Fight Aging!

A number of groups have demonstrated that selectively exposing aged rodent tissues to expression of the Yamanaka factors - OCT4, SOX2, KLF4, and MYC (collectively OSKM) - can induce restoration of more youthful epigenetic patterns and gene expression, accompanied by restoration of tissue function. The Yamanaka factors were first explored as a way to replicate the process by which adult germline cells become embryonic stem cells at the outset of embryogenesis, leading to the now well established capacity to produce what are known as induced pluripotent stem cells from somatic cell samples. Importantly, this process doesn't just lead over time to a radical alteration of cell fate, but also quite rapidly rejuvenates epigenetic regulation of gene expression.

As noted in today's open access paper, one can't just apply Yamanaka factors globally to obtain a good outcome. Some tissues react poorly. Thus researchers have focused initially on a few use cases in which it seems likely that there is a path to therapies at the end of the day, many of which are focused on neural tissue. That said, the work here involves direct injection of gene therapy vectors to specific areas of the brain, and thus is at the very least a lengthy delivery technology research and development program away from adoption. The primary challenge in the development of gene therapy is how to obtain selective delivery to specific areas of the body when direct injection is infeasible, expensive, or risky. There is no clear path ahead at this time for many of the relatively small and deeply internal tissues.

Cognitive rejuvenation in old rats by hippocampal OSKM gene therapy

At the molecular level, gene expression studies in aging rodents have documented significant changes in hippocampal genes related to cholesterol synthesis, inflammation, transcription factors, neurogenesis, and synaptic plasticity. In the hippocampus of female rats, 210 genes have been reported to be differentially expressed in aged individuals compared to their young counterparts, with the majority being downregulated.

Yamanaka genes, along with other pluripotency genes, possess high therapeutic potential for treating the aged central nervous system affected by various neurodegenerative diseases. Recent results revealed that the Yamanaka genes display a dual behavior when expressed continuously in vivo, being regenerative when delivered via viral vectors but highly toxic when expressed in transgenic mice. Thus, it has been reported that delivery of the OSK genes by intravitreally injecting a regulatable adeno-associated viral vector type 2 (AAV2) expressing the polycistron OSK can reverse vision deficits in an experimental model of glaucoma in mice as well as in 11 months old mice showing age-related vison impairment. Fifteen months of continuous expression of the OSK genes in retinal ganglion cells (RGCs) induced neither pathological changes nor proliferation of RGCs. Young- and middle-aged mice injected intravenously with OSK-AAV2 for 15 months did not exhibit any adverse side effects. In contrast, DOX-induced expression of OSK genes in mice transgenic for OSK resulted in rapid weight loss and death, likely due to severe dysplasia in the digestive system.

Administering an adenovector to the hypothalamus of young female rats, which carries both the OSKM transcription factors and the green fluorescent protein (GFP) marker, has not only significantly decelerated the pace of reproductive aging but also tripled the fertility rates in 9-month-old females compared to those receiving a placebo vector. Notably, at 9 months of age, female rats are approaching the age of ovulatory cessation, which typically occurs at around 10 months. Inspired by the pioneering results achieved by a team employing OSK gene therapy in the retina of mice, we decided to conduct a medium-term 39-day OSKM gene therapy trial in another brain region: the hippocampus of aged rats. The main goal was to restore learning and spatial memory performance in this animal model. For comparison, we used control groups of similarly aged rats injected with a placebo adenovector.

The Barnes maze test, used to assess cognitive performance, demonstrated enhanced cognitive abilities in old rats treated with OSKM compared to old control animals. In the treated old rats, there was a noticeable trend towards improved spatial memory relative to the old controls. Further, OSKM gene expression did not lead to any pathological alterations within the 39 days. Analysis of DNA methylation following OSKM treatment yielded three insights. First, epigenetic clocks for rats suggested a marginally significant epigenetic rejuvenation. Second, chromatin state analysis revealed that OSKM treatment rejuvenated the methylome of the hippocampus. Third, an epigenome-wide association analysis indicated that OSKM expression in the hippocampus of old rats partially reversed the age-related increase in methylation.

Rapamycin is arguably the best of the calorie restriction mimetic drugs so far tested in mice. It slows aging robustly in animal studies, and has been used in humans at much higher doses than the anti-aging dose (around 5mg once per week) for decades. Still, there is a lack of human trials conducted for the purposes of slowing aspects of aging. More trial data than the little that presently exists would increase the number of physicians willing to prescribe off-label for anti-aging purposes. The specific focus of the trial doesn't much matter so long as the researchers measure enough data to assemble biomarkers of aging and general health. So, for example, one might look at a recently launched study of gum disease in older patients, and the study noted here that is focused on ovarian aging. Both have the potential to produce data relevant to the general question of aging. There are a few more such studies beside these, either planned or in the early stages.

Research into repurposing the immunosuppressant rapamycin has been hailed a "paradigm shift" in how menopause is studied. The Validating Benefits of Rapamycin for Reproductive Aging Treatment (Vibrant) study is designed to measure whether the drug can slow ovaries ageing, thereby delaying menopause, extending fertility and reducing the risk of age-related diseases. The study, which will eventually include more than 1,000 women, now has 34 participants aged up to 35, with more women joining every day.

Early results suggested it was realistic to hope the drug could decrease ovary ageing by 20% without women experiencing any of the 44 side-effects rapamycin can have, which range from mild nausea and headaches to high blood pressure and infections. In fact, participants in the randomised, placebo-controlled study had self-reported improvements in their health, memory, energy levels and in the quality of their skin and hair: health improvements consistent with other studies into rapamycin.

Ovaries release eggs continuously: women lose about 50 every month, with just one reaching ovulation. A small, weekly dose of rapamycin slows ovaries down, so they release only 15 eggs a month. Because rapamycin is a cheap, generic drug already widely used, once the evidence is established, progress will be fast. "The very features of the drug that make it so promising and give it such great potential for having a quick and major impact for women are, ironically, the very factors that make it hard to find funders for the study. That's why this hasn't been done before: it's an expensive study and a lot of women will benefit from it - but there's no motivation for pharmaceutical companies to invest because there's no possibility of making money from an off-patent drug."

A clinical trial of rapamycin in humans has also been considered impossible because it would take decades to detect any longevity effects. Ovaries, however, age so quickly that change can be measured over six months. The level of rapamycin used is small: women are given 5mg a week for three months compared with the 13mg a day that transplant patients can be prescribed for years.

Link: https://www.theguardian.com/society/article/2024/jul/22/drug-women-fertility-study-rapamycin

The gut microbiome influences long-term health. The balance of microbial populations shifts with age to become more harmful, certainly more inflammatory. While it is possible to produce sizable benefits to health via rejuvenation of the aged gut microbiome with simple approaches, such as fecal microbiota transplantation using a young donor, the future will clearly involve more of the application of biotechnology to the problem. If one can produce lasting change in the composition of the gut microbiome by delivering microbes in sufficient quantity, then why not deliver engineered versions of existing gut microbes that are altered to produce less inflammatory signaling or more beneficial metabolites?

Microbiome research is now demonstrating a growing number of bacterial strains and genes that affect our health. Although CRISPR-derived tools have shown great success in editing disease-driving genes in human cells, we currently lack the tools to achieve comparable success for bacterial targets in situ. Here we engineer a phage-derived particle to deliver a base editor and modify Escherichia coli colonizing the mouse gut. Editing of a β-lactamase gene in a model E. coli strain resulted in a median editing efficiency of 93% of the target bacterial population with a single dose. Edited bacteria were stably maintained in the mouse gut for at least 42 days following treatment.

This was achieved using a non-replicative DNA vector, preventing maintenance and dissemination of the payload. We then leveraged this approach to edit several genes of therapeutic relevance in E. coli and Klebsiella pneumoniae strains in vitro and demonstrate in situ editing of a gene involved in the production of curli in a pathogenic E. coli strain. Our work demonstrates the feasibility of modifying bacteria directly in the gut, offering a new avenue to investigate the function of bacterial genes and opening the door to the design of new microbiome-targeted therapies.

Link: https://doi.org/10.1038/s41586-024-07681-w

It has been a question for some time as to whether immune cells expressing p16 and β-galactosidase, markers of cellular senescence, are in fact all or even majority senescent. Macrophages, for example, can certainly express these proteins without entering a senescent state. Some assays of cellular senescence and associations with disease published in past years are thus likely reflective of both (a) the burden of senescence, but also (b) other responses to aging or processes of aging taking place in immune cell populations, particularly those resident in tissues.

With that in mind, today's open access paper is an interesting exploration of what exactly it is that these maybe-senescent p16 and β-galactosidase expressing immune cells might be doing in the aged body. The authors draw in the concept of disease tolerance, which might be thought of as covering all of the ways in which cells might act, individually or in collaboration, to reduce the impact of infectious disease without killing the pathogens involved. It is not what one might think of the immune system being involved in, but nonetheless, that may be an evolved role for p16 and β-galactosidase expressing immune cells.

Does this mean that it is a bad idea to clear a large fraction of the p16-expressing or β-galactosidase-expressing cells in the body? Probably not, provided one restricts clearance to a short period of time, and avoids doing it while the patient is infected or injured. It has always been known that senescent cells do have useful roles when present for the short-term, including wound healing, suppression of potentially cancerous cells, and so forth. The problem in aging is that there are too many lingering senescent cells, to the point at which any benefit is buried by the downside of constant pro-inflammatory signaling. Getting rid of the excess in a short period of time should allow the useful processes to pick up again.

p16High immune cell - controlled disease tolerance as a broad defense and healthspan extending strategy

Substantial experimental evidence suggests that the accumulation of senescent cells is an important factor in age-related tissue deterioration as it is associated with the production of different molecules capable of restructuring the extracellular matrix, modifying the behavior of neighboring cells and systemically affecting the activity of the immune system. Despite these deleterious functions of senescent cells in the aging process, accumulating evidence supports cellular heterogeneity among p16High cells with some mediating important homeostatic functions that have been identified during embryonic development as well as in adult skin, liver and lung. This suggests that depending on the context, p16High senescent cells could be either beneficial or detrimental. What defines either group remains however largely unknown.

The development of different genetic mouse models is now facilitating the further identification and characterization of p16High cells in vivo. Among the different p16High subtypes, cells of the immune system, including T cells and macrophages, have been identified and further analysis revealed that some express additional markers of senescence such as enhanced senescence-associated β-galactosidase (SA-β-gal) activity and DNA damage. Furthermore, the frequency of such cells increases significantly in animals during natural and accelerated aging, which may highlights their potential importance. On the other hand, a modest or even transient activation of p16, as well as excessive lysosomal activity (and thus higher SA-β-gal activity) in phagocytic cells such as macrophages has been observed under different conditions. Whether such activation indeed reflects classical pathways of senescence activation is unclear.

In our current study, we used a genetic mouse model to trace cells with high expression of p16 in vivo. We found that the p16High program was activated during aging not only in long-lived macrophages and T cells, but in all the immune subsets analyzed. Our detailed analysis of T cells and tissue-resident macrophages as well as the use of a genetic model for selective ablation of p16High cells, allowed us to determine that p16High immune cells play an important regulatory functions in vivo. These functions were further critical for animal survival after severe inflammation and tissue damage. While the ability of an organism to overcome infectious diseases has traditionally been linked to killing invading pathogens, evidence indicates that, apart from restricting pathogen loads, organismal survival is coupled to an additional yet poorly understood mechanism called disease tolerance. Here we argue that induction of p16High immune cells is a key mechanism in establishing disease tolerance.

Ever-shifting epigenetic marks on the genome determine its structure in the cell nucleus, and thus which portions of the genome are accessible to the machinery of gene expression, and thus which proteins are produced at a given time. This epigenetic regulation of gene expression changes in characteristic ways with age, and many of those alterations are clearly maladaptive. Hence the present interest in epigenetic reprogramming, in which researchers adapt some of the processes that take place during embryonic development in order to restore a youthful epigenetic state to adult cells. It is very much a work in progress, but early results in animal studies are promising.

Neurons undergo pronounced alterations in morphology and function throughout the lifespan, and these have been related to disturbed neuronal signaling and impaired information processing in the aged brain. The function of different neuron types in multiple brain areas is affected by aging, with the hippocampus and prefrontal cortex - both brain regions with key roles in memory storage and cognitive flexibility - being particularly compromised.

Since neurons are post-mitotic and mostly generated during early development, they represent one of the oldest cell types in the body. Therefore, to preserve their function throughout life, neurons are dependent on the long-term maintenance of molecular programs that define their neuronal identity and enable activity-induced plasticity in response to environmental cues. Yet, multiple studies have reported impairments in neuron-specific gene expression programs in the aging brain, including alterations in transcription, RNA processing, and protein levels, which have been linked to neuronal dysfunction. The long-term maintenance of neuronal gene expression programs critically depends on the epigenetic machinery, and accumulating evidence suggests impairments of epigenetic regulation as cell-intrinsic drivers of aging in neurons.

Intriguingly, recent studies suggest that neuronal epigenetic aging can be slowed down or reversed by rejuvenating interventions that are known to counteract age-related impairments in brain function, thus opening the field for therapeutic anti-aging strategies. Interventions shown to be effective include changes to lifestyle (such as exercise, environmental enrichment, and caloric restriction), the transfer of young blood factors or cellular reprogramming, among others. The malleability of the neuronal epigenome during aging suggests that it can be targeted to prevent epigenetic aging or even restore a youthful epigenetic state in aged neurons.

Link: https://doi.org/10.1038/s44318-024-00148-8

The influence of the gut microbiome on the long-term trajectory of health is a popular topic these days. Tools for assessing the microbial composition of the gut microbiome are accurate and cost little, and variance in the relative sizes of microbial populations between individuals and across a life span are increasingly correlated with effects on health, disease, and the pace of aging. Of particular interest are the ways in which the gut microbiome may be affecting the operation of the brain, such as via the generation of harmful inflammatory signaling, or the production of metabolites such as butyrate that can influence neurogenesis. Here, researchers focus specifically on connections between the gut microbiome and the supporting astrocyte cells of the brain, known to become dysfunction with age.

As the most abundant type of glial cells, astrocytes perform significant functions in neural activity regulation, synapse formation, neural metabolism, and blood-brain barrier (BBB) integrity and, therefore, maintain the normal physiological functions of the central nervous system (CNS). With continuous advancements in research, the roles of astrocytes in aging and neurodegenerative diseases (NDs) have started to receive scientific attention. There is a loss of morphological structure in star-shaped astrocytes with brain aging that can lead to a decline in their functionality, such as reduced astrocytic synaptic coverage, fewer aquaporin 4 (AQP4) channels expressed in astroglial end-feet followed by decreased lymphatic clearance, compromised BBB integrity, inadequate clearance of glutamate and potassium ions, and impaired energy metabolism. Additionally, with advancing age, and in the context of NDs, reactive astrocytes and aged astrocytes gradually accumulate, triggering neuroinflammation and having detrimental impacts on the tissue microenvironment, and ultimately leading to age-related cognitive decline.

Over the past decade, the roles of the intestinal microbiota in regulating the gut-brain axis and its involvement in the pathophysiology of brain aging have become increasingly emphasized. A previous study has shown that the gut microbiota is an important upstream factor in astrocyte activation, which is closely associated with neuroinflammation and neurodegeneration. Thus, a deeper comprehension of the roles and mechanisms of the gut microbiota-astrocyte axis in age-related cognitive decline is becoming ever more necessary and meaningful. This review aims to elucidate and summarize the unique changes to gut microbiomes seen during the process of aging, alterations in the shape and function of astrocytes within the aging brain, and potential mechanisms, such as the vagus nerve, immune responses, the circadian rhythm, and microbial metabolites, by which gut microbiomes influence cognitive function by impacting CNS astrocyte activity. In this way, we aim to provide new insights into therapeutic avenues for age-related cognitive decline.

Link: https://doi.org/10.4103/NRR.NRR-D-23-01776

Polyadenylation occurs during the creation of messenger RNA (mRNA). It is one part of the complex processes of transcription of the DNA sequence for a gene and assembly of the resulting RNA molecule. In the polyadenylation process, a tail of repeated adenine bases - called the poly(A) tail - is appended to the mRNA molecule. This protects the mRNA from degradation once it has left the nucleus, and also helps in other ways with the process of translation, in which the mRNA molecule is used as a blueprint by a ribosome to assemble protein molecules from amino acids. Changes in the length of the mRNA tail will affect levels of protein production, and thus the behavior of cells.

In today's open access paper, researchers report on their efforts to discover novel age-related changes in the nematode worm species Caenorhabditis elegans via extensive single cell sequencing of the transcriptome. This led them to uncover differences in the polyadenylation process (a) over the course of aging, and (b) between short-lived and long-lived nematode lineages. This age-related change in polyadenylation acts to reduce the pace of production of many proteins, which likely has many complex downstream effects, while longer-lived nematodes are somewhat resistant to this change in polyadenylation. Can this be dysfunction be rescued by a comparatively simple set of changes? Perhaps, as polyadenylation is regulated by a proteins that might be upregulated or downregulated, but it is likely a lengthy road from here to that sort of intervention.

Aging atlas reveals cell-type-specific effects of pro-longevity strategies

Although multiple pro-longevity strategies have been discovered in multicellular organisms ranging from Caenorhabditis elegans to mice, whether and how these strategies slow aging of different tissues in distinct manners are yet to be determined. In recent years, single-cell and single-nucleus RNA sequencing (scRNA-seq and snRNA-seq) have proven to be effective ways to systemically profile transcriptomes at single-cell resolution and have facilitated the discovery of cell-type-specific transcriptomic signatures in different tissues.

In this study, we used snRNA-seq transcriptomic profiling of different somatic cell and germ cell types to build an adult cell atlas. Using snRNA-seq data from wild-type (WT) adults at different ages, we generated tissue-specific transcriptomic aging clocks as well as germ cell differentiation trajectory maps to assess how aging affects the function of different cell types. We also revealed age-associated, tissue-specific transcriptomic changes associated with three different pro-longevity mechanisms. Furthermore, we profiled pre-mRNA alternative polyadenylation (APA) at the genome level in different cell types at different ages and systemically discovered APA events with tissue-specific patterns and how age-associated APA changes in different tissues are attenuated by those pro-longevity mechanisms.

APA plays a crucial role in the control of mRNA metabolism, gene regulation and protein diversification51. Our study provides, to our knowledge, the first systematic profiling of APA changes at the whole transcriptome level. Interestingly, APA events exhibit tissue-specific distribution, undergo significant changes during aging and can be differentially regulated by different pro-longevity mechanisms. We discovered that, during aging, all cell types shift their APA preference toward the distal site, and this shifted preference is suppressed in the long-lived strains. Previous studies revealed that the usage of the distal APA site is inversely correlated with the level of core polyadenylation factors.

Additionally, the increased usage of distal APA sites may lead to longer 3′ UTRs, which are associated with mRNA instability. Based on our findings, we speculate that, with aging, the level of core polyadenylation factors may decrease and the length of 3′ UTRs may increase, potentially resulting in declines in translational efficiency. Thus, suppressing the distal APA usage in the long-lived strains may help improve protein outputs, contributing to their longevity effects.

Researchers here conduct a meta-analysis of systemic reviews of dementia incidence over time. The results indicate that the risk of dementia is decreasing. The authors suggest that the reduction in the prevalence of smoking in recent decades is a major factor. That in turn tends to reinforce the consensus on the relationship between cardiovascular disease and neurodegenerative disease, that declining cardiovascular health strongly influences the risk of dementia.

Some cohort studies have reported a decline in dementia prevalence and incidence over time, although these findings have not been consistent across studies. We reviewed evidence on changes in dementia prevalence and incidence over time using published population-based cohort studies that had used consistent methods with each wave and aimed to quantify associated changes in risk factors over time using population attributable fractions (PAFs).

We identified 1,925 records in our initial search, of which five eligible systematic reviews were identified. Within these systematic reviews, we identified 71 potentially eligible primary papers, of which 27 were included in our analysis. 13 (48%) of 27 primary papers reported change in prevalence of dementia, ten (37%) reported change in incidence of dementia, and four (15%) reported change in both incidence and prevalence of dementia. Studies reporting change in dementia incidence over time in Europe (n=5) and the USA (n=5) consistently reported a declining incidence in dementia. One study from Japan reported an increase in dementia prevalence and incidence and a stable incidence was reported in one study from Nigeria.

Overall, across studies, the PAFs for less education or smoking, or both, generally declined over time, whereas PAFs for obesity, hypertension, and diabetes generally increased. The decrease in PAFs for less education and smoking was associated with a decline in the incidence of dementia in the Framingham study (Framingham, MA, USA, 1997-2013), the only study with sufficient data to allow analysis.

Link: https://doi.org/10.1016/S2468-2667(24)00120-8

The characteristic loss of muscle mass and strength that occurs with age leads to sarcopenia and frailty. While a few companies are targeting this age-related muscle loss via development of small molecule drugs, the recent history of this part of the field is not encouraging. None of the attempted approaches have yet improved on exercise. That may well be due to a failure to specifically target underlying mechanisms that drive degenerative aging, projects instead relying on the sort of adjustments to metabolism that are discussed in the paper referenced here, but only time will tell.

A healthy lifespan relies on independent living, in which active skeletal muscle is a critical element. The cost of not recognizing and acting earlier on unhealthy or aging muscle could be detrimental, since muscular weakness is inversely associated with all-cause mortality. Sarcopenia is characterized by a decline in skeletal muscle mass and strength and is associated with aging. Exercise is the only effective therapy to delay sarcopenia development and improve muscle health in older adults. Although numerous interventions have been proposed to reduce sarcopenia, none has yet succeeded in clinical trials. This review evaluates the biological gap between recent clinical trials targeting sarcopenia and the preclinical studies on which they are based, and suggests an alternative approach to bridge the discrepancy.

The use of hormone replacement and myostatin-based therapies in clinical trials - aimed at promoting muscle hypertrophy - has not resulted in notable advancements in muscle strength or functional performance. The decline in sex hormones that occurs with aging is closely tied to the development of sarcopenia. However, the potential adverse effects of sex hormone replacement therapy outweigh its modest advantages in mitigating muscle aging. There is no conclusive association between circulating myostatin level and muscle aging, and myostatin-based therapy does not affect muscle aging.

While effective in promoting muscle growth, hypertrophic signaling compromises muscle protein quality control, exacerbating age-related muscle dysfunction. An alternative intervention to refine mechanistic target of rapamycin (mTOR) functions is proposed to benefit muscle health in the elderly. Both hormone replacement and myostatin-based therapies stimulate muscle growth by activating mTORC1, which controls growth by responding to nutrient availability and should be active only when nutrients are present. Yet chronic activation of mTORC1 in skeletal muscle accelerates sarcopenia development in mice. The crucial question is whether the interventions focused on increasing muscle size through mTORC1 will truly be beneficial in addressing muscle aging in humans, given that mTORC1 insensitivity is frequently seen in aged individuals

Link: https://doi.org/10.1016/j.molmed.2024.05.016

Adoptive cell therapies involve introducing immune cells to attack a specific issue in the body, most often cancer. The earliest forms of adoptive cell therapy used immune cells from another individual, but more modern approaches use a patient's own cells, expanded in culture and potentially engineered in various ways. Think of chimeric antigen receptor T cell (CAR-T) therapies, for example. Both T cells and natural killer (NK) cells have been employed as a basis for adoptive cell therapies targeted at cancer.

In today's open access paper, researchers consider another potential use for adoptive NK cell therapy, as a way to produce lasting clearance of senescent cells in aged tissues. It is clear that NK cells, along with several other immune cell types, are involved in the normal processes of destruction of senescent cells as they show up in the body. Unfortunately, this immune mediated clearance of senescent cells slows down with advancing age, allowing the build up of lingering senescent cells throughout the body. Senescent cells produce signaling that is useful under various circumstances, such as suppression of potentially cancerous damage and coordination in wound healing, but when sustained for the long term becomes highly disruptive to tissue structure and function.

Researchers have already demonstrated that CAR-T therapies can be adapted to target senescent cells. It is plausible that NK cell therapies can also serve this purpose. The question is whether the cost is worth it, when other forms of senolytic therapy that are capable of training the immune system to more aggressively attack senescent cells, including the Deciduous Therapeutics approach, are far cheaper. The primary issue with adoptive cell therapies at the present time is their high cost, an unavoidable outcome of any therapy that requires weeks or months of effort to grow, engineer, and quality control large numbers of cells from a patient sample. That doesn't compete well with the need to treat every older individual on some intermittent, recurring basis.

Adoptive NK cell therapy: a potential revolutionary approach in longevity therapeutics

As the global population ages, the prevalence of associated diseases becomes increasingly apparent. The pursuit of healthy aging, characterized by heightened resistance to lethal diseases, is the cornerstone of preventive medicine. The aging process is a complex process involving cellular senescence and inflammation, with the immune system playing a pivotal role in managing these aspects. Timely clearance of senescent cells (SNCs) is central to maintaining tissue and organismal homeostasis. Unfortunately, immunosenescence, a progressively dysregulated immune state with age, fails to eliminate SNCs, leading to their accumulation. This often coincides with the release of senescence-associated secretory phenotypes (SASPs), inhibiting immunity and increasing vulnerability to aging-associated diseases (AADs).

Consequently, targeting immunosenescence and SNCs emerges as a crucial therapeutic strategy to preserve and extend healthy aging. While adaptive immunity has traditionally taken center stage in immunogerontological studies, growing evidence underscores the substantial impact of innate immunity in AADs. Natural killer (NK) cells, integral to the innate immune system, uniquely identify and eliminate aberrant cells such as tumor cells and virus-infected cells. Moreover, NK cells promptly address SNCs, and coordinate with other immune components through cytokine and chemokine production to surveil and eliminate cancer cells. Although whether the same occurs against SNCs remains to be determined.

Evidence from healthy elderly individuals, especially those exhibiting physical fitness, independence in daily activities, or adequate cognitive function, the number and function of NK cells are highly preserved. Conversely, diminished NK cell activity in elderly individuals is associated with disorders such as atherosclerosis and an elevated risk of mortality. Accordingly, preserving NK cell function during aging is deemed crucial for healthy aging and longevity. Alternatively, NK-cell-based therapies, notably adoptive NK cell therapy, aligning with their established role in cancer and viral infection treatments, show promise in rejuvenating immunosenescence, eliminating SNCs and alleviating SASPs, that lead to AADs.

The practice of calorie restriction, reducing calorie intake by up to 40% while still obtaining a sufficient level of micronutrients necessary to good health, is well demonstrated to slow aging. It slows near all aspects of aging and progression of near all age-related conditions, and so the literature is packed with papers that investigate just one of those line items. Here, the focus is on loss of bone mineral density with age, a phenomenon that leads to osteoporosis and eventual fracture and incapacity. This is one of the few age-related conditions for which there is some debate over whether moderate or greater calorie restriction is a net benefit, based on apparently contradictory animal data. My impression of the literature, reinforced here, is that the weight of evidence leans towards calorie restriction as a benefit in this matter.

Caloric restriction (CR) is a nutritional intervention that increases life expectancy while lowering the risk for cardiometabolic disease. Its effects on bone health, however, remain controversial. For instance, CR has been linked to increased accumulation of bone marrow adipose tissue (BMAT) in long bones, a process thought to elicit detrimental effects on bone. Qualitative differences have been reported in BMAT in relation to its specific anatomical localization, subdividing it into physiological and potentially pathological BMAT. We here examine the local impact of CR on bone composition, microstructure, and its endocrine profile in the context of aging.

Young and aged male C57Bl6/J mice were subjected to CR for 8 weeks and compared to age-matched littermates with free food access. CR increased tibial BMAT accumulation and adipogenic gene expression. CR also resulted in elevated fatty acid desaturation in the proximal and mid-shaft regions of the tibia, thus more closely resembling the biochemical lipid profile of the distally located, physiological BMAT. In aged mice, CR attenuated trabecular bone loss, suggesting that CR may revert some aspects of age-related bone dysfunction. Cortical bone, however, was decreased in young mice on CR and remained reduced in aged mice, irrespective of dietary intervention. No negative effects of CR on bone regeneration were evident in either young or aged mice.

Our findings indicate that the timing of CR is critical and may exert detrimental effects on bone biology if administered during a phase of active skeletal growth. Conversely, CR exerts positive effects on trabecular bone structure in the context of aging, which occurs despite substantial accumulation of BMAT. These data suggest that the endocrine profile of BMAT, rather than its fatty acid composition, contributes to healthy bone maintenance in aged mice.

Link: https://doi.org/10.3389/fendo.2024.1394263

The measurement of life span is self-evident and obvious, but is little consensus on how to measure healthspan, the length of life spent in good health. Good health is like art, we know it when we see it, but that isn't helpful when trying to compare the effects of interventions where the studies were conducted by different researchers with different ideas as what constitutes good health in an older individual. This issue exists for both human and animal studies, and the lack of consistency makes it hard to make comparisons based on the existing literature on the topic. Researchers are starting to propose rigorous definitions of healthspan, but it seems that we stand some distance removed from any great agreement as to which of these definitions is the one to adopt as a standard.

Unlike lifespan, which has a universal definition, there is no consensus on the definition of healthspan. Previous research has suggested characterizing healthy aging in five domains: physical capability, cognitive function, physiological and musculoskeletal, endocrine, and immune functions. For practical purposes, healthspan typically refers to the period of life spent in good health, free from the chronic diseases and disabilities of aging. Studies aiming to evaluate the effects of interventions on healthspan are challenging due to the need for long follow-up lengths and large sample sizes of healthy individuals to observe the outcomes of interest. Thus, developing surrogate biomarkers that can predict healthspan is crucial for improving the feasibility of clinical trials to test interventions to prolong healthspan and lifespan.

Composite biomarkers incorporating multiple measures are more robust in predicting age-related outcomes than single biomarkers. Several composite biomarkers for predicting lifespan or mortality have been developed using clinical biomarkers or omics data. However, to date, no composite biomarker measures have been developed based on a healthspan definition. To mitigate this gap, we developed a proteomics-based healthspan biomarker (healthspan proteomic score, HPS) using chronological age and expression data of 2,920 proteins at the UK Biobank baseline/recruitment (2006-2010).

A lower HPS was associated with higher mortality risk and several age-related conditions, such as COPD, diabetes, heart failure, cancer, myocardial infarction, dementia, and stroke. HPS showed superior predictive accuracy for these outcomes compared to chronological age and biological age measures. Proteins associated with HPS were enriched in hallmark pathways such as immune response, inflammation, cellular signaling, and metabolic regulation. Our findings demonstrate the validity of HPS, making it a valuable tool for assessing healthspan and as a potential surrogate marker in geroscience-guided studies.

Link: https://doi.org/10.1101/2024.06.26.24309530

What are the biological mechanisms by which centenarians manage to reach 100 years of age or more, significantly outliving near all of their birth cohort peers? This is a question that receives a great deal of interest in the research community and among the public at large. The answer that aging is a stochastic process of damage accumulation that produces a distribution of outcomes, and that some people are lucky, is not very satisfying. So a sizable amount of funding is directed towards analysis of factors that might robustly contribution to the longevity of centenarians: cultural transmission of good practices in long-lived families, longevity-promoting genetic variants, and the topic for today, longevity-promoting variations in the composition of the gut microbiome.

Amidst all of this, it is perhaps worth considering whether finding out why centenarians are so long-lived is actually worth all of the effort. Centenarians are frail, a shadow of their younger selves, and exhibit a sizable mortality rate. Is this really a desirable state to aim for? The research community has a very good list of the causative processes of degenerative aging, the forms of molecular damage that accumulate in aged bodies to produce dysfunction. It requires exactly zero further knowledge of centenarian biochemistry to be able put a great deal of effort into the development of potential rejuvenation therapies that are capable of repairing this damage. The end result of successful, comprehensive rejuvenation via damage repair will not be people who are as damaged and frail as today's centenarians.

Gut microbiota in centenarians: A potential metabolic and aging regulator in the study of extreme longevity

Diverse factors have been associated with healthy or unhealthy aging such as demographic factors; prosociality level, physical and organic health status, mental health, lifestyle factors, and genetics. This converges in the concept of biological aging (BA), defined as the set of processes that cause organ deterioration over time. BA depends on the complex interaction of these factors, which can lead to a heterogeneous aging process across multiple organic systems, and correlate with a specific survival time and health or disease phenotype even in advanced ages. To deeply understand the mechanisms associated with aging and to identify potential targets for intervention to control or delay BA and the onset of diseases, it is necessary to study successful BA models. These models reflect phenotypes that are resistant to external stress factors with a favorable organic response. Centenarians, individuals with a chronological age (CA; defined as the number of years an individual has lived) equal to or greater than 100 years, constitute one such model of successful aging.

Currently, there is a significant knowledge gap from the translational perspective due to the evolutionary and exhaustive nature of aging research, which requires robust and reproducible omics studies on populations (specially in centenarians). These studies would aid in understanding precisely how modifiable and nonmodifiable factors impact the organic evolution of centenarians. Cellular senescence, epigenetic clocks, and alterations in stem cells, are some of the cellular and molecular processes that could theoretically reflect cellular proteodynamics, adaptation to aging, and the development of health phenotypes and prognosis during longevity. Having specific data on these mechanisms could facilitate the identification of aging biomarkers for cells, tissues, organs, or diseases, and predict the onset of age-related chronic diseases. However, there are not enough, studies to corroborate these hypotheses based on centenarians as a model of successful aging. Therefore, evidence regarding possible interventions to delay aging and prevent the onset of age-related chronic diseases into extreme ages remains weak and speculative.

The gut microbiota (GM) has been described as a biological and metabolic regulator of various organs and diseases. Age and diet, determinants in aging, are two factors directly related to the establishment and modification of the composition of the GM. To date, little discussion has taken place regarding the specific changes that occur in the long-lived population, which allow the establishment of an antioxidant system with characteristics similar to those of a young population, as a result of successful evolutionary adaptation. Although the specific mechanisms are unknown, this may possibly be one of the strongest reasons influencing life expectancy and healthy lifespan during aging.

To understand the possible impact generated by the GM, its changes, and the probable causes for successful aging, the aim of this review was to synthesize evidence on the role of the GM as a potential protective factor for achieving extreme longevity, using its relationship with centenarians. Evidence suggests that there are significant changes in the composition of the GM of centenarians, compared to other age groups, which could be associated with specific phenotypes of healthy aging, and be determinants in extreme longevity. However, numerous factors condition the establishment of the GM over time. The origin of the data is limited to certain countries with some blue zones. This field should be extensively studied in regions lacking data and determine the possible specific causal association between genera and species of microorganisms, and extreme longevity.

Researchers here describe an injected immunomodulatory peptide that reduces migration of adaptive immune cells in response to inflammatory signaling. They mount the argument that excessive immune cell migration is a sizable part of the problem in the chronic inflammation of aging, and arises due to age-related changes in immune cell behavior. Delivering the peptide is intended to restore a more youthful regulation of this immune cell behavior.

Growing evidence suggests that the ageing process significantly impacts leukocyte trafficking dynamics during inflammation, thereby compromising protective immunity. We have previously reported that ageing increases homeostatic leukocyte trafficking to the peritoneal cavity in mice through pro-inflammatory mediators and enhanced vascular permeability. Whilst ageing increases neutrophil and monocyte trafficking in response to peritonitis, patterns of lymphocyte trafficking are still unknown in this model.

Here, we investigated how ageing changes leukocyte trafficking dynamics and the impact of a novel immunopeptide (PEPITEM) has on this using an inflammation model of zymosan-induced peritonitis in young (3-month) and aged (21-month) male mice. Zymosan-induced peritonitis typically represents a simplified model of the disease, focusing primarily on the early inflammatory events. It may not adequately capture the later stages of human peritonitis development, including tissue damage and organ dysfunction. Nonetheless, it remains a highly reproducible and robust model, characterised by significant recruitment of various immune cells.

We previously identified PEPITEM as a key regulator of leukocyte trafficking. Indeed, through action of adiponectin on its receptors (AdipoR1 and AdipoR2) on B-cells, PEPITEM is released to then stimulate endothelial production of spingosine-1-phosphate (S1P). S1P will in turn inhibit leukocyte trafficking through modulation on integrin signalling. We analysed whether intraperitoneal injection of PEPITEM could modulate leukocyte migration in older mice. We observed a loss of functionality in the PEPITEM pathway, which normally controls leukocyte trafficking in response to inflammation, in older adults and aged mice and show that this can be rescued by supplementation with PEPITEM. Thus, leading to the exciting possibility that PEPITEM supplementation may represent a potential pre-habilitation geroprotective agent to rejuvenate immune functions.

Link: https://doi.org/10.1038/s41514-024-00160-6

The aging brain malfunctions in complex ways, giving rise to a range of poorly categorized end states beyond the most prevalent, well known neurodegenerative conditions. As an example of research in this part of the field, scientists here discuss a form of age-related memory loss that they call limbic-predominant amnestic neurodegenerative syndrome. Interestingly, this condition appears to be associated with TDP-43 pathology, a comparatively recently discovered form of harmful protein aggregation in the aging brain that is now known to contribute to some forms of neurodegeneration.

Researchers have established new criteria for a memory-loss syndrome in older adults that specifically impacts the brain's limbic system. It can often be mistaken for Alzheimer's disease. Limbic-predominant Amnestic Neurodegenerative Syndrome, or LANS, progresses more slowly and has a better prognosis. Prior to the researchers developing clinical criteria the hallmarks of the syndrome could be confirmed only by examining brain tissue after a person's death. The proposed criteria provide a framework for neurologists and other experts to classify the condition in patients living with symptoms, offering a more precise diagnosis and potential treatments. They consider factors such as age, severity of memory impairment, brain scans, and biomarkers indicating the deposits of specific proteins in the brain.

"Historically, you might see someone in their 80s with memory problems and think they may have Alzheimer's disease, and that is often how it's being thought of today. With this paper, we are describing a different syndrome that happens much later in life. Often, the symptoms are restricted to memory and will not progress to impact other cognitive domains." Without signs of Alzheimer's disease, the researchers looked at the involvement of one possible culprit - a buildup of a protein called TDP-43 in the limbic system that scientists have found in the autopsied brain tissue of older adults. Researchers have classified the build-up of these protein deposits as limbic-predominant age-related TDP-43 encephalopathy, or LATE. These protein deposits could be associated with the newly defined memory loss syndrome, but there are also other likely causes and more research is needed.

Link: https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-scientists-define-new-type-of-memory-loss-in-older-adults/

Senescent cells accumulate with age throughout the body. Cellular senescence occurs most often at the end of a cell's replicative life span, but can also be provoked by damage, a toxic environment, or the signaling of other nearby senescent cells. Senescent cells are metabolically active and secrete a potent mix of pro-inflammatory, pro-growth signals. This state has a number of useful functions, such as coordination of wound healing and elimination of potentially cancerous cells. In youth senescent cells are promptly destroyed by the immune system or programmed cell death processes, but with age this clearance becomes impaired. The signaling of senescent cells, useful in the short term, becomes disruptive to tissue function and structure when sustained over the long term by a growing population of lingering senescent cells.

While much of the research and development of anti-senescence therapies involves the production of senolytic treatments that can selectively destroy these cells, there is some interest in trying to find ways to suppress the harmful signaling of of senescent cells instead. This seems likely to be more challenging and less effective as a strategy, as the regulation of the senescent state is complex, and any one intervention is likely to only affect a modest fraction of the whole. Nonetheless, see today's open access paper as an interesting example of the research taking place into means to reduce senescent cell signaling. Unlike most such research at the present stage of development, the authors did actually test their work in mice, and demonstrated a small extension in life span to result from their approach to suppression of senescent cell signaling.

PKM2 aggregation drives metabolism reprograming during aging process

Aging is a progressive process characterized by the systemic deterioration of organs and tissues, often culminating in chronic diseases such as diabetes, cancer, cardiovascular disorders, and neurodegenerative diseases. In recent years, the disruption of proteostasis has emerged as a well-recognized hallmark of aging. It is principally guarded by the chaperone-mediated folding system and degradation pathways involving lysosomes or proteasome. Dysfunction in either of these systems can precipitate the accumulation of aberrant protein aggregates within cells, thereby contributing to the onset and progression of aging-related pathologies.

In this study, we conducted an analysis of lysosomal proteomics from young and senescent cells, leading us to uncover the role of Pyruvate Kinase M2 (PKM2) aggregates in the aging process. In senescent cells, PKM2 tends to aggregate along with other glycolytic enzymes, such as Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), α-Enolase (ENO1), and others. Furthermore, we found that PKM2 aggregation accompany with impairment of PKM2 enzymatic activity and glycolytic flux in senescent cells, exacerbating senescent phenotypes.

To identify compounds capable of dissolving PKM2 aggregates and alleviating senescence, we conducted a series of screenings. K35 and its analog K27 were identified as compounds capable of inhibiting the formation of PKM2 aggregates. Treatment with K35 or K27 restored PKM2 enzymatic activity and glycolytic flux. Further studies demonstrated that K35 or K27 not only alleviated cellular senescence but also extended the lifespan of both naturally and prematurely aged mice.

Mitochondria are the power plants of the cell, their production of the chemical energy store molecule adenosine triphosphate (ATP) essential to cell function. With advancing age mitochondria become dysfunctional for reasons that in part involve damage to mitochondrial DNA and in part involve changes in gene expression that harm mitochondrial structure and the quality control processes of mitophagy. Mitochondrial dysfunction places stress on cells in a number of ways, from loss of ATP production to increased generation of oxidative molecules. What might be fixed if mitochondria could be restored to a more youthful state of function, and how might that goal be achieved? Researchers here look at these questions in the context of the aging of the ovaries.

Ovarian aging is a complex process characterized by a gradual decline in both the quantity and quality of oocytes. This age-related decline in ovarian function not only results in reduced fertility and an increased risk of pregnancy complications but also significantly impacts critical elements like hormonal balance, bone health, cardiovascular well-being, and cognitive function.

Mitochondria assume a fundamental role in energy generation through oxidative phosphorylation. Considering that the oocyte is the body's most mitochondria-rich cell, these organelles bear significant responsibility in fostering its development, promoting follicular growth, and orchestrating hormone regulation - all crucial factors in ensuring successful reproduction. While several other factors, such as vascular network defects, hormonal dysregulation, genetic and epigenetic alterations, and environmental and lifestyle influences, have been identified as contributing to the aging of the ovary, mitochondrial dysfunction appears to be a more central and significant driver of this process. Moreover, preserving mitochondrial function not only holds promise for enhancing reproductive outcomes but also for delaying aging in women. Exploring therapeutic strategies targeted at maintaining mitochondrial health could offer significant opportunities for addressing age-related fertility decline and promoting reproductive and overall well-being in women.

In this review, we focus on the intricate interplay between mitochondrial function and ovarian aging, and the mechanisms through which mitochondrial health affects oocyte and ovarian follicle quality, and how it contributes to age-related fertility decline. Furthermore, we explore potential therapeutic strategies aimed at preserving mitochondrial function to enhance reproductive outcomes for women as they age.

Link: https://doi.org/10.3389/fendo.2024.1417007

Here find a SENS Research Foundation article covering some of the specifics of progress towards messenger RNA (mRNA) therapies capable of breaking down harmful age-related intracellular protein aggregates, with a focus on those involved in neurodegenerative conditions. Delivery of synthetic mRNA into cells by lipid nanoparticle is an active area of gene therapy development. Once inside cells, mRNA molecules are processed by ribosomes to produce proteins for a short period of time. A range of biochemical problems in the cells of aged tissues can only be solved by expressing suitable proteins inside those cells, such as clearance of protein aggregates. This sort of repair task is well suited to mRNA gene therapies that produce only short-term expression of therapeutic proteins. When damage accumulates slowly, only intermittent and short periods of treatment are needed.

Rejuvenation biotechnologies targeting aberrant tau are in development, ranging from the earliest cell studies all the way up to Phase III clinical trials. In part, this ambition to clear out tau started off as a hedge against the unfounded skepticism about the role of beta-amyloid in Alzheimer's disease. Although biotech companies were forced to abandon many of their first attempts to target tau (often because they interfered with the physiological function of the healthy, non-aggregated tau protein), clinical trials are presently testing numerous therapies targeting tau. Most of these potential therapies are in Phase II.

An important limitation of these candidate therapies is that most of them only clear tau aggregates located outside of cells - in the spaces where neurons interact with one another or in the wider fluid that bathes the brain. Such therapies should do some good, most notably by slowing down the rate at which "seeds" of aberrant tau "infect" other neurons in their network. But they would do nothing to clear existing aberrant tau in the location where those seeds form and where they inflict most of their harm: inside of neurons.

In recent years, scientists began targeting tau inside neurons using functional fragments of antibodies with key subunits that target different segments of the tau protein. When they treated animals that carry forms of mutated human tau that aggregate and drive neurodegenerative disease in humans, these antibody fragments lowered the burden of soluble aberrant tau in these animals' brains - and the effect was almost entirely the result of clearing it from inside the neurons. Scientists then pitted different tau-targeting antibody fragments against each other, and also against the same fragments after further modifying them to turn them into intrabodies. Intrabodies are antibody fragments that have been engineered to remain within and function inside cells, sometimes including targeting them to specific locations within the cell.

But how would we deliver these intrabodies to aging humans? Researchers have seized on the recent revolution of mRNA technology. Researchers realized that they could use mRNA to deliver the instructions for tau-targeting intrabodies into neurons. The cells would then produce free, active antibodies inside of themselves from scratch, avoiding the entire fraught journey required for conventional antibody infusions to reach and become active in the cell without requiring gene therapy. This research is promising, but is still in a very preliminary stage. While the potential of an mRNA vaccine against aberrant tau is exciting, hurdles remain to be overcome.

Link: https://www.sens.org/get-the-message-mrna-to-target-intracellular-aggregates/

Atherosclerosis is the development of fatty plaques in blood vessel walls. It is a universal condition of aging, present to some degree in every older individual. Atherosclerosis contributes to many age-related diseases via narrowing of vessels and reduced blood flow on the one hand, and on the other causing more than a quarter of all human mortality via the stroke and heart attack that can follow rupture of an unstable plaque. We might think of atherosclerosis as a condition of macrophage dysfunction. Macrophages are innate immune cells responsible for clearing excess cholesterol from blood vessel walls. These cells ingest cholesterol and the LDL particles that transport cholesterol from the liver to the rest of the body. Then then hand off that cholesterol to HDL particles for transport back to the liver.

Considered at a high level, and skipping some of the complexities, atherosclerotic plaque develops when the influx of LDL-cholesterol exceeds the capacity of macrophages to clean it up. The research community is near entirely focused on the LDL-cholesterol side of the question, but as a result of decades of such work has now comprehensively demonstrated that even dramatic reductions in circulating LDL-cholesterol only modestly reduce the risk of heart attack and stroke, and cannot reliably or sizeably reverse established atherosclerotic plaque. It is past time to focus on the other side of the equation, the capacity of macrophages to remove cholesterol from blood vessel walls, and even survive and continue this work in the hostile environment of an established plaque in order to reduce its size. Today's open access paper is an example of this sort of work, the search for proximate causes of macrophage dysfunction in the context of atherosclerosis that may form a basis for later drug development.

Mitochondrial dysfunction and metabolic reprogramming induce macrophage pro-inflammatory phenotype switch and atherosclerosis progression in aging

Immune cells, including the circulating monocytes that will transform into macrophages, are recruited to the vascular wall in atherogenesis and play a critical role in sustaining oxidative stress, inflammation, and extracellular matrix degradation. Atherosclerotic lesion macrophages can maintain several phenotypes, including classically activated (M1 or M[IFNγ+LPS]) pro-inflammatory macrophages and alternatively activated (M2 or M[IL4]) pro-resolving macrophages. Macrophage metabolic reprogramming, with pro-inflammatory cells relying on glycolysis and pro-resolving cells on oxidative phosphorylation for energy production, is closely related to the changes in atherosclerotic plaque environment and morphology. Nevertheless, the mechanisms of metabolic reprogramming of macrophages in atherosclerosis and its effects on plaque morphology are incompletely understood.

Mitochondrial dysfunction in macrophages in aging results in reduced ATP production, elevated reactive oxygen species (ROS) generation, and compromised mitochondrial quality control, features that are intricately linked to the shift in metabolism from oxidative phosphorylation to glycolysis and pro-inflammatory phenotype. Consequently, aging-associated atherosclerotic plaque mitochondrial oxidative stress and dysfunction result in increased lesion volume and vulnerable plaque features. Expression of mitochondria-localized NOX4 NADPH oxidase is increased with age in human and mouse vasculature and is associated with increased oxidative stress, vascular inflammation, aortic stiffness, and atherosclerotic lesion size and severity. Similarly, increased NOX4 expression in atherosclerotic plaque was associated with plaque instability and rupture, while direct inhibition, genetic downregulation of NOX4, or blockade of NOX4-dependent signaling pathways inhibited atherogenesis. In human coronary atherosclerotic lesions increased NOX4 expression was observed in nonphagocytic vascular cells, contributing to increased ROS levels, while increased NOX4-derived ROS in human monocytes was associated with higher metabolic priming, vascular recruitment, and atherosclerosis progression.

Targeting NOX4-dependent mitochondrial ROS holds promise in atherosclerosis management. However, the precise mechanisms of mitochondrial dysfunction in aging-associated atherosclerosis, its impact on plaque progression and phenotype, and therapeutic potential are not fully elucidated. Here, we tested the hypothesis that mitochondrial oxidative stress associated with increased NOX4 levels in aging results in metabolic priming in monocytes/macrophages to a pro-inflammatory phenotype switch, fostering atherosclerotic lesion progression. We used Apoe-/- mice as they have high cholesterol levels when fed a Western diet, leading to human-like atherosclerosis progression with similar lesion cellular composition, a prominent inflammatory profile, and aging-related phenotype useful for aging studies. Effects of aging were examined in 16-month-old mice, which represent the age equivalent of humans with exponentially increasing coronary heart disease incidence, making them a useful model to study the pathogenesis of atherosclerosis. Using aged Nox4-deficient Apoe-/- mice, mice we showed that reduced mitochondrial ROS in macrophages preserves mitochondrial function and is associated with pro-resolving phenotype attenuating atherosclerotic disease. We recapitulated our findings by inhibiting NOX4 activity in aged Apoe-/- mice.

Our findings suggest that increased NOX4 in aging drives macrophage mitochondrial dysfunction, glycolytic metabolic switch, and pro-inflammatory phenotype, advancing atherosclerosis. Inhibiting NOX4 or mitochondrial dysfunction could alleviate vascular inflammation and atherosclerosis, preserving plaque integrity.

At present, researchers consider there to be a bidirectional relationship between aging of the gut microbiome and aging of the immune system. The immune system gardens the microbial populations of the gut to minimize the number of problematic microbes, but growth in number of those inflammatory, disruptive microbes can contribute to loss of immune function. As is the case for many processes in aging, interactions between systems are as important as problems that occur within systems. Improving late life immune function should improve the gut microbiome. Conversely, restoring a more youthful balance of microbial populations in the gut microbiome should improve late life immune function.

The gut microbiome has come to prominence across research disciplines, due to its influence on major biological systems within humans. Recently, a relationship between the gut microbiome and hematopoietic system has been identified and coined the gut-bone marrow axis. It is well established that the hematopoietic system and gut microbiome separately alter with age; however, the relationship between these changes and how these systems influence each other demands investigation.

Since the hematopoietic system produces immune cells that help govern commensal bacteria, it is important to identify how the microbiome interacts with hematopoietic stem cells (HSCs). The gut microbiota has been shown to influence the development and outcomes of hematologic disorders, suggesting dysbiosis may influence the maintenance of HSCs with age. Short chain fatty acids (SCFAs), lactate, iron availability, tryptophan metabolites, bacterial extracellular vesicles, microbe associated molecular patterns (MAMPs), and toll-like receptor (TLR) signalling have been proposed as key mediators of communication across the gut-bone marrow axis and will be reviewed in this article within the context of aging.

Link: https://doi.org/10.1016/j.heliyon.2024.e32831

Senescent cells accumulate with age to secrete disruptive inflammatory signaling. Clearing even as few as a third of these cells in some tissues using senolytic therapies has proven to be very beneficial in mice. Senescent cells are not as uniform in their biochemistry as once thought, however, and a primary focus in the development of second generation senolytic therapies is to categorize different types of senescent cells and understand their meaningful differences. For future senolytic therapies, this will allow greater selectivity regarding which senescent cells to clear, but also the ability to remove more senescent cells from more tissue types.

Cellular senescence has been strongly linked to aging and age-related diseases. It is well established that the phenotype of senescent cells is highly heterogeneous and influenced by their cell type and senescence-inducing stimulus. Recent single-cell RNA-sequencing studies identified heterogeneity within senescent cell populations. However, proof of functional differences between such subpopulations is lacking. To identify functionally distinct senescent cell subpopulations, we employed high-content image analysis to measure senescence marker expression in primary human endothelial cells and fibroblasts.

We found that senescent cells arrested in the G2 phase of the cell cycle feature higher senescence marker expression than G1-arrested senescent cells. To investigate functional differences, we compared IL-6 secretion and response to ABT263 senolytic treatment in G1 and G2 senescent cells. We determined that G2-arrested senescent cells secrete more IL-6 and are more sensitive to ABT263 than G1-arrested cells. We hypothesize that cell cycle dependent DNA content is a key contributor to the heterogeneity within senescent cell populations. This study demonstrates the existence of functionally distinct senescent subpopulations even in culture. This data provides the first evidence of selective cell response to senolytic treatment among senescent cell subpopulations. Overall, this study emphasizes the importance of considering the senescent cell heterogeneity in the development of future senolytic therapies.

Link: https://doi.org/10.1101/2024.06.22.600200

The blood-brain barrier is a specialized layer of cells surrounding blood vessels that pass through the central nervous system. It serves to separate the metabolism of the brain from the metabolism of the rest of the body by permitting passage of only certain molecules and cells to and from the brain. It is a complex system, and like all complex systems in biology, it falls apart with advancing age. This manifests as leakage, allowing inappropriate cells and molecules into the brain where they can provoke inflammation and other downstream issues. A growing consensus in the research community places blood-brain barrier dysfunction as an early contributing cause of neurodegenerative conditions and loss of cognitive function.

There is a weight of evidence in favor of the view presented above, obtained from a great many databases of human epidemiological data, as well as animal studies in which blood-brain barrier leakage is assessed. In today's open access paper the authors report on a human study that was set up to generate confirming data for the connection between blood-brain barrier dysfunction and cognitive decline. The results fall into line with other data indicating the importance of blood-brain barrier dysfunction in neurodegeneration.

Blood-Brain Barrier Permeability Is Associated With Cognitive Functioning in Normal Aging and Neurodegenerative Diseases

Vascular risk factors, such as hypertension, high cholesterol, diabetes, and obstructive sleep apnea, have a well-established link to cerebrovascular pathology and accelerated cognitive decline. Vascular risk factors have been hypothesized to cause cerebrovascular disease via chronic hypoperfusion, which leads to a cascade of events that includes blood vessel injury (eg, fibrosis, hyalinosis), hypoxia, and ischemia. These mechanisms cause inflammation that disrupts the blood-brain barrier (BBB), resulting in white matter damage.

Some theories suggest that BBB permeability manifests earlier than structural brain changes and therefore may serve as an early marker of emerging neuropathological processes and cognitive dysfunction. This is supported in rodent models, in which BBB dysfunction has been linked to inflammation and precedes neuropathological processes, including neurodegeneration and cognitive decline and accumulation of β-amyloid, a protein associated with Alzheimer's disease (AD). Ultimately, cognitive dysfunction is a common end point of neurodegeneration that clinically manifests as a neurocognitive disorder. However, few studies have examined theoretical models of the involvement of BBB permeability in the cascade of events leading to neurocognitive impairment, including the relationships between vascular risk factors, BBB permeability, and cognitive dysfunction.

The purpose of this study was to investigate the relationship between blood-brain barrier (BBB) permeability and cognitive functioning in healthy older adults and individuals with neurodegenerative diseases. A total of 124 participants with Alzheimer disease, cerebrovascular disease, or a mix of Alzheimer's and cerebrovascular diseases, and 55 control participants underwent magnetic resonance imaging and neuropsychological testing. BBB permeability was measured with dynamic contrast-enhanced magnetic resonance imaging and white matter injury was measured using a quantitative diffusion-tensor imaging marker of white matter injury. Structural equation modeling was used to examine the relationships between BBB permeability, vascular risk burden, white matter injury, and cognitive functioning.

Vascular risk burden predicted BBB permeability and white matter injury. BBB permeability predicted increased white matter injury and increased white matter injury predicted lower cognitive functioning. The study provides empirical support for a vascular contribution to white matter injury and cognitive impairment, directly or indirectly via BBB permeability. This highlights the importance of targeting modifiable vascular risk factors to help mitigate future cognitive decline.

Long term memories must be maintained by retrieval and update of their storage. Researchers here demonstrate that pharmacological inhibition of HDAC3 reduces issues with maintenance of memories in old mice. Interestingly the strategy is disruptive to initial memory formation in young mice, and this provides some additional insight into how this mechanisms of neurological aging functions. Understanding a great deal more of the fine detail regarding the functioning of mammalian memory will likely prove necessary to make large strides towards addressing this aspect of brain aging.

Long-term memories are not stored in a stable state but must be flexible and dynamic to maintain relevance in response to new information. Existing memories are thought to be updated through the process of reconsolidation, in which memory retrieval initiates destabilization and updating to incorporate new information. Memory updating is impaired in old age, yet little is known about the mechanisms that go awry.

One potential mechanism is the repressive histone deacetylase 3 (HDAC3), which is a powerful negative regulator of memory formation that contributes to age-related impairments in memory formation. Here, we tested whether HDAC3 also contributes to age-related impairments in memory updating using the Objects in Updated Locations (OUL) paradigm. We show that blocking HDAC3 immediately after updating with the pharmacological inhibitor RGFP966 ameliorated age-related impairments in memory updating in 18-month-old male mice. Surprisingly, we found that post-update HDAC3 inhibition in young (3-month-old) male mice had no effect on memory updating but instead impaired memory for the original information, suggesting that the original and updated information may compete for expression at test and HDAC3 helps regulate which information is expressed.

To test this idea, we next assessed whether HDAC3 inhibition would improve memory updating in young male mice given a weak, subthreshold update. Consistent with our hypothesis, we found that HDAC3 blockade strengthened the subthreshold update without impairing memory for the original information, enabling balanced expression of the original and updated information. Together, this research suggests that HDAC3 may contribute to age-related impairments in memory updating and may regulate the strength of a memory update in young mice, shifting the balance between the original and updated information at test.

Link: https://doi.org/10.3389/fnmol.2024.1429880

This open access paper represents a great deal of scientific work. Researchers analyzed transcriptomics from all of the successful Interventions Testing Program (ITP) mouse studies, a very large number of mice, in multiple tissues, to produce clocks for aging and mortality. They then pulled in single cell transcriptomics and human data to validate the clocks for broader use, and assessed the utility of these clocks in states of progeria and rejuvenation via reprogramming. The next decade is going to see the data associated with clock-like measures of biological age expand enormously. We might hope to also see meaningful progress toward connecting specific clock components with the underlying mechanisms of aging - this is much needed in order to be able to use aging clocks to speed up the assessment of potential rejuvenation therapies.

The development of mortality transcriptomic clocks based on gene expression profiles and their functional components across organs and mammalian species could reveal universal and specific molecular mechanisms of the established and novel models of healthspan regulation, rejuvenation and aging. Here, we conducted an RNA-seq analysis of mice subjected to 20 compound treatments in the Interventions Testing Program (ITP). By integrating it with the data from over 4,000 rodent tissues representing aging and responses to genetic, pharmacological, and dietary interventions with established survival data, we developed robust multi-tissue transcriptomic biomarkers of mortality, capable of quantifying aging and change in lifespan in both short-lived and long-lived models.

These tools were further extended to single-cell and human data, demonstrating common mechanisms of molecular aging across cell types and species. Via a network analysis, we identified and annotated 26 co-regulated modules of aging and longevity across tissues, and developed interpretable module-specific clocks that capture aging- and mortality-associated phenotypes of functional components, including, among others, inflammatory response, mitochondrial function, lipid metabolism, and extracellular matrix organization. These tools captured and characterized acceleration of biological age induced by progeria models and chronic diseases in rodents and humans. They also revealed rejuvenation induced by heterochronic parabiosis, early embryogenesis, and cellular reprogramming, highlighting universal signatures of mortality, shared across models of rejuvenation and age-related disease. They included Cdkn1a and Lgals3, whose human plasma levels further demonstrated a strong association with all-cause mortality, disease incidence and risk factors, such as obesity and hypertension.

Overall, this study uncovers molecular hallmarks of mammalian mortality shared across organs, cell types, species and models of disease and rejuvenation, exposing fundamental mechanisms of aging and longevity.

Link: https://doi.org/10.1101/2024.07.04.601982

Chronic, unresolved inflammatory signaling is a feature of aging. It arises from multiple contributing mechanisms, such as the accumulation of senescent cells and the innate immune reaction to mislocalized mitochondrial DNA. The worse the state of accumulated molecular damage, the worse the constant inflammatory response. Ultimately, all of this damage will need to be repaired, but if there are ways to inhibit this maladaptive inflammation without suppressing the entire immune system, then this should improve late life health and life span. Chronic inflammation is highly disruptive to tissue structure and function, and is major contributing component of all of the common fatal age-related conditions.

In today's open access paper, researchers report on the discovery that IL-11 is more important to the chronic inflammation of aging than previously thought. IL-11 is an immune signaling molecule, an inflammatory cytokine. Like most cytokines IL-11 has been shown to influence many fundamental cellular mechanisms and activities. The researchers show that inhibition of IL-11 signaling can extend life in mice by as much as 25%. Few approaches have been shown to robustly increase life span in mice by more than 20%, and now IL-11 inhibition adds to that small selection of interventions. As reported, IL-11 inhibition may work through essentially the same pathways as mTOR inhibition. The degree of life extension is similar to that achieved via mTOR inhibitors such as rapamycin.

Inhibition of IL-11 signalling extends mammalian healthspan and lifespan

The major signalling mechanisms that regulate lifespan across species include ERK, STK11 (also known as LKB1), AMPK, mTORC1, and IGF1-insulin modules. These pathways are collectively perturbed in old age to activate hallmarks of ageing, which include mitochondrial dysfunction, inflammation, and cellular senescence. In aged organisms, the AMPK-mTORC1 axis is uniquely important for metabolic health, with notable effects in adipose tissue, and therapeutic inhibition of mTOR extends lifespan in mice.

The importance of chronic sterile inflammation for ageing pathologies is increasingly recognized and inflammation itself is a central hallmark of ageing. In simplified terms, ageing is associated with a dysfunctional adaptive immune system that is characterized by immunosenescence and thymic involution along with inappropriate activation of innate immune genes such as IL-6, The pro-inflammatory signalling factors NF-κB and JAK-STAT3 are specifically implicated in ageing and JAK inhibitors can alleviate age-related dysfunction.

We proposed that IL-11, a pro-inflammatory and pro-fibrotic member of the IL-6 family, may promote age-associated pathologies and reduce lifespan. This premise was founded on studies showing that IL-11 can activate ERK-mTORC1 and/or JAK-STAT3, the observation that IL-11 is upregulated in older people, and the fact that IL-11 is increasingly recognized to have a role in senescence, a hallmark of ageing. Here, using a range of genetic and pharmacological approaches, we tested the hypothesis that IL-11 signalling has a negative effect on healthspan and lifespan in mice.

Deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity, and frailty in old age. Administration of anti-IL-11 antibodies to 75-week-old mice for 25 weeks improves metabolism and muscle function, and reduces ageing biomarkers and frailty across sexes. In lifespan studies, genetic deletion of Il11 extended the lives of mice of both sexes, by 24.9% on average. Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5% and of female mice by 25%.

Together, these results demonstrate a role for the pro-inflammatory factor IL-11 in mammalian healthspan and lifespan. We suggest that anti-IL-11 therapy, which is currently in early-stage clinical trials for fibrotic lung disease, may provide a translational opportunity to determine the effects of IL-11 inhibition on ageing pathologies in older people.

There is a continued interest in the use of vitamin B3 derivatives as a strategy to increase levels of nicotinamide adenine dinucleotide (NAD) in mitochondria and thus improve function. These compounds include niacin, nicotinamide riboside, and nicotinamide mononucleotide, among others. NAD levels decline with age and this is thought to contribute to loss of mitochondrial function in aged tissues. That said, the human clinical data for these approaches as treatments for a variety of conditions isn't so great, taken as a whole. Further, these pharmacological approaches are not as effective as exercise when it comes to ability to increase NAD levels. Here, researchers add to the mouse evidence for restoration of a more youthful amount of NAD in cells to contribute to health.

Nicotinamide adenine dinucleotide (NAD) is essential for many enzymatic reactions, including those involved in energy metabolism, DNA repair, and the activity of sirtuins, a family of defensive deacylases. During aging, levels of NAD+ can decrease by up to 50% in some tissues, the repletion of which provides a range of health benefits in both mice and humans. Whether or not the NAD+ precursor nicotinamide mononucleotide (NMN) extends lifespan in mammals is not known. Here we investigate the effect of long-term administration of NMN on the health, cancer burden, frailty and lifespan of male and female mice.

Without increasing tumor counts or severity in any tissue, NMN treatment of males and females increased activity, maintained more youthful gene expression patterns, and reduced overall frailty. Reduced frailty with NMN treatment was associated with increases in levels of Anerotruncus colihominis, a gut bacterium associated with lower inflammation in mice and increased longevity in humans. NMN slowed the accumulation of adipose tissue later in life and improved metabolic health in male but not female mice, while in females but not males, NMN increased median lifespan by 8.5%, possible due to sex-specific effects of NMN on NAD+ metabolism.

Together, this data shows that chronic NMN treatment delays frailty, alters the microbiome, improves male metabolic health, and increases female mouse lifespan, without increasing cancer burden. These results highlight the potential of NAD+ boosters for treating age-related conditions and the importance of using both sexes for interventional lifespan studies.

Link: https://doi.org/10.1101/2024.06.21.599604

As in a number of other organs, fibrosis is a feature of the aging and loss of function of the ovaries. Fibrosis is the inappropriate deposition of excess collagen to the extracellular matrix, creating scar-like structures that are disruptive to normal tissue function. Here, researchers show that delivery of low dose antifibrotic drugs in mice can slow this aspect of ovarian aging and lead to improved function and extended reproductive longevity.

The female reproductive system is one of the first to age in humans, resulting in infertility and endocrine disruptions. The aging ovary assumes a fibro-inflammatory milieu which negatively impacts gamete quantity and quality as well as ovulation. Here we tested whether the systemic delivery of anti-inflammatory (Etanercept) or anti-fibrotic (Pirfenidone) drugs attenuates ovarian aging in mice. We first evaluated the ability of these drugs to decrease the expression of fibro-inflammatory genes in primary ovarian stromal cells. Whereas Etanercept did not block Tnf expression in ovarian stromal cells, Pirfenidone significantly reduced Col1a1 expression.

We then tested Pirfenidone in vivo where the drug was delivered systemically via mini-osmotic pumps for 6-weeks. Pirfenidone mitigated the age-dependent increase in ovarian fibrosis without impacting overall health parameters. Ovarian function was improved in Pirfenidone-treated mice as evidenced by increased follicle and corpora lutea number, AMH levels, and improved estrous cyclicity. Transcriptomic analysis revealed that Pirfenidone treatment resulted in an upregulation of reproductive function-related genes at 8.5 months and a downregulation of inflammatory genes at 12 months of age. These findings demonstrate that reducing the fibroinflammatory ovarian microenvironment improves ovarian function, thereby supporting modulating the ovarian environment as a therapeutic avenue to extend reproductive longevity.

Link: https://doi.org/10.1101/2024.06.21.600035

Calcification of blood vessels and structures in the heart is a widespread issue in later life. Cells in the cardiovascular system become altered by the changing signal environment and molecular damage of aging, and adopt behaviors normally associated with the osteoblast cells responsible for building bone. These errant cells deposit calcium into the extracellular matrix structure, stiffening the normally elastic blood vessel and heart tissues and ultimately degrading their function. Prominent contributing factors are thought to include the chronic inflammation of aging and presence of senescent cells in cardiovascular tissues.

There is presently little that can be done about calcification. The progression can be slowed somewhat by good lifestyle choices, as is the case for cardiovascular disease in general, but only EDTA chelation therapy has shown any effectiveness in reducing established calcification - and this isn't a great therapy in the grand scheme of things, only offering modest gains. New approaches are needed. In today's open access paper, researchers dive into the biochemistry of calcification, in search of points of intervention that might more aggressively prevent it from occurring.

Osteopontin stabilization and collagen containment slows amorphous calcium phosphate transformation during human aortic valve leaflet calcification

There is mounting unmet need to discover new clinical therapies for the prevention and treatment of calcification in the human circulatory system. This process of cardiovascular calcification is a significant factor in the more than 18 million lives claimed globally each year by heart disease. Stenosis of vasculature associated with blood flow restriction and heart valve calcification is a common health disorder in people of all ages, genders, and ethnic backgrounds, is associated with other comorbidities, and is the most prevalent form of heart disease in patients 65 and older. Yet beyond invasive valve implants, there are no viable alternative drug therapies or clinical treatment options available.

The evolutionary success of invertebrate and vertebrate organisms through geological time has relied on their ability to harness the precipitation of thermodynamically unstable amorphous calcium phosphate (ACP) before it spontaneously transforms into crystalline hydroxyapatite (HAP). While ACP calcification is fundamental to an organism's ability to precipitate essential hard parts such as bone and teeth, the capacity of ACP to morphologically shape-shift and atomically rearrange also results in various soft tissue pathologies.

Previous research on aortic valve calcification has primarily focused on cellular and molecular pathophysiology processes, including extracellular matrix biochemistry and biomechanics, but has not specifically targeted the etiological processes recorded by the calcification deposits themselves. This is because standard microscopy techniques for pathological screening include stains that dissolve ACP and/or transform ACP to HAP in tissue sections, while x-ray diffraction cannot resolve the short-range ordering of ACP. Since 1975, several comprehensive reviews refer to four basic research studies that have identified ACP as the primary agent of aortic valve and arterial calcification by combining electron diffraction, standard microscopy, and microprobe analyses with optical microscopy on unstained histological cryosections. Now, a half century later, rigorous examination specifically targeting the role of ACP in cardiovascular calcification remains to be completed.

Here, we use transdisciplinary geology, biology, and medicine approaches prove that leaflet calcification is driven by amorphous calcium phosphate (ACP), ACP at the threshold of transformation toward hydroxyapatite (HAP), and cholesterol biomineralization. A paragenetic sequence of events is observed that includes: (1) original formation of unaltered leaflet tissues: (2) individual and coalescing 100's nm- to 1 μm-scale ACP spherules and cholesterol crystals biomineralizing collagen fibers and smooth muscle cell myofilaments; (3) osteopontin coatings that stabilize ACP and collagen containment of nodules preventing exposure to the solution chemistry and water content of pumping blood, which combine to slow transformation to HAP; (4) mm-scale nodule growth via ACP spherule coalescence, diagenetic incorporation of altered collagen and aggregation with other ACP nodules; and (5) leaflet diastole and systole flexure causing nodules to twist, fold their encasing collagen fibers and increase stiffness. These in vivo mechanisms combine to slow leaflet calcification and establish previously unexplored hypotheses for testing novel drug therapies and clinical interventions.

Osteoporosis, the progressive age-related loss of bone mineral density, occurs due to an imbalance between the activities of osteoblast cells that build bone and osteoclast cells that break down bone. Both cell populations are constantly active, and thus balance must be maintained. Regulation of this balance is complicated, unfortunately, and the downstream effects of existing bone-promoting therapies are not fully understood. Researchers here investigate the mechanisms of a parathyroid hormone based treatment for osteoporosis, and find that GPRC5A expression suppresses the activity of osteoblasts. Thus inhibition of GPRC5A is a potential therapeutic target for future therapies aimed at enhancing bone deposition.

Induction of parathyroid hormone (PTH) signaling using the PTH-derived peptide - teriparatide, has demonstrated strong bone-promoting effects in patients with osteoporosis. These effects are mediated by osteogenesis, the process of bone formation involving the differentiation and maturation of bone-forming cells called osteoblasts. However, PTH induction is also associated with the differentiation of macrophages into osteoclasts, which are specialized cells responsible for bone resorption. Although, bone remodeling by osteoblasts and osteoclasts is crucial for maintaining skeletal health, PTH-induced osteoclast differentiation can decrease treatment efficacy in patients with osteoporosis. However, precise molecular mechanisms underlying the dual action of PTH signaling in bone remodeling are not well understood.

Researchers conducted a series of experiments to identify druggable target genes downstream of PTH signaling in osteoblasts. The researchers treated cultured mouse osteoblast cells and mice with teriparatide. They then assessed gene expression changes induced by PTH in both the cultured cells and bone cells isolated from the femurs of the treated animals, using advanced RNA-sequencing analysis. Among several upregulated genes, they identified a novel PTH-induced gene - 'Gprc5a', encoding an orphan G protein-coupled receptor, which has been previously explored as a therapeutic target. However, its precise role in osteoblast differentiation had not been fully understood.

The researchers examined the effect of Gprc5a downregulation on osteoblast proliferation and differentiation. Notably, while PTH induction alone did not affect cell proliferation, Gprc5a knockdown resulted in an increase in the expression of cell-cycle-related genes and osteoblast differentiation markers. These findings suggest that Gprc5a suppresses osteoblast proliferation and differentiation. Diving deeper into the molecular mechanisms underlying the effects of Gprc5a, in PTH-induced osteogenesis, the researchers identified Activin receptor-like kinase 3 (ALK3), a bone morphogenetic protein (BMP) signaling pathway receptor, as an interacting partner of Gprc5a. Overexpression of Gprc5a led to suppression of BMP signaling.

Overall, these findings reveal that Gprc5a, a novel inducible target gene of PTH, negatively regulates osteoblast proliferation and differentiation by partially suppressing BMP signaling. Gprc5a can thus, be pursued as a novel therapeutic target while devising treatments against osteoporosis.

Link: https://www.tus.ac.jp/en/mediarelations/archive/20240618_2891.html

Autoimmune disorders are a major challenge for modern medicine; in most cases, there is little that can be done but suppress the immune system, a strategy that has serious side-effects. The fundamental causes of these conditions are poorly understood, and researchers lack good points of intervention to reprogram an aberrant immune system. The immune system is clearly very complex, and capable of malfunctions in countless different, equally complex ways. Given that, it is always good to see the research community making inroads towards the effective treatment of an autoimmune condition, and here systemic lupus erythematosus is the target. Interestingly, lupus presents quite differently depending on age of onset; late-onset lupus that emerges in old age exhibits both less severe symptoms and greater mortality than the condition in younger individuals.

The autoimmune disease systemic lupus erythematosus - known as lupus - affects more than 1.5 million people in the US. It can result in life-threatening damage to multiple organs including the kidneys, brain, and heart. The causes of this disease have long been unclear. Existing treatments often fail to control the disease and have unintended side effects of reducing the immune system's ability to fight infections. But now researchers have discovered a molecular defect that promotes the pathologic immune response in lupus and show that reversing this defect may potentially reverse the disease.

The scientists report a new pathway that drives disease in lupus. There are disease-associated changes in multiple molecules in the blood of patients with lupus. Ultimately, these changes lead to insufficient activation of a pathway controlled by the aryl hydrocarbon receptor (AHR), which regulates cells' response to environmental pollutants, bacteria, or metabolites, a substance created when the body breaks down food, drugs, chemicals or its own tissue. Insufficient activation of AHR results in too many immune cells that promote the production of disease-causing autoantibodies.

To show this discovery can be leveraged for treatments, the investigators returned the AHR-activating molecules to blood samples from lupus patients. This seemed to reprogram these lupus-causing cells into a type of cell that may promote wound healing from the damage caused by this autoimmune disease. "We found that if we either activate the AHR pathway with small molecule activators or limit the pathologically excessive interferon in the blood, we can reduce the number of these disease-causing cells. If these effects are durable, this may be a potential cure."

Link: https://news.northwestern.edu/stories/2024/july/lupus-immune-response-reversal/

The conventional wisdom propagated by physicians and cardiovascular researchers is that it is good to reduce cholesterol in the bloodstream attached to low-density lipoprotein (LDL) particles. The lower the better. This is cholesterol transported outwards from its creation in the liver for use elsewhere in the body. When sustained over decades, higher LDL-cholesterol increases the pace of development of fatty atherosclerotic plaques in blood vessel walls, the cause of eventual heart attack and stroke. Human mutants with abnormally low LDL-cholesterol levels exhibit as much as a 50% reduction in risk of death due to rupture of a plaque and resulting heart attack or stroke.

Interestingly, however, low levels of total cholesterol in the bloodstream are associated with increased late life mortality. A measure of total cholesterol counts the cholesterol attached to all forms of transport particle - so not just LDL-cholesterol leaving the liver (along with VLDL and IDL cholesterol-bearing particles) but also the high-density lipoprotein (HDL) cholesterol that is carried back to the liver. It remains unclear as to exactly why low total cholesterol is associated with increased mortality, though there is no shortage of hypotheses.

One of those hypotheses is that low total cholesterol is a side-effect of a poor diet. Another is that forms of chronic age-related dysfunction independently produce both low total cholesterol and increased mortality. In today's open access paper, researchers analyze epidemiological data to suggest that the mortality effects of low total cholesterol are not associated with diet, though the database they are working from cannot provide much further insight into mechanisms. On a related note, it is entirely unclear as to whether pharmacological approaches such as PCKS9 inhibitors that can produce very low LDL-cholesterol will also trigger increased mortality in late life, the 80s and beyond, significantly older than the patients typically included in clinical trials for heart disease. These drugs are too new for meaningful amounts of long-term data to exist.

Association between total cholesterol and all-cause mortality in oldest old: a national longitudinal study

The present findings showed that a lower total cholesterol (TC) level was associated with elevated all-cause mortality risk in a population of oldest-old adults (aged ≥85 years). When TC level was used as a continuous variable, the mortality risk increased by 12% with each 1 mmol/L reduction in TC. This is consistent with findings from several previous studies, which demonstrated that a low TC level was a risk factor for all-cause mortality in older people. This could be explained by the increased risk of non-cardiovascular mortality (e.g., from cancers and infections). After identifying this inverse association, we further explored the lower limit of TC and found a continuous increment of all-cause mortality risks when TC levels fell below 3.40 mmol/L. This indicates that a TC level lower than 3.40 mmol/L is associated with higher mortality risk among oldest-old adults. To our knowledge, this is the first study to clarify the lower TC cutoff point in this population, and it has been suggested that lower TC levels are associated with frailty and chronic disease in seniors, which further increases mortality risk.

Some researchers suggest that higher TC levels are associated with better nutritional and chronic health status in the oldest old population; thus, individuals with elevated TC levels are more likely to live longer. In the present study, we attempted to exclude the potential effect of dietary or physiological factors by including these variables in the model. In our study, self-reported diabetes, heart disease, and stroke were not significantly associated with all-cause mortality, and thus not included as covariates in the final multivariable models. The predictive value of traditional risk factors for mortality may diminish in the oldest old compared to younger populations, as supported by some previous studies.

As for dietary factors, fresh fruit consumption and fish consumption were protective factors in the multivariable model, whereas daily consumption of eggs and sugar were risk factors for all-cause mortality, which is consistent with previous findings. Adjustment for dietary behaviors and chronic health conditions did not alter the protective effect of TC on all-cause mortality, indicating that the association between TC and all-cause mortality is independent of nutritional status.

Although the biological pathways that link TC to mortality are poorly understood, several mechanisms may explain this inverse association. For example, blood lipids, which are an important component of cell membranes, may affect cell electrophysiology by modulating the distribution and function of some ion channels. Low TC levels may contribute to the pathogenesis of some common diseases in older people, such as atrial fibrillation. Another potential mechanism is that TC may regulate inflammatory markers such as C-reactive protein and attenuate the biological response to inflammation. Therefore, individuals with low TC levels may be more vulnerable to physiological disorders because of enhanced inflammation.

Upregulation of various forms of cellular stress response has been shown to modestly slow aging in a variety of short-lived laboratory species. Allowing cells to better maintain a healthy state in response to stresses such as heat or low nutrient availability reduces the pace at which age-related damage accumulates to cause dysfunction. This improvement in stress responses is a portion of the calorie restriction response, and thus unlikely to produce effects on life span that are as large in longer-lived species. Nonetheless, it is the subject of a great deal of research. Scientists here discuss the role of Nrf2 in the mechanisms by which some supplements and dietary compounds can provoke greater levels of cellular stress responses. Nrf2, and mechanisms regulating the amount of Nrf2 present in cells, are possible targets for approaches designed to enhance cellular stress responses to a greater degree than is possible via supplement-like strategies.

The cellular stress response is regulated at the transcriptional, translational, and post-translational levels by a family of heat shock transcription factors (HSFs) that are expressed and maintained in an inactive state under non-stress conditions. HSFs, essential for all organisms to survive to acute or chronic stress, are also important for normal development and lifespan-enhancing pathways, and the repertoire of HSF targets has thus expanded well beyond the heat shock genes.

Post-translational regulation of HSFs is emerging to integrate the metabolic state of the cell with stress biology, whereby controlling fundamental aspects of the health of the proteome and aging. In addition to this, the KEAP1/Nrf2/ARE pathway is the basis of the cellular defense. Induction of this pathway has been shown to be protective against various stress conditions. On the other side, under conditions of Nrf2 deficiency with failure to upregulate this pathway, increased sensitization and accelerated disease pathogenesis have been demonstrated.

Transcription factor Nrf2, under basal conditions, is continuously targeted for ubiquitination and proteasomal degradation by KEAP1, a protein acting as a repressor. It is well defined now that many inducers of the Nrf2 pathway chemically modify specific cysteine residues within KEAP1, leading to the loss of its ability to target Nrf2 for degradation. Subsequently, Nrf2 levels accumulate and hence activate transcription of NRF2-dependent genes which encode a large network of cytoprotective proteins, including those that are involved in the metabolism and transport of a wide array of endobiotics and xenobiotics, proteins that have antioxidant functions, as well as those that participate in the synthesis, utilization, and regeneration of glutathione and NAD(P).

Several phytochemicals act through the activation of transcription factor Nrf2. Under basal conditions, these protective systems do not operate at maximum capacity but can be induced to higher activity levels by redox-active compounds, such as hormetic nutrients, thus reducing the risks of developing malignancies and multiple chronic diseases.

Link: https://doi.org/10.1515/med-2024-0986

In this short commentary on omics analysis of the aging retina, researchers make the point that the evidence suggests the use of senolytic therapies to prevent or slow the development of age-related macular degeneration. This condition is associated with an increased burden of senescent cells in the retina and nearby tissues. When present over the long term, the mix of signals secreted by senescent cells induce inflammation, maladaptive tissue remodeling, and other problematic changes in the behavior of other cells.

Senescent retinal pigment epithelium (RPE) was linked to the onset of age-related macular degeneration (AMD), with senolytic agents assessed as potential treatments for AMD. A fact that has been seldom considered among the plethora of processes that are affected and, in turn, effected by cellular senescence (an adaptive cell response to stressors effected by an inflammatory secretome) is that of intercellular communication. In the case of the RPE, its functional and anatomical ties to the choroid are as much, if not more so, functionally relevant as those with the neuroretina.

A study applying a combined approach using bulk RNAseq, scRNAseq, and microarray RPE transcriptomics was able to draw substantial inferential data pertaining to intercellular communication between the RPE and the choroid. Intercellular communications between RPE cells and stromal elements involved in aging and senescence pertained notably to VEGF, BMP- and tenascin-mediated pathways, i.e., these pathways scored higher when mediating interactions between senescent cell populations. Consistently, AMD-derived patient samples scored higher overall in terms of senescence, and bulk RNAseq data showed a positive correlation in score increase with age.

These findings potentially support employing anti-aging therapies such as senolytic pharmacologic compounds to prevent or ameliorate progression to AMD, as well as underscore the necessity of more rigorous investigation into the interplay of senescence and cell-to-cell communication.

Link: https://doi.org/10.18632/aging.205914

There is a trend towards examining drugs that treat cardiovascular and metabolic disease in search of modest effects on aging. This is most obvious in the attempted repurposing of antidiabetic drugs such as metformin, acarbose, and canagliflozin, but this also extends to lipid-lowering drugs such as atorvastatin. Now that SGLT2 inhibitors are popular as weight loss drugs for the control of obesity, rather than just antidiabetics, that portfolio is also under consideration. One might consider that a possible common thread here is manipulation of lipid metabolism to reduce localized excesses of free cholesterol and other lipids that become toxic when present in too large an amount. One might also argue that reduction in blood glucose is also a common thread, but it is worth noting that statins can increase this measure.

The effect on life span in mice resulting from treatment by some these drugs (e.g. arcabose and canagliflozin) is smaller than that produced by mTOR inhibitors such as rapamycin, but large enough to think that there is something real going on under the hood. That said, others such as metformin come with a panoply of very poor animal data and questionable human data for effects on aging, despite their popularity. It may be that these drugs only help in the context of a sedentary, overweight population and are of little use to physically fit individuals. It may also be that effects on aging in long-lived species such as our own are too small to spend much time on - certainly one can already argue that to be the case for calorie restriction mimetics, which as a class have a larger effect on life span in mice than antidiabetics.

Repurposing effect of cardiovascular-metabolic drug to increase lifespan: a systematic review of animal studies and current clinical trial progress

Cardiovascular and metabolic drugs are frequently repurposed due to their diverse molecular mechanism in many diseases. With various molecular mechanisms found in the aging process, cardiometabolic drugs possess the potential to delay aging. For instance, aspirin and statins are potentially beneficial for cancer, or the pleiotropic effect of metformin in cancer, cardiovascular disease, and dementia in diabetic patients. Of note, aspirin and metformin could extend the lifespan of rodents. Our systematic review primarily focused on animal studies, with additional consideration given to clinical trials and their protocols.

Dramatic growth in the variety of longevity medicines that are being identified from animal studies is not always successfully translated to clinical applications. Aspirin treatment failed to prevent mortality and morbidity in healthy older adult people and potentially increased the hemorrhagic risk in those people. In parallel, metformin could not prolong the lifespan in drosophila and rather increased the mortality in female mice. Moreover, the clinical trials of metformin, such as MILES (Metformin In Longevity Study), showed the enhancement of longevity-related gene expressions, but the valid molecular mechanisms by which metformin facilitates this activity remain unknown.

Analysis of 49 animal trials and 10 clinical trial registries show that various cardiovascular and metabolic drugs have the potential to target lifespan. Metformin, acarbose, and aspirin are the three most studied drugs in animal trials. Aspirin and acarbose are the promising ones, whereas metformin exhibits various results. In clinical trial registries, metformin, omega-3 fatty acid, acarbose, and atorvastatin are currently cardiometabolic drugs that are repurposed to target aging. Published clinical trial results show great potential for omega-3 and metformin in healthspan.

Trained immunity is a phenomenon whereby some forms of vaccination can produce a broad improvement in defenses against pathogens, perhaps via a lasting suppression of the chronic inflammation generated by the innate immune system in old age. The innate immune system reacts in a maladaptive way to some of the forms of damage characteristic of aging, such as mislocalization of fragments of mitochondrial DNA. The mechanisms by which trained immunity produces a reduction in this maladaptive reaction are not well understood, but nonetheless, researchers here report on progress towards identifying small molecule inducers of trained immunity. Given a good side-effect profile and low cost, such small molecule drugs could be broadly beneficial.

Trained immunity is characterized by epigenetic and metabolic reprogramming in response to specific stimuli. This rewiring can result in increased cytokine and effector responses to pathogenic challenges, providing nonspecific protection against disease. It may also improve immune responses to established immunotherapeutics and vaccines. Despite its promise for next-generation therapeutic design, most current understanding and experimentation is conducted with complex and heterogeneous biologically derived molecules, such as β-glucan or the Bacillus Calmette-Guérin (BCG) vaccine. This limited collection of training compounds also limits the study of the genes most involved in training responses as each molecule has both training and nontraining effects.

Small molecules with tunable pharmacokinetics and delivery modalities would both assist in the study of trained immunity and its future applications. To identify small molecule inducers of trained immunity, we screened a library of 2,000 drugs and drug-like compounds. Identification of well-defined compounds can improve our understanding of innate immune memory and broaden the scope of its clinical applications. We identified over two dozen small molecules in several chemical classes that induce a training phenotype in the absence of initial immune activation - a current limitation of reported inducers of training. A surprising result was the identification of glucocorticoids, traditionally considered immunosuppressive, providing an unprecedented link between glucocorticoids and trained innate immunity. We chose seven of these top candidates to characterize and establish training activity in vivo. In this work, we expand the number of compounds known to induce trained immunity, creating alternative avenues for studying and applying innate immune training.

Link: https://doi.org/10.1073/pnas.2400413121

The consensus view of the evolution of aging is that it is a consequence of selection pressure for reproductive fitness operating more strongly in early life. This allows for the selection of cellular biochemistry that works well in youth but malfunctions in later life. The more specific and less widely held hyperfunction or quasi-programmed view of aging envisages degenerative aging as a consequence of the continued activity of developmental programs. It is interesting to here see researchers proposing a specific hyperfunction-like mechanism for dysfunction in aging, linking reactivation of developmental gene expression regulation to aging.

A mechanistic connection between aging and development is largely unexplored. Through profiling age-related chromatin and transcriptional changes across 22 murine cell types, analyzed alongside previous mouse and human organismal maturation datasets, we uncovered a transcription factor binding site (TFBS) signature common to both processes. Early-life candidate cis-regulatory elements (cCREs), progressively losing accessibility during maturation and aging, are enriched for cell-type identity TFBSs. Conversely, cCREs gaining accessibility throughout life have a lower abundance of cell identity TFBSs but elevated activator protein 1 (AP-1) levels.

We implicate transcription factor (TF) redistribution toward these AP-1 TFBS-rich cCREs, in synergy with mild downregulation of cell identity TFs, as driving early-life cCRE accessibility loss and altering developmental and metabolic gene expression. Such remodeling can be triggered by elevating AP-1 or depleting repressive H3K27me3. We propose that AP-1-linked chromatin opening drives organismal maturation by disrupting cell identity TFBS-rich cCREs, thereby reprogramming transcriptome and cell function, a mechanism hijacked in aging through ongoing chromatin opening.

Link: https://doi.org/10.1016/j.cmet.2024.06.006

Sarcopenia is the name given to the characteristic, progressive loss of muscle mass and strength that takes place with aging, eventually giving rise to frailty. Many different contributing mechanisms are thought to play a role in this process: lower protein intake; dysfunction in processing of dietary protein; dysfunction in the neuromuscular junctions connecting the nervous system to muscle fibers and consequent loss of signaling needed to maintain muscle tissue; loss of muscle stem cell activity and thus a reduced supply of new muscle cells; and so forth. As is usually the case, it is a work in progress to firmly connect the observed cell and tissue changes of sarcopenia to the low-level causes of aging, forms of damage such as mitochondrial dysfunction and the accumulation of senescent cells. It is also challenging to understand which of the mechanisms contributing to sarcopenia are most important, and therefore a priority for the development of therapies.

A few years ago researchers demonstrated that inhibiting NNMT in aging mice produced increased muscle mass and strength. This appears to work because NNMT is involved in the age-related loss of function and induction of cellular senescence in muscle stem cells. In today's open access paper, the same researchers report further on their work to develop small molecule NNMT inhibitors as a potential treatment for sarcopenia. In particular they note that NNMT inhibition is additive to the effects of resistance exercise on muscle, which is a promising development.

Nicotinamide N-methyltransferase inhibition mimics and boosts exercise-mediated improvements in muscle function in aged mice

Human hallmarks of sarcopenia include muscle weakness and a blunted response to exercise. Nicotinamide N-methyltransferase inhibitors (NNMTis) increase strength and promote the regenerative capacity of aged muscle, thus offering a promising treatment for sarcopenia. Since human hallmarks of sarcopenia are recapitulated in aged (24-month-old) mice, we treated mice from 22 to 24 months of age with NNMTi, intensive exercise, or a combination of both, and compared skeletal muscle adaptations, including grip strength, longitudinal running capacity, plantarflexor peak torque, fatigue, and muscle mass, fiber type, cross-sectional area, and intramyocellular lipid (IMCL) content. Exhaustive proteome and metabolome analyses were completed to identify the molecular mechanisms underlying the measured changes in skeletal muscle pathophysiology.

Remarkably, NNMTi-treated aged sedentary mice showed ~ 40% greater grip strength than sedentary controls, while aged exercised mice only showed a 20% increase relative to controls. Importantly, the grip strength improvements resulting from NNMTi treatment and exercise were additive, with NNMTi-treated exercised mice developing a 60% increase in grip strength relative to sedentary controls. NNMTi treatment also promoted quantifiable improvements in IMCL content and, in combination with exercise, significantly increased gastrocnemius fiber cross-sectional area. Detailed skeletal muscle proteome and metabolome analyses revealed unique molecular mechanisms associated with NNMTi treatment and distinct molecular mechanisms and cellular processes arising from a combination of NNMTi and exercise relative to those given a single intervention.

These studies suggest that NNMTi-based drugs, either alone or combined with exercise, will be beneficial in treating sarcopenia and a wide range of age-related myopathies.

Many groups are working on ways to lower the cost and improve the outcomes of screening for small molecules that slow the pace of aging. Sadly, unbiased screening is great way to produce calorie restriction mimetics and other interventions with a low probability of producing sizable effects on aging in long-lived mammals. The calorie restriction response is so sweeping, so entwined with fundamental cellular biochemistry, that there are many, many ways to induce some fraction of its benefits by altering expression of specific genes or interactions of specific proteins. Nonetheless, screening is the way in which much of the biotech research and development community does its work. The future of the longevity industry will likely involve a great many drug candidates that modestly slow aging, less effective than the actual practice of calorie restriction, at least until more researchers and companies find success in developing repair therapies that actually reverse aspects of aging.

Restraining or slowing ageing hallmarks at the cellular level have been proposed as a route to increased organismal lifespan and healthspan. Consequently, there is great interest in anti-ageing drug discovery. However, this currently requires laborious and lengthy longevity analysis. Here, we present a novel screening readout for the expedited discovery of compounds that restrain ageing of cell populations in vitro and enable extension of in vivo lifespan.

We monitored DNA methylation changes accompanying long-term passaging of adult primary human cells in culture. This enabled us to develop, test, and validate the CellPopAge Clock, an epigenetic clock with underlying algorithm, unique among existing epigenetic clocks for its design to detect anti-ageing compounds in vitro. Additionally, we measured markers of senescence and performed longevity experiments in vivo in Drosophila, to further validate our approach to discover novel anti-ageing compounds.

We find that the CellPopAge Clock can detect decelerated passage-based ageing of human primary cells treated with rapamycin or trametinib, well-established longevity drugs. We then utilise the CellPopAge Clock as a screening tool for the identification of compounds which decelerate ageing of cell populations, uncovering novel anti-ageing drugs, torin2 and dactolisib (BEZ-235). We demonstrate that delayed epigenetic ageing in human primary cells treated with anti-ageing compounds is accompanied by a reduction in senescence and ageing biomarkers. Finally, we extend our screening platform in vivo by taking advantage of a specially formulated holidic medium for increased drug bioavailability in Drosophila. We show that the novel anti-ageing drugs, torin2 and dactolisib (BEZ-235), increase longevity in vivo.

Link: https://doi.org/10.1186/s13073-024-01349-w

Aging clocks can be constructed from any sufficiently large collection of biological data using machine learning techniques. Here, researchers report on the production of aging clocks for specific organs from the circulating proteome assessed in blood samples. New clocks are published constantly; it remains to be seen as to which of these many clocks will become adopted and used more broadly. The primary challenge remains to develop an understanding of how the specific age-related changes that make up a given clock relate to the underlying causes of aging. It is difficult to rely upon a clock to speed up the development of interventions to slow or reverse aging without this knowledge. Just because a clock works fairly well in normally aged individuals doesn't mean that it will accurately reflect all of the contributions to degenerative aging. The clock may be insensitive or overly sensitive to any one specific contribution that is the target of therapy, and thus results will be misleading.

Recent studies show that human organs age at different rates similar to what has been reported in animals, which suggests a need for organ-specific measures of biological age. Previously developed organ age estimates include those developed from clinical metrics of organ function (glomerular filtration rate, blood pressure, etc), clinical blood chemistry, brain MRI scans, immune cell DNA methylation profiles, and the levels of organ-specific proteins in blood plasma. Many questions regarding the reproducibility and utility of organ age estimates remain. For example, it is unclear the extent to which organ age estimates are stable across cohorts and longitudinal sampling, are sensitive to organ-specific diseases and modifiable lifestyle choices, and whether they predict mortality independent of each other and established aging biomarkers. Furthermore, it is unclear which organs are key to longevity in humans.

Organ-derived plasma protein signatures derived from aptamer protein arrays track organ-specific aging, disease, and mortality in humans, but the robustness and clinical utility of these models and their biological underpinnings remain unknown. Here, we estimate biological age of 11 organs from 44,526 individuals in the UK Biobank using an antibody-based proteomics platform to model disease and mortality risk. Organ age estimates are associated with future onset of heart failure (heart age HR=1.83), chronic obstructive pulmonary disease (lung age HR=1.39), type II diabetes (kidney age HR=1.58), and Alzheimer's disease (brain age HR=1.81) and sensitive to lifestyle factors such as smoking and exercise, hormone replacement therapy, or supplements.

Remarkably, the accrual of aged organs progressively increases mortality risk while a youthful brain and immune system are uniquely associated with disease-free longevity. These findings support the use of plasma proteins for monitoring organ health and the efficacy of drugs targeting organ aging disease.

Link: https://doi.org/10.1101/2024.06.07.597771

Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related state in which a hematopoietic stem cell suffers a mutation that gives it and its descendants replication advantages over their peers. Mutations of this nature spread throughout cell populations in an overlapping, layered way as they occur, a form of somatic mosaicism, but occurring in hematopoietic and immune cells. Like somatic mosaicism more generally, this has the look of a problem that should cause undesirable consequences. Drawing solid connections between CHIP and specific age-related diseases is a work in progress, however.

CHIP originated as the description of an early stage of dysfunction leading to leukemia, in that clonal expansion of potentially cancerous mutations in hematopoietic cells is observed. The connection to cancer is thus fairly robust. There is also less extensive evidence for CHIP to contribute to the progression of many age-related diseases via an increase in the chronic inflammation of aging. Much of the discussion to date has involved cardiovascular disease, but in today's open access paper, researchers present evidence for CHIP to accelerate the progression of chronic kidney disease. In both of these cases, inflammation is the easy answer when it comes to questions about mechanisms, but that doesn't mean it is definitely the case.

Clonal hematopoiesis of indeterminate potential contributes to accelerated chronic kidney disease progression

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by the clonal expansion of blood cells carrying somatic mutations in specific driver genes. An age-related disorder, CHIP is rare in the young but its prevalence increases rapidly in older adults, with at least 10% of individuals aged 65 and older affected. Recent studies have identified a causal role for CHIP in several chronic diseases of aging including atherosclerotic cardiovascular disease, heart failure, gout, liver fibrosis and cirrhosis, osteoporosis, and chronic obstructive pulmonary disorder (COPD).

CHIP is also recognized as a risk factor for acute kidney injury (AKI) severity and non-recovery. Mouse model evidence and human genetic studies point to inflammation as the key mediator of the CHIP-associated risk in each of these conditions. A hallmark feature of chronic kidney disease (CKD), chronic inflammation confers higher risks of kidney failure in CKD patients. CHIP has been associated with incident kidney function decline in the general population, though it is not clear whether the inflammatory burden of CHIP would meaningfully intensify the already-inflamed CKD state and affect clinical outcomes.

In this study, we first examined the prospective associations between CHIP and CKD progression events in four large CKD cohorts, totaling 6,216 individuals: the Chronic Renal Insufficiency Cohort (CRIC), the African American Study of Kidney Disease (AASK), subjects with CKD from the BioVU biorepository, and the Canadian study of prediction of death, dialysis and interim cardiovascular events (CanPREDDICT). We then used Mendelian randomization as an orthogonal method to assess the contribution of CHIP to estimated glomerular filtration rate (eGFR) decline. Finally, we evaluated the effect of experimental Tet2-CHIP on kidney function in a mouse model of CKD.

n the present work, we identify that non-DNMT3A CHIP is associated with a greater risk of kidney function decline in individuals with CKD, both when examining incident 50% eGFR decline or kidney failure events and annualized eGFR slopes. In Mendelian randomization analysis, a genetic predisposition for CHIP development was associated with a faster eGFR decline in those with CKD and diabetes. Additionally, in a Tet2-CHIP mouse model - the most common type of non-DNMT3A CHIP - dietary adenine administration led to more pronounced kidney functional impairment, inflammatory cell infiltration into kidney parenchyma, increased cytokine expression, and development of renal fibrosis when compared to mice without CHIP mutations fed the same diet. These findings are in line with our pilot study and with our work identifying non-DNMT3A CHIP as a risk factor for incident kidney function decline in the general population as well as for impaired recovery after AKI.

Extracellular vesicles for use in therapy can be derived from engineered cells in order to adjust their contents in favorable ways. Here, researchers derive vesicles from genetically engineered osteoblasts in order to promote bone formation in a mouse model of osteoporosis. Osteoporosis is the name given to the age-related loss of bone mineral density. Bone is constantly remodeled, deposited by osteoblast cells and removed by osteoclast cells. In youth these activities are balanced, but the molecular damage of aging produces changes that favor osteoclasts. The result is a steady loss of bone density, leading to brittle, fracture-prone bones. Any approach that restores the balance between osteoblasts and osteoclasts is likely to work, even if it is essentially compensatory rather than addressing the causes of the problem.

This research investigated the role of WIF1 in controlling the osteogenic differentiation stage of the osteoblast precursor cell line (MC3T3-E1 cells) and assessed its potential therapeutic impact on osteoporosis. Using MC3T3-E1 cells, the researchers found that Wif1 expression increased significantly during the terminal stage of osteoblast differentiation, indicating its role as a marker gene in regulating osteogenesis. Knockdown of Wif1 reduced mineralization and osteogenic potential, while Wif1 overexpression enhanced osteogenic differentiation. Furthermore, Wif1 overexpression activated mitophagy, as evidenced by increased autophagosome formation around mitochondria.

The study also explored the therapeutic potential of extracellular vesicles (EVs) derived from Wif1-overexpressing osteoblasts. These EVs significantly promoted osteogenesis in bone marrow mesenchymal stem cells (BMSCs) in vitro and demonstrated bone-targeting capabilities in vivo. In a mouse model of osteoporosis induced by ovariectomy, treatment with EVs derived from Wif1-overexpressing osteoblasts reversed bone loss, highlighting their potential as a therapeutic intervention for osteoporosis. These findings underscore the significance of Wif1 in bone biology and suggest its potential as a therapeutic target for osteoporosis.

Link: https://www.eurekalert.org/news-releases/1050445

An aneurysm is a weakened section of a major blood vessel that expands and grows into a balloon-like structure. Rupture is often fatal. Aneurysms tend to form in specific locations, and researchers here ask why this is the case. Associating a characteristic set of changes in cell biochemistry with the formation of aneurysms in mice is a first step on a long road towards better detailed understanding of the mechanisms involved, and the development of interventions to prevent formation of aneurysms.

A vascular dilatation in the aorta can be life-threatening if it bursts. These so-called aortic aneurysms typically form in the same sites of the large blood vessel: either on the upper arch or in the abdominal cavity. In order to find out what distinguishes the repeatedly affected vascular regions from others, researchers developed a method to specifically examine the endothelium of the aorta: the innermost layer of the blood vessel. "We know from other vascular diseases such as arteriosclerosis that there are changes in this innermost layer long before symptoms appear."

The researchers analyzed the gene activity at different sites of the aorta and compared the sites where aneurysms frequently form with those that don't show this tendency. "We identified certain patterns of upregulated genes in the sites where dilatations frequently form. These remarkably active genes affect, for example, changes in the extracellular matrix, the formation of new blood vessels and some inflammatory reactions." Such genetic abnormalities are also found in tissue from human aneurysms. The researchers also determined the stiffness of the endothelium in the healthy aortic samples. The less elastic the endothelium, the more detrimental it is to vascular health. They proved that the endothelium was stiffer in the sites where aneurysms frequently develop than in the control areas.

The team used an established model of a knock-out mouse that tends to form aneurysms due to a targeted genetic modification. If high blood pressure is additionally induced in these mice, aortic aneurysms form. They compared the genetic activity in the aortic endothelium of the genetically modified mice without aneurysm with that of mice that had developed an aneurysm due to added high blood pressure. "In the mice with aneurysms, we found a much greater degree of gene alterations that belong to the same category as the gene alterations in healthy mice. In the mice with an aneurysm, the vessel wall was also altered." The researchers conclude that the sites where aneurysms frequently form are weak points from the outset. We don't know exactly why this happens - perhaps it has to do with the mechanical conditions and the blood flow there, or perhaps the altered gene activity at these sites is inherited from birth." The latter seems plausible, as the aorta develops at different heights from different embryonic precursor cells.

Link: https://news.rub.de/english/press-releases/2024-07-05-medicine-why-aortic-aneurysms-form-arch-or-abdominal-segment

The primary function of mitochondria is production of the chemical energy store molecule adenosine triphosphate (ATP) to power cell activity, though mitochondria are also integrated into many core cellular processes. Loss of mitochondrial function is an important determinant of the pace of aging, and mitochondrial dysfunction is characteristic of cells in aged tissues. A cell contains hundreds of mitochondria, these organelles descended from the first ancient symbiotic bacteria to take up residence in what would become the ancestor of all eukaryotes. Mitochondria retain an atrophied bacterial genome, and can replicate like bacteria. They also frequently fuse together and promiscuously pass around component parts. The quality of mitochondria is assured in part by these ongoing dynamics, but more importantly by mitochondrially-targeted autophagy, known as mitophagy, that flags dysfunctional mitochondria for delivery to a lysosome where they are broken down and recycled.

The balance between mitochondrial fission and fusion appears important to mitochondrial function, though there is some debate as to why exactly this is the case. Too many small mitochondria and too many large mitochondria may both be bad, and for different reasons. The second order consequences of changes in the complex regulation of mitochondrial fission and fusion are poorly mapped and understood, especially when it comes to how these changes interact with mitophagy and the capacity to remove dysfunctional mitochondria before they cause harm to the cell. Today's open access paper provides an example of this lack of understanding, as the authors are surprised to note that increasing expression of fission regulators has much the same outcome as increasing expression of fusion regulators. In both cases, mitochondria appear to exhibit dynamics associated with greater fission, and the life span of engineered nematode worms is increased. This is not an intuitive outcome.

Overexpression of mitochondrial fission or mitochondrial fusion genes enhances resilience and extends longevity

The dynamicity of the mitochondrial network is crucial for meeting the ever-changing metabolic and energy needs of the cell. Mitochondrial fission promotes the degradation and distribution of mitochondria, while mitochondrial fusion maintains mitochondrial function through the complementation of mitochondrial components. Previously, we have reported that mitochondrial networks are tubular, interconnected, and well-organized in young, healthy C. elegans, but become fragmented and disorganized with advancing age and in models of age-associated neurodegenerative disease.

In this work, we examine the effects of increasing mitochondrial fission or mitochondrial fusion capacity by ubiquitously overexpressing the mitochondrial fission gene drp-1 or the mitochondrial fusion genes fzo-1 and eat-3, individually or in combination. We then measured mitochondrial function, mitochondrial network morphology, physiologic rates, stress resistance, and lifespan.

Surprisingly, we found that overexpression of either mitochondrial fission or fusion machinery both resulted in an increase in mitochondrial fragmentation. Similarly, both mitochondrial fission and mitochondrial fusion overexpression strains have extended lifespans and increased stress resistance, which in the case of the mitochondrial fusion overexpression strains appears to be at least partially due to the upregulation of multiple pathways of cellular resilience in these strains.

Overall, our work demonstrates that increasing the expression of mitochondrial fission or fusion genes extends lifespan and improves biological resilience without promoting the maintenance of a youthful mitochondrial network morphology. This work highlights the importance of the mitochondria for both resilience and longevity.

The paper noted here is an illustrative snapshot of one tiny part of the search for new mechanisms of action that takes place constantly in academia and the pharmaceutical industry. Cell metabolism remains an only partially charted expanse, the high points filled in, and mostly a blank canvas in between. The poorly explored regions of metabolism could yield any number of interesting points of intervention, each a starting point for the present industry-standard approach of small molecule drug discovery. That said, there isn't that much of an incentive to pour funds into search initiatives because the odds of success in the current paradigm are very low. The vast majority of discoveries do not lead to even marginally useful drugs. Hence there is considerable interest at the present time in the development of new computational infrastructure technologies that can reduce the cost of discovery in some way.

Traf2- and Nck-interacting kinase (TNIK) has emerged as a key regulator of pathological metabolic signaling in several diseases and is a promising drug target. Originally studied for its role in cell migration and proliferation, TNIK possesses several newly identified functions that drive the pathogenesis of multiple diseases. Specifically, we evaluate TNIK's newfound roles in cancer, metabolic disorders, and neuronal function. We emphasize the implications of TNIK signaling in metabolic signaling and evaluate the translational potential of these discoveries.

TNIK signaling appears to converge on four critical hallmarks of aging: cellular senescence, deregulated nutrient sensing, chronic inflammation, and altered intercellular communication. TNIK's contribution to these processes implicate it as a possible contributor to aging-related pathology, particularly by promoting conditions like cancer and metabolic dysregulation. Thus, as aging has been revealed to increase the incidence and severity of the aforementioned diseases in this opinion article, an interesting hypothesis would be whether TNIK dysregulation contributes to the aging process itself or is a consequence of it.

Link: https://doi.org/10.1016/j.tips.2024.04.010

Based on the animal data, mTOR inhibition by rapamycin is the best of the presently well studied pharmacological approaches to slow aging. Rapamycin is cheap, has decades of safety data, and produces a greater extension of life span in animal models than exercise. Sad to say, but improving on the benefits of exercise remains the low bar by which we can judge and reject the vast majority of efforts to slow the progression of aging. Human studies of rapamycin in the context of aging have yet to be conducted in any extensive manner, despite a fair amount of off-label use. So it is pleasant to see that one group has recently obtained funding to conduct a study in older people with periodontal disease; the specific condition that is the target of the study is less important than the range of data on biomarkers relevant to general health and aging that will be collected.

A clinical trial is starting to test a drug taken by many so-called longevity enthusiasts. Rapamycin was first approved by the FDA for transplant patients in the 1990s. At high doses, it suppresses the immune system. At low doses, it seems to help tamp down inflammation. It works by inhibiting a pathway in the body called mTOR, which appears to be key to healthy aging. Rapamycin is not approved for pain or anti-aging, though doctors can prescribe it off-label. Researcher Matt Kaeberlein has surveyed about 300 people who take low doses, and many report benefits. But anecdotes are no replacement for science, and that's where dental group at the University of Washington comes in. The researchers have FDA approval to test rapamycin in patients with gum disease, a common condition that tends to accelerate with age.

There is already some evidence from transplant patients that rapamycin may help improve oral health, and as part of the study, researchers will also measure changes in participants' microbiomes and their biological clocks. The study will enroll participants over the age of 50 who have gum recession. They will take the drug for eight weeks. The researchers think of gum disease as a kind of canary in the coal mine. It's linked to a higher risk of heart disease, for instance, so they may share a common root cause. The researchers have received grants to conduct this trial, which could open the door to further studies to determine whether rapamycin can help slow down other age-related diseases.

Link: https://www.npr.org/2024/07/02/nx-s1-5008777-e1/rapamycin-is-being-studied-to-see-if-it-can-slow-down-age-related-diseases-in-humans

I attended this year's Longevity Summit Dublin in June, hosted by the Longevity Escape Velocity (LEV) Foundation folk, but was so buried in work that there was no chance I would be able to take comprehensive notes for later formatting into a post here. Fortunately there are a good number of patient advocates in the community who can do just as good a job as I might, were I less encumbered, and thus Lifespan.io has published notes on some of the highlights from the conference.

The Longevity Summit Dublin is, if you like, the spiritual successor to the Strategies for Engineered Negligible Senescence (SENS) conference series of past years: scientists presenting novel research aimed at the goal of treating aging as a medical condition; biotech startups showcasing their programs of development relevant to the treatment of aging; patient advocates arguing for more funding and faster progress for all of the above. It is well worth attending if this is an area of research and development that interests you.

Four Days of Longevity in Dublin: Conference Highlights

The first day began with a "pre-session" before the official opening, and the very first talk set an interesting tone. It was given by Michael Suk, the newly elected chair of the American Medical Association (AMA)'s Board of Trustees. The AMA is the biggest organization of medical doctors in the US, and having its leader talk at a longevity conference is an important event and an encouraging sign of our field inching closer to the mainstream. Suk, through a remote connection, praised the recent scientific advances that bring us closer to personalized medicine that would allow for continuing healthspan extension. "The work you do here," he said, "has the potential to change lives, to offer hope where there is none, and to redefine the future of healthcare. Together, we are building a future where technology and compassion go hand in hand, where surgical care is not just about precision, but about people, and where the promise of a longer, healthier life is within reach for all."

Aubrey de Grey welcomed the participants and expanded on longevity escape velocity (LEV), the concept he has been promoting for decades that gave the name to his foundation. LEV means buying time by eliminating age-related damage (another concept that de Grey pioneered and is now entering the mainstream): "If you take someone who is, let's say, 60 years both chronologically and biologically, and you rejuvenate them reasonably well so that they're back to being biologically 40, then they won't be biologically 60 again until they're 80." However, some types of damage are harder to tackle, and they will continue to accumulate, but their effect will not be as devastating as today's combined effects of all types of damage. Hopefully, during those 20 extra years of life, geroscientists "will have been continuing to improve this rejuvenation arsenal. The idea is that there's some finite, in fact quite modest, minimum rate at which we need people like the people in this room to be improving the comprehensiveness of rejuvenation technologies in order to stay one step ahead of the problem."

Revel Pharmaceuticals is one of those brave small companies to literally boldly go where no one has gone before: in this case, towards reversing the molecular damage produced by advanced glycation end products (AGEs). Like their name suggests, AGEs accumulate with age in blood and tissues, causing inflammation and the stiffening of the extracellular matrix by binding to molecules like collagen. Aaron Cravens, Revel's CEO, told the audience that his company is after a specific AGE, carboxymethylysine (CML). It exists in two forms: a free form present in cells and a bound form that accumulates in the extracellular matrix (for instance, in arterial walls). "The body has no physiological means of removing this," Cravens said. Revel built an enzyme engineering platform to develop bespoke enzymes. Currently, it focuses on removing the free-floating form of CML. It strongly contributes to inflammation, in particular by binding to the RAGE receptor and initiating inflammatory signaling.

Michael Ringel of the Boston Consulting Group talked about the recent trends in the longevity field. After decades of not taking geroscience seriously, there is apparently a growing understanding in society that investigating the biology of aging is the only way to ward off the economic threats of population aging and to meaningfully increase human lifespan. If we do nothing, global resources might be devastated by the need to care for the increasingly aged population, exacerbated by slumping birth rates. However, even a slight slowing of the rate of aging would bring unprecedented prosperity, adding hundreds of trillions of dollars to the global economy over the course of a decade.

The Rising Star Award this year went to Alexander Fedintsev from the Radical Life Extension Group. In his talk, Fedintsev proposed a new hallmark of aging: clonal hematopoiesis of indeterminate potential (CHIP). Clonal hematopoiesis is a condition in which a single hematopoietic stem cell (HSC) acquires genetic mutations that give it a growth advantage, allowing it to expand clonally within the bone marrow. This results in a significant proportion of blood cells being derived from this single mutated stem cell rather than from a diverse population of HSCs. Currently, we don't have good tools to combat CHIP. However, prolonged inhibition of the pro-inflammatory cytokine IL-6 has shown some promise, including in non-human primates. Answering a question about how safe lifelong IL-6 inhibition is, Fedintsev noted that rheumatoid arthritis patients receive such therapy, which only causes a slight increase in infections but is associated with less cardiovascular risk.

The Lifetime Achievement Award was given this year to Maria Blasco, a veteran geroscientist whose contribution to the longevity field is formidable. After a short ceremony Maria proceeded to give a keynote talk on telomeres, the leading topic of her research for the last three decades. Maria described some of the most important experiments with telomeres. For instance, telomerase deficiency in mice causes accelerated aging, while transgenic mice with extra-long telomeres live longer and, importantly, get less cancer, which is the leading cause of death in lab mice. These mice also showed significant improvements in healthspan: better metabolism, less cognitive decline, less osteoporosis, and so on. Another study that Maria mentioned might provide an explanation of why turning back telomerase expression seems to lower the risk of cancer instead of elevating it: shorter telomeres cause chromosomal instability, which increases the risk of oncogenic mutations. Genetically engineered telomerase-expressing mice were more protected from cancer even when challenged with oncogenic mutations.

Melissa King has over two decades of experience in business, non-profits, and public affairs. About two years ago, she co-founded Healthspan Action Coalition with another veteran medical research advocate, Bernard Siegel. Melissa has steered important campaigns and projects in patient advocacy and biomedical research funding. For example, she led a successful ballot initiative in California to secure $8.5 billion in funding for the California Institute for Regenerative Medicine, which specializes in stem cell research. Patient advocacy, Melissa argued, is impressively effective in mobilizing public opinion and funds for health research initiatives. Now is the time to apply the principles of patient advocacy to prolonging healthspan. After all, when it comes to aging, every person on the planet is a patient. This creates a potential for a truly massive movement.

Short-term inflammation is a necessary part of the immune response to pathogens, injury, and problematic cells. Lasting unresolved inflammation is harmful, however. It is a feature of aging, but can also occur to significant degrees in earlier life as a result of autoimmunity or being very overweight. Researchers here show that early adult chronic inflammation correlates with worse cognitive function nearly two decades later. One can debate the degree to which this is a measure of accelerated degenerative aging versus the progression of existing conditions, but it is certainly true that chronic inflammation is to be avoided and minimized to the degree that it is possible to do so.

There are two kinds of inflammation. Acute inflammation happens when the body's immune response jumps into action to fight off infection or an injury. It is localized, short-term and part of a healthy immune system. Chronic inflammation is not considered healthy. It is a low-grade inflammation that lingers for months or even years throughout the body. It can be caused by autoimmune disorders like rheumatoid arthritis or multiple sclerosis, physical stress or other causes. Symptoms of chronic inflammation include joint pain or stiffness, digestive problems, and fatigue.

The study involved 2,364 people age 24 to 58. They were followed for 18 years. Participants' inflammation levels were measured at the start of the study and three more times throughout the study. The study looked at levels of C-reactive protein (CRP) in the blood. CRP is produced by the liver and increases when there is inflammation in the body. Researchers divided participants into three groups based on inflammation levels: consistently higher, moderate or increasing and lower stable. Of the total participants, 911 people, or 39%, had consistently higher inflammation; 381 people, or 16%, had moderate or increasing inflammation; and 1,072, or 45%, had lower stable inflammation.

Five years after their last inflammation measurement, participants were given six tests to examine thinking and memory skills. On a test that measures processing speed and memory, participants were given a key showing numbers and corresponding symbols. They then drew those symbols on a separate list of random numbers as quickly as possible. Of those in the low group, 10% had poor cognitive performance, compared to 21% in the middle group and 19% in the high group. After adjusting for factors such as age, physical activity and total cholesterol, researchers found that both the high and moderate groups were more likely to have poor performance in processing speed and executive function. For processing speed, researchers found that those in the moderate group were more than two times more likely to have poor performance and those in the highest group were nearly two times more likely to have poor performance than those in the lowest group. For executive function, those with the highest CRP levels had a 36% higher risk of poor performance.

Link: https://www.aan.com/PressRoom/Home/PressRelease/5183

You may recall that Greenland sharks are extremely long-lived, a trait only comparatively recently discovered as, like many marine species, these sharks are nowhere near as well studied as tends to be the case for larger land animals. Researchers have now started in on the process of trying to understand why this is the case. As reported here, initial measurements of muscle metabolism show little variation with age. An absence of declining function with age over near all of a lifespan is characteristic of many long-lived species. It remains to be seen as to whether studying the biochemistry of these unusually long-lived species will yield means of enhancing longevity in humans in the near term of the next few decades. It is too soon to say, even if commenting on the much more extensive study of long-lived mammalian species such as the naked mole-rat.

Greenland sharks (Somniosus microcephalus) are the longest living vertebrate with an expected lifespan of at least 270 years and possible lifespan beyond 500 years. Previously it was thought that this long lifespan was due to the shark's cold environment and minimal movement, but the factors behind this species extreme longevity appear to be far more complex - prompting researchers to investigate alternative theories. "Most species show variation in their metabolism when they age. We want to determine if Greenland sharks also show this traditional sign of aging or if their metabolism remains unaltered over time."

To measure the metabolism of the sharks, researchers conducted enzyme assays on preserved muscle tissue samples from Greenland sharks. They measured the metabolic activity of these enzymes with a spectrophotometer across a range of different shark ages and environmental temperatures. Surprisingly, researchers found no significant variation in muscle metabolic activity across different ages, suggesting that their metabolism does not appear to decrease over time and may play a key role in their longevity. The results of this study also show that the Greenland shark's metabolic enzymes were significantly more active at higher temperatures. "This would suggest that the shark's red muscle metabolism is not specially adapted for the polar environment, otherwise we would have expected to see less of a temperature related difference in activity."

Link: https://www.eurekalert.org/news-releases/1049496

Aging is by definition a loss of function and capacity, an accumulation of damage. A person can certainly turn out to be in much better shape than equivalently aged peers in later life, via some combination of lifestyle choices, proactive use of medical resources, and a little good fortune. But that doesn't mean that this individual is healthy in comparison to the younger version that existed decades ago. Again, aging is by definition a loss of function and capacity, a disruption of the normal healthy operation of tissues. An old person is unhealthy when compared to his or her younger self.

Today's research materials make this point in the course of presenting new data on the prevalence of heart valve disease in the older population. As is the case for recent research demonstrating that many people in their 40s and 50s exhibit the early development of atherosclerotic lesions, hidden and lacking evident symptoms, here it was found that more than a quarter of older people lacking evident symptoms do in fact have heart valve disease. This asymptomatic stage of dysfunction is a foundation for later, more severe, and more evident cardiovascular disease.

More than a quarter of 'healthy' over-60s have heart valve disease, according to new research

The sheer scale of undiagnosed heart valve disease in our ageing population has been revealed for the first time, thanks to new research. More than a quarter of healthy and symptom-free over 60s examined in the study were found to have previously undetected heart valve disease. "This study focused on understanding how widespread heart valve issues of any severity are among healthy, symptom-free adults without any known heart diseases. We examined almost 4,500 individuals aged 60 and older from three regions in the UK: Norfolk, West Midlands, and Aberdeen, using echocardiography, which is an ultrasound of the heart."

"Our findings showed that more than 28% of these adults had some form of heart valve disease, although reassuringly it was only mild in the majority of the cases. The data also indicated that age was the main factor associated with these heart valve problems, meaning that the older a person is, the higher their chance of having a significant valve issue. The main problems are caused by the valve not opening fully (valve stenosis) which restricts the flow of blood, or the valve not closing properly (valve regurgitation) which means blood can leak back in the wrong direction. These problems can put extra strain on the heart and make the heart work harder. Over time, it can increase the risk of having a heart attack, stroke, and other heart conditions."

Prevalence of asymptomatic valvular heart disease in the elderly population: a community-based echocardiographic study

With an ageing population, the presence of asymptomatic valvular heart disease (VHD) in the community remains unknown. This was a prospective cohort study conducted between 2007 and 2016 in the UK. Asymptomatic patients with no prior indication for echocardiography were invited to participate and evaluated with a health questionnaire, clinical examination, and transthoracic echocardiography. A total of 10,000 individuals were invited through their general practices. A total of 5429 volunteered to participate, of whom 4237 were eligible for inclusion. VHD was diagnosed in more than a quarter of patients (28.2%). Age is strongly associated with an increased incidence of significant VHD.

A robust discussion is underway in the cancer research community regarding the merits of targeting senescent cells for destruction as a part of cancer therapy. While it is generally agreed that clearing lingering senescent cells following successful treatment with present cancer therapies is a good idea, as those senescent cells contribute to the greater burden of age-related disease and mortality observed in cancer survivors, it is less clear that destroying senescent cancer cells during treatment of the cancer will always provide a net benefit. Those senescent cells can in some cases contribute to the destruction of the cancer rather than enable its growth. Nonetheless, researchers here argue that adapting T cell immunotherapies to target senescent tumor cells is a promising avenue of investigation.

The exploitation of the patient's immune system to eliminate cancer cells has long been tested through the development of innovative strategies with remarkable success and high expectations. Our growing understanding of the immune system has allowed the design of novel anticancer therapies. However, tumor cells are generally poor antigen-presenting cells, evading the immune response in early stages of the pathophysiology and restricting immunotherapeutic efficacy to only a minor group of cancers. Nevertheless, targeting of senescent cells in the context of cancer and aging may upsurge as an alternative to this critical limitation, through the selective activation of a T cell-specific response against senescent cells within the tumor or its vicinity.

Recent evidence supports the use of tumor-associated senescent cells (TASCs) as sources of peptide antigens and adjuvants for anticancer vaccine development. Their senescence-associated secretory phenotype (SASP) provides abundant release of stimulatory cytokines, which, in conjunction with high levels of antigen presentation, generates a robust tumor specific T cell response. As discussed here, this approach will potentiate their adjuvanticity in cancer targeting, allowing the design of stronger and directed immunotherapeutic strategies. Moreover, since cancer and senescent cells share common antigens, this immunotherapeutic approach could also be effective against aging and age-related diseases. Therefore, cancer immunotherapy based on TASCs and other types of senescent cells may achieve exciting outcomes beyond cancer therapy.

Link: https://doi.org/10.18632/aging.205975

In wet macular degeneration, excessive formation of leaky blood vessels in the retina leads to photoreceptor cell death and blindness. Current treatments try to sabotage part of the signaling system responsible for angiogenesis, the process of blood vessel creation. Here, researchers instead look at inhibition of telomerase after finding increased expression of telomerase in mouse models of the condition. This is interesting, but it is worth remembering that telomerase dynamics are very different in mice and humans. Mice normally express telomerase in a range of somatic cells, where humans do not. There is some doubt that mechanisms involving telomerase that are discovered and characterized in mice will prove to be usefully relevant in humans in the same way.

Choroidal neovascularization (CNV) is the principal driver of blindness in neovascular age-related macular degeneration (nvAMD). Increased activity of telomerase has been associated with endothelial cell proliferation, survival, migration, and invasion in the context of tumor angiogenesis. Expanding on this knowledge, we investigated the role of telomerase in the development of CNV in a mouse model. We observed increased gene expression and activity of telomerase in mouse CNV. Genetic deficiency of the telomerase components, telomerase reverse transcriptase (Tert) and telomerase RNA component (Terc) suppressed laser-induced CNV in mice. Similarly, a small molecule inhibitor of TERT (BIBR 1532), and antisense oligonucleotides (ASOs) targeting Tert and Terc reduced CNV growth.

Bone marrow chimera studies suggested that telomerase activity in non-bone marrow-derived cells is crucial for the development of CNV. Comparison of BIBR 1532 with VEGF neutralizing therapeutic strategy in mouse revealed a comparable level of angiosuppressive activity. However, when BIBR and anti-VEGF antibodies were administered as a combination at sub-therapeutic doses, a statistically significant suppression of CNV was observed. These findings underscore the potential benefits of combining sub-therapeutic doses of BIBR and anti-VEGF antibodies for developing newer therapeutic strategies for NV-AMD. Telomerase inhibition with BIBR 1532 suppressed induction of multiple cytokines and growth factors critical for neovascularization.

In conclusion, our study identifies telomerase as a promising therapeutic target for treating neovascular disease of the eye and thus provides a proof of principle for further exploration of telomerase inhibition as a novel treatment strategy for nvAMD.

Link: https://doi.org/10.1016/j.bbadis.2024.167156

Epidemiological researchers have for been slowly moving away from body mass index and towards measures that more directly reflect the burden of visceral fat tissue. Waist circumference and measures such as weight-adjusted waist index are now often used. Here, researchers show a correlation between shorter telomere length and larger weight-adjusted waist index; people who are more overweight tend to have shorter telomeres.

Telomere length taken from white blood cells in a blood sample correlates with aging, but only in large studies. It isn't a great measure of biological age, but in principle reflects some combination of (a) replication stress placed upon the immune system, as telomeres shorten with each cell division, and (b) the pace at which replacement immune cells with long telomeres are generated by hematopoietic stem cells. In the case of T cells of the adaptive immune system it also reflects the degeneration of the thymus, as T cells mature in that organ. Degenerative aging will tend to lead to worse stem cell function and greater stress placed upon the immune system, but there is a lot of variability from individual to individual.

Does being overweight accelerate aging? One can mount a good argument that it does, based on a survey of mechanisms involved in aging and how they are altered in overweight individuals. Certain, excess visceral fat tissue appears to increase the pace at which senescent cells accumulate. This is a noteworthy feature of aging, as lingering senescent cells disrupt tissue structure and function via pro-inflammatory signaling. Excess visceral fat tissue also generates chronic inflammation via a range of other mechanisms.

Associations between weight-adjusted-waist index and telomere length: Results from NHANES: An observational study

Telomeres, which are also known as the "protective caps" of chromosomes, are DNA-protein complexes located at the tip of chromosomes consisting of DNA repetitions and a small number of protective binding proteins. They protect chromosomal ends from genomic damage and instability. Telomeres shorten with each cell cycle, and when they become severely short, cells either enter senescence, cell cycle arrest, or undergo apoptosis. Telomere attrition is widely recognized as a prominent hallmark of aging. Telomere attrition has been linked to numerous ailments, including diabetes mellitus, Alzheimer disease, and major cardiovascular diseases (CVD) such as atherosclerosis, hypertension, and heart failure. Moreover, shortened telomeres are connected with an elevated risk of all-cause mortality among the general population.

Obesity poses a significant threat to public health worldwide. However, the most commonly used traditional metric to define being overweight, Body mass index (BMI), cannot distinguish between fat mass and lean mass, nor between central fat and peripheral fat. It is worth noting that weight-adjusted-waist index (WWI) has the potential to compensate for both of these deficiencies. WWI, which is standardized by adjusting the waist circumference (WC) based on body weight, was first proposed in 2018. The initial objective was to construct an obesity index that indicates WC, which exhibits a weak connection with BMI. The aim was to alleviate the obesity paradox of BMI versus mortality. Like telomere length, WWI was found to be directly proportional to age, suggesting its unique function to reflect the age-related alteration of body composition.

This article presents the results of the inaugural study on the relationship between WWI and telomere length in adult populations. The cross-sectional investigation analyzed data from 3479 participants from the National Health and Nutrition Examination Survey (NHANES) conducted from 1999 to 2000. To inspect linear and nonlinear correlations, we adopted weighted multiple logistic regression analysis and smooth curve fit, respectively. In addition, threshold effects and subgroup analyses were accomplished. In the fully adapted model, a significant adverse association of WWI with telomere length was detected. The adverse correlation remained consistent across all subcategories. We also discovered an inverted U-shaped curve linking WWI and telomere length, with a conspicuous inflection point. The inflection point suggests that controlling WWI within an optimum range might be essential for aging and health.

Microglia are innate immune cells resident in the central nervous system, analogous to macrophages elsewhere in the body, but with an extended portfolio of activities that include assisting in management of synaptic connections between neurons. In recent years, researchers have placed an ever greater focus on the behavior of microglia, particularly their contribution to chronic inflammatory signaling in the brain, in the context of aging and neurodegenerative disease. Aging is characterized by overly active inflammatory microglia and greater numbers of senescent microglia. Ways to clear and regenerate the microglial population, or otherwise change their behavior for the better, have shown some promise in animal models. Here, researchers review the evidence for some of the benefits of physical fitness, improved cognitive function and slowed cognitive aging, to be mediated by favorable changes in the behavior of microglia.

It is largely accepted that physical exercise (PE) can promote brain health and cognitive function. Reports in humans show that moderate to vigorous PE can enhance cognition. However, the cellular mechanisms that underlie this phenomenon are still an active area of exploration. Traditionally, studies have examined how PE regulates wiring of neuronal connections to enhance cognitive function. However, recent focus has shifted toward how exercise may regulate inflammation and the immune response in the central nervous system (CNS).

Microglia are the resident immune cells of the CNS responsible for mediating inflammatory responses, tissue maintenance, and synapse remodeling. Microglia are key mediators of neuroinflammatory processes and play a role in maintaining brain homeostasis in healthy and pathological settings. Here, we explore the evidence suggesting that physical activity has the potential to regulate microglia activity in various animal models. We emphasize key areas where future research could contribute to uncovering the therapeutic benefits of engaging in physical exercise.

Link: https://doi.org/10.3389/fnins.2024.1420322

Bone tissue is constantly remodeled, created by osteoblasts and broken down by osteoclasts. Osteoporosis, a progressive age-related loss of bone density that leads to fracture and incapacity, occurs due to an imbalance between these cell populations that favors osteoclasts over osteoblasts. Researchers here note that Men1 expression declines with age in osteoblasts, and may be an important proximate cause of osteoporosis via mechanisms that include increased cellular senescence in bone tissue. Finding ways to increase Men1 expression in bone-related cell populations may prove to be a useful point of intervention.

Recent evidence suggests an association between age-related osteoporosis and cellular senescence in the bone; however, the specific bone cells that play a critical role in age-related osteoporosis and the mechanism remain unknown. Results revealed that age-related osteoporosis is characterized by the loss of osteoblast Men1. Osteoblast-specific inducible knockout of Men1 caused structural changes in the mice bones, matching the phenotypes in patients with age-related osteoporosis.

Histomorphometrically, Men1-knockout mice femurs decreased osteoblastic activity and increased osteoclastic activity, hallmarks of age-related osteoporosis. Loss of Men1 induces cellular senescence via mTORC1 activation and AMPK suppression, rescued by metformin treatment. In bone morphogenetic protein-indued bone model, loss of Men1 leads to accumulation of senescent cells and osteoporotic bone formation, which are ameliorated by metformin. Our results indicate that cellular senescence in osteoblasts plays a critical role in age-related osteoporosis and that osteoblast-specific inducible Men1-knockout mice offer a promising model for developing therapeutics for age-related osteoporosis.

Link: https://doi.org/10.1111/acel.14254

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

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

Creating supranormal hearing in mice

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

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

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

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

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

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

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

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

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

Link: https://www.bcm.edu/news/serotonin-2c-receptor-regulates-memory-in-mice-and-humans-implications-for-alzheimers-disease

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

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

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

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

Link: https://doi.org/10.1016/j.medp.2024.100032

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

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

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

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

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

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

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

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

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

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

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

Link: https://www.aan.com/PressRoom/Home/PressRelease/5180

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

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

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

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

Link: https://corporate.dukehealth.org/news/study-shows-how-liver-damage-stress-and-aging-might-be-reversible

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

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

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

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

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

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

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

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

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

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

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

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

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

Link: https://doi.org/10.1098/rsob.240035

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

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

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

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

Link: https://hku.hk/press/press-releases/detail/27471.html

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

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

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

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

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

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

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

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

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

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

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

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

Link: https://www.crg.eu/en/news/how-make-ageing-fairer-game-all-wormkind

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

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

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

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

Link: https://www.pnas.org/post/journal-club/energy-mismatch-helps-mice-eat-less-live-longer

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

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

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

Activating molecular target reverses multiple hallmarks of aging

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

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

TERT activation targets DNA methylation and multiple aging hallmarks

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

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

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

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

Link: https://news.uthscsa.edu/research-finds-causal-evidence-tying-cerebral-small-vessel-disease-to-alzheimers-dementia/

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

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

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

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

Link: https://doi.org/10.1126/science.adj7050