Fight Aging!

Any sufficiently complex set of biological data can be used to build an aging clock via machine learning techniques, finding combinations of parameters that correlate with biological age, mortality, disease risk, and other outcomes. Phenotypic clocks use measures such as physical performance and clinical chemistry, while epigenetic clocks use DNA methylation or other epigenetic marks. New clocks of all sorts are being produced at a fair pace these days, while some groups are pushing for standardization to some of the better explored epigenetic clocks. Here find a review of the present landscape of phenotypic and epigenetic clocks, while noting that there are many other forms of clock beyond just these: transcriptomic, proteomic, and so forth.

Aging is the leading driver of disease in humans and has profound impacts on mortality. Biological clocks are used to measure the aging process in the hopes of identifying possible interventions. Biological clocks may be categorized as phenotypic or epigenetic, where phenotypic clocks use easily measurable clinical biomarkers and epigenetic clocks use cellular methylation data. In recent years, methylation clocks have attained phenomenal performance when predicting chronological age and have been linked to various age-related diseases. Additionally, phenotypic clocks have been proven to be able to predict mortality better than chronological age, providing intracellular insights into the aging process.

This review aimed to systematically survey all proposed epigenetic and phenotypic clocks to date, excluding mitotic clocks (i.e., cancer risk clocks) and those that were modeled using non-human samples. We reported the predictive performance of 33 clocks and outlined the statistical or machine learning techniques used. We also reported the most influential clinical measurements used in the included phenotypic clocks. Our findings provide a systematic reporting of the last decade of biological clock research and indicate possible avenues for future research.

Link: https://doi.org/10.18632/aging.206098

A fair sized body of evidence shows that physical activity improves memory function, both in the short term immediately following exercise, and over the long term for people engaging in regular exercise. This occurs in both younger and older people; it isn't just a matter of compensating for the effects of aging. The brain operates at the edge of its capacity, and delivery of greater nutrients and oxygen via increased cerebral blood flow following exercise enables greater activity. Thus it isn't surprising to see associations between memory function and the level of physical activity required to be an athlete. Of note, this study isn't all that great for older demographics - older athletes are relatively small in number.

This meta-analysis investigated the differences in working memory (WM) performance between athletes and non-athletes in non-sports-specific tasks. A comprehensive evaluation of 21 studies encompassing different age groups, genders, and sports types identified a small but statistically significant advantage in WM accuracy or capacity for athletes compared to non-athletes. Notably, this advantage was more pronounced when athletes were contrasted with a sedentary population.

We conducted seven subgroup analyses as part of this study. An age-specific investigation revealed a small but significant advantage in WM for young adult athletes over non-athletes. However, our investigation into the link between sports expertise and WM across various age groups is limited by a lack of substantial research focusing on older adults and children. Therefore, we are unable to confirm whether older athletes exhibit superior WM enhancement in comparison to other demographic groups. Considering the benefits of exercise for mitigating age-related cognitive decline, as well as its role in improving cognitive and learning abilities during childhood and adolescence, studies focusing on these age groups would be important. In particular, studies on older adults who are ex-athletes could provide insights into the long-term effects of sports.

Subgroup analysis based on sports types revealed that athletes from individual sports outperformed non-athletes in experimental WM tasks, while athletes from team sports showed no such significant advantage. Contrary to our expectations, no significant difference was found between individual and team sports subgroups in WM performance. These results suggest that the cognitive gains afforded by engaging in sports likely arise from general physiological and psychological effects.

Our comparison of WM performance of elite and non-elite athletes with that of non-athletes identified a WM advantage for elite athletes, while the advantage for non-elite athletes approached but did not reach statistical significance. Additionally, there was no significant difference in WM performance between the two subgroups. This finding prompts introspection regarding the sports performance-cognition nexus. Our results imply that cognitive benefits, particularly with respect to WM, stem more from sustained engagement in workout than from the high competitive level achieved.

The WM advantage observed in athletes in comparison to non-athletes is likely based on both physiological and psychological mechanisms. Physiologically, sports confer efficiency advantages in information processing and cognitive function by increasing cerebral blood flow, triggering the release of brain-derived neurotrophic factor, and promoting neural network plasticity. Psychologically, sports confer benefits that optimise cognitive performance through improved control, enhanced attention allocation, and accelerated information processing.

Link: https://doi.org/10.1080/09658211.2024.2423812

The composition of the gut microbiome, the specific microbial species that are present and their numbers relative to one another, varies from individual to individual and appears to influence health significantly, perhaps to a similar degree as lifestyle choices regarding diet and exercise. Further, the composition of the gut microbiome shifts with age in harmful ways, reducing the number of microbes that produce beneficial metabolites such as butyrate, while increasing the number of microbes that act to provoke an ever greater inflammatory reaction from the immune system. The chronic inflammation of aging is disruptive to tissue structure and function throughout the body, and in this way a poor gut microbiome can accelerate the onset and progression of age-related conditions and mortality.

The relationship between the gut microbiome and immune system is bidirectional. The immune system gardens the gut microbiome, so the aging of the immune system allows problematic microbes to grow in number. But equally, the aged gut microbiome can negatively affect the immune system. Today's open access paper looks at one of the ways in which this can happen, by accelerating the atrophy of active tissue in the thymus, a process known as thymic involution. The thymus is a small organ near the heart. Its primary function is to host the maturation of thymocytes produced in the bone marrow; these cells migrate to the thymus and undergo a process of selection to become T cells of the adaptive immune system. As the thymus atrophies with age, the supply of new T cells declines. With reinforcements, the adaptive immune system becomes ever more dysfunctional over time, populated by senescent, exhausted, and malfunctioning T cells.

Age-related loss of intestinal barrier integrity plays an integral role in thymic involution and T cell ageing

The epithelium of the gastrointestinal tract represents the largest mucosal lining in the body that effectively limits the permeation of luminal microorganisms, antigens, and toxins through its paracellular space, a process that is regulated by intercellular tight junctions. Advancing age is accompanied by physiological changes to the intestine, including mucus layer thinning and remodelling of intestinal epithelial tight junction proteins, which contribute towards the breakdown of intestinal barrier function. This permits commensal bacteria and their products, such as lipopolysaccharide, from the gut lumen into the bloodstream (referred to as a leaky gut). Age-related intestinal barrier dysfunction is closely linked to the progressive deterioration of systemic health and the gradual appearance of metabolic defects. Moreover, recent evidence from animal studies indicates that it is a major contributor to low-grade systemic inflammation, termed inflammaging. Human intestinal barrier dysfunction, determined by elevated circulating lipopolysaccharide-binding protein (LBP) levels, is also associated with impaired physical function and inflammaging in healthy aged adults; highlighting the importance of investigating the role of intestinal barrier dysfunction in ageing.

Concurrently with changes to intestinal homeostasis, ageing is accompanied by remodelling of the immune system that attenuates the host's ability to mount robust immune responses, resulting in an immunocompromised state, termed immunesenescence. One of the most striking features of immune ageing is the progressive shrinkage (involution) of the thymus that is characterised by the loss of thymic epithelial cells (TECs), expansion of perivascular spaces, increased thymic adiposity and the accumulation of senescent cells; together resulting in a loss of functional spaces for the development of thymocytes. Collectively this compromises the process of thymopoiesis and result in a reduced thymic output of naïve T cells and the homeostatic expansion of peripheral memory T cell subsets. Further, chronic lifelong antigenic stimulation leads to the accumulation of senescent T cells in the periphery, which impair tissue immunosurveillance and drive a state of prolonged basal inflammation in aged individuals, termed inflammageing.

Despite these interesting findings, the relationship between intestinal barrier dysfunction and immune ageing is poorly understood. Herein we report that intestinal membrane permeability increases with age in humans and is accompanied by enhanced systemic microbial translocation that contributes to the lifelong antigenic burden, driving a reduction in naïve T cell thymic output and an accumulation of terminally differentiated, senescent T cells in the periphery. The emergence of these hallmarks of T cell ageing hinders the ability of these cells to fight invading pathogens and enhances their ability to produce pro-inflammatory cytokines, which ultimately contribute to the inflammatory state of the aged host. Further, we demonstrate that aged germ-free mice, which do not exhibit age-related intestinal barrier dysfunction, are protected from the accumulation of microbial products in the thymus and maintain their thymic architecture. Together, these findings provide novel evidence of a causal relationship between intestinal barrier dysfunction and T cell ageing.

If measures of biological age are in fact reflections of the burden of damage and dysfunction making up degenerative aging, then we should expect there to be correlations between an accelerated biological age greater than chronological age and risk of conditions such as diabetes that are already known to be associated with increased mortality and reduced life span. The study here shows that to be the case for two aging clocks that are derived from blood chemistry measures rather than omics data.

Cardiometabolic diseases (CMDs) have emerged as the most significant health challenges. Cardiometabolic multimorbidity (CMM) refers to the coexistence of two or more CMDs, including conditions such as stroke, ischemic heart disease (IHD), and type 2 diabetes (T2D). Populations with CMM have a two-fold increased mortality risk and a 12-15 year reduced life expectancy than those with single CMDs. Biological aging, which is associated with decreased metabolic rates, vascular stiffening, chronic inflammation, and oxidative stress, as well as the interplay of comorbidities, may underlie the progression of CMDs to CMM.

The ideal measurement strategy for biological aging should include as many system indicators as possible. For predicting disease, the PhenoAge and Klemera-Doubal method Biological Age (KDM-BA) are the best-validated algorithms according to blood-chemistry-derived measures in multi-ethnic cohorts of older adults. Accelerated aging refers to the phenomenon where an individual's biological age advances more rapidly than their chronological age. This concept goes beyond the mere passage of time, as it emphasizes the underlying biological processes and pathological changes. Thus, this study used both algorithms to test the association between biological aging and CMM.

The study included 415,147 individuals with an average age of 56.5 years. During the average 11-year follow-up period, CMD-free individuals with accelerated aging had a significantly greater risk of CMD (KDM-BA, hazard ratio [HR] 1.456; PhenoAge, HR 1.404), CMM (KDM-BA, HR 1.952; PhenoAge, HR 1.738), dementia (KDM-BA, HR 1.243; PhenoAge, HR 1.212), and mortality (KDM-BA, HR 1.821; PhenoAge, HR 2.047) in fully-adjusted Cox regression models. Accelerated aging had adjusted HRs of 1.489 (KDM-BA) and 1.488 (PhenoAge) for CMM, 1.434 (KDM-BA) and 1.514 (PhenoAge) for dementia, and 1.943 (KDM-BA) and 2.239 (PhenoAge) for mortality in participants with CMD at baseline.

Link: https://doi.org/10.3389/fpubh.2024.1423016

Here find an interesting review of the sex differences observed in the development of atherosclerosis in humans. This condition, in which fatty plaques develop to narrow arteries, is the leading cause of mortality in our species. Plaques rupture to cause blockage of a downstream vessel and a heart attack or stroke. The authors here focus on differences between the sexes in cellular senescence and inflammation in the vasculature. Men tend to bear a greater burden of both of these mechanisms. The implication is that senolytic and anti-inflammatory therapies will benefit men more than women in the specific context of atherosclerotic cardiovascular disease.

The prevalence of coronary artery disease (CAD) is higher in men than in women, but the underlying molecular basis for this sexual dimorphism are poorly understood. There is a consensus on the protective role of estrogens and CAD risk increasing following menopause. Likewise, men develop lipid-rich plaques, whereas women are more likely to develop fibrous plaques with a unique transcriptomic and proteomic signatures in the plaque. Otherwise, presentation of oxidative stress and inflammation may differ between women and men but are inconsistent.

In healthy humans, aging is associated with a progressive endothelium-dependent dilatory decline, which appears 10 years earlier in men than in women and is highly predictive of future cardiovascular events. In recent years, research has established that age-related accumulation of senescent cells could cause chronic low-grade cold inflammation, also known as inflammaging, through the release of the senescence-associated secretory phenotype (SASP). Because SASP involves a range of proinflammatory factors with important paracrine and autocrine effects on cell and tissue biology, inflammaging could promote cardiovascular disease (CVD).

We prospectively collected distal segments of lesion-free internal thoracic arteries during coronary artery bypass graft surgeries from both men and women. Our data show that endothelial dysfunction is more pronounced in men compared to women. Importantly, using single-nuclei transcriptomics, senescent and inflammatory transcriptomic signatures suggestive of the inflammaging were only identified in male endothelial cells, not in female endothelial cells. Therefore, senescence-associated endothelial dysfunction may contribute to atherogenesis in men.

Link: https://doi.org/10.1016/j.jacbts.2024.06.012

The composition of the gut microbiome, the species present and their relative proportions, varies between individuals. Further, the balance of populations shifts with age in ways that are harmful to health. A growing body of animal and human data suggests that the composition of the gut microbiome is just as influential on long-term health as lifestyle choices such as level of physical activity. Some inroads have been made into identifying distinct features of the gut microbiome that are characteristic of specific age-related conditions, or of long-lived individuals.

As is the case for gene variants, even very small effects on mortality risk will lead to sizable enrichment of a specific gut microbiome characteristic in long-lived people. Thus we might expect that most of what is discovered via this sort of research will be of little practical use as a basis for interventions to slow aging and extend healthy life span. Nonetheless, it is interesting to watch the research community move from identifying specific microbial species that are present in greater numbers in long-lived individuals to trying to figure out exactly what those microbes are doing to increase the odds of living longer.

Biosynthetic potential of the gut microbiome in longevous populations

The gut microbiome plays a pivotal role in combating diseases and facilitating healthy aging, and natural products derived from biosynthetic gene clusters (BGCs) of the human microbiome exhibit significant biological activities. However, the natural products of the gut microbiome in long-lived populations remain poorly understood. Here, we integrated six cohorts of long-lived populations, encompassing a total of 1,029 fecal metagenomic samples, and employed the metagenomic single sample assembled BGCs (MSSA-BGCs) analysis pipeline to investigate the natural products and their associated species.

Our findings reveal that the BGC composition of the extremely long-lived group differed significantly from that of younger elderly and young individuals across five cohorts. Terpene and Type I PKS BGCs were enriched in the extremely long-lived, whereas cyclic-lactone-autoinducer BGCs were more prevalent in the young. Association analysis indicated that terpene BGCs were strongly associated with the abundance of Akkermansia muciniphila, which was also more abundant in the long-lived elderly across at least three cohorts.

We assembled 18 A. muciniphila draft genomes using metagenomic data from the extremely long-lived group across six cohorts and discovered that they all harbor two classes of terpene BGCs, which aligns with the 97 complete genomes of A. muciniphila strains retrieved from the NCBI database. The core domains of these two BGC classes are squalene/phytoene synthases involved in the biosynthesis of triterpenes and tetraterpenes. Furthermore, the abundance of fecal A. muciniphila was significantly associated with eight types of triterpenoids. Targeted terpenoid metabolomic analysis revealed that two triterpenoids, Holstinone C and colubrinic acid, were enriched in the A. muciniphila culture solution compared to the medium, thereby confirming the production of triterpenoids by A. muciniphila. The natural products derived from the gut of long-lived populations provide intriguing indications of their potential beneficial roles in regulating health.

Brain age is a measure of volume and structure of the brain derived from machine learning techniques applied to databases of imaging of brain tissue at various ages and in healthier individuals versus patients with neurodegenerative conditions. Here, researchers demonstrate that, as one might expect, brain age is higher in patients with mild cognitive impairment and Alzheimer's disease. Surprisingly, however, there is a greater acceleration of brain aging in the earlier mild cognitive impairment stage than in the later Alzheimer's disease stage. This is another data point indicating the need for early intervention in the path towards Alzheimer's disease.

Brain age is a machine learning-derived estimate that captures lower brain volume. Previous studies have found that brain age is significantly higher in mild cognitive impairment and Alzheimer's disease (AD) compared to healthy controls. We utilized data from an archival dataset, mainly Alzheimer's disease Neuroimaging Initiative (ADNI). We included control participants (healthy controls or HC), individuals with mild cognitive impairment (MCI), and individuals with Alzheimer's disease (AD). We conducted longitudinal modeling of age and brain age by group using time from baseline in one model and chronological age in another model.

We predicted brain age with a mean absolute error (MAE) of less than 5 years. Brain age was associated with age across the study and individuals with MCI and AD had greater brain age on average. We found that the MCI group had significantly higher rates of change in brain age over time compared to the HC group regardless of individual chronologic age, while the AD group did not differ in rate of brain age change. We essentially found that while the MCI group was actively experiencing faster rates of brain aging, the AD group may have already experienced this acceleration (as they show higher brain age). AD may represent a homeostatic endpoint after significant neurodegeneration. Future work may focus on individuals with MCI as one potential therapeutic option is to alter rates of brain aging, which ultimately may slow cognitive decline in the long-term.

Link: https://doi.org/10.3389/fnagi.2024.1433426

Since its discovery, there has been some interest in the longevity-associated variant of human BPIFB4. It appears to reduce inflammation and improve function in the aging heart, reducing the incidence and impact of heart disease. Of particular interest is that it improves capillary density in heart tissue; recall that capillary density declines with age. Researchers are now working towards gene therapies and protein therapies that deliver the variant BPIFB4 as a way to treat forms of cardiomyopathy in the aged heart. Interestingly it appears that this protein can be delivered orally, which is quite unusual, and no doubt one of the reasons why there is greater interest in this approach versus others.

Aging is influenced by genetic determinants and comorbidities, among which diabetes increases the risk for heart failure with preserved ejection fraction. There is no therapy to prevent heart dysfunction in aging and diabetic individuals. In previous studies, a single administration of the longevity-associated variant (LAV) of the human BPIFB4 gene halted heart decline in older and type 2 diabetic mice. Here, we asked whether orally administered LAV-BPIFB4 protein replicates these benefits.

Proteins are effective biotherapeutics and have several advantages over gene therapy, especially for prolonged treatments. In the present study, we investigated the possibility that the LAV-BPIFB4 protein protects cardiac health in older and obese mice with type 2 diabetes. Results show that LAV-BPIFB4 therapy can benefit both conditions, indicating that this longevity-associated protein can antagonize two prevalent risk factors for heart failure. In aging mice, LAV-BPIFB4 increased myocardial Bpifb4 expression, improving heart contractility and capillarity while reducing perivascular fibrosis and senesce. In male diabetic mice, LAV-BPIFB4 therapy improved systolic function, microvascular density, and senescence, whereas the benefit was limited to systolic function in females.

Link: https://doi.org/10.1186/s12933-024-02487-6

The transparent cornea covers the eye, and a range of age-related and other issues can cloud that transparency to produce blindness. Engineering corneal tissue is an easier prospect than many other goals in tissue engineering, particular given that transplantation surgery is a good deal easier than is the case for internal organs. This line of research and development has nonetheless proven to have its challenges, such as rejection of transplanted corneal tissue. Work on building engineered corneal tissue has been ongoing for more than twenty years at this point, and has arrived at the point of bioprinted corneas.

Alongside tissue engineering efforts, cell therapy programs have also aimed at repairing the damaged cornea. First generation stem cell transplants, such as the use of mesenchymal stem cells, have shown signs of promise, while the research community aims at the production of cell banks from induced pluripotent stem cells for this use, rather than donor cells.

Today's clinical trial update reports on progress on a middle path between these two approaches, one that has been underway for some years. Here, induced pluripotent stem cells are used to produce sheets of corneal epithelial cells, a structure that is somewhat less than a real tissue, but somewhat more than just a set of cells in suspension. The researchers note that these cells naturally express low levels of surface markers that might provoke an immune response and rejection, a fortunate occurrence that was not deliberately engineered in. So far, this corneal cell sheet seems to produce favorable outcomes when used to replace sections of natural cornea.

Induced pluripotent stem-cell-derived corneal epithelium for transplant surgery: a single-arm, open-label, first-in-human interventional study in Japan

Autologous therapy by means of induced pluripotent stem cells (iPSCs) has advantages that include the avoidance of immunological rejection, but it also comes with disadvantages related to the time and expense required for cultivation and the need for tumourigenicity tests. Additionally, from a practical point of view, any instability in the quality of the iPSCs or the graft materials derived from them will lead to the unwanted cancellation of scheduled surgeries. With allogeneic therapy, there is a ready supply of cells, although immunological rejection now becomes an important consideration. However, somewhat unexpectedly, experiments have shown that corneal epithelial cell sheets derived from human iPSCs express lower levels of HLA class I and II compared with somatic cell-derived sheets. Indeed, mixed lymphocyte reaction tests showed no difference in the immune response to iPSC-derived corneal epithelial cell sheets (iCEPSs) between HLA-matched and HLA-mismatched peripheral blood mononuclear cells.

Another important consideration is that the iCEPS construct does not contain immunocompetent cells. It has been reported that a high rate of rejection (about 40%) occurs following an allogeneic corneal limbal transplantation. Previous studies have also indicated that donor-derived Langerhans cells promote early and acute corneal allograft rejection, acting in concert with allogeneic MHC-specific cytotoxic T cells. Graft material for corneal limbal tissue transplantation contains copious antigen-presenting cells, which might increase the probability of a direct pathway to rejection; iCEPSs, however, do not contain immunocompetent cells because only induced corneal epithelial progenitor cells are used to fabricate them. Thus, we hypothesise that HLA compatibility and the use of immunosuppressive agents (above and beyond corticosteroid use) is not necessary for iCEPS transplantation, and incorporate an initial examination of this in our study design. Herein, we report the 52-week follow-up (plus an additional 1-year additional safety monitoring period) of the first-in-human iCEPS transplant surgery in four eyes of four patients with vision loss.

Parkinson's disease is characterized by the spread and aggregation of misfolded α-synuclein, toxic to neurons and the cause of motor neuron loss. A misfolded molecule of α-synuclein encourages other α-synuclein molecules to also misfold in the same way, and the dysfunction spreads slowly from neuron to neuron. When present in a neuron, misfolded α-synuclein will appear inside the extracellular vesicles, such as exosomes, secreted by that cell. Some of these vesicles enter the circulatory system, where they can be detected in a blood sample.

The possibility to detect misfolded α-synuclein (α-syn) in different tissues and body fluids is currently revolutionizing the diagnosis of Parkinson's disease (PD) and it is hoped that a more secure and much earlier diagnosis will soon be possible. In this context one of the most promising advances is the use of α-syn seed amplification assays (SAA), utilizing the seeding activity of pathological α-syn conformers to introduce aggregation of recombinant α-syn.

We recently demonstrated that a SAA for the detection of pathological α-syn in neuronal-derived extracellular vesicles (NEs) purified from blood, distinguishes PD patients from healthy controls with high sensitivity. This study set out to 1) confirm the previously reported high sensitivity of this blood-based SAA in a larger cohort of individuals with PD and 2) additionally explore changes of α-synuclein seeding in blood in the course of PD.

In the cross-sectional dataset, 79 of 80 PD patients (mean age 69 years; 56% male) and none of the healthy controls (n = 20, mean age 70 years; 55% male) showed seeding activity (sensitivity 98.8%). When comparing subgroups divided by disease duration, longer disease duration was associated with lower α-synuclein seeding activity. In the longitudinal analysis 10/11 patients showed a gradual decrease of α-synuclein seeding activity over time. This study cannot explain the pathophysiological processes behind this observed decrease. However, it can be hypothesized that spreading of α-syn is more pronounced in the early stages of the disease.

Link: https://doi.org/10.3233/JPD-230390

One of the components of declining mitochondrial function throughout the body with advancing age is a reduction in mitochondrial quality control, the complex process of mitophagy responsible for recycling damaged mitochondria. Increased mitophagy has been shown to improve mitochondrial function in a number of contexts. Researchers here note the contribution of mitochondrial dysfunction to the aging of the lacrimal gland, contributing to dry eye syndrome - an underappreciated and highly unpleasant feature of aging. Improved mitophagy leads to improved lacrimal gland function, a potential basis for novel therapies.

Dry eye disease (DED) is one of the most common ocular surface diseases affecting the quality of life of the elderly population, and aging is also one of the independent risk factors for DED. The lacrimal gland is an exocrine gland that contributes mainly to the aqueous component of the tear film, and its secretion constitutes the majority of the tear film (98% to 99%). It consists of three main cell types: acinar epithelial cells, ductal epithelial cells, and myoepithelial cells. The most abundant type (about 80%), the acinar epithelial cells are highly polarized epithelial cells responsible for the synthesis and secretion of aqueous fluid.

The lacrimal gland is highly susceptible to the effects of aging, which manifests as structural and functional damage, with major pathological changes, including acinar epithelial cells atrophy, periductal fibrosis, and chronic inflammatory cells infiltration, as well as a decrease in the density of nerves driving lacrimal secretion, which ultimately leads to qualitative and quantitative abnormalities in lacrimal gland secretions.

In this study, we discovered that aging increased oxidative stress, which increased apoptosis, and generated reactive oxygen species (ROS) in acinar epithelial cells. Furthermore, activation of PINK1/Parkin-mediated mitophagy by rapamycin reduced lacrimal gland ROS concentrations and prevented aging-induced apoptosis of acinar cells, thereby causing histological alterations, microstructural degradation, and increasing tear secretion associated with ROS accumulation. Overall, our findings suggested that aging could impair mitochondrial function of acinar cells, and age-related alterations may be treated with therapeutic approaches that enhance mitophagy while maintaining mitochondrial function.

Link: https://doi.org/10.1167/iovs.65.13.12

To what degree should we be enthused by programs aiming to adjust expression of genes in cells to restore function in aged tissues? Evidence from recent years is suggestive that patterns of change in gene expression arise as a consequence of repeated repair of nuclear DNA damage, even if that damage itself is harmless to the cell. Adjusting those changes in gene expression therefore seems something close to rejuvenation. To the degree that harmful changes in gene expression instead arise from maladaptive reactions to damage, it may be that there is less to gain from trying to force a more youthful pattern of gene expression - the underlying damage remains, causing whatever other issues it causes.

Any given transcription factor regulates the expression of many other genes, and thus it has been suggested that one should focus on changes in transcription factor expression as a starting point in any attempt to understand the shifting landscape of gene expression in aging. It is plausible that more of gain could be achieved on a gene by gene basis by restoring youthful transcription factor expression than by focusing on other genes. In today's open access paper, researchers focus on skin aging and identify a transcription factor that can be upregulated to restore some of the function lost in aged skin. Of note, they conducted studies in human skin samples and skin models and skin cells; I'd be happier seeing a mouse study in addition to this work, assuming the biochemistry is similar.

Human skin rejuvenation via mRNA

Aging is characterized by a gradual decline in function, partly due to accumulated molecular damage. Human skin undergoes both chronological aging and environmental degradation, particularly UV-induced photoaging. Detrimental structural and physiological changes caused by aging include epidermal thinning due to stem cell depletion and dermal atrophy associated with decreased collagen production. Here, we present a comprehensive single-cell atlas of skin aging, analyzing samples from young, middle-aged, and elderly individuals, including both sun-exposed and sun-protected areas. This atlas reveals age-related cellular composition and function changes across various skin cell types, including epidermal stem cells, fibroblasts, hair follicles, and endothelial cells.

Using our atlas, we have identified basal stem cells as a highly variable population across aging, more so than other skin cell populations such as fibroblasts. In basal stem cells, we identified ATF3 as a novel regulator of skin aging. ATF3 is a transcriptional factor for genes involved in the aging process, with its expression reduced by 20% during aging. Based on this discovery, we have developed an innovative mRNA-based treatment to mitigate the effects of skin aging. Cell senescence decreased 25% in skin cells treated with ATF3 mRNA, and we observed an over 20% increase in proliferation in treated basal stem cells. Importantly, we also found crosstalk between keratinocytes and fibroblasts as a critical component of therapeutic interventions, with ATF3 rescue of basal cells significantly enhancing fibroblast collagen production by approximately 200%.

We conclude that ATF3-targeted mRNA treatment effectively reverses the effects of skin aging by modulating specific cellular mechanisms, offering a novel, targeted approach to human skin rejuvenation.

Epidemiological data on human health doesn't lend itself to concrete interpretation. For example, the role of time spent sitting or otherwise sedentary in the development of cardiovascular disease remains debated. Some studies suggest that sedentary time contributes to risk independently of level of exercise, others suggest that recommended levels of exercise eliminate any relationship between sedentary time and risk of disease. There remain the questions of the degree to which sedentary behavior is a proxy for other contributions to long-term health such as diet and weight. This is before we even arrive at the question of biological mechanisms and their relative importance.

Insufficient exercise is a known risk factor for cardiovascular disease (CVD). Over 150 minutes of moderate-to-vigorous physical activity per week is recommended by current guidelines to promote heart health. However, study experts say exercise is only a small fraction of overall daily activity, and the current guidelines don't provide specific guidance on sedentary behavior which accounts for a much larger portion of daily activity, despite evidence that it's directly linked with CVD risk. This study examined the amount of sedentary time at which CVD risk is greatest and explored how sedentary behavior and physical activity together impact the chances of atrial fibrillation (AF), heart failure (HF), myocardial infarction (MI), and cardiovascular mortality.

Among the 89,530 study participants of the UK Biobank, the average age was 62 years and 56.4% were women. Participants submitted data from a wrist-worn triaxial accelerometer that captured movement over seven days. The average sedentary time per day was 9.4 hours. After an average follow-up of eight years, 3,638 individuals (4.9%) developed incident AF, 1,854 (2.1%) developed incident HF, 1,610 (1.84%) developed indecent MI, and 846 (0.94%) died of cardiovascular causes, respectively.

The effects of sedentary time varied by outcome. For AF and MI, the risk increased steadily over time without major shifts. For HF and CV mortality, increase in risk was minimal until sedentary time exceeded about 10.6 hours a day, at which point risk rose significantly, showing a "threshold" effect for the behavior. For study participants who met the recommended 150 minutes of moderate-to-vigorous physical activity or more, the effects of sedentary behavior on AF and MI risks were substantially reduced, but effects on higher risk of HF and cardiovascular mortality remained prominent.

Link: https://www.eurekalert.org/news-releases/1064762

Many lines of evidence strongly suggest that alterations to the gut microbiome are an important contributing factor in the onset and progression of many different conditions, including age-related conditions. Comparatively few clinical trials touch on this relationship, however, despite the recent approval of a fecal microbiota transplant intervention for the treatment of Clostridioides difficile infection. That will change with time, but for now there is sufficiently little clinical trial data that a short paper can summarize it all.

Composed of an elaborate ecosystem of bacteria, fungi, viruses, and protozoa residing in the human digestive tract, the gut microbiome influences metabolism, immune modulation, bile acid homeostasis, and host defence. Through observational and preclinical data, the gut microbiome has been implicated in the pathogenesis of a spectrum of chronic diseases ranging from psychiatric to gastrointestinal in nature. Until recently, the lack of unequivocal evidence supporting a causal link between gut microbiome and human health outcomes incited controversy regarding its significance. However, recent randomised controlled trial (RCT) evidence in conditions, such as Clostridioides difficile infection, cancer immunotherapy, and ulcerative colitis, has supported a causal relationship and has underscored the potential of the microbiome as a therapeutic target.

This review delineates the RCT evidence substantiating the potential for a causal relationship between the gut microbiome and human health outcomes, the seminal observational evidence that preceded these RCTs and the remaining knowledge gaps. The association between the gut microbiome and human health has long been supported by multiple lines of observational evidence including in vitro, in vivo, and epidemiologic data. Recent RCTs of microbiome therapeutics have bridged the gap between association and causation and have definitively demonstrated that microbiome-altering therapeutics can improve human health outcomes in CDI. Further, smaller RCTs in UC and cancer immunotherapy, but not obesity, suggest the probable benefit of microbiome therapeutics across other indications as well.

Link: https://doi.org/10.1136/egastro-2024-100086

Cells become senescent constantly throughout life, in response to damage, stress, injury, or simply reaching the Hayflick limit on replication. In youth the immune system promptly removes this cells, but with age this clearance becomes inefficient, allowing senescent cells to accumulate. When senescent, a cell ceases to replicate and devotes its energies to the secretion of a mix of pro-growth, pro-inflammatory signals, the senescence-associated secretory phenotype (SASP). This is useful in the short term context of coordinating recovery from injury or drawing the immune system to destroy potentially cancerous cells, but becomes harmful when sustained. It is disruptive to tissue structure and function, a contribution to the chronic inflammation of aging.

Worse, and as noted in today's open access paper, the SASP provokes a greater incidence of senescence in distant cells. The more senescent cells in any one location, the more likely it is that cells elsewhere in the body will become senescent in response to stresses. Cellular senescence may be one of the more important mechanisms linking the age-related decline of function in any one organ with the age-related decline in function of other organs. The authors of this paper focus on the liver, but the point could just as well be made of the kidney, or visceral fat deposits, or other internal organs.

Hepatocellular senescence induces multi-organ senescence and dysfunction via TGFβ

The SASP is a central mediator of the non-autonomous effects of senescent cells. Here, we demonstrate that senescence can be transmitted to and affect the function of distant organs in a systemic manner. In the context of acute injury, senescence has often been described as part of a finely tuned mechanism with overall beneficial effects for wound healing. SASP factors have been shown to induce reprogramming in neighbouring cells, facilitating tissue regeneration. However, following severe injury, this mechanism may have the opposite effect, systemically, through excessive SASP production, including senescence itself. In turn, this excessive stimulus for senescence can be associated with compromised organ function.

Systemic transmission of senescence may be relevant to several diseases. Here, we use a series of models of hepatocyte-specific senescence to model an acute senescence phenotype, such as the one observed during acute liver failure. Acute liver failure is, itself, characterized by sequential multi-organ failure, typically beginning with the kidney progressing to also involve the brain, lungs, and other organs. This clinical progression may, at least in part, be underpinned by the systemic transmission of senescence. The data in patients with acute indeterminate hepatitis, showing that increased hepatocellular expression of p21 at initial presentation before multi-organ failure can predict ensuing multi-organ failure, requirement for liver transplant and/or death, provide evidence for a biomarker that both allows early risk stratification and selection of patients for specific therapies.

Similarly, the observation that TGFβ signalling is a central driver of systemic transmission of senescence may pave the way for therapeutic approaches in diseases where this phenomenon occurs. Whilst this effect may either be independent of solely p21-dependent senescence or a phenomenon related to TGFβ activity outside of senescence, it is in line with the beneficial effects of senolytics and senomorphics that have been elegantly demonstrated on numerous pathologies. Further research is required to dissect out the direct causal link between senescence in the primary tissue and the systemic effects and how they are affected by factors such as disease site or specific senescence phenotype, chronicity of senescence, and the interaction with concurrent or pre-existing senescence in other organs. Our results demonstrate that systemic transmission of senescence can induce systemic organ dysfunction, which may be central to multi-systemic sequelae in many diseases.

Researchers here find a way to reduce atherosclerotic plaque in mice by delivering an anti-inflammatory metabolite associated with low fat diets directly to immune cells in the bone marrow and plaque. It is an interesting result, though the degree to which it will be applicable to humans is a question. Mice are more resistant to plaque formation, requiring both high fat diets and mutations affecting cholesterol transport to produce sizable plaques. When switched to a low fat diet, there will be some degree of plaque regression in mice previously on a high fat diet - but that doesn't tend to happen in humans. Will dialing up the mechanisms involved in mouse plaque regression on a low fat diet perform to any great degree in humans? It may be worth a try, given that even very small degrees of plaque regression produce sizable reductions in risk of heart attack and stroke.

Laboratory animals that develop atherosclerotic plaque when fed a prolonged high-cholesterol, high-fat diet (HCHFD) demonstrate plaque resolution when they are subsequently switched to a normal low-fat diet ("dietary cessation"). Here, we studied dietary cessation in two well-known atherogenic mouse models: AроE-/- and Ldlr-/-. Using these models, we discovered that dietary cessation-driven plaque resolution is characterized by altered levels of the tricarboxylic acid (TCA) cycle metabolite itaconate (ITA), an immunomodulatory molecule, and of the ITA-synthesizing enzyme immunoresponsive gene 1 (IRG1). We also report elevated levels of IRG1 in vulnerable human carotid plaques and the absence of IRG1 in early or stable plaques.

We next tested whether exposing plaques to exogenously delivered ITA could directly achieve plaque resolution. While the ITA derivative 4-octyl itaconate (OI) has been previously shown to induce plaque resolution, current ITA derivatives are not ideal for studying or replicating the biological effects of endogenous, unconjugated ITA, which differs from its derivatives. Thus, to achieve targeted and efficient delivery of unconjugated ITA, we synthesized an ITA-based lipid nanoparticlen.wikipedia.org/wiki/Solid_lipid_nanoparticle">lipid nanoparticle, termed ITA-LNP. We demonstrate that ITA-LNPs deliver unconjugated ITA intracellularly, accumulate in myeloid cells in plaque and bone marrow, and recapitulate immunomodulatory effects that are unique to unmodified ITA. We also show that ITA-LNPs are non-toxic and elicit epigenetic changes that lead to anti-inflammatory activity in plaques and myeloid progenitor cells in bone marrow. Additionally, we report that ITA-LNPs safely stimulate plaque resolution in several murine models with and without dietary cessation, including a model of unstable, vulnerable plaque that represents highly advanced atherosclerotic cardiovascular disease.

Link: https://doi.org/10.1016/j.celrep.2024.114911

Autophagy is a complex collection of processes that recycle structures in the cell. Structures are in some way identified as damaged or surplus, then engulfed in an autophagosome membrane. That autophagosome is transported to a lysosome, where it fuses with the lysosome. The cargo is then broken down into raw materials by the enzymes contained in the lysosome. Measuring autophagy is difficult. Any given approach can be interpreted in different ways. Is increased expression of one autophagy protein indicative of more efficient autophagy or indicative of a part of the process that is breaking, degrading overall efficiency? This gives rise to some debate over how autophagy changes with age, and whether the interventions thought to slow aging via improved autophagy are in fact doing so. Here, for example, researchers argue that autophagy of mitochondria, called mitophagy, doesn't in fact decline with age in brain cells.

Autophagy is a disease-relevant homeostatic quality control mechanism. While we understand how different forms of cellular stress induce specific autophagy pathways in cultured cells, our knowledge of how physiological autophagy pathways are regulated in healthy brain aging is extremely limited. Studies in short-lived model systems suggest that diminished mitophagy and autophagic capacity may sensitize certain brain cell types to degenerative processes as we age. However, the spatiotemporal modulation of mitophagy during healthy brain aging remains unclear.

Here, we establish the first dynamic landscape of mitochondrial turnover in the intact, aging mammalian brain at the single-cell level using high-resolution confocal imaging and cutting-edge reporter mice. Our findings reveal that decreased mitophagy is not a general hallmark of healthy aging in vivo but that different brain regions and neural subsets exhibit distinct mitophagy dynamics over time, usually remaining stable or even increasing throughout the mouse lifespan. By comparing different regions of the brain, including disease-associated neuronal and non-neuronal cell types, we revealed uncoupled and cell type-specific regulation of mitophagy and generalized autophagy throughout natural aging.

We found that mitophagy levels gradually increased throughout the aging process in several cell types, including cerebellar granule cells and microglia, seemingly independent of basal autophagy levels. In some cases, we observed more complex trajectories: we detected an age-dependent increase in mitophagy in the hippocampus CA1 and dentate gyrus subregions up until middle age, followed by a significant decline during old age, although not falling below those of young subjects. It will be crucial to determine whether these altered autophagy dynamics are causally linked to age-related cognitive changes observed in healthy aging. Clarifying the mechanisms driving age-dependent mitophagy dynamics in these hippocampal subregions may hold interventional relevance for memory-related pathologies such as dementia and Alzheimer's disease.

Link: https://doi.org/10.1038/s44318-024-00241-y

If you are familiar with research into those parts of lipid metabolism presently considered relevant to the development of atherosclerosis, near entirely focused on the mechanisms by which cholesterol is transported around the body in the bloodstream, then you will know that the CETP protein is considered a target for therapies. This is due to (a) its role in transferring cholesterol between transport particles such as high density lipoprotein (HDL) and low-density lipoprotein (LDL), and (b) suggestive data for gene variants to affect risk of cardiovascular disease.

LDL particles carry cholesterol outwards from the liver into the arteries where atherosclerotic plaques form. HDL particles carry cholesterol back to the liver from the rest of the body. Present therapies aimed at reducing the amount of LDL-cholesterol, such as statins and PCSK9 inhibitors, have their origins in the discovery of human mutants with lower LDL-cholesterol and lower lifetime cardiovascular risk. In practice, the resulting drugs produce only modest benefits, failing to reverse atherosclerosis even when greatly reducing LDL-cholesterol, and only reducing risk of heart attack and stroke by at most 20%, if we are being generous in our interpretation of the data. Similarly, attempts to enhance HDL transport to drain cholesterol from arteries have met with failure.

Today's open access paper is an interesting look at one slice of all of this biochemistry, focused on CETP and whether or not it is a target worth pursuing. The development of many ways to achieve small gains derived from evidence for influence of one gene or another on cholesterol transport has perhaps made some people a little hesitant to jump on yet another similar gene and similar attempt. Yet one can line up a bunch of evidence to suggest that targeting CETP will achieve some benefits, not just for cardiovascular disease, and funding has been found for clinical trials of CETP-targeted therapies.

Cholesteryl ester transfer protein inhibition: a pathway to reducing risk of morbidity and promoting longevity

Cholesteryl ester transfer protein (CETP) is a hydrophobic glycoprotein that is a member of the lipid transfer protein family. It facilitates the bidirectional exchange of cholesteryl esters and triglycerides among lipoprotein particles leading to a net mass transfer of cholesteryl esters from high-density lipoprotein (HDL) to low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) particles. In addition, triglycerides are transferred in the opposite direction from LDL and VLDL to HDL.

Interest in CETP inhibition as a therapeutic target began with the discovery in observational studies that some CETP gene polymorphisms were associated with reduced coronary heart disease (CHD) incidence and CHD mortality, although these results have not been entirely consistent. However, taking all evidence into consideration, observational studies, Mendelian randomization (MR) analyses, and randomized clinical trials of pharmaceutical agents indicate that CETP inhibition confers cardiovascular benefit and reduces risk of atherosclerotic cardiovascular disease (ASCVD). Additionally, emerging evidence suggests that CETP inhibition may promote longevity, presumably by lowering the risk of several conditions associated with aging such as new-onset type 2 diabetes mellitus (T2D), dementia, chronic kidney disease (CKD), and age-related macular degeneration (AMD), as well as promoting survival in septicemia. Some of these effects are likely mediated through improved functionality of the HDL particle, including its role on cholesterol efflux and antioxidative, anti-inflammatory, and antimicrobial activities.

At present, there is robust clinical evidence to support the benefits of reducing CETP activity for ASCVD risk reduction, and plausibility exists for the promotion of longevity by reducing risks of several other conditions. An ongoing large clinical trial program of the latest potent CETP inhibitor, obicetrapib, is expected to provide further insight into CETP inhibition as a therapeutic target for these various conditions.

Senescent cells accumulate with age and cause harm via their inflammatory signaling, contributing to the chronic inflammation of aging that is disruptive to tissue structure and function throughout the body. One faction of the research and development community wants to selectively destroy senescent cells via the use of a wide variety of senolytic therapies presently under development. Another faction wants to instead find ways to suppress the inflammatory signaling of these cells. Here find an example of this second area of research, a search for targets that can be manipulated to reduce harmful signaling generated by senescent cells, but which will produce minimal side-effects in non-senescent cells.

In this review, we summarize the current research progress on non-histone high mobility group proteins (HMGs) in the field of aging, particularly their structural characteristics and functional roles in regulating the aging process. As chromatin architectural regulators, HMGs, in collaboration with histones, exert critical influence on chromatin dynamics and gene expression. By competitively binding to specific DNA sites, HMGs alter chromatin accessibility and regulate gene activity, thereby exerting profound effects at various stages of cellular senescence. This regulation involves a wide array of mechanisms and pathways, with a particularly notable impact on the senescence-associated secretory phenotype (SASP) and senescence-associated heterochromatin foci (SAHF).

HMG proteins, particularly members of the HMGA and HMGB families, play pivotal roles in the formation and regulation of SASP and SAHF. SASP comprises pro-inflammatory factors and proteins secreted during cellular senescence, which not only drive the aging process but are also closely associated with various age-related diseases, including chronic inflammation, cardiovascular diseases, and cancer. HMGA proteins promote or inhibit the spread of inflammatory signals by affecting chromatin structure and regulating the expression of SASP-related genes. Meanwhile, HMGB proteins, acting as damage-associated molecular patterns (DAMPs), activate inflammatory pathways and exacerbate the release of SASP. SAHF, as highly compacted heterochromatin regions, silence genes related to proliferation and the cell cycle, marking cells' entry into a state of permanent cell cycle arrest. The dynamic regulation of HMG proteins is crucial for the formation and maintenance of SAHF.

Recent studies have shown that targeting and blocking HMG proteins, particularly HMGB1 and HMGA2, not only reduces the release of SASP but also effectively inhibits inflammatory responses, thereby slowing the progression of age-related diseases. By inhibiting the extracellular release of HMGB1, researchers have found that sterile inflammation and tissue damage can be alleviated, protecting cardiovascular health and delaying the development of age-related cardiovascular diseases. Targeting these proteins has become a key direction in aging research. Compared to traditional therapies, targeting HMG proteins offers a more precise means of modulating age-related pathophysiological processes with fewer effects on normal cells.

Link: https://doi.org/10.3389/fragi.2024.1486281

Generally speaking, one should expect greater disability and disease in later life to correlate with greater mortality. Yet in many mammalian species, including our own, males die younger and females exhibit greater frailty while living longer. Biology is complicated! Here, researchers single out for attention the age-related dysfunction of the immune system that leads to a growing state of unresolved, constant inflammatory signaling. This state of inflammaging is thought to differ in women versus men, and may be one of the more important contributions to the observed sex-specific differences in outcomes.

Aging is a dynamic process that requires a continuous response and adaptation to internal and external stimuli over the life course. This eventually results in people aging differently and women aging differently than men. The "gender paradox" describes how women experience greater longevity than men, although linked with higher rates of disability and poor health status. Recently, the concept of frailty has been incorporated into this paradox giving rise to the "sex-frailty paradox" which describes how women are frailer because they manifest worse health status but, at the same time, appear less susceptible to death than men of the same age. However, very little is known about the biological roots of this sex-related difference in frailty.

Inflamm-aging, the chronic low-grade inflammatory state associated with age, plays a key pathophysiological role in several age-related diseases/conditions, including Alzheimer's disease (AD), for which women have a higher lifetime risk than men. Interestingly, inflamm-aging develops at a different rate in women compared to men, with features that could play a critical role in the development of AD in women. According to this view, a continuum between aging and age-related diseases that probably lacks clear boundaries can be envisioned in which several shared biological mechanisms that progress at different pace may lead to different aging trajectories in women than in men.

Link: https://doi.org/10.1016/j.exger.2024.112619

Cellular biochemistry changes in characteristic ways with age. Aging is a stochastic process of damage accumulation, followed by diverse consequences, but there are considerable similarities under the hood for all that the final dysfunctions are so varied and individual. An intricate iron structure left unprotected in the rain will collapse in any one of a hundred different ways, but underlying all of those possible breakages is the one common process of rust. Thus any sufficiently large body of data derived from individuals of various ages, whether omics or clinical chemistry or functional tests, can be used to produce algorithm combinations of values that reflect biological age. These algorithms are known as aging clocks.

The first, and still most widely used clocks are based on epigenetic data. Specifically they make use of the methylation status of CpG sites on the genome, decorations to nuclear DNA that change its structure to expose or hide specific regions, and thus change patterns of gene expression - which proteins are produced, and in what amount. A cell is in constant feedback with itself and its environment, DNA methylation constantly changing. But some of those changes are characteristic of damage and damaged environment of aged tissues.

The challenge with DNA methylation clocks, or any other aging clock, lies in understanding how the measurements made connect to underlying processes of aging and age-related diseases. Since the clocks are produced by machine learning approaches operating on data, that understanding doesn't exist yet. It is hard to take a clock measurement at face value without either knowing how its data relates to mechanisms of aging, or without a great deal of validation using real world data. It seems plausible that the real world validation approach will beat out the slow path to sufficient understanding, at least when it comes to justifying the use of some forms of aging clock for some forms of intervention in the matter of aging.

As today's open access paper notes, DNA methylation clocks have been used in a fair number of clinical trials for interventions that might be expected to modestly adjust the pace of aging or state of aging. There is enough data to start talking about when and how we should trust these DNA methylation clock measures. Nonetheless, this is still only the first step along a much longer road. In a world in which people continue to debate the conclusions of extensive clinical data for common therapies decades after their introduction - consider aspirin use for example - rapid consensus should not be the expected outcome for any tool or treatments.

DNAm aging biomarkers are responsive: Insights from 51 longevity interventional studies in humans

Aging biomarkers can potentially allow researchers to rapidly monitor the impact of an aging intervention, without the need for decade-spanning trials, by acting as surrogate endpoints. Prior to testing whether aging biomarkers may be useful as surrogate endpoints, it is first necessary to determine whether they are responsive to interventions that target aging. Epigenetic clocks are aging biomarkers based on DNA methylation (DNAm) with prognostic value for many aging outcomes. Many individual studies are beginning to explore whether epigenetic clocks are responsive to interventions. However, the diversity of both interventions and epigenetic clocks in different studies make them difficult to compare systematically.

Here, we curate TranslAGE-Response, a harmonized database of 51 public and private longitudinal interventional studies and calculate a consistent set of 16 prominent epigenetic clocks for each study, along with 95 other DNAm biomarkers that help explain changes in each clock. With this database, we discover patterns of responsiveness across a variety of interventions and DNAm biomarkers. For example, clocks trained to predict mortality or pace of aging have the strongest response across all interventions and show consistent agreement with each other, pharmacological and lifestyle interventions drive the strongest response from DNAm biomarkers, and study population and study duration are key factors in driving responsiveness of DNAm biomarkers in an intervention. Some classes of interventions such as TNF-alpha inhibitors have strong, consistent effects across multiple studies, while others such as senolytic drugs have inconsistent effects. Clocks with multiple sub-scores (i.e. "explainable clocks") provide specificity and greater mechanistic insight into responsiveness of interventions than single-score clocks.

Our work can help the geroscience field design future clinical trials, by guiding the choice of interventions, specific subsets of epigenetic clocks to minimize multiple testing, study duration, study population, and sample size, with the eventual aim of determining whether epigenetic clocks can be used as surrogate endpoints.

The brain has evolved to operate at the edge of its capacity; the normal operation of neural tissue requires a lot of energy, derived from nutrients and oxygen provided in the blood stream. That the increased blood flow that occurs following exercise improves cognitive function in the short term is indicative that there is room for improvement in the physiological support provided by the body for the normal operation of the brain. This remains true in later life, as the data here shows.

The research team leveraged smartphone technology to interact with participants multiple times during their regular daily lives. Over the course of nine days, participants checked in six times a day, approximately every 3.5 hours. During each check-in, participants reported if they had been physically active since their last check-in. If they were active, they were asked to rate the intensity of their activity - light, moderate or vigorous. For example, walking and cleaning were considered light intensity while running, fast biking, and effortful hiking were considered vigorous intensity. Participants were then prompted to play two "brain games," one designed to assess cognitive processing speed and the other designed to assess working memory, which can be a proxy for executive function.

The team analyzed data from 204 participants who were recruited for the Multicultural Healthy Diet Study to Reduce Cognitive Decline & Alzheimer's Risk. Data was collected during the study's baseline period. Participants were between the ages of 40 and 65 and residents of the Bronx, NY who had no history of cognitive impairment. The team found that when participants reported being physically active sometime in the previous 3.5 hours, they showed improvements in processing speed equivalent to being four years younger. While there were no observed improvements in working memory, the response time during the working memory task mirrored the improvements observed for processing speed.

Additionally, people who reported being active more often experienced greater short-term benefits compared to those who reported less physical activity overall. This suggests that cognitive health benefits may increase with regular physical activity. However, more research is needed to understand how much physical activity and the frequency and timing of being active influences cognitive health.

Link: https://www.psu.edu/news/research/story/can-everyday-physical-activity-improve-cognitive-health-middle-age

Cancers evolve to co-opt aspects of the immune system in order to suppress the immune response to cancerous cells. All tumor tissues make use of a variety of such mechanisms. In principle, sabotaging the immune suppression produced by tumor tissue should be a basis for both novel effective cancer therapies and enhancement of existing immunotherapies for cancer. Here is an example of early stage research in this part of the field, in which researchers identify mechanisms operating in regulatory T cells in tumor tissue. The metabolism of tumor resident regulatory T cells may be sufficiently distinctive to build approaches to treatment that can inhibit regulatory T cell function to harm the tumor without also harming necessary immune function elsewhere in the body.

T cells are central to the body's defense against cancer, with one subset, regulatory T cells (Tregs), playing a unique and often contradictory role in immune response. Unlike conventional T cells that attack tumors, Tregs prevent excessive inflammation and maintain immune tolerance. While this is essential for immune balance, Tregs within tumors, known as tumor-infiltrating Tregs (TIL-Tregs), allow cancer to evade immune attacks by suppressing the activity of effector T cells - the immune cells that actively target and kill tumor cells. Although targeting Tregs to restore anti-tumor immunity is an emerging area in cancer therapy, systemically inhibiting Tregs can cause severe autoimmune reactions.

TIL-Tregs possess unique characteristics compared to Tregs in systemic circulation, maintaining heightened suppressive capabilities within the nutrient-poor conditions of the tumor microenvironment, where effector T cells often falter. While GLUT1 is the primary glucose transporter in conventional T cells, GLUT3 plays a central role in glucose metabolism in TIL-Tregs. Typically associated with neurons, GLUT3 enables TIL-Tregs to efficiently absorb glucose from the tumor microenvironemnt, supporting their suppressive activity.

GLUT3-driven glucose absorption activates a metabolic pathway leading to protein modification with uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a sugar molecule. This modification process, called O-GlcNAcylation, regulates various proteins, including the transcription factor c-Rel, which is essential for TIL-Tregs' tumor-specific properties. By facilitating O-GlcNAcylation, GLUT3 provides TIL-Tregs with a metabolic advantage that enhances immune suppression within tumors.

This research highlights that TIL-Tregs have unique metabolic adaptations. This paves the way for innovative strategies in cancer immunotherapy that focus on rebalancing immune responses while minimizing adverse effects. Targeting GLUT3 or the O-GlcNAcylation pathway could precisely manipulate Treg activity within tumors, leading to better outcomes in cancer patients.

Link: https://www.postech.ac.kr/eng/postech-team-pioneers-new-cancer-therapy-strategy-targeting-glut3-in-regulatory-t-cells-to-supercharge-anti-tumor-immunity/

Cells have evolved a variety of ways to compensate for stress-inducing circumstance, such as heat, cold, low nutrient availability, mutational damage caused by toxins, and so forth. Perhaps the most studied of these mechanisms is autophagy, which recycles damaged cell components into raw materials. A cell structure is flagged, then engulfed by a membrane called an autophagosome, which is then transported to a lysosome, where it deposits its contents to be broken down by enzymes. It is clear from many lines of research that increased autophagy slows the progression of aging, most likely by removing more of the molecular damage that contributes to dysfunction.

Autophagy is far from the only stress resistance mechanism that operates in cells. Others focused on recycling of damaged proteins such as the ubiquitin-proteasome system and unfolded protein response are also influential on the pace of aging. So in humans, can one trace variants in gene sequence and gene expression to correlate performance of these stress resistance systems with longevity? That is the topic of today's open access paper, in which the researchers compare associations with stress resistance system performance and longevity in human data.

Biology of Healthy Aging: Biological Hallmarks of Stress Resistance Related and Unrelated to Longevity in Humans

Stress resistance is highly associated with longer and healthier lifespans in various model organisms, including nematodes, fruit flies, and mice. However, we lack a complete understanding of stress resistance in humans; therefore, we investigated how stress resistance and longevity are interlinked in humans. Using more than 180 databases, we identified 541 human genes associated with stress resistance. The curated gene set is highly enriched with genes involved in the cellular response to stress. The Reactome analysis identified 398 biological pathways, narrowed down to 172 pathways using a medium threshold. We further summarized these pathways into 14 pathway categories, e.g., cellular response to stimuli/stress, DNA repair, gene expression, and immune system.

There were overlapping categories between stress resistance and longevity, including gene expression, signal transduction, immune system, and cellular responses to stimuli/stress. The categories include the PIP3-AKT-FOXO and mTOR pathways, known to specify lifespans in the model systems. They also include the accelerated aging syndrome genes (WRN and HGPS/LMNA), while the genes were also involved in non-overlapped categories. Notably, nuclear pore proteins are enriched among the stress-resistance pathways and overlap with diverse metabolic pathways.

This study fills the knowledge gap in humans, suggesting that stress resistance is closely linked to longevity pathways but not entirely identical. While most longevity categories intersect with stress-resistance categories, some do not, particularly those related to cell proliferation and beta-cell development. We also note inconsistencies in pathway terminologies with aging hallmarks reported previously, and propose them to be more unified and integral.

Alzheimer's disease progresses through stages. The well known, slow accumulation of misfolded amyloid-β over years is only the early foundation of the condition, in and of itself producing little more than mild cognitive impairment. Amyloid-β, however, enables the onset of a state of chronic inflammation and tau protein aggregation that feeds upon itself and grows in severity, disrupting function and killing brain cells until it ultimately kills the patient. Researchers here find a potential target to slow or prevent the aggregation of altered tau protein in mouse models. Since these models are highly artificial, as aged mice do not normally suffer anything resembling a tauopathy, further work will be needed to demonstrate relevance to the natural human condition of Alzheimer's disease.

Over two dozen different diseases have been identified so far whose hallmark neuropathological feature is the presence of neuronal and/or glial accumulations of tau protein. Tau is a predominantly neuronal protein that binds to tubulin to promote assembly of the microtubule network that underpins intracellular transport. Its function is regulated by numerous post-translational modifications, such as phosphorylation, ubiquitination, and acetylation. In pathological states, tau protein undergoes aberrant modifications - predominantly hyperphosphorylation - then dissociates from microtubules, misfolds, propagates to neighboring cells and accumulates into intracellular neurofibrillary tangles (NFTs).

Alzheimer's disease is one of at least 26 diseases characterized by tau-positive accumulation in neurons, glia or both. However, it is still unclear what modifications cause soluble tau to transform into insoluble aggregates. We previously performed genetic screens that identified tyrosine kinase 2 (TYK2) as a candidate regulator of tau levels. Here we verified this finding and found that TYK2 phosphorylates tau at tyrosine 29 (Tyr29) leading to its stabilization and promoting its aggregation in human cells. We discovered that TYK2-mediated Tyr29 phosphorylation interferes with autophagic clearance of tau. We also show that TYK2-mediated phosphorylation of Tyr29 facilitates pathological tau accumulation in P301S tau-transgenic mice. Furthermore, knockdown of Tyk2 reduced total tau and pathogenic tau levels and rescued gliosis in a tauopathy mouse model. Collectively, these data suggest that partial inhibition of TYK2 could thus be a strategy to reduce tau levels and toxicity.

Link: https://doi.org/10.1038/s41593-024-01777-2

Hunter-gatherer populations in which fairly high levels of exercise are the norm have excellent heart health in later life in comparison to more sedentary first world populations. Hunter-gatherers exhibit very little atrial fibrillation, for example. So it isn't all that surprising to see that greater levels of exercise in those first world populations correlate with reduced incidence of atrial fibrillation, one more item in the long list of reasons to undertake more rather than less physical activity.

Researchers focused on atrial fibrillation, a condition in which the heart's upper two chambers beat rapidly and irregularly instead of at a consistent pace. If left untreated, this can lead to stroke, heart failure, and other issues. While past studies have linked exercise to reduced risk of this type of arrhythmia, nearly all of these analyses have relied on participants' often inaccurate estimates of their own activity levels. The current study used data recorded from the fitness tracker Fitbit to objectively measure physical activity in more than 6,000 men and women across the United States. The results showed that those with higher amounts of weekly physical activity were less likely to develop atrial fibrillation. Notably, even modest amounts of moderate to vigorous exercise, which can range from taking a brisk walk or cleaning the house to swimming laps or jogging, were associated with reduced risk.

Specifically, study participants who averaged between 2.5 and 5 hours per week, the minimum amount recommended by the American Heart Association, showed a 60 percent lower risk of developing atrial fibrillation. Those who averaged greater than 5 hours had a slightly greater (65 percent) reduction. In the sole earlier study that used activity monitors to investigate atrial fibrillation, researchers provided Fitbit-style monitors to the participants and tracked them for only a week, an approach that may not have accurately captured their normal workout habits. The new investigation assessed participants for a full year and included only those who already owned the devices.

Link: https://nyulangone.org/news/though-more-better-even-moderate-amounts-exercise-may-reduce-risk-common-heart-condition

Harmful changes in the behavior of the innate immune cells known as macrophages, and their analogous counterparts in the brain, called microglia, show up everywhere in investigations of aging and age-related disease. Macrophages are resident in all tissues, and participate in normal tissue maintenance and function in addition to chasing down pathogens and eliminating errant cells. Which activities are undertaken by a given macrophage are determined by its state; a crude division can be made between M1 macrophages that are pro-inflammatory and aggressive versus M2 macrophages that are anti-inflammatory and engage in tissue maintenance. Circumstances such as the level of damage in the tissue environment and level of inflammatory signaling will bias macrophages into one camp or the other.

The presence of too many inflammatory M1 macrophages may be an important feature of aging, a maladaptive reaction to rising levels of damage and inflammatory signaling - that signaling then further amplified by the macrophages themselves. But beyond this, there is also the question of cellular senescence. Cells become senescent in response to replication stress and mutational damage, as well as in response to tissue injury. These cells pump out inflammatory signaling but are efficiently removed by the immune system in youth. The immune system becomes less capable with age, and thus senescent cells accumulate. Many of these are macrophages. At some point all of this inflammation tips over into tissue dysfunction.

Today's open access paper is an example of the consequences of too many inflammatory and senescent macrophages. The researchers trace a path from the reduced estrogen production of menopause to excessive inflammatory and senescent macrophages in bone tissue, leading to disruption of the usual maintenance of bone. That in turn leads to an accelerated loss of bone density, manifesting as osteoporosis. Regular clearance of these errant macrophages, or some form of reprogramming to alter their state, may help to sever the link between menopause and osteoporosis, and slow the age-related decline of bone density.

Dynamic transcriptome analysis of osteal macrophages identifies distinct subset with senescence features in experimental osteoporosis

Given the potential fundamental function of osteal macrophages in bone pathophysiology, we study here their precise function in experimental osteoporosis. Gene profiling of osteal macrophages from ovariectomized mice demonstrated the upregulation of genes that were involved in oxidative stress, cell senescence, and apoptotic process. Single cell RNA sequencing analysis revealed that osteal macrophages were heterogenously clustered into 6 subsets that expressed proliferative, inflammatory, anti-inflammatory, and efferocytosis gene signatures.

Importantly, postmenopausal mice exhibited a 20-fold increase in the subset that showed a typical gene signature of cell senescence and inflammation. These findings suggest that the decreased production of estrogen due to postmenopause altered the osteal macrophages subsets, resulting in a shift toward cell senescence and inflammatory conditions in the bone microenvironment.

Furthermore, adoptive macrophage transfer onto calvarial bone was performed and mice that received oxidative-stressed macrophages exhibited greater osteolytic lesions than control macrophages, suggesting the role of these cells in development of inflammaging in bone microenvironment. Consistently, depletion of senescent cells and oxidative-stressed macrophages subset alleviated the excessive bone loss in postmenopausal mice. In conclusion, our data provided a new insight into the pathogenesis of osteoporosis and sheds light on a new therapeutic approach for the treatment/prevention of postmenopausal osteoporosis.

Some forms of therapy can be delivered to the brain by being sprayed into the nasal cavity; viral vectors, for examples, and extracellular vesicles in the example here. Extracellular vesicles carry much of the signaling that passes between cells, and can be harvested from cell culture populations of stem cells. The benefits of first generation stem cell therapies are thought to result from the signaling produced by the transplanted cells in the short time before they die, and thus the field is shifting towards the use of stem cell derived vesicles instead. Researchers here show that stem cell derived extracellular vesicles delivered via nasal spray can beneficially dampen inflammation in microglia, innate immune cells of the brain. Overly inflammatory microglia are implicated in the development of neurodegenerative conditions such as Alzheimer's disease.

As current treatments for Alzheimer's disease (AD) lack disease-modifying interventions, novel therapies capable of restraining AD progression and maintaining better brain function have great significance. Anti-inflammatory extracellular vesicles (EVs) derived from human induced pluripotent stem cell (hiPSC)-derived neural stem cells (NSCs) hold promise as a disease-modifying biologic for AD. This study directly addressed this issue by examining the effects of intranasal (IN) administrations of hiPSC-NSC-EVs in 3-month-old 5xFAD mice.

IN administered hiPSC-NSC-EVs incorporated into microglia, including plaque-associated microglia, and encountered astrocytes in the brain. Single-cell RNA sequencing revealed transcriptomic changes indicative of diminished activation of microglia and astrocytes. Multiple genes linked to disease-associated microglia, NLRP3-inflammasome, and IFN-1 signalling displayed reduced expression in microglia. Astrocytes also displayed reduced expression of genes linked to IFN-1 and interleukin-6 signalling. Furthermore, the modulatory effects of hiPSC-NSC-EVs on microglia in the hippocampus persisted 2 months post-EV treatment without impacting their phagocytosis function. The extent of astrocyte hypertrophy, amyloid-beta plaques, and p-tau were also reduced in the hippocampus. Such modulatory effects of hiPSC-NSC-EVs also led to better cognitive and mood function.

Thus, early hiPSC-NSC-EV intervention in AD can maintain better brain function by reducing adverse neuroinflammatory signalling cascades, amyloid-beta plaque load, and p-tau. These results reflect the first demonstration of the efficacy of hiPSC-NSC-EVs to restrain neuroinflammatory signalling cascades in an AD model by inducing transcriptomic changes in activated microglia and reactive astrocytes.

Link: https://doi.org/10.1002/jev2.12519

There is some evidence for the gut microbiome to play an important role in a range of comparatively poorly understood conditions involving pain, inflammation, and at least the suspicion of autoimmunity, from the better researched rheumatoid arthritis to the dark forest of overlapping symptoms containing fibromyalgia, myofascial pain syndrome, idiopathic peripheral neuropathies, and more. If many of these conditions do derive from microbial activities, however indirectly, this may go some way towards explaining the lack of progress towards finding definitive mechanisms and causes - until comparatively recently, no-one was looking at the gut microbiome.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder. The hallmark of RA is progressive joint disease, with potential for systemic involvement. Understanding the RA disease spectrum with recognition of at risk individuals has propelled RA research into prevention strategies. The generation of IgA class anticitrullinated protein antibodies (ACPAs) in individuals at risk of RA, combined with epidemiological links with smoking and periodontal disease, points to a mucosal origin of inflammation. The mucosal origin hypothesis proposes that localised inflammation at mucosal sites can initiate a broader immune response, via T cell activation and a subsequent inflammatory cytokine cascade, leading to B cell antibody production. Supporting this, an immunoglobulin class switch from IgA ACPAs to IgG ACPAs indicates potential triggering of systemic autoimmunity by diverse antigenic stimuli at mucosal sites. This shift, accompanied with broadening of antibody targets, suggests that mucosal barrier deterioration and the ensuing spread of an IgG ACPA response might be more significant in the initial stages of RA than the loss of tolerance to self-antigens.

Profiling of the gut microbiome in individuals at risk of RA and people diagnosed with RA consistently demonstrates a dysbiotic microbiome when compared with healthy controls. However, there remains little consensus on the bacterial constituent members of an RA-related dysbiosis. Subsequently, a variety of gut bacteria have been implicated as a potential impetus in the development of RA, none more so than Prevotella copri. Prevotella species have been demonstrated to be overabundant in new-onset rheumatoid arthritis (NORA), in at risk individuals and especially those with genetic risk. Their abundance decreases after disease-modifying antirheumatic drug (DMARD) therapy, with reversion to a eubiotic state on treatment. Furthermore, mouse models support a role for Prevotellaceae strains derived from patients with RA in RA development. However, Prevotellaceae overabundance does not appear to be an ubiquitous finding across all RA gut microbiome studies.

This work aimed to resolve the conflicting reports on Prevotellaceae abundance in the development of rheumatoid arthritis (RA) and to observe structural, functional and temporal changes in the gut microbiome in RA progressors versus non-progressors. Our data suggest conflicting reports on Prevotellaceae overabundance are likely due to sampling within a heterogeneous population along a dynamic disease spectrum, with certain Prevotellaceae strains/clades possibly contributing to the establishment and/or progression of RA. Gut microbiome changes in RA may appear at the transition to clinical arthritis as a late manifestation, and it remains unclear whether they represent a primary or secondary phenomenon.

Link: https://doi.org/10.1136/ard-2024-226362

Most proteins in the body are continually replaced on a fairly short time frame, either because replacement takes place inside cells, or because the cells themselves are replaced over time. In the few lasting cell populations, such as neurons in the brain and oocytes in the ovaries, there is the potential for cells and even individual protein molecules in those cells to have a life span that is as long as the overall life span of the animal or person. This is a point of concern because large molecules in the cell can become chemically altered in harmful ways over time, negatively affecting cell function. At the present time, it is far from clear as to how best to approach this problem, and how much of a contribution to age-related loss of function it provides.

In today's open access paper, researchers characterize long-lived proteins in oocytes and the surrounding ovary structures. This characterization doesn't demonstrate that the presence of long-lived proteins, and thus loss of function due to damaging chemical alterations, is a major contributing cause of dysfunction. But is is strongly suggestive that there will be some contribution to loss of function. Unlike the brain, another location of long-lived proteins, the ovaries age into loss of function comparatively early in life. Are long-lived proteins meaningful in this early aging, or is it other factors? That question remains to be answered.

Exceptional longevity of mammalian ovarian and oocyte macromolecules throughout the reproductive lifespan

The female reproductive system is the first to age in the human body with fertility decreasing for women in their mid-thirties and reproductive function ceasing completely at menopause. In the ovary, aging is associated with a loss in gamete quantity and quality which contributes to infertility, miscarriages, and birth defects. Moreover, the age-dependent loss of the ovarian hormone, estrogen, has adverse general health outcomes. These sequelae are significant as women globally are delaying childbearing and the gap between menopause and lifespan is widening due to medical interventions.

Although aging is a multifaceted process, loss of proteostasis and dysfunctional protein quality control pathways are hallmarks of reproductive aging. The mammalian ovary is comprised of a fixed and nonrenewable pool of long-lived cells or oocytes. In humans, oocytes initiate meiosis during fetal development, and by birth, all oocytes are arrested in the cell cycle. This cell cycle arrest is maintained until ovulation, which occurs any time between puberty and menopause, and thus can span decades. The oocytes are particularly sensitive to protein metabolism alterations because they contribute the bulk cytoplasm to the embryo following fertilization. Thus, maternal proteins produced during oogenesis are essential to generate high-quality gametes.

The ovarian microenvironment is a critical determinant of gamete quality and has been shown to become fibro-inflamed and stiff with age. Although a small number of oocyte-specific proteins have been identified as long-lived, including cohesins and several centromere-specific histones, there has not been a discovery-based approach to define the long-lived proteome of the ovary and oocyte. Thus, the potential contribution of long-lived proteins (LLPs) to the age-related deterioration of the reproductive system in mammals remains to be elucidated. In this study we used multi-generational whole animal metabolic stable isotope labeling and leading mass spectrometry (MS)-based quantitative proteomic approaches to visualize and identify ovarian and oocyte long-lived macromolecules in vivo during milestones relevant to the reproductive system.

LLPs tend to be part of large protein complexes and include histones, nuclear pore complex proteins, lamins, myelin proteins, and mitochondrial proteins. In the ovary, the major categories of LLPs included histones, cytoskeletal proteins, and mitochondrial proteins. Our findings provide a novel framework for how long-lived structures may regulate gamete quality. Long-lived macromolecules localized throughout the ovary including the follicular compartment with prominent signals in the granulosa cells of primordial and primary follicles relative to later stage growing follicles. These findings are consistent with the knowledge that the squamous pre-granulosa cells surrounding the oocyte within primordial follicles form early in development. These squamous granulosa cells are generally thought to lack the ability to undergo mitotic division until follicles are activated to grow, so it is not surprising that we observed long-lived macromolecules persisting within them. Thus, it is possible that these long-lived molecules will accumulate more damage in primordial follicles that remain quiescent for longer periods relative to those that activate earlier. Whether such damage occurs and how it translates into decreased follicle survival or gamete quality will require further investigation.

Within the extrafollicular ovarian environment, the ovarian surface epithelium (OSE) exhibited a striking enrichment of long-lived molecules. The OSE is highly dynamic due to repeated post-ovulation wound healing and repair, and its regenerative capacity occurs through a somatic stem/progenitor cell-mediated process. Interestingly, LLPs are retained in other cells undergoing repeated asymmetric divisions and are speculated to contribute to the reproductive aging process. Consistent with this possibility, the architecture and wound healing ability of the OSE is altered with advanced reproductive age.

With old age, everyone develops atherosclerosis, a condition characterized by the formation and growth of fatty plaques that narrow and weaken blood vessels. The more cholesterol present in an atherosclerotic plaque, the softer the plaque structure, and the greater the likelihood of fragmentation and rupture leading to a heart attack or stroke. Local excesses of cholesterol cause cell dysfunction, and in plaque this is particularly important in the macrophages that arrive to attempt to return excess cholesterol to the blood stream and otherwise repair the local damage. Instead of conducting repair, the cells instead become dysfunction and inflammatory. Many become senescent cells, and there is compelling evidence for the presence of senescent cells to make the dysfunction in plaque worse.

Recently, cellular senescence-induced unstable carotid plaques have gained increasing attention. In this study, we utilized bioinformatics and machine learning methods to investigate the correlation between cellular senescence and the pathological mechanisms of unstable carotid plaques. Our aim was to elucidate the causes of unstable carotid plaque progression and identify new therapeutic strategies. First, differential expression analysis was performed on a test set to identify differentially expressed genes (DEGs) between the unstable plaque group and the control group. These DEGs were intersected with cellular senescence-associated genes to obtain 40 cellular senescence-associated (CSA)-DEGs.

First, we investigated the expression and function of CSA-DEGs in unstable carotid plaques. The expression of CSA-DEGs in cells from unstable carotid plaques differed significantly from the control group. These genes are mainly related to cellular senescence, apoptosis, cell proliferation regulation, and inflammatory response. Typically, the characteristics of cellular senescence are described as irreversible proliferation arrest and senescence-associated secretory phenotype (SASP). Additionally, these genes are involved in pathways such as the MAPK signaling pathway, PI3K-Akt signaling pathway, FoxO signaling pathway, and HIF-1 signaling pathway. These pathways play crucial roles in the aging process, and their dysregulation is closely associated with the progression of unstable carotid plaques. Interestingly, we also observed that CSA-DEGs are closely related to T lymphocyte proliferation and cellular immunity, which is consistent with previous studies.

Link: https://doi.org/10.1038/s41598-024-78251-3

We live in a world in which near all species exhibit degenerative aging, yet some few species exhibit negligible aging until very late life, and a very much smaller number of species appear not to age at all. Aging isn't inevitable, yet it is near universal. Why has evolution produced this outcome? While there is a consensus answer to this question centered around the concept of antagonistic pleiotropy, the evolution of aging is a field of research characterized by continual debate, an ever changing sea of novel ideas that come and go from year to year. In part this is because it is challenging to prove any given theory definitively right or definitively wrong, but also in part because we live in an age of biotechnology, in the midst of a flood of new data on the biochemistry of aging, any piece of which might be argued to change the bigger picture in some way.

Ageing is generally regarded as a non-adaptive by-product of evolution. Based on this premise three classic evolutionary theories of ageing have been proposed. These theories have dominated the literature for several decades. Despite their individual nuances, the common thread which unites them is that they posit that ageing results from a decline in the intensity of natural selection with chronological age. Empirical evidence has been identified which supports each theory. However, a consensus remains to be fully established as to which theory best accounts for the evolution of ageing.

A consequence of this uncertainty are counter arguments which advocate for alternative theoretical frameworks, such as those which propose an adaptive origin for ageing, senescence, or death. Given this backdrop, this review has several aims. Firstly, to briefly discuss the classic evolutionary theories. Secondly, to evaluate how evolutionary forces beyond a monotonic decrease in natural selection can affect the evolution of ageing. Thirdly, to examine alternatives to the classic theories. Finally, to introduce a pluralistic interpretation of the evolution of ageing. The basis of this pluralistic theoretical framework is the recognition that certain evolutionary ideas will be more appropriate depending on the organism, its ecological context, and its life history.

Link: https://doi.org/10.1007/s10522-024-10143-5

The aging of the immune system is of great importance to aging more generally, likely a major contributing factor in the onset and progression of age-related dysfunction and disease. Researchers tend to draw a distinction between two forms of immune aging: (a) loss of the capacity of the immune system to destroy pathogens and errant cells, known as immunosenescence, and (b) overactivation of the immune system in the form of constant, unresolved inflammatory signaling in the absence of pathogens, known as inflammaging. Both of these forms of immune aging are serious issues.

In today's open access review paper, the authors start with immunosenescence and inflammaging before moving on to the topic of immune resilience, which we might define as an older individual exhibiting lesser degrees of both immunosenescence and inflammation. The paper points out that despite a general acceptance of immune aging as consisting of some combination of immunosenescence and inflammaging, there is little unity when it comes to how to define and assess immune resilience. Lack of a consensus on measurement is a hindrance when it comes to developing approaches to improve immune resilience by reducing immunosenescence and inflammaging.

The 3 I's of immunity and aging: immunosenescence, inflammaging, and immune resilience

As we age, our immune system's ability to effectively respond to pathogens declines, a phenomenon known as immunosenescence. This age-related deterioration affects both innate and adaptive immunity, compromising immune function and leading to chronic inflammation that accelerates aging. Immunosenescence is characterized by alterations in immune cell populations and impaired functionality, resulting in increased susceptibility to infections, diminished vaccine efficacy, and higher prevalence of age-related diseases.

Chronic stress and accumulated damage, whether occurring naturally or from acute and chronic infections, can lead to persistent inflammation, a precursor to altered cellular states known as the hallmarks of aging. As we age, our immune systems can aberrantly produce persistent low-grade, chronic, and systemic inflammation in non-pathogenic or "sterile" conditions referred to as "inflammaging". Aged individuals frequently exhibit this pro-inflammatory state characterized by elevated levels of pro-inflammatory markers within cells and tissues. Inflammaging can affect both the innate and adaptive immune responses and multiple molecular mechanisms can drive this inflammation, including cellular senescence, mitochondrial dysfunction, defective autophagy, inflammasome activation, DNA damage, and changes in the microbiome. Inflammaging is theorized to contribute to the development of chronic age-related conditions such as cancer, cardiovascular disease, diabetes, frailty, neurodegeneration, and osteoarthritis.

Immune resilience (IR) is a critical component of fully understanding immunosenescence. Immune resilience refers to the ability of the immune system to maintain or quickly restore its functions, thus promoting disease resistance and controlling inflammation during infectious diseases and other inflammatory stressors. Individuals with immune resilience are likely to have high immunocompetence and functionality, along with minimal background inflammation, which can potentially help buffer against the immune and systemic effects of harmful stimuli. However, reliably capturing this remains elusive. Much of the knowledge in this area is derived from disparate animal studies that lack standardized models, cross-sectional or short-term longitudinal analyses, and have limited endpoints. While previous studies suggest that immune variation is largely driven by non-heritable factors, investigating heritable influences on immunity is still worthwhile and presents an opportunity to identify novel therapeutic targets.

Current studies on immune resilience have been largely limited to basic immunophenotyping of common immune populations, cytokine analyses, or transcriptomic studies on leukocytes. Although cytokine analysis can provide information on the inflammatory background and immunophenotyping can describe population shifts, additional functional studies are needed to properly assess immunocompetence and how it changes in response to age, immune challenges, or other forms of stress. Furthermore, these endpoints need to be accessible, practical, and cost-effective for widespread clinical deployment. These steps are critical for identifying and benchmarking biomarkers or surrogate endpoints for immune resilience that can: 1) be translated back to pre-clinical animal models to generate standardized models with translational potential, and 2) be used to more reliably assess interventions that promote immune resilience and allow for comparisons between them.

One of the many challenges facing researchers attempting to understand and treat neurodegenerative conditions is that the human brain ages quite differently in comparison to the brains of our nearest neighbor species, the non-human primates. Alzheimer's disease is almost uniquely a human phenomenon, for example, with only limited evidence for Alzheimer's-like mechanisms in other primates. If branching out beyond a focus on Alzheimer's, one can find many aspects of brain aging in humans that are absent or notably different in other primates.

Brain aging is compared between Cercopithecinae (macaques and baboons), non-human Hominidae (chimpanzees, orangutans, and gorillas), and their close relative, humans. β-amyloid deposition in the form of senile plaques (SPs) and cerebral β-amyloid angiopathy (CAA) is a frequent neuropathological change in non-human primate brain aging. SPs are usually diffuse, whereas SPs with dystrophic neurites are rare. Tau pathology, if present, appears later, and it is generally mild or moderate, with rare exceptions in rhesus macaques and chimpanzees. Behavior and cognitive impairment are usually mild or moderate in aged non-human primates.

In contrast, human brain aging is characterized by early tau pathology manifested as neurofibrillary tangles (NFTs), composed of paired helical filaments (PHFs), progressing from the entorhinal cortex, hippocampus, temporal cortex, and limbic system to other brain regions. β-amyloid pathology appears decades later, involves the neocortex, and progresses to the paleocortex, diencephalon, brain stem, and cerebellum. SPs with dystrophic neurites containing PHFs and CAA are common.

Cognitive impairment and dementia of Alzheimer's type occur in about 1-5% of humans aged 65 and about 25% aged 85. In addition, other proteinopathies, such as limbic-predominant TDP-43 encephalopathy, amygdala-predominant Lewy body disease, and argyrophilic grain disease, primarily affecting the archicortex, paleocortex, and amygdala, are common in aged humans but non-existent in non-human primates. These observations show that human brain aging differs from brain aging in non-human primates, and humans constitute the exception among primates in terms of severity and extent of brain aging damage.

Link: https://doi.org/10.18632/aging.206143

Red blood cells are an underrepresented area of study when it comes to omics data, as these cells eject their nucleus and organelles when they are formed from hematopoietic progenitor populations. They do not synthesize proteins and have no gene expression to study. Nonetheless, there is still a lot biochemistry going on in there. Here researchers take a look at some of that red blood cell biochemistry, and find characteristic changes with age in arginine metabolism. Pulling on that thread may lead to a novel measure of biological age, or perhaps a way to influence some of the downstream consequences of aging on red blood cell function.

Increasing global life expectancy motivates investigations of molecular mechanisms of aging and age-related diseases. This study examines age-associated changes in red blood cells (RBCs), the most numerous host cell in humans. Four cohorts, including healthy individuals and patients with sickle cell disease, were analyzed to define age-dependent changes in RBC metabolism. Over 15,700 specimens from 13,757 humans were examined, a major expansion over previous studies of RBCs in aging.

Multi-omics approaches identified chronological age-related alterations in the arginine pathway with increased arginine utilization in RBCs from older individuals. These changes were consistent across healthy and sickle cell disease cohorts and were influenced by genetic variation, sex, and body mass index. Integrating multi-omics data and metabolite quantitative trait loci (mQTL) in humans and 525 diversity outbred mice functionally linked metabolism of arginine during RBC storage to increased vesiculation - a hallmark of RBC aging - and lower post-transfusion hemoglobin increments. Thus, arginine metabolism is a biomarker of RBC and organismal aging, suggesting potential new targets for addressing sequelae of aging.

Link: https://doi.org/10.1111/acel.14388

The vestibular system provides the sensory inputs needed for balance and orientation. Residing in the inner ear, it consists of distinct physical structures that are responsive to rotation (the semicircular canals) and linear acceleration (the otoliths). Like all complex biological systems, the vesibular system becomes dysfunctional with age. This dysfunction leads to loss of balance and increased incidence of falls, a potentially life-threatening event when taking place in an already frail older population.

Today's open access paper is an interesting look at how the otolith ages into dysfunction, evaluating the response to acceleration in mice of various ages. An otolith is a small calcified structure suspended in a viscous medium that presses upon sensory hair cells when it is shifted by the movement of the body. The strength of the sensory response depends on both the degree of acceleration and the weight of the otolith. If the otolith's weight changes, then sensory dysfunction will result - and otolith density declines with advancing age. There are, however, other changes in the aging of the otolith and its surroundings that could negatively impact the sensory response to acceleration, and which may or man not be more important. Considering only otolith weight is an oversimplification, and it is worth reading the discussion section of the paper for a more nuanced view.

Effects of aging on otolith morphology and functions in mice

Increased fall risk caused by vestibular system impairment is a significant problem associated with aging. A vestibule is composed of linear acceleration-sensing otoliths and rotation-sensing semicircular canals. Otoliths, composed of utricle and saccule, detect linear accelerations. Otolithic organs partially play a role in falls due to aging. Aging possibly changes the morphology and functions of otoliths. However, the specific associations between aging and otolith changes remain unknown. Therefore, this study aimed to clarify these associations in mice.

Young C56BL/6N (8 week old) and old (108-117 weeks old) mice were used in a micro-computed tomography (μCT) experiment for morphological analysis and a linear acceleration experiment for functional analysis. Young C56BL/6N (8 week old) and middle-aged (50 week old) mice were used in electron microscopy experiments for morphological analysis. μCT revealed no significant differences in the otolith volume but significant differences in the otolith density between young and old mice. μCT and electron microscopy revealed significant differences in the structure of striola at the center of the otolith. Significant differences were also observed in the amplitude of the eye movement during the vestibulo-ocular reflex induced by linear acceleration, indicating that the otolith function was worse in old mice than in young mice.

This study demonstrated the decline in otolith function with age caused by age-related morphological changes. Specifically, when otolith density decreased, inertial force acting on the hair cells decreased, and when the structure of striola collapsed, the function of cross-striolar inhibition decreased, thereby causing a decline in the overall otolith function.

There is no shortage of theories when it comes to why women tend to live longer than men. There is little consensus on the mechanisms at a detail level, however. Looking out across species other than our own doesn't help all that much, as even when only considering mammals one sees a variety of outcomes. There are enough species in which females live longer than males to be uncomfortable with hypotheses involving culture and lifestyle choices in humans, and enough species in which females do not live longer than males to undermine and complicate most of the potential biochemical and evolutionary explanations.

It has become increasingly evident that males and females across species show differences in lifespan and ageing. In many mammals, females live longer than males, while in birds, males are the longer-lived sex. In humans, women live on average 5 years longer than men. Paradoxically, women are frailer later in life (usually after the onset of menopause) and do not necessarily have a longer healthspan.

Age-associated illnesses are often sex-biased. For example, in 2018, men older than 65 years showed higher death rates of cancer, heart disease, stroke, and diabetes, while Alzheimer's disease (AD), influenza, and pneumonia showed higher death rates in women. Women are also more susceptible to autoimmunity. Such age-associated sex biases deserve more attention, as the elderly population worldwide is expected to double from 12% to 22% between 2015 and 2050.

One reason why either sex can be more prone to certain age-associated phenotypes are the sex chromosomes. In mammals, females are XX and males XY, where the presence of the Y chromosome triggers the development of male gonads and secondary sexual traits. Mammals share evolutionarily conserved sex chromosomes, but in wild populations, not all mammalian females live longer than males. However, when they do, they have a longer median lifespan of around 20%. How the sex chromosome complement impacts longevity is an active area of research.

Link: https://doi.org/10.1098/rsob.240177

There has been some debate in past years over the degree to which time spent sitting is harmful to long-term health, and whether the negative effects of time spent sitting can be removed by suitable amounts of exercise. We live in a sedentary age, and many people spend most of their working lives in a seat, punctuated by the exercise that they do carry out. Evidently a fully sedentary lifestyle is a bad thing, the evidence is clear on that front. But does extended sitting time cause harms even in those who are exercising to a reasonable degree? The epidemiological evidence leans towards yes, if we're prepared to assume that correlations in human data between sedentary time and health are indicative of causation. In animal studies that causation is well demonstrated, but human data sets can only ever indicate correlation.

We examined whether physical activity buffers high levels of sitting time on cardiovascular and metabolic health indices of total cholesterol/high-density lipoprotein ratio (TC/HDL) and body mass index (BMI) in a sample of young adults. The expected negative associations of sitting on health indices were apparent in this relatively healthy period of adulthood. However, meeting the current physical activity recommendations did not buffer the impacts of sitting on BMI or TC/HDL fully, although engagement in vigorous physical activity is associated with lower, healthier levels.

For females in their early 30s and males in their late 20s, the TC/HDL is shown to cross into the moderate cardiac risk territory when sitting 8.5 hours per day even after meeting current physical activity recommendations. Performing vigorous physical activity reveals a notable age-equivalent benefit with any level of sitting where an individual exercising 30 minutes of day of vigorous intensity exercise has comparable TC/HDL and BMI values to someone 5 or 10 years younger respectively sitting the same amount of time without any vigorous physical activity. Our findings suggest maintaining sedentary behavior throughout young adulthood may contribute to later cardiovascular and metabolic disease susceptibility.

The co-twin control analyses with the monozygotic pairs further illustrates the importance of additional vigorous physical activity in place of sitting time or in addition to prolonged sitting time to improve one's TC/HDL. Failing to disrupt sedentary behavior could set a course towards poorer health and functioning across the lifespan, particularly since once disease onset occurs for many chronic conditions, disease maintenance will be the primary focus of health intervention instead of recovery. This has been illustrated in previous work implicating elevated BMI and dyslipidemia measurements in early adulthood linked to adverse impacts occurring later in life as they relate to issues such as coronary heart disease, stroke, and other major health issues. Given these links, early intervention of suboptimal BMI and TC/HDL values is critical to prevent a multitude of health-related issues past early adulthood.

Link: https://doi.org/10.1371/journal.pone.0308660

The most common and well-researched age-related neurodegenerative conditions, such as Alzheimer's disease, Parkinson's disease, and so forth, are associated with the aggregation of proteins into harmful solid deposits in the brain, usually also associated with a secondary halo of toxic and out of place molecules. Some few proteins can misfold or become altered by post-translational modifications in ways that encourage other molecules of the same protein to become altered in the same way, and join together to form growing structures. The plaque formed from misfolded amyloid-β is one example, the neurofibrillary tangles formed by hyperphosphorylated tau another. In some cases, as for α-synuclein in Parkinson's disease, the altered protein spreads from cell to cell in a prion-like way, producing dysfunction as it goes.

In today's open access paper, researchers look into one aspect of the regulation of aggrephagy, a form of autophagy targeted to protein aggregates. Autophagy flags unwanted structures in the cell, engulfing them into a membrane called an autophagosome, and then transporting it to a lysosome where it merges to allow the cargo to be broken down by lysosomal enzymes. Upregulation of autophagy to produce benefits to health is a popular topic, though efforts to produce drugs targeting autophagy have not progressed all that much past calorie restriction mimetics such as rapamycin. The hope here is that finding a way to specifically upregulate aggrephagy could slow the progression of neurodegenerative conditions driven by pathological protein aggregation; it remains to be seen as to how well this approach works in practice.

The essential role of CCT2 in the regulation of aggrephagy

Protein aggregation, the abnormal accumulation of misfolded or unfolded proteins, is a ubiquitous phenomenon associated with numerous human pathologies, including neurodegenerative diseases, metabolic disorders, and cancer. These aggregations often lead to cellular dysfunction and, ultimately, tissue damage and organ failure. To combat this threat, cells have evolved intricate mechanisms to maintain protein homeostasis (proteostasis), including the molecular chaperones, ubiquitin-proteasome system (UPS), and autophagy. Among these, autophagy, particularly aggrephagy - a subtype of autophagy specifically targeting protein aggregates - has garnered significant attention due to its pivotal role in the clearing toxic protein aggregates.

Chaperonin Containing TCP-1 (CCT) is a multi-subunit protein complex essential for the folding of approximately 10% of cytosolic proteins. CCT is composed of eight distinct subunits (CCT1-8), each playing a critical role in maintaining the structural integrity of nascent polypeptides. Among these, CCT2, a subunit of CCT, has recently emerged as a novel player in the regulation of aggrephagy, shedding light on the intricate interplay between protein folding and degradation

This mini review outlines CCT2's dual roles: as a molecular chaperone crucial for protein folding and homeostasis, and recently, as an autophagy receptor in aggrephagy, degrading solid protein aggregates to maintain proteostasis. We detail CCT2's mechanisms in aggrephagy, emphasizing its interplay with cellular clearance machinery. The selectivity of CCT2-mediated aggrephagy for solid aggregates has implications for neurodegenerative diseases. Further research is warranted to explore the therapeutic potential of enhancing CCT2-mediated aggrephagy in such diseases.

Stem cell populations become exhausted with advancing age, unwilling to respond to the usual signaling and generate new daughter somatic cells to support tissue function. This is accompanied by changes in the expression of genes in these cell populations, a complex web of relationships that is far from fully explored. Gene expression is determined by the structure of chromatin, the packaged DNA in the cell nucleus. Epigenetic modifications to that structure occur constantly, changing its shape. This epigenetic regulation unfolds portions of the chromatin to allow the machinery of transcription access to specific gene sequences, and folds away other portions to hide them. Here, researchers engage with this complexity in search of genes that regulate intestinal stem cell exhaustion in flies, a starting point for later explorations in mammals.

Although stem cell quiescence and exhaustion in aged tissues share the same property of suppressed proliferation, they are distinct in a sense that quiescent cells, but not exhausted cells, can proliferate upon receiving stresses. Aging-induced stem cell exhaustion occurs in many types of tissue stem cells in mice, including hematopoietic stem cells, intestinal stem cells (ISCs), skeletal muscle stem cells, and hair follicle stem cells. Stem cell exhaustion can occur due to two mechanisms: (1) replicative stress in response to proliferation and (2) mechanisms independent of cell proliferation. The resulting phenotype, proliferation or exhaustion, likely depends on the tug of war competition between conflicting signals.

In Drosophila, ISCs demonstrate a proliferative phenotype during aging. Although PIWI was suggested to suppress Jak-Stat-mediated exhaustion of ISCs, signaling that skews ISCs toward exhaustion during aging is not known. There might be some undiscovered signals that lead cells toward exhaustion. During aging, changes in chromatin structures and gene expression occur simultaneously in tissue stem cells. Changes in chromatin structures may underlie changes of some gene expression. We discovered changes of chromatin accessibility and gene expression that have a propensity to exhaust intestinal stem cells (ISCs). During aging, Trithorax-like (Trl) target genes, ced-6 and ci, close their chromatin structures and decrease their expression in intestinal progenitor cells. Inhibition of Trl, ced-6, or ci exhausts ISCs. This study provides new insight into changes of chromatin accessibility and gene expression that have a potential to exhaust ISCs during aging.

Link: https://doi.org/10.1016/j.isci.2024.110793

Metabolism is regulated by regions of the brain, as well as by other tissues, and alterations to metabolism can affect the pace of aging. The hypothalamus has been identified as one of the brain regions relevant to aging in this way. In recent years, researchers have managed to tie more specific aspects of the aging of the hypothalamus to age-related changes elsewhere in the body. For example, loss of neural stem cells and the signaling that they produce appears to induce dysfunction and accelerated aging. Along similar lines, researchers here find another population of neurons in the hypothalamus that quite indirectly improve energy metabolism and thereby slow the pace of aging.

Recent studies have shown that the hypothalamus functions as a control center of aging in mammals that counteracts age-associated physiological decline through inter-tissue communications. We have identified a key neuronal subpopulation in the dorsomedial hypothalamus (DMH), marked by Ppp1r17 expression (DMHPpp1r17 neurons), that regulates aging and longevity in mice. DMHPpp1r17 neurons regulate physical activity and white adipose tissue (WAT) function, including the secretion of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), through sympathetic nervous stimulation.

Within DMHPpp1r17 neurons, the phosphorylation and subsequent nuclear-cytoplasmic translocation of Ppp1r17, regulated by cGMP-dependent protein kinase G (PKG; Prkg1), affect gene expression regulating synaptic function, causing synaptic transmission dysfunction and impaired WAT function. Both DMH-specific Prkg1 knockdown, which suppresses age-associated Ppp1r17 translocation, and the chemogenetic activation of DMHPpp1r17 neurons significantly ameliorate age-associated dysfunction in WAT, increase physical activity, and extend lifespan. Thus, these findings clearly demonstrate the importance of the inter-tissue communication between the hypothalamus and WAT in mammalian aging and longevity control.

Link: https://doi.org/10.1016/j.cmet.2023.12.011

A growing weight of evidence indicates that changes in the gut microbiome taking place over the course of aging contribute to the onset and progression of neurodegenerative conditions. Species producing beneficial metabolites, such as butyrate to upregulate expression of BDNF to encourage neurogenesis, decline in number. Species that are harmful because they contribute to the constant, unresolved inflammation that is characteristic of old age increase in number. It is thought that the decline of immune function plays a role in this shift, as the immune system becomes ever less capable of gardening the gut microbiome to remove problematic microbes. Other factors are likely in play, such as barrier dysfunction, both in the intestine and brain, allowing microbes and unwanted, pro-inflammatory metabolites to pass into tissue in increasing numbers.

The aging of the gut microbiome is longer-term process of change, taking place over decades and leading to a distinctly dysfunctional gut microbiome in patients with neurodegenerative conditions. But in the short term, the presence of infectious agents in the aged gut microbiome can accelerate neurodegenerative processes via the same inflammatory mechanisms. In today's open access paper, researchers illustrate this point using a mouse model of Alzheimer's disease infected with a common species of bacteria that causes pneumonia. Infection clearly worsens the neurodegenerative pathology in these mice, as one might expect for any significant cause of inflammation.

An Enteric Bacterial Infection Triggers Neuroinflammation and Neurobehavioral Impairment in 3xTg-AD Transgenic Mice

Klebsiella pneumoniae is infamous for hospital-acquired infections and sepsis, which have also been linked to Alzheimer disease (AD)-related neuroinflammatory and neurodegenerative impairment. However, its causative and mechanistic role in AD pathology remains unstudied. Thus a preclinical model of K. pneumoniae enteric infection and colonization is developed in an AD model (3xTg-AD mice) to investigate whether and how K. pneumoniae pathogenesis exacerbates neuropathogenesis via the gut-blood-brain axis.

K. pneumoniae, particularly under antibiotic-induced dysbiosis, was able to translocate from the gut to the bloodstream by penetrating the gut epithelial barrier. Subsequently, K. pneumoniae infiltrated the brain by breaching the blood-brain barrier. Significant neuroinflammatory phenotype was observed in mice with K. pneumoniae brain infection. K. pneumoniae-infected mice also exhibited impaired neurobehavioral function and elevated total tau levels in the brain. Metagenomic analyses revealed an inverse correlation of K. pneumoniae with gut biome diversity and commensal bacteria, highlighting how antibiotic-induced dysbiosis triggers an enteroseptic "pathobiome" signature implicated in gut-brain perturbations.

The findings demonstrate how infectious agents following hospital-acquired infections and consequent antibiotic regimen may induce gut dysbiosis and pathobiome and increase the risk of sepsis, thereby increasing the predisposition to neuroinflammatory and neurobehavioral impairments via breaching the gut-blood-brain barrier.

A range of interesting research delves into the relevance of circadian rhythm to aging, from both (a) the perspective of how the regulation of circadian rhythm becomes dysfunctional with age, and (b) the evolutionary perspective of how differences in circadian rhythm may be relevant to differences in species life span. The research noted here falls into the second camp, looking at the evolution of genes that regulate circadian rhythm. The data is suggestive of the importance of circadian rhythm to the evolution of longevity in a species, but strangely, this importance is not universal across the varieties of mammal.

The relationship between genomic characteristics and species traits is of paramount importance for biology. We proposed a novel technique that allows one to determine the relationship between any genomic characteristic and species traits, such as maximal reported lifespan, the body weight of an adult animal, and the related longevity quotient. This technique is exemplified in the physiologically significant genes involved in regulating circadian rhythms, which change quite rapidly during evolution.

Regardless of devising this technique, the study of the genes that are critical for circadian rhythms is of interest on its own. For instance, we thoroughly examined the paralogous genes Fbxl21 and Fbxl3, which are involved in the regulation of circadian rhythms. We found out that the above-mentioned characteristic of the Fbxl21 gene correlates with the maximal reported lifespan and body weight only in two superorders of placental mammals, Euarchontoglires (the clades Euarchonta, Lagomorpha, and Rodentia) and Afrotheria. On the contrary, such a correlation is not observed in other superorders, such as Laurasiatheria and Xenarthra. The presence or absence of the correlation is confirmed statistically with a very high accuracy.

Thus for certain genes (such as Fbxl21), the accumulation of amino acid substitutions up to pseudogenization or gene loss, as well as the preference for certain amino acids in the encoded protein, is an effective way to achieve a significant phylogenetic change. The Fbxl21 gene and the species-specific maximal reported lifespan, together with body weight, are examples of such a phylogenetic change in Euarchontoglires and Afrotheria, which is also observed in relatively small taxonomic groups, as, for example, in anthropoid apes and the Cercopithecidae.

Link: https://doi.org/10.3390/biology13100792

Researchers here correlate obstructive sleep apnea in older individuals with a greater risk of the later development of dementia. In the present environment of widespread excess body weight, and the harms caused by excess visceral fat tissue, we might reasonably anticipate that correlations between obstructive sleep apnea and dementia risk are the result of excess weight contributing independently to both outcomes. The Stop-BANG screening questionnaire used to define the presence of obstructive sleep apnea in a patient includes a weight threshold as a factor, but it nonetheless seems an oversight to not also control for the weight of study participants.

This study included 18,815 women and men age 50+ years (dementia-free at baseline) who participated in the Health and Retirement Study (HRS), a nationally representative cohort of US adults. Presence of obstructive sleep apnea (OSA) was defined by self-reported diagnosis or key HRS items that correspond to elements of a validated OSA screening tool (STOP-Bang). Incident dementia cases were identified using a validated, HRS-based algorithm derived from objective cognitive assessments. Survey-weighted regression models based on pseudo-values were utilized to estimate sex- and age-specific differences in cumulative incidence of dementia by OSA status.

Data from 18,815 adults were analyzed, of which 9% of women and 8% of men (weighted proportions) met criteria for incident dementia. Known/suspected OSA was more prevalent in men than in women (weighted proportions 68% vs. 31%). Unadjusted sex-stratified analyses showed that known/suspected OSA was associated with higher cumulative incidence of dementia across ages 60-84 years for women and men. By age 80, relative to adults without known/suspected OSA, the cumulative incidence of dementia was 4.7% higher for women with known/suspected OSA, and 2.5% for men with known/suspected OSA, respectively. Adjusted associations between age-specific OSA and cumulative incidence of dementia attenuated for both women and men but remained statistically significant.

Link: https://doi.org/10.1093/sleepadvances/zpae077

Loss of muscle mass and strength is universal across the aging population. A perhaps surprising amount of this loss is the result of lifestyle choice, however. We live in an age of comfort, in which people conduct lesser degrees of physical activity than was normally the case in past centuries. Compare the average modern first world individual with the average modern hunter-gatherer, and the hunter-gatherer is in better shape, better maintaining muscle function into later life. Given than people age at different rates, and people undertake different degrees of physical activity, one might expect to see variations in muscle mass and strength in later life, and indeed this is the case.

In today's open access paper, researchers examine the correlation between measures of strength and mortality in a population over 90 years of age. The more muscle, the lower the mortality risk. It is worth bearing in mind other studies that have shown programs of resistance exercise, which builds muscle and strength, to lower mortality risk in older individuals. A fair degree of the state of muscle in later life is under our control. Muscle is a metabolically active tissue, producing a comparatively poorly understood set of myokine signals that are generally beneficial to the operation of metabolism throughout the body. So having more muscle, and better quality muscle tissue, isn't just a matter of avoiding frailty, it is also beneficial in other ways.

Association of Muscle Strength With All-Cause Mortality in the Oldest Old: Prospective Cohort Study From 28 Countries

Ageing is associated with a gradual loss of muscle strength, which in the end may have consequences for survival. Whether muscle strength and mortality risk associate in a gradual or threshold-specific manner remains unclear. This study investigates the prospective association of muscle strength with all-cause mortality in the oldest old. We included 1890 adults aged ≥ 90 years (61.6% women, mean age 91.0 ± 1.5 years) from 27 European countries and Israel participating in the Survey of Health, Ageing and Retirement in Europe (SHARE) study. Muscle strength was assessed using handgrip dynamometry. We determined the prospective association of muscle strength with mortality, controlling for age, sex, smoking, BMI, marital status, education, geographical region, and self-perceived health.

Over a mean follow-up of 4.2 ± 2.4 years, more than half of the participants died (n = 971, 51.4%). The mean handgrip strength was 20.4 ± 8.0 kg for all participants, with men (26.7 ± 7.5 kg) showing significantly higher strength than women (16.4 ± 5.4 kg). Using the median level of muscle strength as reference (18 kg), lower and higher levels were associated in a gradual and curvilinear fashion with higher and lower mortality risk, respectively. The 10th percentile of muscle strength (10 kg) showed a hazard ratio (HR) of 1.27. The 90th percentile (31 kg) showed an HR of 0.69. Stratified for sex, the median levels of muscle strength were 26 kg for men and 16 kg for women. The 10th percentile of muscle strength showed HRs of 1.33 at 15 kg for men and 1.19 at 10 kg for women. The 90th percentile of muscle strength showed HRs of 0.75 at 35 kg for men and 0.75 at 23 kg for women. Sensitivity analyses, which excluded individuals who died within the first 2 years of follow-up, confirmed the main findings.

Rather than a specific threshold, muscle strength is gradually and inversely associated with mortality risk in the oldest old. As muscle strength at all ages is highly adaptive to resistance training, these findings highlight the importance of improving muscle strength in both men and women among the oldest old.

The work conducted at Calico Labs is representative of the broad faction of the aging research community that aims to alter metabolism in order to modestly slow the progression of aging. The damaged and dysfunctional environment of aged tissues and cell structures produces cell stress via many different mechanisms. Cells respond to that stress in a smaller set of ways, and some of those responses are maladaptive, making the situation worse. The best way forward would be to repair the damage that causes cell stress; the approach taken here is to instead alter the behavior of cells in order to selectively sabotage some of the maladaptive response to cell stress.

The Integrated Stress Response (ISR) is a conserved signaling pathway across species and an important area of focus for Calico because of its possible link to many age-related diseases and its potential as a target for new drug development. Calico is currently developing an ISR inhibitor, Fosigotifator (ABBV-CLS-7262), which is being tested in the clinic as a potential treatment for two neurodegenerative diseases. To gain a deeper understanding of how the ISR controls cell states, the Calico team used a highly specific and tunable cellular model to disentangle the effects of the ISR from other processes that are engaged when cells encounter stress or damage that disrupts them.

A key discovery was the suppression of a process known as the tricarboxylic acid (TCA) cycle which is a series of reactions that are essential for creating energy via cellular respiration. The researchers found that when the ISR is turned on even at low levels, carbon is redirected from mitochondria to make amino acids and glutathione, a key antioxidant that protects cells. This shows how the ISR may help cells adapt to mitochondrial dysfunction or starvation, two common triggers of the pathway, by rewiring their metabolism. Using a synthetic tool researchers also showed that activation of the ISR can lead to the formation of droplets that store fats, also known as lipids. This is interesting because lipid droplets have been linked to neurodegenerative diseases.

Link: https://www.calicolabs.com/story/calico-scientists-get-a-close-up-look-at-cell-stress/

This article from the National Institutes of Health (NIH) takes a look at some of the mainstream research efforts aimed at measuring and better understanding the processes of biological aging. Where intervention arises from this part of the field, efforts tend to focus on altering the operation of metabolism to modestly slow aging, such as via the use of autophagy-promoting drugs like rapamycin and other mTOR inhibitors. The alternative, much better approach of identifying and repairing specific forms of cell and tissue damage in order to produce rejuvenation, continues to receive less attention, despite the compelling data produced by senolytic drugs that clear senescent cells.

With advancing age comes an increased risk of disease and disability. As people live longer, they are more likely to develop at least one age-related disease. Aging in people results from the gradual accumulation of defects and damage to the molecules and cells that make up our bodies. Unlike a car, our bodies have built-in mechanisms for repairing this damage. But even these repair mechanisms wear out over time. Eventually, enough damage accumulates to affect the function of whole organs and systems. NIH-funded researchers have been working to better understand aging at the molecular level. They're studying ways to measure differences in how people age before health problems appear. They're also exploring possible ways to slow, or even reverse, aging at the molecular level. This could lead to better approaches to prevent or treat age-related disease and disability.

Before you can tell if a treatment could slow or even reverse aging, you need to know how fast someone is aging in the first place. It's no secret that people age at different rates. Some people remain healthy and disease-free well into their ninth or even tenth decade of life. Others develop age-related diseases, such as cancer, heart disease, and dementia, much earlier. The concept of "biological age" is often used to describe these differences. Biological age reflects the molecular damage that accumulates over the years and eventually leads to disease and disability. Differences in biological age can develop years before age-related diseases appear. So a treatment to slow aging would also need to start well before such diseases appear. Then, to find out if a treatment worked or not, you'd have to track people for the rest of their lives. That's why researchers have been working to develop "aging clocks" to measure a person's biological age.

Age-reversing therapies like these are still some way in the future. Still, there are hints of lifestyle interventions that may have potential to lengthen life and delay aging. One that's been particularly well-studied is calorie restriction (CR). This is where you reduce the total number of calories you consume, but still get enough of the essential nutrients. To find out whether CR might have benefits in humans, too, NIH funded the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) study. More than 200 healthy, middle-aged volunteers were randomly assigned to two groups. Participants in one group were challenged to reduce their daily caloric intake by 25% for two years and given dietary and behavioral strategies for doing so. Those in the other group continued to eat their normal diets. Researchers examined the pace of biological aging in CALERIE participants. Those in the CR group had a much slower pace of aging as measured by clinical blood biomarkers. They also had a small but significant decrease in DunedinPACE, a rate of aging clock, while participants in the other group did not.

Link: https://www.nih.gov/news-events/nih-research-matters/research-context-can-we-slow-aging

The practice of calorie restriction alters near all aspects of cellular biochemistry throughout the body. The result is improved function and modestly slowed aging, an evolved response to low nutrient levels that serves to increase the odds of surviving a famine to reproduce once plenty returns. Seasonal famine is the most common such circumstance, and while the calorie restriction response appears to be near universal across all forms of life, short-lived species exhibit a much greater extension of life span as a result than is the case for long-lived species. A season is a sizable fraction of a mouse life span, but not of a human life span. So mice can live up to 40% longer on a low calorie diet, while humans likely gain only a few years.

Since calorie restriction changes just about everything for the better in the aging body, one can find any number of papers examining one very specific aspect of the calorie restriction response. Today's open access paper, for example, is focused on how beta cells are improved, and their functional decline with aging is slowed, in calorie restricted mice. Beta cells reside in the pancreas, produce insulin, and are thus of central importance in insulin metabolism and glucose metabolism. This portion of overall metabolism affects the pace of aging, as illustrated by the accelerated aging exhibited by diabetic patients.

Calorie restriction increases insulin sensitivity to promote beta cell homeostasis and longevity in mice

Beta cells secrete insulin in response to increases in blood glucose levels to sustain normal glucose homeostasis for an entire lifetime. Several studies have investigated the impact of aging on beta cells and established that aging beta cells have compromised expression of transcription factors (TFs) and re-organization of gene regulatory networks (GRNs) that maintain beta cell identity, accumulation of islet fibrosis, inflammation, and ER stress, reduced KATP channel conductance, loss of coordinated beta cell calcium dynamics, impaired beta cell autophagy and accumulation of beta cell DNA damage, and/or beta cell senescence. When combined with an unhealthy lifestyle during old age, these aging signatures could pre-dispose beta cells to failure and lead to type 2 diabetes (T2D) onset.

Caloric restriction (CR) and CR-mimicking approaches (e.g., time-restricted feeding (TRF)) can prolong organismal longevity and delay aging from yeast to non-human primates. These beneficial effects are associated with improved glucose homeostasis due to prolonged fasting and enhanced peripheral insulin sensitivity, enhanced insulin signaling, lower adiposity, enhanced mitochondrial homeostasis and lower ATP generation, increased autophagy, enhanced protein homeostasis and reduced ER stress and inflammation. In the pancreas, 20-40% CR or CR achieved via TRF are linked to lower islet cell mass in lean mice, whereas in pre-diabetic mice, CR restores normal beta cell secretory function, identity, and preserves beta cell mass in a process dependent on activation of beta cell autophagy via Beclin-2. In patients with a recent T2D diagnosis, the efficacy of extreme CR (average of 835 kcal/day or greater than 50% CR based on a 2000 kcal/day diet) to reverse T2D depends on the capacity of beta cells to recover from previous exposure to a T2D metabolic state. However, how beta cells adapt during CR, and whether CR can delay the hallmarks of beta cell aging remains largely unknown.

We investigated these questions by exposing adult male mice to mild CR (i.e., 20% restriction) for up to 12 months and applied comprehensive in vivo and in vitro metabolic phenotyping of beta cell function followed by single-cell multiomics and multi-modal high-resolution microscopy pipelines. Our data reveals that CR reduces the demand for beta cell insulin release necessary to sustain euglycemia by increasing peripheral insulin sensitivity. Ad-libitum (AL) consumption of a diet with reduced caloric intake failed to trigger a similar phenotype, thus indicating that CR and CR-associated fasting periods are required for this adaptive metabolic response. During CR, the transcriptional architecture of beta cells is re-organized to promote a largely post-mitotic and long-lived phenotype with enhanced cell homeostasis and mitochondrial structure-function. This is associated with reduced onset and/or expression of beta cell aging and senescence signatures. When exposed to a high-fat diet (HFD), CR beta cells upregulate insulin release, however they have a compromised adaptive response due to limited cell proliferation resulting in reduced beta cell mass. Therefore, our results provide a molecular footprint of how CR modulates adult beta cell function and insulin sensitivity to promote beta cell longevity and delay aging in mice.

Lower animals that are essentially tiny blobs of stem cells are in principle capable of immortality, as illustrated by hydra and the jellyfish Turritopsis dohrnii that cycles from immaturity to adulthood and back again. Even if not actually immortal, their potential life spans absent predation are too long to be experimentally confirmed in any practical way. These species are so very different from higher animals with complex nervous systems that store data that it is quite possible there is little of practical use to medicine to be learned here. A blob of stem cells can continually regrow and replace all of its component parts, or change its shape and state of maturity as needed, whereas a vertebrate is more vulnerable, more locked in to its structure and the state of that structure. We might think that aging has the look of an inevitable consequence of having a nervous system that stores data, coming to rely on the structural state of that tissue, no longer being able to easily discard cells and replace them.

To date, the capacity of one life cycle stage to transform back to the preceding stage by morphological reorganization has been regarded as a distinctive and unparallelled feature of cnidarians. This ability for reverse development known for a few cnidarian species was first reported over a century ago and gained wide renown with the discovery of the peculiar life cycle of the so-called immortal jellyfish, Turritopsis dohrnii. This hydrozoan is currently considered the only animal able to repeatedly rejuvenate after sexual reproduction, challenging our understanding of aging and suggesting a potential for biological immortality.

Ctenophores (or comb jellies) are one of the oldest extant animal lineages. Accumulated evidence supporting their phylogenetic position as the sister group to all other animals place them as a pivotal model to study unique evolutionary innovations potentially rooted within the deepest branches of the animal tree of life. Here, we demonstrate that the ctenophore Mnemiopsis leidyi is capable of reversal from mature lobate to early cydippid when fed following a period of stress. Our findings illuminate central aspects of ctenophore development, ecology, and evolution and show the high potential of M. leidyi as a unique model system to study reverse development and rejuvenation.

Link: https://doi.org/10.1073/pnas.2411499121

The tricarboxylic acid (TCA) cycle is an important part of the process by which mitochondria generate chemical energy store molecules to power the cells. With age, mitochondrial function diminishes throughout the body. This produces disruption to cell and tissue function, particularly in energy-hungry tissues such as the brain and muscles. This loss of mitochondrial function is thought to be the consequence of some combination of damage to mitochondrial DNA and maladaptive changes in the expression of relevant genes, such as those coding for proteins necessary to mitochondrial energy production. For example, researchers here point out the reduced production of TCA cycle proteins in aged tissues, and note it as as a contribution to age-related mitochondrial dysfunction.

Aging is associated with a decline in physiological functions and an increased risk of metabolic disorders. The liver, a key organ in metabolism, undergoes significant changes during aging that can contribute to systemic metabolic dysfunction. This study investigates the expression of genes involved in the tricarboxylic acid (TCA) cycle, a critical pathway for energy production, in the aging liver. We analyzed RNA sequencing data from the Genotype-Tissue Expression (GTEx) project to assess age-related changes in gene expression in the human liver. To validate our findings, we conducted complementary studies in young and old mice, examining the expression of key TCA cycle genes using quantitative real-time PCR.

Our analysis of the GTEx dataset revealed a significant reduction in the expression of many genes that are critical for metabolism, including fat mass and obesity associated (FTO) and adiponectin receptor 1 (ADIPOR1). The most overrepresented pathway among the statistically enriched ones was the TCA cycle, with multiple genes exhibiting downregulation in older humans. This reduction was consistent with findings in aging mice, which also showed decreased expression of several TCA cycle genes. These results suggest a conserved pattern of age-related downregulation of TCA cycle, potentially leading to diminished mitochondrial function and energy production in the liver. The reduced expression of TCA cycle genes in the aging liver may contribute to metabolic dysfunction and increased susceptibility to age-related diseases. Understanding the molecular basis of these changes provides new insights into the aging process and highlights potential targets for interventions aimed at promoting healthy aging and preventing metabolic disorders.

Link: https://doi.org/10.1016/j.bbrc.2024.150917

The enormous cost of medical regulation ensures that natural compounds that may be useful receive little rigorous attention in the form of clinical trials and correspondingly little adoption in the mainstream medical community. Since the use of these compounds cannot be patented in a way that prevents competition, companies focused on these compounds cannot become valuable enough to raise the funding needed to conduct extensive development and formal clinical trials. Thus little tends to be known in certain about even quite widely used natural compounds, far less than is known about the average small molecule drug.

We can see these incentives at work in the case of the senolytic flavonoid fisetin; despite the existence of animal data suggesting it to be as good at clearing senescent cells from aged tissues as the combination of dasatinib and quercetin, we still don't know if it works in the same way in humans, what the optimal dose might be, how delivery is best improved given its low bioavailability, and so forth. No-one is putting significant funds into answering any of those questions, and it is unlikely that anyone ever will. What does tend to happen, as illustrated by today's open access research, is that groups attempt the slow process of producing patentable variants of the molecule in question and move ahead with those into the regulatory system.

Development of novel flavonoid senolytics through phenotypic drug screening and drug design

Accumulation of senescent cells drives aging and age-related diseases. Senolytics, which selectively kill senescent cells, offer a promising approach for treating many age-related diseases. Using a senescent cell-based phenotypic drug discovery approach that combines drug screening and drug design, we developed two novel flavonoid senolytics, SR29384 and SR31133, derived from the senolytic fisetin. These compounds demonstrated enhanced senolytic activities, effectively eliminating multiple senescent cell types, reducing tissue senescence in vivo, and extending healthspan in a mouse model of accelerated aging.

Mechanistic studies utilizing RNA-Seq, machine learning, network pharmacology, and computational simulation suggest that these novel flavonoid senolytics target PARP1, BCL-xL, and CDK2 to induce selective senescent cell death. This phenotype-based discovery of novel flavonoid senolytics, coupled with mechanistic insights, represents a key advancement in developing next-generation senolyticss with potential clinical applications in treating aging and age-related diseases.

The more visceral fat you have, and the longer you have it for, the worse off you are. Visceral fat contributes to chronic inflammation and metabolic dysfunction, accelerating the onset and progression of age-related conditions. This is well understood in the case of obesity, but even lesser degrees of being overweight are harmful to long-term health, as the data here illustrates.

Visceral fat tissue, interspersed with resident immune cells, when activated, increases local or systemic inflammation, leading to the production of cytokines and other immune and pro-inflammatory mediators, promoting insulin resistance, oxidative stress, and altered cell metabolism. Abdominal fat accumulation is associated with changes in glucose metabolism and lipid metabolism, primarily due to insulin resistance, resulting in hyperlipidemia, hypertension, glucose intolerance, and mitochondrial abnormalities in skeletal muscle.

An individual's leanness or corpulence is commonly assessed using the Body Mass Index (BMI), but this measure does not account for fat distribution or differentiate between fat and muscle mass. Therefore, clinicians have explored alternative anthropometric measurements that better reflect body composition and mortality risk, such as waist circumference (WC) and waist-to-hip and waist-to-height ratios. Most of these measures fail to reflect body composition effectively or are easily affected by variations in other body measurements. A new body shape index (A Body Shape Index, ABSI) has been introduced as an anthropometric measure unrelated to BMI, based on waist circumference adjusted for weight and height. ABSI offers a better explanation of how central abdominal adiposity is strongly associated with mortality than other anthropometric measurements, and it captures additional harmful effects not captured by BMI.

This prospective cohort study included 159 volunteers (94 women, aged 60-80 years), recruited in the frame of the "Physical Activity and Nutrition for Great Ageing" (PANGeA) Cross-border Cooperation Program Slovenia-Italy 2007-2013, and followed for 10 years. During the 10-year follow-up, 10 deaths (6.7%) were recorded. ABSI (adjusted for age, smoking, comorbidities, and therapy) was an independent predictor of mortality (hazard ratio = 4.65). Higher ABSI scores were linked to reduced VO2max (r = -0.190) and increased systolic blood pressure (r = 0.262). An ABSI-based predictive model showed strong discriminatory power, and thus ABSI is a reliable predictor of 10-year mortality in active, non-obese elderly individuals and may improve risk stratification in clinical practice.

Link: https://doi.org/10.3390/jcm13206155

Researchers can measure a great many facets of aging in the brain and elsewhere in the body, ranging across structural changes, gene expression changes, cell behavior changes, and so forth ad infinitum. The challenge lies in establishing cause and effect, and the relative importance of different possible mechanisms of damage and dysfunction. So, as researchers point out here, there is a compelling picture to be painted of the way in which the innate immune cells called microglia change in biochemistry and behavior in the aging brain, but no concrete certainty that these changes are the major contribution to neurodegenerative conditions that many researchers argue them to be. Inflammatory microglia may well be an important proximate cause of dysfunction in the brain, and a range of animal studies strongly suggest this to be the case, but as ever solid proof lags somewhat behind inference.

Microglia signatures refer to specific profiles of microglia activity or gene expression. Through a comprehensive analysis of gene and protein expression profiles, we can identify specific genes and proteins that characterize different states of microglial activation, including those associated with pro-inflammatory and anti-inflammatory states. This approach contributes to the knowledge base regarding the dynamics of microglial activation in both physiological and pathological conditions. The question of whether these signatures are a cause or a consequence of microglia-related brain disorders is highly relevant since understanding whether alterations in microglia are a primary cause of brain pathologies (e.g., neurodegenerative diseases such as Alzheimer's disease) or whether they are a secondary response to such pathologies can significantly influence therapeutic strategies.

Microglia can become hyperactive or dysfunctional, releasing inflammatory cytokines and neurotoxic factors that can damage neurons and the extracellular matrix. This may contribute to the pathogenesis of diseases such as Alzheimer's disease and Parkinson's disease. Microglia can have a proactive role in shaping the neuronal environment. If altered, they can negatively affect synaptogenesis, synaptic plasticity, and clearance of cellular debris, leading to brain dysfunction. Microglia interact closely with neurons, astrocytes, and other cell types in the brain. Alterations in these interactions caused by primary diseases may lead to changes in microglia signatures as an adaptive response, which could exacerbate the disease. Microglia may be activated in response to brain damage or other pathologies. In this scenario, alterations in their signatures could be a consequence of the presence of pathogens, abnormal protein deposits, or neuronal damage. In neurodegenerative disorders, neuroinflammation may be a secondary response to primary pathological processes. For example, in Alzheimer's disease, microglia may be activated by amyloid-β deposits.

The relationship between microglia signatures and brain disorders is likely to be bidirectional and dynamic. In some conditions, dysfunctional microglia may actively contribute to disease onset and progression (cause), while in other situations, they may represent an adaptive or maladaptive response to pre-existing damage or pathology (consequence). Understanding this complex interaction requires further research, including longitudinal studies and experimental models that can isolate the various factors involved. Unraveling these dynamics may lead to new and more effective therapeutic strategies for microglia-related brain diseases.

Link: https://doi.org/10.3390/ijms252010951

Here are two interesting points about the gut microbiome that have become clear in recent years: (a) the composition of the gut microbiome, the relative sizes of microbial populations, changes with age in ways that contribute to inflammation and tissue dysfunction throughout the body; and (b) it is possible to produce lasting change in the composition of the gut microbiome through either engineering of an immune response against target microbes or the procedure of fecal microbiota transplantation from a donor with a very different microbiome.

A simple example of the immune engineering approach is to inject small amounts of flagellin, the protein making up bacterial flagellae, to rouse the immune system into greater efforts to destroy anything it can find equipped with a flagellum. In the gut, most such bacteria are undesirable. Like fecal microbiota transplantation from a younger donor, the effects are unknowable in advance, generally in the direction of producing benefit, but these are not precision approaches to therapy. One can't yet engineer the exact gut microbiome one desires. Unfortunately strategies involving oral probiotics, which seem the most obvious path towards obtaining more of the specific microbes desired in the gut, have yet to advance to the point at which they are capable of producing lasting change; their effects are very transient.

As today's open access paper illustrates, the aged gut microbiome is clearly harmful. It is harmful in ways that even a young body and immune system cannot escape from. Just as fecal microbiota transplantation from young to old animals produces a lasting change to a young-looking microbiome in an old body and consequent benefits to health, the reverse produces a lasting change to an old-looking microbiome in a young body and consequent damage and dysfunction to tissues throughout the body. This is a good argument for replacement of the microbiome to be the primary thrust of development when it comes to finding ways to remove this aspect of aging. It seems unlikely that rousing the aged immune system is going to solve enough of the problem if a young immune system cannot wrestle an aged gut microbiome into shape.

Aged Gut Microbiome Induces Metabolic Impairment and Hallmarks of Vascular and Intestinal Aging in Young Mice

The aging vasculature is associated with endothelial dysfunction, arterial stiffness, increased oxidative stress and chronic inflammation, contributory to higher risks of cardiovascular diseases, such as heart failure and coronary artery disease. 'Dysbiosis' is considered as a new integrative hallmark of aging. During aging, the microbial composition in intestine varies that the homeostatic relationship between the host and gut microbiome deteriorates, contributory to altered immune and inflammatory responses in the elderly. Age-associated dysbiosis also increases the risks of various diseases, particularly cancers, cardiovascular diseases (CVDs), and diabetes, potentially through shift in intestinal microbial composition from providing benefits to causing chronic inflammation, and through alterations in the production of gut-derived substances to influence host nutrient-sensing pathways. However, the comprehensive mechanism of how age-related dysbiosis promotes other recognized hallmarks of aging remains elusive.

Of note, the vasculature serves as the first-line barrier vulnerable to the changes in gut microbiome due to close proximity between the intestine and blood circulation. Besides, the increased intestinal permeability, known as 'leaky gut', during aging further aggravates the vulnerability of vasculature towards dysbiosis. However, whether age-associated dysbiosis promotes host premature aging remains unclear. Previous studies showed that gut microbiome suppression by antibiotics ameliorates endothelial dysfunction in aged mice, and age-associated hyperproduction of harmful gut-derived metabolite (e.g., trimethylamine-N-oxide) drives endothelial dysfunction. It is therefore reasonable to hypothesize that age-associated dysbiosis shall promote vascular aging by triggering aging hallmarks in the vasculature, such as telomere attrition, endothelial dysfunction, and vascular inflammation and oxidative stress.

In this study, we performed fecal microbiome transfer (FMT) from aged to young mice to (i) study whether age-associated dysbiosis causes premature vascular and intestinal dysfunction; (ii) unveil whether such transfer changes the metabolic profiles; (iii) uncover microbiome alterations and underlying mechanism that are potentially critical; and (iv) identify potential interventions that might partially reverse age-related harmful effects. We demonstrated that age-associated dysbiosis, achieved by aged-to-young FMT, caused endothelial dysfunction, telomere dysfunction, inflammation, and oxidative stress in vascular tissues, partially reflective of premature vascular aging. Moreover, aged-to-young FMT also caused metabolic impairment and altered gut microbial profiles in young mice, along with disrupted intestinal integrity. Interestingly, aged-to-young FMT caused telomere dysfunction in both intestinal and aortic tissues. These findings highlight the harmful effects of aged microbiome on intestine and vasculature, providing important insight that gut-vascular connection represents a potential intervention target against age-related cardiometabolic complications.

Mifepristone is known to slow aging in flies. While mifepristone is not a drug that one should take to slow aging, as it has complex, sizeable effects on hormone levels that would tend to outweigh any benefits obtained, it is interesting to see that it has some of the same effects as rapamycin on life span and aspects of autophagy. Autophagy recycles damaged cell structures, and improved autophagy is a feature of many of the interventions known to slow aging in short-lived laboratory species, such as the flies used in this study. The researchers focused on measuring autophagy targeting mitochondria, known as mitophagy. Given the importance of mitochondrial dysfunction to aging, that is a reasonable choice. Nonetheless, it is hard to imagine much in the way of further research emerging based on the use of mifepristone or other near analog small molecules because of the effects on hormonal metabolism.

The drugs mifepristone and rapamycin were compared for their relative ability to increase the life span of mated female Drosophila melanogaster. Titration of rapamycin indicated an optimal concentration of approximately 50 μM, which increased median life span here by average +81%. Meta-analysis of previous mifepristone titrations indicated an optimal concentration of approximately 466 μM, which increased median life span here by average +114%. Combining mifepristone with various concentrations of rapamycin did not produce further increases in life span, and instead reduced life span relative to either drug alone.

Assay of maximum midgut diameter indicated that rapamycin was equally efficacious as mifepristone in reducing mating-induced midgut hypertrophy. The mito-QC mitophagy reporter is a previously described green fluorescent protein (GFP)-mCherry fusion protein targeted to the outer mitochondrial membrane. Inhibition of GFP fluorescence by the acidic environment of the autophagolysosome yields an increased red/green fluorescence ratio indicative of increased mitophagy. Creation of a multi-copy mito-QC reporter strain facilitated assay in live adult flies, as well as in dissected midgut tissue. Mifepristone was equally efficacious as rapamycin in activating the mito-QC mitophagy reporter in the adult female fat-body and midgut. The data suggest that mifepristone and rapamycin act through a common pathway to increase mated female Drosophila life span, and implicate increased mitophagy and decreased midgut hypertrophy in that pathway.

Link: https://doi.org/10.1080/19336934.2024.2419151

Researchers here report on an interesting mechanism by which the cell maintenance processes of autophagy are inhibited in the aging brain, in flies at least. Changes in the maintenance of the actin cytoskeleton inside a cell cause this reduction in autophagy, but can be blocked via small molecules in order to restore a more youthful function in brain tissue. In general, approaches to improve autophagy in aging tissue have been shown to produce a slowing of aging and improved function of aged tissues in short-lived species. From what we know of interventions such as exercise and calorie restriction, both of which improve autophagy, the effects on life span are not as large in long-lived species such as our own, even if some of the short term benefits are similar.

The actin cytoskeleton is a key determinant of cell structure and homeostasis. However, possible tissue-specific changes to actin dynamics during aging, notably brain aging, are not understood. Actin can be found in two forms: monomeric (G-actin) and filamentous (F-actin). Assembly and disassembly of actin filaments are regulated by a large number of actin-interacting proteins, making maintenance of the actin cytoskeleton highly susceptible to disruption caused by aging. Here, we show that there is an age-related increase in filamentous actin (F-actin) in Drosophila brains, which is counteracted by prolongevity interventions.

Critically, decreasing F-actin levels in aging neurons prevents age-onset cognitive decline and extends organismal healthspan. Mechanistically, we show that autophagy, a recycling process required for neuronal homeostasis, is disabled upon actin dysregulation in the aged brain. Remarkably, disrupting actin polymerization in aged animals with cytoskeletal drugs restores brain autophagy to youthful levels and reverses cellular hallmarks of brain aging. Finally, reducing F-actin levels in aging neurons slows brain aging and promotes healthspan in an autophagy-dependent manner. Our data identify excess actin polymerization as a hallmark of brain aging, which can be targeted to reverse brain aging phenotypes and prolong healthspan.

Link: https://doi.org/10.1038/s41467-024-53389-w

Bats are a popular choice in the study of the comparative biology of aging because there is considerable variation in life span between closely related species, a good place to start looking for specific genes that might be important in determining species differences in life span. Further, some bat species are particularly long-lived for their small size, which is again a place to start if seeking to understand how genetics determines life span. While some inroads have been made, these are still early days in the process of building a robust set of bridges between the islands represented by the present understanding of (a) genetics, (b) cell metabolism, and (c) aspects of aging. Much remains unknown.

As is the case for investigations of the biochemistry of naked mole-rats, elephants, and whales, some fraction of research into the genetics of long-lived bat species is motivated by their resistance to cancer. Cancer is a numbers game; either a greater number of cells or a given number of cells existing for a longer period of time implies an increased risk of cancerous mutation. Larger species and long-lived species can only be large or long-lived because they have evolved means of cancer suppression that do not exist in their smaller or short-lived relatives. Will study of the comparative biology of aging find mechanisms that can be used to produce therapies to treat and prevent cancer in humans in the near future? At this point it is too early to tell whether discoveries will be amenable to therapeutic development in this way, but this is the hope.

Extensive longevity and DNA virus-driven adaptation in nearctic Myotis bats

Bats are widely known for their long lifespan, cancer resistance, and viral tolerance. As highly complex and pleiotropic processes, the genes and mechanisms underlying these phenotypes can be challenging to identify. Here we outline an approach that enables functional comparative biology by generating cell lines from wing punches of wild caught bats for genome assembly, comparative genomics, and functional follow up. Cell lines are generated from minimally-invasive biopsies collected in the field thus avoiding disturbing natural populations. Given the high density of bat species concentrated at single locations world-wide, it is feasible to collect wing punches from a large number of individuals across a wide phylogenetic range; these wing punches can be used to generate cell lines and sequencing libraries for reference genomes in a matter of weeks.

By explicitly modeling the evolution of lifespan separately from body size, we recapitulate the extant relationship between body size and lifespan across mammals in evolutionary time. Contrary to prior work, we show that overall bats exhibit allometric lifespan scaling, comparable to other mammals. However, two bat clades - Myotis and Phyllostomidae - exhibit distinct trends with Myotis demonstrating an increased rate of change in lifespan given body size compared to other mammals. This altered scaling of longevity in Myotis has dramatic consequences for their intrinsic, per-cell cancer risk and for the evolution of tumor-suppressor genes and pathways.

We found a number of genes under selection across multiple longevity-associated pathways, consistent with the pleiotropic nature of the aging process. These include members of canonical longevity pathways such as mTOR-IGF signaling, DNA damage repair, oxidative stress, and the senescence-associated secretory phenotype. We additionally identified selection in various pathways that have likely emerged as a result of the unique biology of bats, including genes at the intersection of immunity and senescence, such as Serpin-family genes; genes in metabolic pathways including amino acid metabolism; and pervasive selection observed in the ferroptosis pathway, which sits at the intersection of bats' extreme oxidative challenges, metabolic demands, immune function, and cancer resistance.

By quantifying the relative contributions of genes under selection to cancer-related pathways at each node, we found significant enrichment of these processes across the phylogeny, especially at nodes undergoing the greatest changes in lifespan and cancer risk. While cancer risk scales linearly with body size, it scales over time as a power law of 6. Unlike other systems where the evolution of cancer resistance has been driven by rapid changes in body size, the body size of Myotis has not significantly changed since their common ancestor. Instead, the rapid and repeated changes in lifespan across an order of magnitude in Myotis lead to some of the most significant changes in intrinsic cancer risk seen across mammals.

While no reports or studies of neoplasia rates have been published in Myotis, the use of in vitro models of carcinogenesis provides a promising avenue for comparative studies of cancer resistance under controlled conditions. In agreement with our results, in vitro and xenograft transplant models have shown that cells of long-lived bats, including M. lucifugus, are more resistant to carcinogenesis than shorter-lived bats and other mammals.

Efforts to produce therapies based on cellular reprogramming aim to restore cell function without changing cell state. The original reprogramming research involved the production of induced pluripotent stem cells from somatic cells via expression of the Yamanaka factors, recapturing a process that takes place in early embryonic development. Since then, researchers have found that transient, partial reprogramming can restore youthful epigenetic patterns and behaviors in aged cells without the change of state, and the question is now how to constrain this partial reprogramming activity in a useful way in a living organism. A perhaps surprisingly large fraction of the work currently taking place on cellular reprogramming is aimed at the brain and nervous system. As an example of this sort of work, researchers here show that expression of the Yamanaka factors in the adult mouse hippocampus is protective against the pathology induced in a mouse model of Alzheimer's disease.

Yamanaka factors (YFs) can reverse some aging features in mammalian tissues, but their effects on the brain remain largely unexplored. Here, we employed a controlled spatiotemporal induction of YFs in the mouse brain across two distinct scenarios: during brain development and in adult stages within the context of neurodegeneration. Our focus on the impact of YFs on neurogenesis during development was influenced by recent findings that a subset of these factors is expressed in various neural progenitors early in this phase.

Here, we report that transient, low-level expression of YFs increased proliferation, resulting in an augmented output of neurons and glia, which led to an enlarged neocortex. This expansion was functionally reflected in enhanced motor and social behavior in adult mice. Because this induction protocol enhanced cognitive skills, we hypothesized that it could exert a similar effect in the context of a neurodegenerative disorder. Thus, we expressed YFs only in mature hippocampal neurons, using the 5xFAD mouse model of Alzheimer's disease. We show that these neurons tolerate intermittent YF expression while preserving their identity. This safe approach led to cognitive, molecular, and histological improvements in the 5xFAD mice.

Our results establish transient YF induction as a powerful tool for modulating neural proliferation, and it may open new therapeutic strategies for brain disorders.

Link: https://doi.org/10.1016/j.stem.2024.09.013

The SENS Research Foundation staff here continue their series of posts on the problems with studies of metformin as a potential means to modestly slow aging. Taken as a whole, the animal data for metformin is dismal, and the human data often touted as a rationale for use of metformin is problematic. If one feels motivated to make use a small molecule drug that may act to modestly slow aging, and which has extensive existing safety data for human use in other contexts, then look to rapamycin instead, where the animal data is robust.

Serious scientists have championed the diabetes drug metformin as a potential longevity therapeutic for more than two decades, but more careful scientific testing of the hypothesis over the last ten years has soured many critical thinkers on this use of the drug. Notable evidence against the idea include that metformin failed to extend lifespan in rodents in the National Institute on Aging (NIA)'s Interventions Testing Program and other well-done lifespan studies, and the debunking of the human epidemiological study that appeared to show that people with diabetes who took metformin lived longer than nondiabetics who didn't.

But interest was rekindled by a new study of metformin in aging cynomolgus monkeys. The authors claim to have shown that metformin preserved brain structure, "enhanced" cognitive function, and slowed biological aging by more than six years after less than three and a half years of treatment, as measured on a new species-specific aging clock. So like gamblers who have lost their shirt but can't stop themselves from playing, the conviction that this time it's different has set into the longevity community.

The monkeys in the metformin trial began the study at a body mass index (BMI) of 28, which is in the "overweight" category, and remarkably, the control animals ballooned to BMI 32 (obese) just three months later. By contrast, the monkeys on metformin remained 3 to 5 BMI points lighter than the controls through most of the experiment, up until the control animals began their late-life decline. That's a quite profound weight-protective effect, comparable to the new GLP-1 receptor agonist drugs.

So the first two interrelated problems with the study are that the control animals were obese throughout almost the entire study and that metformin had such a profound protective effect against weight gain in these animals. Why would metformin have made these monkeys so much lighter than their untreated labmates? Metformin is known to cause modest weight loss in humans, especially when it is "enhanced" by common side effects like indigestion or diarrhea. But the weight-buffering effect in these monkeys is much greater than you'll typically see in humans on the drug. Whatever the mechanism, the protective effect against the substantial weight gain seen in the control animals seems highly likely to be responsible for much or all of the benefits in the metformin-treated monkeys, for reasons that have nothing to do with a direct effect on aging processes.

Link: https://www.sens.org/monkeying-with-clocks-metformin/