function, coordination, grip strength and speed in these models, reversing sarcopenia - a condition under which muscle mass, strength and performance naturally worsen with advancing age.

TERT activation targets DNA methylation and multiple aging hallmarks

Insufficient telomerase activity, stemming from low telomerase reverse transcriptase (TERT) gene transcription, contributes to telomere dysfunction and aging pathologies. Besides its traditional function in telomere synthesis, TERT acts as a transcriptional co-regulator of genes pivotal in aging and age-associated diseases. Here, we report the identification of a TERT activator compound (TAC) that upregulates TERT transcription via the MEK/ERK/AP-1 cascade. In primary human cells and naturally aged mice, TAC-induced elevation of TERT levels promotes telomere synthesis, blunts tissue aging hallmarks with reduced cellular senescence and inflammatory cytokines, and silences p16INK4a expression via upregulation of DNMT3B-mediated promoter hypermethylation. In the brain, TAC alleviates neuroinflammation, increases neurotrophic factors, stimulates adult neurogenesis, and preserves cognitive function without evident toxicity, including cancer risk. Together, these findings underscore TERT's critical role in aging processes and provide preclinical proof of concept for physiological TERT activation as a strategy to mitigate multiple aging hallmarks and associated pathologies.

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Ketogenesis Increases BDNF Expression to Improve Late Life Cognitive Function

Ketone bodies are a family of metabolites produced during the metabolic stress of fasting or calorie restriction. A ketogenic diet is intended to produce a similar degree of ketogenesis without a low calorie intake by reducing carbohydrate intake relative to fat intake. Too much ketogenesis is a bad thing, but modest increases appear generally beneficial, one part of the big puzzle that is the sweeping metabolic response to a low calorie diet.

The brain receives a sizable fraction of its energy supply in the form of ketone bodies, and ketogenic diets have been shown in animal studies to improve cognitive function, particularly memory, in late life. Other lines of evidence suggest that parts of the mammalian brain are operating right at the edge of their capacity even in youth. For example, exercise increases cerebral blood flow for a time, and during that short period of time, memory function is improved. Thus one might look at any approach that increases delivery of nutrients and oxygen to the brain as a possible way to improve cognitive functions.

In today's open access paper, researchers report on their study of the effects of a ketogenic diet in mice. The authors were searching for mechanisms to explain the established improvement in cognitive function observed as a result of this intervention. Interestingly, they find that a ketogenic diet upregulates BDNF expression in the brain. There is a sizable body of work showing that increased BDNF expression can improve function in the aging brain. For example, changes in metabolite levels influencing BDNF expression may be an important mechanism linking the composition and activity of the gut microbiome to cognitive aging. BDNF can also dampen neuroinflammation and boost neurogenesis, both very relevant to brain aging.

Ketogenic diet administration later in life improves memory by modifying the synaptic cortical proteome via the PKA signaling pathway in aging mice

In this work, we provide cellular and molecular mechanistic evidence that an intermittent ketogenic diet (KD) in aged animals improves brain functions. We show that KD improves memory and potentiates synaptic function, remodels the synaptic proteome, and activates protein kinase A (PKA) signaling. The activation of the cAMP-dependent signaling connects the different layers here studied, providing a novel mechanism for the beneficial effects observed after KD administration in aged mice. KD consumption prompts cells to transition from using glucose to ketone bodies as a primary source of energy. To this end, the liver synthesizes acetoacetate and β-hydroxybutyrate (BHB) from fatty acids, with BHB being the most abundant one. Although dysregulated elevation of ketone body blood levels are associated with pathological conditions such as diabetes, physiological range concentrations are beneficial in experimental models of aging.

Studies in the field of aging have consistently demonstrated that a KD reduces midlife mortality and modifies brain function in mice after long-term administration. Recently, a study showed that ingesting a KD, starting at age 18 months, improves spatial memory and muscle endurance after 5 months of administration. Here, we report that 4 months of a cyclic KD administration (alternated weekly with a control diet to prevent obesity) starting at age 20-23 months significantly improves working memory and long-term memory in 26- to 27-month old mice.

This cyclic KD restores long-term potentiation (LTP) in the hippocampus of aged mice, as it was significantly improved compared with the control group, resulting in a performance closer to young mouse values. Interestingly, this was consistent with the reduced latency to find the escape hole in the Barnes maze, 12 days after the test was initiated, which supports a role of a KD in long-term memory. When PKA levels were compared between groups, no significant differences were registered, although an increasing trend was observed in the KD conditions. Thus, we postulate that changes in the cAMP-pathway induced by the KD modify the activity, rather than the amount, of PKA. Although PKA expression was not substantially upregulated by the KD, we confirmed the activation of the signaling pathway, as BDNF, a canonical target of this route, was overexpressed in the KD group. BDNF regulates synaptic plasticity and structural changes in dendritic spines, promoting learning and memory processes. In addition, it is well known that BDNF and neurotrophic factor signaling is impaired in the aging brain.

In summary, our data provide new insights into molecular mechanisms and biological processes that a cyclic KD regulates in brain function, an aspect that has been understudied in the field of aging. In addition, we reveal here that a KD has the potential to modify brain function and motor activity in aged mice, even when administered later in life. This study also proposes new mechanisms by which the administration of a cyclic KD improves memory and neuronal function in aging that had not been discovered previously. Specifically, a KD induces changes in the proteome landscape of cortical synapses that directly impact the structure and function of synaptic organization, proposing a scenario whereby ketone bodies (specifically BHB) play a crucial role not only as an energy metabolite, but also as a signaling metabolite.

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Results from a Phase 2 Trial of Senolytic Therapy Dasatinib and Quercetin for Osteoporosis

Senescent cells accumulate with age to cause disruption to tissue structure and function throughout the body. So far the only senolytic therapy demonstrated in clinical trials to clear senescent cells in humans as well as it does in mice is the dasatinib and quercetin combination. In general, senolytic therapies have produced very impressive results in mice, but the few clinical research groups presently running human studies are still in the process of figuring out dosing and optimal use cases for the various first generation small molecule senolytics, such as dasatinib and quercetin, and perhaps fisetin.

Initial results from a Mayo Clinic phase 2 study in older women with osteoporosis covered by today's research material are actually quite positive, despite the failure to produce a significant difference when considering the whole treatment group. Only those women with a larger burden of senescent cells responded well to the therapy, showing reduced markers of underlying processes of osteoporosis. They did respond, however, including improvement in bone mineral density. This is a good demonstration of the point that a better clinical means of assessment of the burden of cellular senescence is very much needed. Given simple robust and cost-effective assays, the widespread off-label use of the low-cost treatment of dasatinib and quercetin would arrive that much more rapidly.

Interestingly, this clinical trial does include a fisetin treated arm, but the researchers do not discuss that here. The Mayo Clinic has been conducting other human trials of fisetin as a senolytic treatment for various age-related conditions, and this absence of information is also the case there as well. Fisetin performed well in early studies in mice, but did not do well in the Interventions Testing Program study - for reasons that may have had more to do with the study design rather than the properties of fisetin. It is somewhat frustrating that the Mayo Clinic is choosing not to present their human study data on fisetin.

Drugs that kill "zombie" cells may benefit some older women, but not all

In the 20-week, phase 2 randomized controlled trial, 60 healthy women past menopause intermittently received a senolytic combination composed of FDA-approved dasatinib and quercetin, a natural product found in some foods. It is the first randomized controlled trial of intermittent senolytic treatment in healthy aging women, and the investigators used bone metabolism as a marker for efficacy. Subjects received 100mg dasatinib plus 1000mg quercetin taken orally daily for three consecutive days on an intermittent schedule repeated every 28 days over 20 weeks, resulting in five total three-day dosing periods throughout the entire intervention.

Researchers found that this combination, known as D+Q, had beneficial effects on bone formation but did not reduce bone resorption or the breakdown and removal of bone tissue. Furthermore, D+Q mainly benefited people with evidence of a high number of senescent cells. This group had more robust increases in bone formation, decreases in bone resorption, and an increase in bone mineral density at the wrist. "Our findings argue against what many people are already doing - using commercial products like quercetin or related compounds like fisetin that may show some senolytic properties. They're using them as anti-aging agents without knowing if they have high enough senescent cell numbers to benefit, or what dose or dosing regimen is needed to be effective yet safe."

Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial

Preclinical evidence demonstrates that senescent cells accumulate with aging and that senolytics delay multiple age-related morbidities, including bone loss. Thus, we conducted a phase 2 randomized controlled trial of intermittent administration of the senolytic combination dasatinib plus quercetin (D + Q) in postmenopausal women (n = 60 participants). The primary endpoint, percentage changes at 20 weeks in the bone resorption marker C-terminal telopeptide of type 1 collagen (CTx), did not differ between groups. The secondary endpoint, percentage changes in the bone formation marker procollagen type 1 N-terminal propeptide (P1NP), increased significantly (relative to control) in the D + Q group at both 2 weeks and 4 weeks, but was not different from control at 20 weeks. No serious adverse events were observed.

In exploratory analyses, the skeletal response to D + Q was driven principally by women with a high senescent cell burden (highest tertile for T cell p16 mRNA levels) in which D + Q concomitantly increased P1NP and reduced CTx at 2 weeks, and increased radius bone mineral density at 20 weeks. Thus, intermittent D + Q treatment did not reduce bone resorption in the overall group of postmenopausal women. However, our exploratory analyses indicate that further studies are needed testing the hypothesis that the underlying senescent cell burden may dictate the clinical response to senolytics.

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The Gene Expression Patterns of Inflammaging and Immunosenescence in Cynomolgus Macaques

The aging of the immune system is an important contribution to frailty and age-related disease. Firstly the immune system becomes overactive, reacting to forms of the molecular damage of aging as though they were cancer, injury, or infection. Pathways evolved to be protective in youth instead become maladaptive in the damaged environment of aged tissue. The resulting constant inflammatory signaling is itself disruptive to tissue structure and function. This state is known as inflammaging.

Secondly, the immune system becomes progressively less able to coordinate its activities in order to attack and destroy pathogens and cancerous or senescent cells. Infections that a young person would shrug off can kill older individuals. Cancer is an age-related condition. Senescent cells accumulate to cause further harm rather than being promptly destroyed by immune cells. This loss of immune capabilities is known as immunosenescence.

In today's open access paper, researchers report on an assessment of immune aging in a non-human primate species. Cynomolgus macaques are commonly used in research, and are a much more relevant species than mice when it comes to examining the fine details of age-related changes in immune cell populations. Looking at gene expression, the researchers find examples of increased inflammatory activity in the innate immune system, aspects of inflammaging, versus evidence of specific losses of capacity in the adaptive immune system, aspects of immunosenescence.

Transcriptome analysis of cynomolgus macaques throughout their lifespan reveals age-related immune patterns

Alterations in the immune system are currently the subject of lively debate in aging research. The chronic low-grade inflammation caused by activation of innate immunity is a crucial phenomenon that occurs with aging and is globally known as "inflammaging". Additionally, impaired function of immunity changes in older individuals, known as "immunosenescence", prompt susceptibility to infectious or age-related diseases, damaging the overall biological system of the body and accelerating their biological age. Epigenetic factors have recently been regarded as mediators between aging and immune response.

We investigated the transcriptomic features of healthy and specific pathogen-free cynomolgus macaques (Macaca fascicularis). To explore whole lifespan, eight male macaques were divided into four age group each containing two individuals. As a laboratory animal, the macaques were protected from all environmental factors other than aging. Three years of this study revealed immune-related gene expression patterns.

The results showed recent findings of certain immune response and the age-associated network of primate immunity. Three important aging patterns were identified and each gene clusters represented a different immune response. The increased expression pattern was predominantly associated with innate immune cells, such as Neutrophils and NK cells, causing chronic inflammation with aging whereas the other two decreased patterns were associated with adaptive immunity, especially "B cell activation" affecting antibody diversity of aging. Furthermore, the hub gene network of the patterns reflected transcriptomic age and correlated with human illness status, aiding in future human disease prediction. Our macaque transcriptome profiling results offer systematic insights into the age-related immunological features of primates.

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NTF3 Upregulation Produces Better than Normal Hearing in Mice

A few of the possible treatments for age-related conditions presently under development are essentially enhancement therapies. They compensate in some way for losses incurred over the course of degenerative aging by adding functionality. Some of these treatments, by their nature, can in principle enhance function in young individuals as well. In age-related hearing loss, part of the problem is the loss of sensory hair cells in the inner ear, and part of the problem is the loss of axonal connections between those cells and the brain. What if a therapy could provoke the growth of new axons (and possibly new hair cells), and what if that therapy gave an individual more than the natural number of such connections and sensory cells?

In the course of evaluating NTF3 as a target for axon regrowth, researchers here produce mice lineages that have a greater than usual density of axons connecting sensory hair cells to the brain. These mice can apparently make use of that additional connectivity, and outperform their unmodified peers in tests of hearing that rely upon sensory processing in the brain. It is interesting to speculate as to whether life-long presence of the additional connections is needed in order to develop this improved sensory processing, or whether connections added in adult life would be integrated to incrementally improve sensory processing.

Creating supranormal hearing in mice

Researchers have previously increased the amount of the neurotrophic factor neurotrophin-3 (Ntf3) in the inner ear to promote the recovery of auditory responses in mice that had experienced acoustic trauma, and to improve hearing in middle-aged mice. Here, the researchers altered the expression of the Ntf3 to increase the number of synapses between inner hair cells and neurons. "We knew that providing Ntf3 to the inner ear in young mice increased the number of synapses between inner hair cells and auditory neurons, but we did not know what having more synapses would do to hearing. We now show that animals with extra inner ear synapses have normal thresholds - what an audiologist would define as normal hearing - but they can process the auditory information in supranormal ways."

The mice with increased synapses exhibited enhanced peaks in measured Acoustic Brain Stem response, but also performed better on the Gap-Prepulse Inhibition test, suggesting an ability to process an increased amount of auditory information. "We were surprised to find that when we increased the number of synapses, the brain was able to process the extra auditory information. And those subjects performed better than the control mice in the behavioral test." Hair cell loss had once been believed to be the primary cause of hearing loss in humans as we age. Now, however, it's understood that the loss of inner hair cell synapses can be the first event in the hearing loss process, making therapies that preserve, regenerate and/or increase synapses an exciting possible approache for treating some hearing disorders.

From hidden hearing loss to supranormal auditory processing by neurotrophin 3-mediated modulation of inner hair cell synapse density

Loss of synapses between spiral ganglion neurons and inner hair cells (IHC synaptopathy) leads to an auditory neuropathy called hidden hearing loss (HHL) characterized by normal auditory thresholds but reduced amplitude of sound-evoked auditory potentials. It has been proposed that synaptopathy and HHL result in poor performance in challenging hearing tasks despite a normal audiogram. However, this has only been tested in animals after exposure to noise or ototoxic drugs, which can cause deficits beyond synaptopathy. Furthermore, the impact of supernumerary synapses on auditory processing has not been evaluated.

Here, we studied mice in which IHC synapse counts were increased or decreased by altering neurotrophin 3 (Ntf3) expression in IHC supporting cells. As we previously showed, postnatal Ntf3 knockdown or overexpression reduces or increases, respectively, IHC synapse density and suprathreshold amplitude of sound-evoked auditory potentials without changing cochlear thresholds. We now show that IHC synapse density does not influence the magnitude of the acoustic startle reflex or its prepulse inhibition. In contrast, gap-prepulse inhibition, a behavioral test for auditory temporal processing, is reduced or enhanced according to Ntf3 expression levels. These results indicate that IHC synaptopathy causes temporal processing deficits predicted in HHL. Furthermore, the improvement in temporal acuity achieved by increasing Ntf3 expression and synapse density suggests a therapeutic strategy for improving hearing in noise for individuals with synaptopathy of various etiologies.

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The Useful Functions of Senescent Cells

Cells that become senescent cease to replicate and begin to secrete a pro-growth, pro-inflammatory mix of signals. Senescent cells do perform useful functions in the body, usually emerging for a short time before being cleared. It is only when senescent cells linger, accumulating to provoke disruption of tissue structure and immune function, that their presence becomes a harmful contribution to degenerative aging. Thus constant clearance of senescent cells is probably not the desired goal for medical science, but rather periodic clearance of the excess senescent cells via intermittent treatment with senolytic drugs, or some form of restoration of lost immune function in older individuals in order to allow the body to clear excess senescent cells in a timely fashion.

The aging of the world's population has intensified interest in understanding the aging process and devising strategies and interventions to prolong a healthy life span. Cellular senescence, when cells become irreversibly growth arrested after a period of in vitro cell proliferation or in response to sublethal stress or oncogene expression, plays a role in aging phenotypes and age-associated diseases. Increasing evidence shows that senescent cells also have essential physiological functions, such as in tumor suppression, development, wound healing, tissue remodeling, regeneration, and vasculature. This raises important questions about the similarities and differences between senescent cell types and how they function in homeostasis and pathology, and it creates additional challenges in targeting them therapeutically.

Although several studies in mouse models support the hypothesis that senescent cells can trigger or contribute to age-associated phenotypes, more recent studies have revealed additional roles for senescent cells in nonharmful and even physiological processes. Indeed, eliminating senescent cells in mice can be detrimental to health, highlighting the importance of these cells in mammalian homeostasis and physiology. For example, senescent cells become more prevalent with age, particularly in the liver, and are often vascular endothelial cells. The continuous or acute removal of these senescent cells in mice disrupted blood-tissue barriers and led to the buildup of blood-borne macromolecular waste, resulting in perivascular fibrosis in a variety of tissues and subsequent health deterioration.

Although damage and stress can induce cellular senescence, perhaps to recruit immune cells through the senescence-associated secretory phenotype (SASP) and promote tissue repair and remodeling, cellular senescence can also arise independently of molecular damage or injury, for example, during development. Furthermore, senescence induced by injury can encourage regeneration and wound healing, and the degree of senescent cell involvement in the regeneration of different tissues is an exciting avenue for future research. Although a role for senescent cells in aging has been suggested by many studies, the recent findings that demonstrate normal physiological functions of senescent cells reveal a more complicated picture of the potential role of cellular senescence in mammalian aging.

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Cerebral Small Vessel Disease as a Contribution to Alzheimer's Disease

For all that a great deal of evidence points to cardiovascular disease as a contributing factor in the development of forms of dementia, there remains debate over the degree to which this is the case, and which aspects of cardiovascular disease are more or less important. Here, researchers on cerebral small vessel disease, a catch-all bucket for all dysfunctions affecting the microvasculature of the brain as a result of the accumulated molecular damage of aging, either directly or indirectly. The visible signs seen in imaging are tiny volumes of damaged tissue where vessels have ruptured. The brain doesn't recover this lost tissue, and over time this is though to have a growing effect on cognitive function. Separately, leakage of the blood-brain barrier likely sets up a disrupted, inflamed metabolism in the brain, the foundation for neurodegenerative conditions such as Alzheimer's disease.

The scientific community widely recognizes that most dementia cases, including Alzheimer's disease, are related to a combination of vascular and neurodegenerative lesions. And cerebral small-vessel disease is thought to be the main underlying contribution to cognitive decline and dementia, with nearly half of dementia cases showing both Alzheimer's and cerebral small-vessel disease neuropathologic characteristics. Still, while observational studies had shown evidence of an association between white matter hyperintensity burden and increased risk of stroke and dementia, causal evidence had been limited. White matter hyperintensities (WMHs) are lesions in the brain that show up as areas of increased brightness in magnetic resonance imaging.

In the new study, researchers were able to provide evidence of a causal link between vascular traits and Alzheimer's disease, using genetic instrument variable analyses known as Mendelian randomization - a method that leverages the natural randomization of genetic alleles to test how differences in the genetic effect on modifiable exposure influence disease risk. Specifically, in a two-year analysis ending in 2022, and using Alzheimer's disease genome-wide association studies of up to 75,000 European dementia cases, they found causal evidence of an association of larger WMH burden with increased risk of the disease, accounting for pulse-pressure effects. "As vascular disease is a treatable contributor to dementia risk, our findings have broad significance for prevention strategies of Alzheimer's and dementia as a whole."

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Evidence for the Calorie Restriction Response to be Triggered by Energy Imbalance

Calorie restriction, eating fewer calories while still obtaining needed levels of micronutrients, reliably extends life in mice. The metabolic response to calorie restriction is sweeping, changing near every aspect of cellular biochemistry. This makes it challenging to understand how calorie restriction works in detail to improve health and slow the aging process: when everything is changing, how to pick out the important changes? There is a good argument for the effects on life span to derive from upregulation of the cellular maintenance process of autophagy, but there are a great many other potentially contributing mechanisms. The calorie restriction response is triggered by nutrient sensing mechanisms, but even when only considering these triggers there is considerable room to debate how exactly this works, as the research here demonstrates.

Researchers have long debated why restricting a rodent's food intake increases its lifespan. One theory, he explains, suggests that rodents fed less food have fewer calories to metabolize and so produce less oxidants and other by-products of metabolism that damage cells. Another possibility is that the absolute number of calories matters less than the difference in calories consumed versus calories metabolized. Perhaps eating a massive number of calories is not detrimental to health as long as the animal is burning them off efficiently. But testing this theory by encouraging mice to exercise more, for example, can be tricky, because exercise comes with all sorts of other health benefits.

Researchers instead tested the impact of accelerated calorie burning by studying mice that were kept in cages at two different temperatures. Mice in the warmer cages were allowed to eat as much as they liked, and then mice in the cooler cages were given the same amount of food that their warmer-caged counterparts consumed. The key difference was that the cooler mice had to burn more energy to maintain their body temperatures.

In one experiment, researchers tracked biomarkers of health in mice kept at cooler temperatures for 11 weeks. Some mice were housed at 10 °C and fed the same diet as mice in 21 °C cages. Others were housed at 21 °C and fed the same diet as mice in 30 °C cages. In both cases, the cooler mice had lower levels of insulin. Their body weights also dropped and then stabilized at roughly 75% of the warmer-caged mice. A second experiment, which tracked mice over the course of their lifespans, revealed that mice housed at 22 °C lived about 20% longer, on average, than mice fed the same diet at 27 °C. The cooler mice also seemed to remain healthier as they aged, maintaining better balance and a more coordinated gait compared to those in warmer cages. "It's not simply the caloric intake or the macronutrient or protein intake or any one component. It is the interaction of those relative to the energy balance overall."

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It is Possible to Suppress the Random Variance in Life Span in Nematode Worms

Species have evolved to exhibit natural variations in life span. Even genetically identical clones exhibit variable life spans. This may because this variation in metabolic processes helps to ensure that at least some individuals are better adapted to the details of the present environment, in a world in which aspects of the local environment do indeed vary over time. Species that did not exhibit this variability in characteristics between individuals would be outcompeted by those that did, sabotaged by environmental changes. Any effects on life span are likely only a side-effect of this specific aspect of the ruthless evolutionary competition for early life reproductive success. Thus, as researchers demonstrate here, it is possible to adjust the expression of specific genes to reduce this natural variation in life span, ensuring that short-lived individuals live longer. Doing so may reduce their ability to thrive in a less comfortable environment, but that remains to be determined.

Researchers observed thousands of genetically identical C. elegans nematode worms living in a controlled environment. Even when diet, temperature and exposure to predators and pathogens are the same for all worms, many individuals continue to live for a longer or shorter period of time than the average. The study traced the primary source of this variation to changes in the mRNA content in germline cells (those involved in reproduction) and somatic cells (the cells forming the body). The mRNA balance between the two types of cells is disrupted, or 'decouples', over time, causing ageing to run faster in some individuals than others. The study also found that the magnitude and speed of the decoupling process is influenced by a group of at least 40 different genes. These genes play many different roles in the body ranging from metabolism to the neuroendocrine system. However, the study is first to show they all interact to make some individuals live longer than others.

Knocking down some of the genes extended a worm's lifespan, while knocking down others shortened it. The findings suggest a surprising possibility: the natural differences seen in ageing worms might reflect randomness in the activity of many different genes, making it look as if individuals have been exposed to knockdowns of many different genes. Knocking down three genes - aexr-1, nlp-28, and mak-1 - had a particularly dramatic effect on lifespan variance, reducing the range from around 8 days to just 4. Rather than prolonging the lives of all individuals uniformly, removing any one of these genes drastically increased the life expectancy of worms on the low end of the spectrum, while the life expectancies of the longest-lived worms remained more or less unchanged. The researchers observed the same effects on healthspan, the period of life spent healthy, rather than simply how long an individual is physically alive. The researchers measured this by studying how long the worms maintain vigorous movement. Knocking down just one of the genes was enough to disproportionately improving healthy ageing in worms on the low end of the healthspan spectrum.

The study doesn't address why knocking down the genes doesn't seem to negatively affect the worm's health. "Several genes could interact to provide built-in redundancy after a certain age. It could also be that the genes aren't needed for individuals living in benign, safe conditions where the worms are kept in the lab. In the harsh environment of the wild, these genes might be more critical for survival. These are just some of the working theories."

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Statins Can Modestly Reduce Cardiovascular Events in Later Old Age

Therapies that lower serum LDL cholesterol can modestly reduce the risk of cardiovascular events in people with raised serum LDL cholesterol, meaning heart attack and stroke resulting from rupture of an atherosclerotic plaque. Greater circulating LDL cholesterol maintained over years and decades is one of the contributing factors leading to the growth of these fatty plaques in blood vessel walls. Statins and other LDL-lowering approaches slow the growth of plaque and over the course of years will change the plaque composition from soft and vulnerable to more calcified, fibrotic, and stable. This approach cannot regress existing plaque meaningfully in more than a fortunate few patients, however. The average plaque reduction reported in meta-analyses is near zero. The cardiovascular event risk reduction is generally thought to top out at 20% or so, while many studies show little to no risk reduction. Better therapies are needed.

Researchers have provided the first comprehensive evidence of the benefits of statin use in elderly patients, addressing longstanding uncertainties. The robust evidence demonstrated that continuous statin therapy resulted in a substantial relative risk reduction in cardiovascular diseases (CVDs) of 21% for those aged 75-84 and 35% for those aged 85 or above, without any heightened safety concerns.

CVD is a leading healthcare burden globally, particularly in ageing populations. Effective management of high cholesterol is a crucial intervention in the prevention of CVDs. According to the latest 'Population Health Survey' in Hong Kong, 65.6% of individuals aged 65-84 have high cholesterol. While statins have been used for decades to improve lipid profiles and reduce the risk of CVDs, there is little consensus on the use of statins for primary prevention in patients aged 75 or above in the existing international clinical guidelines.

The research team analysed the public electronic medical records from January 2008 to December 2018 of over 80,000 older individuals in Hong Kong who had suboptimal lipid levels and high-risk conditions, such as diabetes or other risk factors for CVDs. The findings indicate that the continual use of statins was linked to a 21% reduction in relative risk and an absolute risk reduction of 5% over five years in CVDs among people aged 75-84. The relative risk reduction was an even more substantial 35%, and the absolute risk reduction after five years was 12.5% in those aged 85 or above. The study also found no increased risk of major adverse events, including liver dysfunction or myopathies, identified with statin use in this population.

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An Emphasis on Impaired Neurogenesis as an Early Stage of Alzheimer's Disease

There is a diversity of thought regarding the mechanisms of Alzheimer's disease, even if it may seem that the vast majority of funding and attention is focused on protein aggregation, whether amyloid-β or tau. There was a great deal of alternative theorizing during the long years in which amyloid-β clearance was failing, and that has given rise to numerous research and development programs focused on inflammatory signaling or other mechanisms that might be relevant to neurodegenerative pathology. The theorizing continues apace, even now that amyloid-β clearance is starting to show some signs of working, at least in the early stages of Alzheimer's disease. The paper here is an example of the type, seeking to draw attention away from protein aggregates and toward other aspects of the complex biology of the aging brain.

Despite the wealth of new insights into the dysregulated processes underlying the appearance of toxic amyloid plaques and hyperphosphorylated tau protein, treatments targeting these continue to fail to cure Alzheimer's disease (AD), and offer only minimal symptomatic relief. This raises a pivotal question: have we thoroughly explored the classic amyloid and tau hypotheses with no causative mechanism identified, signalling a need for a paradigm shift? Furthermore, the current affinity among researchers to view new evidence solely through the lens of the well-established amyloid and tau hypotheses could be hindering the exploration of other genes and proteins and their multifaceted roles within the human brain as potential initiators and drivers of AD pathology.

Perhaps it is time to consider a novel perspective on AD, emphasizing impaired neurogenesis as an early aetiological factor. In this review, we explore the existing knowledge of adult hippocampal neurogenesis (AHN) and extend our inquiry into the perspective that compromised AHN could serve as a fundamental player in the prodromal and preclinical phases of AD, even preceding the amyloid and tau features. We aim to unravel the molecular interplay underlying impaired AHN, thus contributing to a deeper understanding of the complex landscape of AD pathogenesis.

A novel hypothesis is presented, interweaving the roles of Notch signalling and heparan sulfate proteoglycans (HSPGs) in compromised AHN. While acknowledging the significance of the amyloid and tau hypotheses, it calls for further exploration beyond these paradigms, suggesting the potential of altered heparan sulfate (HS) sulfation patterns in AD initiation. Future directions propose more detailed investigations into early HS aggregation, aberrant sulfation patterns, and examination of their temporal relationship with tau hyperphosphorylation. In challenging the conventional 'triggers' of AD and urging their reconsideration as symptoms, this review advocates an alternative approach to understanding this disease, offering new avenues of investigation into the intricacies of AD pathogenesis.

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Aging Promotes Harmful Levels of Ferroptosis in the Liver and other Organs

Aging makes obesity-related liver conditions such as metabolic dysfunction-associated steatotic liver disease (MASLD) both more likely to occur and worse when they do occur, more likely to progress towards fibrosis and liver failure. Researchers here point to an increased propensity to the cell death process of ferroptosis in liver cells as an important difference between old and young livers, and demonstrate that blocking ferroptosis can make old livers more youthful in the context of metabolic disease.

Researchers set out to understand how non-alcoholic liver disease develops into a severe condition called cirrhosis, in which scarring can lead to organ failure. Aging is a key risk factor for cirrhosis among those who have been diagnosed with non-alcoholic liver disease, known as metabolic dysfunction-associated steatotic liver disease, or MASLD. One in three adults worldwide have the disease. Studying the livers of mice, the researchers identified a genetic signature distinct to old livers. Compared to young livers, the old organs had an abundance of genes that were activated to cause degeneration of hepatocytes, the main functioning cells of the liver. "We found that aging promotes a type of programmed cell death in hepatocytes called ferroptosis, which is dependent on iron. Metabolic stressors amplify this death program, increasing liver damage."

Armed with their genetic signature of old livers, the researchers analyzed human liver tissue and found that the livers of people diagnosed with obesity and MASLD carried the signature, and the worse their disease, the stronger the signal. Importantly, key genes in the livers of people with MASLD were highly activated to promote cell death through ferroptosis. This gave the researchers a definitive target. Again turning to mice, the researchers fed young and old mice diets that caused them to develop MASLD. They then gave half the animals a placebo drug and the other half a drug called Ferrostatin-1, which inhibits the cell death pathway. Upon analysis after treatment, the livers of the animals given Ferrostatin-1 looked biologically like young, healthy livers - even in the old animals that were kept on the disease-inducing diet.

The team also looked at how the ferroptosis process in the liver impacts the function of other organs, which are often damaged as MASLD progresses. The genetic signature was able to differentiate between diseased and healthy hearts, kidneys and pancreases, indicating that damaged livers amplify ferroptotic stress in other tissues.

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Exercise and Physical Fitness Correlate with a Lower Risk of Amyotrophic Lateral Sclerosis

The cause of amyotrophic lateral sclerosis (ALS) is presently unclear despite a wealth of data. It may have many distinct possible causes that progress to converge on a phenotype of maladaptive neuroinflammation at motor neurons and other locations. ALS tends to emerge in later life, but lacking good insight into its causes makes it unclear as to exactly how the processes of aging may contribute to its onset. Certainly, greater neuroinflammation is a feature of aging, and so any condition that involves localized inflammatory reactions may be theorized to be worse or more likely to occur in later life.

ALS is a rare, progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. People with ALS lose the ability to initiate and control muscle movement, which often leads to total paralysis and death. The average life span after diagnosis is two to five years. Researchers looked at 373,696 people in Norway with an average age of 41. They were followed for an average of 27 years. Of the total participants, 504 people developed ALS. Of those who developed ALS, 59% were male participants.

Participants recorded their level of physical activity for the past year into one of four categories: sedentary; a minimum of four hours per week of walking or cycling; a minimum of four hours per week of recreational sports or heavy gardening; or participation in hard training or sports competitions regularly, several times a week. Due to few participants with the highest level of physical activity, researchers combined the third and fourth categories into one high activity group.

Researchers found that of the 41,898 male participants that had the highest level of physical activity, 63 developed ALS; of the 76,769 male participants with the intermediate level of physical activity, 131 developed ALS; and of the 29,468 male participants with the lowest level of physical activity, 68 developed ALS. After adjusting for other factors that could affect the risk of ALS, such as smoking and body mass index, researchers found that for male participants, when compared to those with the lowest level of physical activity, those with moderate levels of physical activity had a 29% lower risk of ALS and those with high levels of physical activity had a 41% lower risk of ALS. Researchers also looked at resting heart rate. Men in the lowest of four categories of resting heart rate, which indicates good physical fitness, had a 32% reduced risk of ALS compared to those with higher resting heart rates.

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RIP3 Inhibition Slows the Progression of Osteoarthritis

RIP3 has been shown to be involved in system inflammatory signaling. Inhibition of its pathways or genetic deletion reduces the chronic inflammatory signaling of old age. Osteoarthritis is an inflammatory condition, and here researchers show that RIP3 is involved in the pathological loss of cartilage and alteration of bone tissue characteristic of the condition. They conclude that RIP3 is a good target for drugs to prevent or slow the progression of osteoarthritis.

Osteoarthritis (OA) is a debilitating joint disorder characterized by progressive cartilage degeneration. This study aims to investigate the role of receptor-interacting protein kinase-3 (RIP3) in OA progression, focusing on bone-cartilage metabolic homeostasis. RIP3-mediated pathological and metabolic alterations in chondrocytes, osteoblasts, and bone marrow-derived macrophages (BMMs) were evaluated. RIP3-mediated OA manifestations in cartilage and, more importantly, subchondral bone were determined by intra-articular overexpression of RIP3 in rats. The protective effect of RIP3 deficiency on the bone-cartilage unit during OA was systematically investigated using RIP3 knockout mice.

RIP3 was upregulated in the cartilage and subchondral bone of OA patients and post-traumatic OA mouse model. RIP3 overexpression not only inhibited extracellular matrix (ECM) anabolism in chondrocytes but also attenuated osteoblast differentiation, whereas RIP3 deficiency blunted receptor activator of NF-kappaB ligand-mediated osteoclastogenesis of BMMs. RIP3 deletion significantly improved the structural outcomes of the bone-cartilage unit, and achieved pain relief as well as functional improvement in surgery-induced and spontaneous OA mouse models. Mechanistically, RIP3 initiates OA by perturbing critical events, including cartilage metabolism, inflammatory responses, senescence, and osteoclast differentiation. Clofibrate, a hypolipidemic drug, was identified as a novel RIP3 inhibitor that reverses ECM catabolism in OA.

In conclusion, RIP3 is an essential governor of whole joint metabolic homeostasis by regulating both cartilage metabolism and subchondral bone remodeling. Reconstruction of the bone-cartilage unit by targeting RIP3 might provide a two-birds-one-stone approach for the development of future OA therapies.

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Serotonin Signaling Necessary for Memory Function is Lost in Alzheimer's Disease

Alzheimer's disease is a very complex condition, as the brain is a very complex organ. Researchers here show that the many pathological dysfunctions in Alzheimer's disease include a disruption to serotonin signaling that inhibits memory consolidation. Since this is a problem of too little serotonin interacting with serotonin receptors necessary for function, it is possible in principle to deliver small molecule receptor agonist drugs to compensate for this loss. The challenge lies in delivering the right amount of receptor stimulation to the right places, as undesirable side-effects will arise from too much receptor stimulation in the wrong places. This is the present mainstream of drug development in a nutshell: ignore root causes, attempt to compensate for one specific undesirable pathological consequence of those root causes, and struggle to find an acceptable compromise between dose, benefit, targeting, and side-effects.

Serotonin communicates messages to brain cells by binding to receptors on the cell surface, which signal the receiving cell to carry on a certain activity. "We had previously identified five individuals carrying variants of the serotonin 2C receptor gene (HTR2C) that produce defective forms of the receptor. People with these rare variants showed significant deficits on memory questionnaires. These findings led us to investigate the association between HTR2C variants and memory deficits in animal models."

The animal models enabled researchers to dig deeper into how the receptor mediates memory. They discovered a brain circuit that begins in the midbrain where serotonin-producing neurons are located. These neurons project to the ventral CA1 (vCA1) region of the hippocampus, which has abundant serotonin 2C receptors. "When neurons in the midbrain reaching out to neurons in the vCA1 region release serotonin, the neurotransmitter binds to its receptor signaling these cells to make changes that help the brain consolidate memories." Importantly, the researchers also found that this serotonin-associated neural circuit is damaged in a mouse model of Alzheimer's disease. "The neural circuit in the Alzheimer's disease animal model cannot release sufficient serotonin into the vCA1 region that would need to bind to its receptor in the downstream neurons to signal the changes required to consolidate a memory."

However, it is possible to bypass this lack of serotonin and directly activate the downstream serotonin receptor by administering a serotonin analog, lorcaserin, a compound that selectively activates the serotonin 2C receptor in these cells. "We tested this strategy in our animal model and were excited to find that the animals treated with the serotonin analog improved their memory. We hope our findings encourage further studies to evaluate the value of serotonin analogs in the treatment of Alzheimer's disease."

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