Fight Aging!

Transposable elements in the genome are capable of hijacking cellular machinery to copy themselves into new locations in the genome. Many of these sequences are clearly the remnants of ancient infections by retroviruses, degraded and disabled by millions of years of evolutionary mutational change. In other cases, the origin is less clear. An infectious retrovirus arriving from the environment copies its own genetic material into the genome in order to replicate. Alteration of the genome by retroviral infection and unfettered activation of transposable elements is both a cause of pathology and an important mechanism of evolutionary change. It has been going on for a long time: a sizable fraction of any given mammalian genome is made up of transposable elements.

Transposable elements, including the genetic remains of ancient retroviruses, are repressed in youth. These sequences are packaged away in compact DNA and hidden from transcriptional machinery. Aging brings changes to the epigenetic control of the structure of DNA, however. Transposable elements begin to be exposed, allowing replication to cause genetic damage. Perhaps worse, the engagement of the machinery of gene expression with retroviral transposable elements can produce molecules that the immune system recognizes as foreign, in some cases appearing similar to viral particles. This provokes harmful inflammation, disruptive to cell and tissue function.

It was recently noted that expression of the transposable element human endogenous retrovirus K (HERVK) increases with age and can be implicated in age-related inflammation and an increased burden of cellular senescence. This is one of many lines of evidence in support of significant harm arising from a greater activation of transposable elements in later life. Importantly, inhibiting the activity of HERKV and analogous retroviruses reduces the burden of cellular senescence and slows aging in animal models. Today's open access paper is interesting to read in this context, as the authors look at the capacity of the immune system in human study participants to recognize HERVK retroviral particles, and find that a greater capacity correlates with survival to very old age. That said, one should bear in mind that it requires only a small reduction in mortality risk for specific gene variants to appear significantly more often in older people.

Immunogenetics of longevity and its association with human endogenous retrovirus K

The human immune system is equipped to neutralize and eliminate viruses and other foreign antigens via binding of human leukocyte antigen (HLA) molecules with foreign antigen epitopes and presenting them to T cells. HLA is highly polymorphic, resulting in subtle differences in the binding groove that influence foreign antigen binding and elimination. Here we tested the hypothesis that certain HLA alleles may promote longevity by enhanced ability to counter virus antigens that may otherwise contribute to morbidity and mortality.

We utilized high-resolution genotyping to characterize HLA and in a large sample (N = 986) of participants ranging in age from 24 to 90+ years old (mean age: 58.10 years) and identified 244 HLA alleles that occurred in the sample. We determined in silico the median predicted binding affinity for each individual and each of 13 common viruses (Human Herpes Virus 1 [HHV1], HHV2, HHV3, HHV4, HHV5, HHV6A, HHV6B, HHV7, HHV8, human papilloma virus [HPV], human polyoma virus [JCV], human endogenous retrovirus K [HERVK], and HERVW).

The analyses yielded only one statistically significant effect - namely, a positive association between age and HERVK. Furthermore, we identified 13 HLA alleles (9 HLA-I and 4 HLA-II) that occurred at greater frequency in very old individuals (age ≥90 years) as compared to younger individuals. Remarkably, for those 13 alleles, the predicted binding affinities were significantly higher for HERVK than for the other viruses. Taken together, the results showed that HLA-HERVK binding affinity is a robust predictor of longevity and that HLA alleles that bind with high affinity to HERVK were enriched in very old individuals. The findings of the present study highlight the influence of interactions between host immunogenetics and virus exposure on longevity and suggest that specific HLA alleles may promote longevity via enhanced immune response to specific common viruses, notably HERVK.

Age-associated B cells are a distinct population of B cells that grows in number with age. Evidence suggests that these cells are meaningfully dysfunctional and contribute to immune aging, including an impaired immune response and the chronic inflammation characteristic of later life. As researchers note here, there is plenty of evidence for age-associated B cells to contribute to autoimmune conditions as well. Temporary clearance of B cells is possible and has been demonstrated in animal models. The B cell population regenerates rapidly afterwards, but lacking the age-associated B cells that were present beforehand. This approach to therapy should be developed for widespread use.

As a heterogeneous B cell subset, age-associated B cells (ABCs) exhibit distinct transcription profiles, extrafollicular differentiation processes, and multiple functions in autoimmunity. TLR7 and TLR9 signals, along with IFN-γ and IL-21 stimulation, are both essential for ABC differentiation, which is also regulated by chemokine receptors including CXCR3 and CCR2 and integrins including CD11b and CD11c.

Given their functions in antigen uptake and presentation, autoantibody and proinflammatory cytokine secretion, and T helper cell activation, ABCs display potential in the prognosis, diagnosis, and therapy for autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren's syndrome, multiple sclerosis, neuromyelitis optica spectrum disorders, and ankylosing spondylitis.

Specifically targeting ABCs by inhibiting T-bet and CD11c and activating CD11b and ARA2 represents potential therapeutic strategies for SLE and RA. Although single-cell sequencing technologies have recently revealed the heterogeneous characteristics of ABCs, further investigations to explore and validate ABC-target therapies are still warranted.

Link: https://doi.org/10.1007/s12016-025-09021-w

Studies of correlations between physical activity and long term health tend to show a large difference in outcomes between people who are sedentary versus people who exercise even a little; it is a big step up to go from no exercise to a little exercise. The dose response curve for physical activity as an intervention starts out quite steep, and then further activity even beyond the present recommendations of 150 minutes per week continues to add benefits in terms of reduced mortality and reduced risk of age-related disease.

Dementia, usually from Alzheimer's disease, is one of the most common conditions of old age. It is estimated to affect about seven million people in the U.S., including about a third of those who are 85 years or older. Although the risk of dementia rises with age, studies in recent years have suggested that dementia is somewhat preventable, within a normal lifespan, by lifestyle changes that include better control of cholesterol, blood pressure, and blood sugar, and being more active.

Researchers analyzed data on British adults generated as part of the UK Biobank project, a long-running, ongoing study of approximately 500,000 individuals. The dataset for the new study covered 89,667 adults, mostly in their 50s and older, who used wrist-worn accelerometers to track their physical activity for a week during the period from February 2013 to December 2015. Follow-up of their health status extended for an average of 4.4 years, through November 2021, during which 735 of the participants were diagnosed with dementia.

The analysis compared individuals whose trackers showed some weekly moderate to vigorous physical activity to those whose trackers showed none and accounted for age and other medical conditions. The associations between higher activity and lower dementia risk were striking. Participants in the lowest activity category, ranging from one to 34.9 minutes per week, had an apparent risk reduction of about 41% versus sedentary individuals. When the researchers took into account participants who met their definitions of frailty or pre-frailty, they found that the association between more activity and less dementia was essentially unchanged. Dementia risk decreased further with higher amounts of physical activity. Dementia risks were 60% lower in participants in the 35 to 69.9 minutes of physical activity/week category; 63% lower in the 70 to 139.9 minutes/week category; and 69% lower in the 140 and over minutes/week category.

Link: https://www.eurekalert.org/news-releases/1074304

It is interesting to compare the level of interest in mapping genetic variations to effects on aging and life expectancy with the results of studies that use the largest databases of genetic material. The more data used, the more it becomes apparent that gene variants have very little effect on life expectancy, considered across the breadth of the population. The average person is very little different from their associates when it comes to the interaction between genotype and mortality risk. The effects of lifestyle choices far outweigh the effects of genes.

There are rare genetic variants capable of bestowing additional years of life. The small effect of genetics on life expectancy is the consequence of the fact that neither you, I, nor near the the entire population of the world is blessed with such a variant. Yet even looking at the inherited mutation with the largest known effect size on mortality risk in humans, PAI-1 loss of function, which appears to influence the late life burden of cellular senescence and adds seven years of life expectancy for the very few people known to exhibit it, that is still a gain that that most people could achieve via suitable lifestyle choices. Exercise a great deal more, eat a very optimal diet, and so forth.

Lifestyle and environmental factors affect health and ageing more than our genes

Researchers used data from nearly half a million UK Biobank participants to assess the influence of 164 environmental factors and genetic risk scores for 22 major diseases on ageing, age-related diseases, and premature death. Environmental factors explained 17% of the variation in risk of death, compared to less than 2% explained by genetic predisposition (as we understand it at present). Of the 25 independent environmental factors identified, smoking, socioeconomic status, physical activity, and living conditions had the most impact on mortality and biological ageing. Early life exposures, including body weight at 10 years and maternal smoking around birth, were shown to influence ageing and risk of premature death 30-80 years later. Environmental exposures had a greater effect on diseases of the lung, heart and liver, while genetic risk dominated for dementias and breast cancer.

Integrating the environmental and genetic architectures of aging and mortality

Both environmental exposures and genetics are known to play important roles in shaping human aging. Here we aimed to quantify the relative contributions of environment (referred to as the exposome) and genetics to aging and premature mortality. To systematically identify environmental exposures associated with aging in the UK Biobank, we first conducted an exposome-wide analysis of all-cause mortality (n = 492,567) and then assessed the associations of these exposures with a proteomic age clock (n = 45,441), identifying 25 independent exposures associated with mortality and proteomic aging. These exposures were also associated with incident age-related multimorbidity, aging biomarkers and major disease risk factors.

Compared with information on age and sex, polygenic risk scores for 22 major diseases explained less than 2 percentage points of additional mortality variation, whereas the exposome explained an additional 17 percentage points. Polygenic risk explained a greater proportion of variation (10.3-26.2%) compared with the exposome for incidence of dementias and breast, prostate, and colorectal cancers, whereas the exposome explained a greater proportion of variation (5.5-49.4%) compared with polygenic risk for incidence of diseases of the lung, heart, and liver. Our findings provide a comprehensive map of the contributions of environment and genetics to mortality and incidence of common age-related diseases, suggesting that the exposome shapes distinct patterns of disease and mortality risk, irrespective of polygenic disease risk.

In the years since the first demonstration that clearance of senescent cells produces rejuvenation in old mice, and the first programs to develop senolytic drugs that can selectively destroy senescent cells, ever more research has been directed into better understanding the distinctive biochemistry of senescent cells. Any novel feature could turn out to be the basis for a better senolytic drug, or a way to suppress the inflammatory signaling of senescent cells. Here, for example, researchers focus on the relevance of one specific aspect of RNA processing in cells that appears relevant to senescence.

m6A (N6-methyladenosine) RNA modification has emerged as a key regulator of cellular processes, including senescence. m6A is the most prevalent internal modification in eukaryotic mRNA and is dynamically regulated by "writers" (methyltransferases, such as METTL3 and METTL14), "erasers" (demethylases, such as FTO and ALKBH5), and "readers" (m6A-binding proteins, such as YTHDF1 and YTHDC1). By modulating RNA stability, splicing, translation, and decay, m6A modifications influence a wide array of biological functions, including cell proliferation, differentiation, and stress responses. Recent studies have highlighted the role of m6A in regulating the pathways associated with cellular senescence, including p53, NF-κB, and senescence-associated secretory phenotype (SASP) components. However, the intricate interplay between m6A modifications and senescence remains incompletely understood, warranting further exploration.

While targeting m6A modifications holds great potential for senescence therapy, several limitations and challenges must be addressed before its clinical translation. First, the dynamic and reversible nature of m6A modifications, mediated by "writers" (methyltransferases), "erasers" (demethylases), and "readers" (binding proteins), adds significant complexity to their regulation. Targeting these components may lead to off-target effects due to the widespread role of m6A in various cellular processes beyond senescence, such as stem cell maintenance, immune responses, and tumor progression. This non-specificity could result in unintended disruptions to normal physiological functions. Furthermore, the heterogeneity in senescence mechanisms across cell types and tissues complicates the development of universal m6A-targeted therapies. A therapy effective in one cellular context may exhibit limited efficacy or even adverse effects in another.

Finally, the detection and quantification of m6A modifications remain challenging due to the lack of standardized and highly sensitive tools. Current techniques, such as m6A-seq, provide valuable insights but have limitations in resolution and scalability. Without precise detection methods, identifying specific m6A targets for therapeutic intervention is difficult, which hinders progress in the field. Developing small molecules or RNA-based therapeutics targeting m6A modulators poses challenges related to specificity and toxicity. Ensuring efficient delivery to senescent cells while avoiding off-target effects in non-senescent cells remains a major hurdle. Advanced delivery systems, such as nanoparticle-based or cell-specific delivery platforms, are needed but require further optimization for clinical use. Overcoming these limitations requires a multidisciplinary approach, integrating advances in molecular biology, bioinformatics, drug delivery systems, and clinical research. Continued efforts to refine m6A-targeted strategies and deepen our understanding of m6A's role in senescence will pave the way for safer and more effective therapies.

Link: https://doi.org/10.3389/fimmu.2025.1534263

Cancer vaccines are an area of active development, but have yet to succeed in obtaining clinical approval. The principle is much the same as any vaccine: deliver a suitably designed molecule or combination of molecules that will provoke the immune system into recognizing a distinctive feature of the target cell, pathogen, or other structure as a candidate for attack and destruction. Unfortunately tumor cells employ a wide range of mechanisms to suppress, co-opt, and subvert the activities of immune cells, and so it may well be the case that cancer vaccines will remain poorly effective without the addition of means to block these mechanisms.

Despite advancements in traditional cancer treatments such as surgery, chemotherapy, and radiotherapy, many cancers remain difficult to cure, particularly in advanced stages where treatment options are limited. Recently, immunotherapies such as immune checkpoint inhibitors (ICIs), adoptive cell therapy (ACT), and cancer vaccines have emerged as promising approaches to leverage the host immune system against malignancies. While ICIs and ACT have shown efficacy in specific patient populations, their success remains limited, with only a subset of patients achieving sustained responses. Cancer vaccines, however, offer a unique advantage by priming new T cells, potentially targeting a broader array of tumor antigens and inducing more durable immune responses.

Cancer vaccines deliver target antigens, often in combination with adjuvants, to evoke or amplify the host immune system, especially T-cell immunity, to recognize and eliminate malignant cells. They are broadly categorized into two types: therapeutic and prophylactic cancer vaccines. Therapeutic cancer vaccines are post-exposure treatments that induce potent cellular immune responses to eliminate existing cancer cells and establish long-lasting immune memory to prevent recurrence. In contrast, prophylactic cancer vaccines are designed to stimulate the immune system in tumor-free individuals, generating antibodies and immune memory cells that reduce the risk of cancer development.

Numerous cancer vaccines have progressed to clinical evaluation, demonstrating the ability to elicit strong immune responses. However, despite some early successes, the majority have not achieved durable responses or significant clinical efficacy in large phase III trials, presenting both opportunities and challenges for future development. Decades of research have greatly deepened our understanding of cancer vaccines, and the design of an optimal vaccine remains a delicate process. This process requires careful consideration of antigen selection, adjuvant incorporation, administration methods, combination with other therapies, and identification of the appropriate patient population.

Link: https://doi.org/10.1186/s13045-025-01670-w

Cells become senescent constantly throughout the body and throughout the life. These are largely somatic cells reaching the Hayflick limit on replication, but cells can also become senescent in response to excessive stress or damage. A senescent cell ceases to replicate and begins to secrete pro-growth, pro-inflammatory signals. Most senescent cells are destroyed by immune cells that are attracted by this signaling. It serves as a useful mechanism to draw the attention of the immune system to regions of damage and dysfunction in tissue. It helps to prevent cancer, for example, and assists in regeneration from injury.

With age, however, the immune system becomes less able to clear senescent cells. Senescent cells linger, their numbers growing. The inflammatory secretions of senescent cells become disruptive to tissue structure and function when sustained over time. This is an important mechanism of degenerative aging, and a number of companies are presently developing senolytic therapies intended to selectively destroy senescent cells. Animal studies show that clearing senescent cells produces some degree of rapid reversal for many aspects of aging and age-related disease.

One of the more interesting features of senescent cells is that they grow in size quite dramatically, relative to their non-senescent counterparts. Researchers have used this feature to sort circulating senescent cells for analysis. As noted by the authors of today's open access paper, this isn't just a side-effect. The growth in size is essential for the energetic signaling produced by senescent cells. Interestingly, one can find ways to sabotage this enlargement of cells on entering the senescent state, and doing so dramatically reduces the harmful senescent cell signaling.

Cell enlargement modulated by GATA4 and YAP instructs the senescence-associated secretory phenotype

Dynamic changes in cell size are associated with development and pathological conditions, including aging. Although cell enlargement is a prominent morphological feature of cellular senescence, its functional implications are unknown; moreover, how senescent cells maintain their enlargement state is less understood. Here we show that an extensive remodeling of actin cytoskeleton is necessary for establishing senescence-associated cell enlargement and pro-inflammatory senescence-associated secretory phenotype (SASP). This remodeling is attributed to a balancing act between the SASP regulator GATA4 and the mechanosensor YAP on the expression of the Rho family of GTPase RHOU.

Genetic or pharmacological interventions that reduce cell enlargement attenuate SASP with minimal effect on senescence growth arrest. Mechanistically, actin cytoskeleton remodeling couples cell enlargement to the nuclear localization of GATA4 and NF-κB via the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. RhoU protein accumulates in mouse adipose tissue under senescence-inducing conditions. Furthermore, RHOU expression correlates with SASP expression in adipose tissue during human aging. Thus, our study highlights an unexpected instructive role of cell enlargement in modulating the SASP and reveals a mechanical branch in the senescence regulatory network.

Researchers here assess the transcriptomes of immune cells in blood samples taken from hundreds of older patients with and without Alzheimer's disease. It is a good illustration of the capabilities and limitations of these studies. One can obtain interesting insights into what is going on in the immune system, but meaningfully connecting these insights to disease processes and the development of therapies is challenging. For example, pointing to changes in ribosomal function is all well and good, but the ribosome, where messenger RNA is used as a blueprint to produce proteins, is such a fundamental part of the cell that its activity influences everything else. It is following a trail into a swamp, there is no good way forward towards specific answers.

The prevalence of Alzheimer's disease (AD) is increasing as society ages. The details of AD pathogenesis have not been fully elucidated, and a comprehensive gene expression analysis of the process leading up to the onset of AD would be helpful for understanding the mechanism. We performed an RNA sequencing analysis on a cohort of 1227 Japanese blood samples, representing 424 AD patients, 543 individuals with mild cognitive impairment (MCI), and 260 cognitively normal (CN) individuals. A total of 883 and 1169 statistically significant differentially expressed genes (DEGs) were identified between CN and MCI (CN-MCI) and between MCI and AD (MCI-AD), respectively.

Pathway analyses using these DEGs, followed by protein-protein interaction network analysis, revealed key roles of ribosomal function in MCI progression, whereas immune responses, cell cycle, and protein processing in endoplasmic reticulum were involved in AD progression. Our findings indicate that the onset of AD might be associated with gene expression changes in the immune system, cell cycle, and protein processing following alterations in the expression of ribosomal protein genes during the MCI stage, although validation using brain tissue samples will be necessary in the future. Given the known effectiveness of delaying MCI progression in preventing AD, the genes related to ribosomal function might emerge as biomarkers for early diagnosis.

Link: https://doi.org/10.1038/s41598-025-88526-y

Hevin is a circulating signal molecule that appears to be involved in the regulation of connectivity between neurons in the brain, inducing the formation of synapses. To the degree that this increases neuroplasticity, one would expect it to help resist the harmful effects of Alzheimer's disease pathology. It does this not by reducing the ongoing damage to neurons and their connections, but by allowing the brain to better adapt to or recover from that damage. This sort of approach is a losing game in the long term, as pathology will grow to outpace attempts to compensate, but it is better than nothing.

Dementia, characterized by loss of cognitive abilities in the elderly, poses a significant global health challenge. This study explores the role of astrocytes, one of most representative glial cells in the brain, in mitigating cognitive decline. Specifically, we investigated the impact of Hevin (also known as SPARC-like1/SPARCL-1), a secreted glycoprotein, on cognitive decline in both normal and pathological brain aging. Hevin has been reported to induce the development of structurally formed but functionally silent synapses. Importantly, Hevin has been pointed out as a candidate factor that reverts age-associated cognitive decline following administration of blood from young to aged animals.

By using adeno-associated viruses, we overexpressed Hevin in hippocampal astrocytes of middle-aged APP/PSEN mice, an established Alzheimer's disease (AD) model. Results demonstrated that Hevin overexpression attenuates cognitive decline, as evidenced by cognitive tests, increased pre- and postsynaptic markers colocalization, and altered expression of synaptic mediators, as revealed by proteomic profiling. Importantly, Hevin overexpression did not influence the deposition of amyloid-β plaques in the hippocampus, a hallmark of AD pathology. Furthermore, the study extended its findings to middle-aged wild-type animals, revealing improved cognitive performance following astrocytic Hevin overexpression.

Link: https://doi.org/10.1111/acel.14493

The eye is relatively isolated from the rest of the body. The potential scope of adverse effects resulting from treatments targeting the eye is much reduced relative to treatments that enter the body as a whole, or are targeted to one internal organ. Thus eye conditions tend to be a testbed for novel advanced forms of therapy. Further, the state of the more accessible retina is a convenient window into the state of the less accessible central nervous system, and so you'll find researchers focused on retinal cells as a way into gain insight into the mechanisms and progression of neurodegenerative conditions.

In today's open access paper, the authors discuss the effects of multiple sclerosis on the neurons of the retina and optic nerve. Multiple sclerosis is an autoimmune condition characterized by central and peripheral nervous system inflammation and loss of the myelin sheathing needed for nerves to function. The consequent damage also extends to the retina. In an animal model relevant to this pathology, the researchers demonstrate that features of cellular senescence are prevalent in retinal ganglion cells, a type of neuron in the retina. Further, exposure to Yamanaka factors to induce partial reprogramming in retinal cells can reduce this senescence and improve function.

Cellular rejuvenation protects neurons from inflammation-mediated cell death

Multiple sclerosis (MS) is an immune-mediated disease with a neurodegenerative component. While immune-mediated demyelination of axons constitutes a primary pathogenic mechanism in MS, sustained clinical deficits are associated with neuronal degeneration, including loss of neurons in the gray matter and loss of axons in white matter lesions and normal-appearing white matter. Notably, the retina and optic nerve acquire extensive pathology in MS. Optic nerve lesions are frequently detected in patients with MS by MRI. Additionally, there is significant retinal nerve fiber layer and ganglion cell layer thinning evidenced by optical coherence tomography, and this correlates with clinical deficits and brain volume loss. This is mirrored in the experimental autoimmune encephalomyelitis (EAE) mouse model, where there is optic nerve demyelination, immune cell infiltration, and gliosis, retinal nerve layer thinning, neuron loss, and axonal pathology, making the EAE mouse retina and optic nerve a useful model to study inflammation-mediated neurodegeneration.

Recent studies have explored the relationships between aging, cellular senescence, and MS. Cellular senescence is also highly correlated with aging and age-related disease. Although cellular senescence was originally defined by aberrant cell cycle exit, it is also characterized by other features, including altered autophagy, the senescence-associated secretory phenotype (SASP), accumulation of DNA damage, and epigenetic changes. Targeting aging and senescence programs in MS may be a beneficial strategy to address immune cell or glial dysfunction; however, there is limited data about the neuronal gene signature in MS and thus whether rejuvenating therapies may promote neuroprotection.

Here, we profile the transcriptome of retinal ganglion cells (RGCs) in EAE mice. Pathway analysis identifies a transcriptional signature reminiscent of aged RGCs with some senescent features, with a comparable signature present in neurons from patients with MS. This is supported by immunostaining demonstrating alterations to the nuclear envelope, modifications in chromatin marks, and accumulation of DNA damage. Transduction of RGCs with an Oct4-Sox2-Klf4 adeno-associated virus (AAV) to rejuvenate the transcriptome enhances RGC survival in EAE and improves visual acuity. Collectively, these data reveal an aging-like phenotype in neurons under pathological neuroinflammation and support the possibility that rejuvenation therapies or senotherapeutic agents could offer a direct avenue for neuroprotection in neuroimmune disorders.

Here find a review of what is known of relationships between the aging of the gut microbiome and aging of skeletal muscle. With age, everyone loses muscle mass and strength, leading eventually to sarcopenia and frailty. A perhaps surprisingly large fraction of this is a consequence of too little physical activity, as judged when comparing hunter-gatherer populations with the much more sedentary developed world. Other mechanisms of aging are important, however. The gut microbiome changes in composition with age, and this both increases chronic inflammation and reduces the supply of beneficial metabolites to tissues in the body. It remains to be seen as to how large this effect is versus others, but it is at least a contribution that can be addressed more readily than most.

Sarcopenia is a skeletal muscle disorder, with primary sarcopenia defined as an age-related progressive loss of skeletal muscle mass, strength, and physical function. This condition is notably prevalent, ranging from 10% to 27% in individuals aged 60 years and older. At present, it is known that primary sarcopenia is multifactorial and not limited to age-related lifestyle changes (e.g., physical inactivity and low-protein diet), inflammation, and insulin resistance. These factors contribute to alterations in muscle protein turnover as well as the development and progression of sarcopenia. However, the extent of other factors that may contribute to sarcopenia development is not fully understood, and the precise underlying mechanisms of sarcopenia remain elusive.

The gut microbiota, consisting of over 100 trillion bacterial cells, plays a vital role in human metabolic and immunological health. The gut microbiota can produce a wide range of bioactive compounds, mainly including short-chain fatty acids (SCFAs), secondary bile acids, branched-chain amino acids, and many others, to impact host physiology and health via different host-microbe metabolic pathways. Once in the bloodstream, SCFAs exhibit epigenetic and immunomodulatory effects on various organs, contributing to the development of a range of human diseases, including primary sarcopenia.

Gut dysbiosis, an imbalanced gut microbiota resulting from compositional changes, has been associated with aging as well as various age-related health conditions and diseases, including sarcopenia. Gut dysbiosis and sarcopenia commonly occur in older individuals. Convincing evidence from animal and human studies has linked gut dysbiosis to sarcopenia, with a recent study suggesting a causal relationship. While the factors influencing human gut microbiomes are complex throughout the lifespan, age itself has been shown to adversely affect the diversity of gut microbiomes and their beneficial metabolites. This impact may contribute to age-related diseases, including sarcopenia.

Studies have demonstrated that Bifidobacterium and Lactobacillus supplements enhance muscle mass and strength in aged mice, and similar benefits have been observed with a prebiotic formulation in elderly individuals. However, it remains unclear whether there is a direct impact of gut microbiota on muscle mass, function, and the development of sarcopenia. It is also challenging to pinpoint the specific gut microbiomes and their metabolites that are beneficial to muscle health and could serve as therapeutic targets. Additionally, it is still elusive how the gut microbiome and its metabolites regulate the gut-muscle axis, a topic of ongoing investigation. Further research is needed to fully understand the mechanisms and to explore potential therapeutic interventions targeting the gut microbiota to prevent or treat sarcopenia, thus promoting healthy aging.

Link: https://doi.org/10.3389/fmicb.2025.1526764

Mitochondria are the power plants of the cell, generating chemical energy store molecules to power cellular operations. The endoplasmic reticulum is a structure studded with ribosomes for protein assembly, and where protein folding and transport within the cell takes place. Nothing in the cell has only one function, however, and both of these structures influence many cell processes. Researchers here discuss what is known of the direct interactions that take place between mitochondrion and endoplasmic reticulum, and the possible relevance of this still largely unexplored activity to aging and disease.

For decades, scientists viewed the various compartments within cells, called organelles, as relatively independent entities. This perspective, while useful for understanding basic cellular structure, has proven to be an oversimplification of the complex and dynamic nature of cellular organization. Recent research has revealed a far more interconnected and fluid cellular landscape, where organelles interact and communicate in sophisticated ways.

At the heart of this paradigm shift is the discovery of specialized regions where two critical organelles - mitochondria and the endoplasmic reticulum (ER) - are in close apposition. These regions, known as mitochondria-associated ER membranes (MAMs), are revolutionizing our understanding of cellular function and disease. MAMs act as cellular 'communication hubs', allowing for rapid and precise exchange of signals and molecules between mitochondria and the ER. This communication is crucial for maintaining cellular health, responding to stress and regulating energy production. The strategic positioning of MAMs allows for efficient transfer of molecules and signals, facilitating precise control of cellular functions.

Alterations in MAM structure and function have been implicated in a wide range of conditions, including neurodegenerative diseases, metabolic disorders, and cardiovascular disease. Disruption of MAMs impairs the structural and functional connectivity between the ER and mitochondria, leading to significant cellular dysfunction. For instance, studies have shown that high glucose levels can disrupt MAM integrity through the pentose phosphate pathway, resulting in mitochondrial fragmentation and altered respiration. While some age-related changes in MAMs have been observed, such as alterations in calcium signalling and mitochondrial function, the full impact of these changes on cellular function and organismal health remains an open question. Understanding how MAMs change throughout the lifespan could provide insights into the ageing process and potentially lead to interventions to promote healthy ageing.

Link: https://doi.org/10.1098/rsob.240287

Microglia are innate immune cells of the brain, analogous to macrophages elsewhere in the body. They attack pathogens, remove damaged cells, clear up debris, and assist in some aspects of the function of neural networks. With age, microglia become more prone to inflammatory behavior. Chronic, unresolved inflammation is harmful to tissue structure and function. Some of this is a maladaptive reaction to growing levels of molecular waste present in the brain, such as protein aggregates characteristic of neurodegenerative conditions, some the result of other processes of aging operating inside microglia, such as mitochondrial dysfunction.

Inhibiting CSF1R kills microglia (and macrophages), and there is a small molecule cancer drug that can achieve this in practice, called pexidartinib or PLX-3397. Clearance of microglia requires a much lower dose than is used in cancer patients, and so the side-effect profile is much more reasonable. The population of microglia and macrophages regenerates from progenitor populations within a few weeks following clearance, and in animal studies of neurodegeneration and brain aging this treatment has been shown to reduce the number of inflammatory microglia, reduce inflammation in the brain, and otherwise improve function. In today's open access paper, researchers try a lower dose and lesser degree of clearance of microglia, and still see benefits to cognitive function in aged mice.

Partial microglial depletion through inhibition of colony-stimulating factor 1 receptor improves synaptic plasticity and cognitive performance in aged mice

Microglia depletion, followed by repopulation, improves cognitive functions in the aged mouse brain. However, even temporary ablation of microglia puts the brain at a high risk of infection. Hence, in the present work, we studied if the partial reduction of microglia with PLX3397 (pexidartinib), an inhibitor of the colony-stimulating factor 1 receptor (CSF1R), could bring similar benefits as reported for microglia ablation. Aged (two-years-old) mice were treated with PLX3397 for a total of 6 weeks, which reduced microglia numbers in the hippocampus and retrosplenial cortex (RSC) to the levels seen in young mice and resulted in layer-specific ablation in the expression of microglial complement protein C1q mediating synaptic remodeling.

This treatment boosted long-term potentiation in the CA1 region and improved performance in the hippocampus-dependent novel object location recognition task. Although PLX3397 treatment did not alter the number or total intensity of Wisteria floribunda agglutinin-positive perineuronal nets (PNNs) in the CA1 region of the hippocampus, it changed the fine structure of PNNs. It also elevated the expression of perisynaptic proteoglycan brevican, presynaptic vGluT1 at excitatory synapses, and vGAT in inhibitory synapses in the CA1 stratum radiatum. Thus, targeting the CSF1R may provide a safe and efficient strategy to boost synaptic and cognitive functions in the aged brain.

The age-related failure of the glands around the eye to generate the right mix of compounds to form tears is not given a great deal of thought by most people, at least until it happens to them. Dry eye syndrome is unpleasant to experience, but in world in which cardiovascular disease and cancer exist, the causes of the age-related onset of dry eye syndrome are perhaps not as well studied as they might be. Resources are directed to more severe issues.

Researchers here note age-related changes in a stem cell population that supports one of the glands around the eye. Stem cell populations in general decline in function with age, and much of this appears to be an inappropriate reaction to the aged environment. Evidence accumulated in the study of muscle stem cells and hematopoietic stem cells suggests that aged tissue maintenance could be improved by forcing stem cells back to work, but the specific approaches needed are likely to vary widely from tissue to tissue.

Meibomian glands secrete lipid-rich meibum, which prevents tear evaporation. Aging-related Meibomian gland shrinkage may result in part from stem cell exhaustion and is associated with evaporative dry eye disease, a common condition lacking effective treatment. The identities and niche of Meibomian gland stem cells and the signals controlling their activity are poorly defined.

Using single cell RNA sequencing, in vivo lineage tracing, ex vivo live imaging, and genetic studies in mice, we identify markers for stem cell populations that maintain distinct regions of the gland and uncover Hedgehog (Hh) signaling as a key regulator of stem cell proliferation. Consistent with this, we show that human Meibomian gland carcinoma exhibits increased Hh signaling. Aged glands display decreased Hh and EGF signaling, deficient innervation, and loss of collagen I in niche fibroblasts, indicating that alterations in both glandular epithelial cells and their surrounding microenvironment contribute to age-related degeneration. These findings suggest new approaches to treat aging-associated Meibomian gland loss.

Link: https://doi.org/10.1038/s41467-025-56907-6

Researchers have shown that the aging of lymph nodes prevents restoration of immune cell populations from improving the immune response. The immune system uses lymph nodes as centers of coordination, but with age these structures deteriorate and become fibrotic. Here, researchers review what is known of this structural and functional lymph node aging. At this point it is unclear as to the best approaches to restore aged lymph nodes, as fibrosis in general remains an unsolved problem. Clearing senescent cells may help, but other strategies may be needed, such as the creation and transplantation of artificial lymph nodes.

Studies have indicated that as individuals age, there is a reduction in the size of the lymph node (LN), accompanied by degenerative changes such as the development of fibrosis and lipomatosis. There is also evidence of changes in the structure of the LN endothelium, leading to decrease in immune cell recruitment. As a result, the immune cell number present in the LN diminishes. Furthermore, during ageing, the number and size (area) of germinal centres (GC) is reduced by approximately 30%-50% . This deficit results in reduced humoral immunity, leading to impaired antibody production and an increased susceptibility to infections in individuals over the age of 65. Consequently, it can be speculated that the disorganisation of the LN structure play a significant role in the ageing of the immune system.

The architecture of the LN is created and supported by LN stroma cells (LNSCs), comprising heterogeneous populations of mesenchymal cells and endothelial cells. LNSCs organise the LN into distinct compartments to support immune cell retention, activation, proliferation, and differentiation in homeostatic conditions and in response to antigenic stimulation. To support and maintain the distinct yet diverse immune cell niches within the LN, LNSCs secrete various growth factors and chemokines to ensure immune cells are correctly localised to their unique niches and receive appropriate survival signals. Thus, LNSC plays an important role in ensuring immune cell homeostasis, activation of immune responses during infection, and accordingly, any age-associated changes to LNSCs may significantly hamper the overall function of the LN as a hub for immunosurveillance.

As a matter of fact, studies performed in the recent years have begun to shed light how age-associated changes to LNSCs impairs the generation of protective immunity against infection and after vaccination. The observation that the older adults are not able to generate effective long-term protective immunity after vaccination highlights the necessity to comprehend how underlying age-associated changes to LNSC precipitates into impaired immune responses, and further research may potentiate development of therapeutic strategies that could enhance immune responses by targeting the aged LNSCs.

Link: https://doi.org/10.1111/acel.70000

The Rejuvenation Science Institute (ICR) is a Brazilian group engaged in advocacy and research initiatives, in many ways analogous to Lifespan.io in the US. At present, the ICR staff are seeking to reproduce and improve on the study sponsored by Yuvan Research in which a plasma fraction derived from young pigs was used to produce benefits in aged rats. Yuvan Research is somewhere in the process of trying to bring this to the clinic as a therapy.

Independent reproduction of results is important in the scientific community, and more generally in the development of new technologies. The ICR principals recently sent me their pitch for charitable donations to help crowdfund this reproduction study. As they note, they have already set things in motion, conducted a preliminary proof of concept study for the treatment, and are now just waiting on their laboratory rats to age into the right age range for treatment. If you want to support this work, visit the ICR website and donate.

The Rejuvenation Science Institute (ICR) is preparing the reproduction of the seminal Yuvan Research experiment in which rats were rejuvenated with extracellular particles from young pig's blood. The experiment will be carried out in June 2026 and it is partially funded, but we need donations for its complete funding. Back in 2020, when the Yuvan Research principals published the first article about the experiment, it was not reveal what was given to the rats, but in October 2023, the full article was published in Geroscience journal, detailing the whole procedure. So, now, after a lot of hard work to organize the reproduction in Brazil of this experiment, we finally scheduled the beginning of the injections in the rats to June 2026, as we need 25-months-old animals, and we need to wait for them to age.

By the way, our institute has already carried out a small experiment together with the State University of Campinas, commonly known as Unicamp - one of the leading research universities in Latin America, that will also collaborate with ICR in the full experiment of rats rejuvenation - in which we injected the extracellular particles in young rats to assess acute immunogenicity and toxicity, described in our recent scientific publication.

Regarding the funding for the full reproduction of the Yuvan Research experiment, the ICR received the promise of a donation from an institution that will partially cover the costs of the experiment. This donation will cover the costs from Unicamp, the university we are collaborating with. However, the work the ICR will perform still needs to be funded. So we are asking the people interested in the experiment results to become financial collaborators to our institute, which can be done via the donations page of our website.

The ICR is committed to publishing all the results obtained, be them positive or negative. Also, all methods and materials will be published immediately after the experiment, together with those results. Yuvan Research used 6 rats per group, but we will use 10 rats per group, in order for the study to be more robust. Also, by suggestion of professor Marcelo Mori from Unicamp, we will also include a group of young treated rats, to see if we are able to keep young rats young, and not just rejuvenate old rats. And if the rats are rejuvenated (or kept young, regarding the young treated rats), we intend to let them live indefinitely, applying the treatment periodically, as there will be no better evidence of success than extension of life span.

Even though the experiment is still 1 year and 4 months away, we are already working to make all the necessary preparations, both technical and bureaucratic. To follow the preparations for the experiment, you can subscribe to our newsletter.

One should probably expect inflammatory and autoimmune conditions that are known to increase mortality risk, such as psoriasis, to also accelerate biological age, as measured by various aging clocks. Or at least a clock that doesn't exhibit this behavior is not a good clock in this context. Conducting assessments of biological age in many contexts and conditions is a necessary part of establishing confidence in aging clocks, so expect to see many studies similar in nature to the one noted here in the years ahead. Here, researchers obtained aging clock measurements for patients with psoriasis and assessed the degree to which these measures of biological age are predictive of actual mortality. Given fifty such studies for a range of conditions, one might gain a sense of how a given clock performs, enough to provide guidance and comfort regarding its use in a new context, or to assess a potential rejuvenation therapy.

Psoriasis is an immune-mediated genetic disorder characterized by scaly skin lesions, affects approximately 0.14%-1.99% of the global population. Compared to the general population, patients with psoriasis are at increased risk for immune and metabolic comorbidities including cardiovascular disease, diabetes mellitus, metabolic dysfunction-associated steatotic liver disease and inflammatory bowel disease. A survey based on the United States population noted that psoriasis was associated with a two-fold increased risk of all-cause mortality.

Patients with psoriasis and non-psoriasis were recruited from National Health and Nutrition Examination Survey (NHANES) (12,973 cases), Medical Information Mart for Intensive Care (MIMIC-IV) (558 cases) and The First Clinical Medical College of Zhejiang Chinese Medical University (206 cases). Biological age was calculated using Klemera-Doubal method age (KDM-age) and phenotypic age (PhenoAge). Linear regression and logistic regression were used to explore the association between psoriasis and biological age advance. Cox regression was used to investigate the association between biological age advance and mortality. Finally, biological age advance was used to predict the death of psoriasis patients.

In NHANES, linear regression showed that psoriasis led to an increase in PhenoAge (Beta: 0.54). The KDM-age increase due to psoriasis was not statistically significant. Using data from China, we came to the new conclusion that for every unit rise in Psoriasis Area and Severity Index, PhenoAge rose by 0.12 (Beta: 0.12). Using NHANES data, cox regression shows for every unit rise in PhenoAge advance patients had an 8% rise in mortality. Using MIMIC-IV, logistic regression showed a 13% increase in mortality within 28 days of admission for every 1 unit rise in PhenoAge advance. Finally, we used PhenoAge advance to predict death, with an area under curve (AUC) of 0.71 in the NHANES, an ACU of 0.79 for predicting death within 1 years in the general ward of MIMIC-IV. In the ICU of MIMIC-IV, the AUC for predicting death within 28 days was 0.71.

Link: https://doi.org/10.1186/s12979-025-00500-4

You might recall a recent paper in which researchers showed that senescent cells in the inflamed gum tissue. Removing those senescent cells helps. To accompany that paper, here is another in which researchers examine periodontitis in the P16-3MR mouse model, which is genetically engineered to allow senescent cells to be efficiently and selectively cleared by treatment with ganciclovir. Here too, clearance of senescent cells is beneficial, reducing both inflammation and bone loss.

The occurrence and severity of periodontitis (PD) tend to increase with age, and yet the underlying mechanisms remain unclear. Immune senescence is known to be triggered in mice and humans as they age. Experimental PD in mice has been shown to induce senescence biomarkers p16INK4a and p21, dysfunction of antigen-presenting cells (APCs), and activation of the senescence-associated secretory phenotype (SASP). However, the causal links of senescence to experimental PD are not yet established. This study aims to elucidate the role of senescence in experimental PD at a causal level.

The P16-3MR mouse model harbors the p16INK4a (Cdkn2a) promoter, driving in vivo expression of synthetic Renilla luciferase, monomeric red fluorescent protein (mRFP), and herpes simplex virus-1 thymidine kinase (HSV-TK). This facilitates in vivo identification of p16INK4a activation at the cellular level and the consequences of selective elimination of p16INK4a-positive cells by ganciclovir (GCV) treatment. Mice were treated with/without GCV for two weeks during ligature-induced PD. In vivo bioluminescence imaging quantified p16INK4a activation, while Western blot and immunofluorescence analyses assessed key senescence and inflammatory markers (p16, p21, p53, Cyclin D1, p-H2A.X, IL17, and IL1β). Alveolar bone volume was analyzed by micro-CT and histomorphometry.

Our findings demonstrate that clearance of senescent cells in mice subjected to experimental PD alleviates inflammation and mitigates bone loss. These results suggest a causal role for senescence in PD pathology, raising the future prospect of senolytic agents for therapeutic intervention in PD.

Link: https://doi.org/10.3390/cells14030226

Erythrocytes, the red blood cells that carry oxygen around the body, are not often the topic of the day in aging research. Red blood cells are made by the hematopoietic cells that reside in the bone marrow, and a great deal of effort is spent on studying the aging of the hematopoietic system. This research is largely focused on changes in the production and behavior of white blood cells and consequent harms to the function of the immune system, however.

In today's open access paper, researchers report on an analysis of the biochemistry of erythrocytes in a study population that included a group of long-lived individuals over the age of 90. The long-lived individuals exhibited a more youthful erythrocyte metabolism. The researchers propose mechanisms linking this to improved function throughout the body, but as is always the case in aging and cell biochemistry, the challenge lies in determine which of the many options on the table is actually the most important. The only way to find out in certainty is to fix that one mechanism in isolation and observe the outcomes.

Longevity Humans Have Youthful Erythrocyte Function and Metabolic Signatures

Individuals who live past the age of 90 are defined as longevity individuals and are examples of highly successful aging, often referred to as increased healthspan. These individuals are equipped with a better capability to counteract chronic tissue hypoxia, inflammation, and oxidative stress and thus a lower susceptibility to age-related diseases including cardiovascular disease and Alzheimer's disease. Such an advantage makes longevity individuals an ideal population for the investigation of cellular and molecular mechanisms underlying better aging with the ultimate goal of promoting lifespan and healthspan and decreasing the burden of degenerative diseases with important social and economic benefits.

We unexpectedly discovered that longevity individuals exhibit erythrocyte oxygen release function similar to young individuals, whereas most elderly show reduced oxygen release capacity. Untargeted erythrocyte metabolomics profiling revealed that longevity individuals are characterized by youth-like metabolic reprogramming and these metabolites effectively differentiate the longevity individual from the elderly individual. Quantification analyses led us to identify multiple novel longevity-related metabolites within erythrocytes including adenosine, sphingosine-1-phosphate (S1P), and glutathione (GSH) related amino acids.

Mechanistically, we revealed that increased bisphosphoglycerate mutase (BPGM) and reduced MFSD2B protein levels in the erythrocytes of longevity individuals collaboratively work together to induce elevation of intracellular S1P, promote the release of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from membrane to the cytosol, and thereby orchestrate glucose metabolic reprogramming toward the Rapoport-Luebering Shunt pathway to induce the 2,3-BPG production and trigger oxygen delivery. Furthermore, increased glutamine and glutamate transporter expression coupled with the enhanced intracellular metabolism underlie the elevated GSH production and the higher anti-oxidative stress capacity in the erythrocytes of longevity individuals.

As such, longevity individuals displayed less systemic hypoxia-related metabolites and more antioxidative and anti-inflammatory metabolites in the plasma, thereby healthier clinical outcomes including lower inflammation parameters as well as better glucose-lipid metabolism, and liver and kidney function.

Epigenetic mechanisms determine the structure of nuclear DNA, largely via specific chemical decorations attached to specific locations on the genome or to the histone molecules that act as spindles for nuclear DNA to wrap around. The structure of DNA, which regions are spooled and hidden versus unspooled and exposed, determines which proteins are manufactured from their genetic blueprints, and thus the behavior of the cell. Here, researchers report on a search for genetic interventions that might reduce the magnitude or slow the progression of harmful age-associated epigenetic changes. The researchers found that knockout of TOP2B produces this outcome in yeast, nematode worms, and mice. In mice, reducing TOPB2 expression adds about 10% to life expectancy. While a fair amount is known of the specific functions of TOP2B within the complex processes of managing the structure of DNA, it remains unknown as to how it is that reduced TOP2B expression can produce modestly slowed aging.

In the simple model organism yeast, the lifespans of the nonessential gene knockout mutants have been measured systematically through a multi-year effort and ~200 mutants with extended lifespans were identified. As a significant fraction of the nonessential gene knockout mutants have been profiled transcriptionally, we analyzed the correlation between the gene expression profile and the lifespan of the mutants and identified a number of essential genes whose downregulation strongly correlates with extended lifespan across multiple mutants. Among the top hits is the DNA topoisomerase Top2, with an essential function in managing DNA topology and regulating replication and transcription.

Yeast Top2 has two mammalian homologs, TOP2A and TOP2B. While TOP2A is primarily expressed in proliferating cells and is crucial for DNA replication, TOP2B is expressed in all cell types and plays a more prominent role in DNA replication, chromatin remodeling, and transcriptional regulation that is closely tied to aging. TOP2B is an essential double-stranded DNA topoisomerase, pivotal in identifying DNA topological configurations and relieving DNA torsional strain via cutting, rotating, and reconnecting DNA strands. TOP2B has been much less studied in the context of aging.

In this study, we investigate whether reduction of Top2 or TOP2B confers a longevity phenotype across species and explore the potential mechanisms. We found that knocking down Top2 or TOP2B extends the lifespan of yeast, C. elegans, and mice. TOP2B reduction also extends the health span of mice, and alleviates the characteristics and pathologies of aging in multiple tissues. At the cellular/molecular level, Top2 or TOP2B reduction attenuates the major hallmarks of aging, such as cellular senescence, deregulated nutrient-sensing, epigenetic alterations, and lysosomal dysfunction. We observed that TOP2B reduction alters the epigenetic landscape of various tissues in old mice toward those of the young animals, and differentially downregulates genes with active promoter and high expression. Our observations suggest that Top2 or TOP2B reduction confers longevity effect via remodeling of epigenetic and transcriptional landscapes and suppression of aberrantly expressed genes in old cells.

Link: https://doi.org/10.1111/acel.70010

There is now enough human data for immunotherapies that clear amyloid-β from the brain for researchers to say something useful and coherent about the effects of these drugs on Alzheimer's disease. It is clear that the effect size is nowhere close to the hoped for reversal of disease, and is small enough to be hard to detect without sizable patient populations or long-term follow up. This indicates that amyloid-β aggregation is not the most important pathological mechanism in later stages of the condition. It may well be the initially important mechanism that sets the stage for other forms of dysfunction, such as tau aggregation and neuroinflammation, but it will require years more to produce sufficient data in patients with early, mild cognitive symptoms to know whether or not these anti-amyloid immunotherapies can prevent Alzheimer's disease to any meaningful degree.

Alzheimer's patients and their families are faced with the tough question of whether to undergo a treatment that will not make them better. It won't even stop them from getting worse. At best, treatment with lecanemab or donanemab could slow the inevitable cognitive decline that characterizes Alzheimer's. Add to this the facts that treatment is expensive, requires biweekly or monthly infusions, and carries risks such as brain bleeds and brain swelling that are usually mild and go away on their own but can, in rare cases, be life-threatening. But just because the benefits are limited doesn't mean they are not valuable to patients and their families.

There are two critical inflection points on the continuum between independence and dependency. The first is the point where a person can no longer live independently because of an impaired ability to manage everyday tasks such as preparing meals, driving, paying bills and remembering appointments. The second point comes when a person can no longer care for his or her own body, and requires assistance with bathing, dressing, and toileting. To calculate the effects of treatment, researchers first estimated when people could expect to lose each of the two kinds of independence if left untreated. They analyzed the experiences of 282 people who participated in research studies. All participants met the criteria for treatment with the two new drugs, but hadn't received them previously. The researchers also calculated how quickly symptoms progressed without treatment.

Using these data on independence and progression, combined with the reported effects of the two drugs, the researchers calculated the amount of time a person at each stage of the disease could be expected to live or care for themselves independently without treatment, and how this progression would compare to those who received treatment. A typical person with very mild symptoms could expect to live independently for another 29 months without treatment, 39 months with lecanemab, and 37 months with donanemab. Most people with mild symptoms - as opposed to very mild symptoms - were already unable to live independently at baseline, so for them the more relevant measure was how much longer they would be able to care for themselves. The researchers calculated that a typical person at this stage of the disease could expect to manage self-care independently for an additional 26 months if treated with lecanemab, 19 months with donanemab.

Link: https://medicine.washu.edu/news/next-gen-alzheimers-drugs-extend-independent-living-by-months/

Cytomegalovirus, CMV, is a prevalent form of herpesvirus, a persistent infection that cannot be effectively cleared by the immune system and continues to resurface over time following the initial exposure. Upwards of 90% of older people in the developed world have been exposed to CMV at some point in their lives. The immediate symptoms of CMV infection for most people are mild to non-existent, but there is reason to suspect that CMV acts over time to corrode the effectiveness of the adaptive immune system.

The adaptive immune system is a complex collection of many subpopulations of cells. One high-level view of the harm done by CMV is that its presence forces an expansion of the population of memory T cells dedicated to this one infectious agent at the expense of the myriad other duties that the T cell population should be undertaking. Any given category of T cells is not a monolith, however, is made up of many different T cell subtypes and behaviors, and the real picture is no doubt more complex than a simple expansion of one subtype.

Further, CMV most likely affects other portions of the immune system to a similar degree, and some of those influences may also be harmful over the long term, contributing to degenerative aging. In today's open access paper, researchers report on their investigation of the effects of CMV infection on immune cell populations that include innate immune cells known as monocytes. Monocytes and their descendant macrophages are involved in defense against pathogens, modulation of inflammatory signaling, tissue maintenance, and other duties. Note that the study is only comparing young versus old individuals with exposure to CMV, not uninfected individuals, however.

Markers of immunosenescence in CMV seropositive healthy elderly adults

A significant increase in life expectancy has accompanied the growth of the world's population. Approximately 10% of the global population are adults over 60, and it is estimated that 2050 this figure will double. This increase in the proportion of older adults leads to a more significant burden of age-related diseases. Immunosenescence predisposes elderly individuals to a higher incidence of infectious and chronic non-communicable diseases with higher mortality rates. Despite advances in research, it is necessary to evaluate the cellular characteristics of the aging immune system in populations with a high incidence of latent viruses such as cytomegalovirus (CMV). To that end, this study employed a group of 10 young people (18-28 years old with an average age of 24.5 ± 2.98 years, five men and five women) and a group of ten older adults (60-85 years old with a mean age of 67.9 ± 9.07 years, five men and five women).

Monocytes play a fundamental role in the immune response due to their phagocytic capacity, which is necessary for the processing and presentation of antigens and the production of cytokines. In aging, monocytes are critical cells in age-related immune dysfunction. Our study observed a decrease in classical CD14++CD16- monocytes and an increase in CD14+CD16+ intermediate monocytes in older adults. The intermediate monocytes are characterized as proinflammatory cells that produce cytokines such as TNFα and IL-6. These cytokines have been associated with chronic low-grade inflammation or inflammaging. Furthermore, previous studies have shown an association between variation in circulating monocyte subpopulations and the development of diseases such as coronary heart disease and various types of cancer.

When we analyzed natural killer (NK) cells in our sample, we observed a significant increase in CD56neg cells, increased expression of CD57, and a notable decrease in CD56bright cells in older adults. These findings align with previous immunosenescence research reporting a decrease in immature NK and an increase in CD56dim cells with CD57 expression. Studies have shown that CD56neg cells are less functional regarding cytotoxicity and responsiveness, especially in CMV+ individuals.

In this study, using the differential expression of CD62L and CD45RO, the distribution of memory subpopulations in the T cells was determined. A significant decrease in the naïve cell subpopulation was observed in CD4+ and CD8+ T cells in the older adult group. Although the total number of T cells remains relatively constant with aging, reducing the naïve T cells is a hallmark of immunosenescence. Furthermore, we observed a significant increase in terminally differentiated effector CD8+ T cells in older adults. This increase in T cell effectors has been observed in both aging and chronic infections, such as those caused by CMV, which is the case for our individuals.

Researchers here note the discovery of a marker of dysfunctional hematopoietic cells in bone marrow. Hematopoietic stem cells and their immediate descendants are responsible for producing red blood cells and immune cells. The activities of hematopoietic cells are detrimentally affected by aging, as for every other cell population in the body, and some fraction of immune system aging derives from changes in the behavior and numbers of hematopoietic cells. If only some of these cells are very dysfunctional, however, then selectively clearing out the most problematic cells, or at least reducing their relative numbers as a fraction of all hematopoietic cells, should help to restore lost immune function.

Aging is a process accompanied by functional decline in tissues and organs with great social and medical consequences. Developing effective anti-aging strategies is of great significance. In this study, we demonstrated that transplantation of young hematopoietic stem cells (HSCs) into old mice can mitigate aging phenotypes, underscoring the crucial role of HSCs in the aging process.

Through comprehensive molecular and functional analyses, we identified a subset of HSCs in aged mice that exhibit "younger" molecular profiles and functions, marked by low levels of CD150 expression. Mechanistically, CD150low HSCs from old mice but not their CD150high counterparts can effectively differentiate into downstream lineage cells. Notably, transplantation of old CD150low HSCs attenuates aging phenotypes and prolongs lifespan of elderly mice compared to those transplanted with unselected or CD150high HSCs. Importantly, reducing the dysfunctional CD150high HSCs can alleviate aging phenotypes in old recipient mice.

Thus, our study demonstrates the presence of "younger" HSCs in old mice, and that aging-associated functional decline can be mitigated by reducing dysfunctional HSCs.

Link: https://doi.org/10.1038/s41422-024-01057-5

Why do traumatic brain injury survivors exhibit an increased risk of Alzheimer's disease? Researchers here observe a specific set of changes in the vasculature of the injured brain that appear to accelerate deposition of amyloid-β, an outcome supportive of the amyloid cascade hypothesis for the development of Alzheimer's disease. Despite the inability of amyloid-β clearance to much affect patient outcomes in the later stages of Alzheimer's disease, it remains the case that many lines of evidence support amyloid-β aggregation as the foundational pathology that initially causes Alzheimer's disease.

Traumatic brain injury (TBI) often leads to impaired regulation of cerebral blood flow, which may be caused by pathological changes of the vascular smooth muscle cells (VSMCs) in the arterial wall. Moreover, these cerebrovascular changes may contribute to the development of various neurodegenerative disorders such as Alzheimer's-like pathologies that include amyloid beta aggregation. Despite its importance, the pathophysiological mechanisms responsible for VSMC dysfunction after TBI have rarely been evaluated.

Here, we show that acute human TBI resulted in early pathological changes in leptomeningeal arteries, closely associated with a decrease in VSMC markers such as NOTCH3 and alpha smooth muscle actin (α-SMA). These changes coincided with increased aggregation of variable-length amyloid peptides including Aβ1-40/42, Aβ1-16, and β-secretase-derived fragment (βCTF) (C99) caused by altered processing of amyloid precursor protein (APP) in VSMCs. The aggregation of Aβ1-40/42 peptides were also observed in the leptomeningeal arteries of young TBI patients.

These pathological changes also included higher β-secretase (BACE1) in the leptomeningeal arteries, plausibly caused by hypoxia and oxidative stress as shown using human VSMCs in vitro. Importantly, BACE1 inhibition not only restored NOTCH3 signalling but also normalized ADAM10 levels in vitro. Furthermore, we found reduced ADAM10 activity and decreased NOTCH3, along with increased βCTF (C99) levels in mice subjected to an experimental model of TBI. This study provides evidence of early post-injury changes in VSMCs of leptomeningeal arteries that can contribute to vascular dysfunction and exacerbate secondary injury mechanisms following TBI.

Link: https://doi.org/10.1007/s00401-025-02848-9

Bimagrumab is a monoclonal antibody targeting αActRIIA and αActRIIB. These receptors are involved in the inhibition of muscle growth via the activity of myostatin; circulating myostatin binds to αActRIIB. Various means of preventing this from happening produce sizable muscle growth in a variety of animal species. Most of the examples involve mutation of the myostatin gene, but a few of the other approaches have made it into clinical trials, including antibodies to reduce circulating myostatin levels and gene therapies to increase circulating levels of follistatin, a protein that blocks the activity of myostatin. The point of all of this is to find a viable approach to produce muscle growth without the need for exercise, and turn back the loss of muscle mass and strength that occurs with age.

Bimagrumab is currently in clinical trials aimed at obesity, as the present generation of GLP-1 receptor agonist drugs used for weight loss produce significant loss of muscle mass alongside loss of fat mass. Drugs that might counteract that undesirable loss of muscle mass are much sought after. In today's open access paper, researchers demonstrate that bimagrumab treatment is quite effective at increasing muscle mass and bone mineral density in mice. This increase in bone mineral density is also a feature of other approaches centered around myostatin, though not so often reported or the focus of research aimed at muscle tissue.

The Effect of Anti-Activin Receptor Type IIA and Type IIB Antibody on Muscle, Bone and Blood in Healthy and Osteosarcopenic Mice

Anti-Activin Receptor Type IIA and Type IIB antibody (αActRIIA/IIB ab) is a recently developed drug class that targets the activin receptor signalling pathway. Inhibition of receptor ligands (activins, myostatin, growth differentiation factor 11, etc.) can lead to skeletal muscle hypertrophy and bone formation. Despite the αActRIIA/IIB ab, bimagrumab, having progressed to clinical trials, two crucial questions about αActRIIA/IIB ab therapy remain: Does αActRIIA/IIB ab influence bone metabolism and bone strength similarly to its generic classmates (activin receptor-based ligand traps)? Therefore, the aim of the present study was to investigate the therapeutic potential of αActRIIA/IIB ab in a mouse model of concurrent sarcopenia and osteopenia and to investigate the effect on bonein more detail.

In C57BL/6JRj mice, combined sarcopenia and osteopenia were induced locally by injecting botulinum toxin A into the right hindlimb, resulting in acute muscle paresis. Immediately after immobilization, mice received twice-weekly intraperitoneal injections with αActRIIA/IIB ab (10 mg/kg) for 21 days, after which they were sacrificed. Muscle mass, skeletal muscle fibre size and Smad2 expression were analysed in the rectus femoris and gastrocnemius muscles. Bone mass and bone microstructure were analysed in the trabecular bone and cortical bone.

αActRIIA/IIB ab caused a large increase in muscle mass in both healthy (+21%) and immobilized (sarcopenic and osteopenic) (+12%) mice. Furthermore, αActRIIA/IIB ab increased trabecular bone (bone volume fraction) for both healthy (+65%) and immobilized (+44%) mice. For cortical bone, αActRIIA/IIB ab caused a small, but significant, increase in bone area (+6%) for immobilized mice, but not for healthy mice. These results suggest a potential in the treatment of concurrent osteopenia and sarcopenia.

The Golgi apparatus receives relatively little attention in the context of aging, but it suffers dysfunction like all structures in the cell. It is involved in directing newly manufactured proteins to their destination, whether inside the cell or to be secreted in extracellular vesicles. Researchers here show that extracellular vesicles harvested from a particular form of stem cell culture can act to improve Golgi apparatus function in aged tissues, and in doing so aid in improving bone density and bone regeneration in aged mice.

The production of stem cell aggregates (CA) is a regenerative technique that promotes normal stem cell function by encouraging high-density stem cells to secrete large amounts of extracellular matrix (ECM), which serves as an excellent cellular scaffold. Our previous studies have further revealed that CA-derived extracellular vesicles (CA-EVs) are featured with proteins that effectively promote tissue/organ regeneration.

In this study, we investigated the mechanisms underlying bone marrow mesenchymal stem cell (BMSCs) senescence in bone aging and explored whether CA-EVs can improve bone mass and regeneration with the advanced age. Surprisingly, we discovered that alterations of Golgi apparatus contributed to senescence of resident BMSCs and led to a reduction in the release of endogenous EVs, which has not been previously reported. We further found that locally transplanted CA lost its ability to promote bone regeneration in the aging microenvironment, which was also attributed to impaired structure and function of Golgi.

Intriguingly, in-depth analysis suggested that CA-EVs exposed functional surface proteins to assemble the Golgi apparatus, such as Syntaxin 5 (STX5), which helped restore function of senescent BMSCs. Importantly, CA-EV replenishment promoted regeneration of bone defects and counteracted osteoporosis in aging mice. These findings provide the first evidence that Golgi-based vesicular disorders contribute to cell senescence and that CA-EVs effectively mitigate BMSC aging to retard age-related osteoporosis and safeguard aging bone regeneration.

Link: https://doi.org/10.1038/s41413-024-00386-w

Older patients exhibiting multimorbidity, meaning the presence of two or more diagnosed age-related conditions, are typically in relatively poor shape. Researchers here note that, in this population specifically, greater levels of exercise still correlate with reduced mortality over time. While human data can only show correlation and not causation, extensive animal studies of physical activity give us good reason to think that exercise does in fact act to improve health and that this isn't just a case of less healthy individuals being less able to exercise.

Our study represents one of the pioneering multinational efforts to investigate the longitudinal relationship between physical activity (PA) levels and mortality in individuals with multimorbidity. We found that higher levels of physical activity could significantly reduce mortality risk over an average 12-year follow-up period, even among those dealing with multiple chronic conditions. Our results show that, after adjusting for several potential confounding factors, individuals with multimorbidity who reported moderately low, moderately high and high levels of PA had a 36%, 47%, and 51% reduced mortality risk, respectively, compared to those with low levels of PA.

PA may reduce mortality through several mechanisms. First, engaging in regular PA boosts mitochondrial function, enhancing energy production and decreasing oxidative stress, thereby protecting cells from damage. PA also increases the expression of antioxidant enzymes, which help neutralize harmful free radicals. Second, PA regulates inflammation by lowering pro-inflammatory cytokine levels and raising anti-inflammatory interleukins. It also stimulates autophagy, the process by which cells remove damaged proteins and organelles, ensuring cellular health. Thirdly, PA enhances insulin sensitivity, aiding in blood glucose regulation and potentially slowing the accumulation of molecular damage. Together, these hormonal and molecular changes reduce the risk of chronic diseases and decrease overall mortality.

Link: https://doi.org/10.1002/jcsm.13695

Many drugs have their origin in a human gene variant or mutation that was discovered to be protective in some way. Typically such drugs are less effective than possessing the mutation, for all the usual reasons. A drug is only used for some years rather than the whole lifespan, doesn't give the 100% coverage of cells in a tissue that the mutation does, and usually only recreates a fraction of the effects of the mutation in any given cell. Thus mutations that lower circulating LDL-cholesterol in the bloodstream can produce as much as a 50% reduction in lifetime risk of cardiovascular mortality, but drugs that reduce LDL-cholesterol levels produce only a 10-20% reduction, depending on which studies one chooses to take as representative.

Nonetheless, the discovery of protective mutations and gene variants is a sizable concern that continues to lead to drug development programs. Today's open access paper reviews the mechanisms by which a longevity-associated variant of BPIFB4 is thought to lower risk of mortality. It appears to act in two ways, firstly by improving vascular function in older people, and secondly by reducing inflammation. The effects on vascular function are complex, involving reduced stiffening of vessels due to smooth muscle dysfunction, increased formation of new vessels, and increased antioxidant activity to reduce oxidative stress. As is usually the case, it is unclear as to which of these mechanisms is most important in determining the observed outcome of reduced late life mortality; one could make a good case for most of them.

Protective role of the longevity-associated BPIFB4 gene on cardiac microvascular cells and cardiac aging

The longevity-associated variant (LAV) of BPIFB4 was discovered using a stringent threshold of statistical significance for genome-wide association studies (GWAS) in three independent cohorts of centenarians in Italy, Europe, and the US. The LAV-BPIFB4 haplotype was inversely correlated with frailty in elderly subjects, strengthening its relevance in influencing the health status and longevity of the elderly.

Further analyses showed that the LAV homozygous genotype was positively associated with high endothelial nitric oxide (eNOS) phosphorylation in mononuclear cells, which translates to augmented nitric oxide (NO) production and beneficial functions in the cardiovascular system. In keeping with the benefits to the vascular compartment, recombinant LAV-BPIFB4 protein supplementation enhanced the proangiogenic activity of young and senescent endothelial cells. Importantly, these advantages can be transferred through LAV-BPIFB4 gene therapy in older mice, whereas eNOS phosphorylation and vessel activity are restored to levels observed in young mice.

Alongside the eNOS downstream substrate, the SDF-1/CXCR4 axis is a crucial effector of the cardiovascular protective and immunomodulatory activity of LAV-BPIFB4. In this regard, LAV-BPIFB4 activates SDF-1/CXCR4 signaling to remodel the immune system and resolve inflammation through various mechanisms involving protective macrophage polarization toward the pro-resolving M2 phenotype, favorable redistribution of circulating monocyte cell subsets, and reduction in T-cell activation.

The body changes with age, and many of those changes are fairly similar from person to person in their relationship with disease and mortality. Thus any sufficiently large set of data on body structure or biochemistry can be used to produce a clock algorithm that reflects mortality risk and the burden of age-related damage and dysfunction. Typically the result is framed as a measure of age, and called biological age, though there are some who think that researchers should be more careful in how they talk about what exactly is being measured by a clock.

Biological age (BA) is a potentially useful construct that attempts to reflect the cumulative physiologic effect of lifestyle habits, genetic predisposition, and superimposed disease processes beyond simply the number of years lived. Attempts at deriving an effective BA date back at least half a century, but with only limited success. Much of the current geroscience focus to date for attempting to derive an effective BA has centered on various "frailomics" at the cellular and subcellular levels, including genomics and epigenomics (e.g., telomere length and epigenetic clock), proteomics, and metabolomics, as well as various other laboratory and clinical measures.

Imaging biomarkers have generally received less attention for estimating BA, but arguably may better reflect the cumulative macroscopic effects of aging at the tissue and organ levels. In particular, abdominal computed tomography (CT) represents an appealing candidate for a more personalized investigation. Thus we derived and tested a CT-based biological age model for predicting longevity that quantifies skeletal muscle, abdominal fat, aortic calcification, bone density, and solid abdominal organs.

We applies this tool to abdominal CT scans from 123,281 adults (mean age, 53.6 years; 47% women). The final weighted CT biomarker selection was based on the index of prediction accuracy. The CT model significantly outperforms standard demographic data for predicting longevity (index of prediction accuracy, IPA = 29.2 vs. 21.7). Age- and sex-corrected survival hazard ratio for the highest-vs-lowest risk quartile was 8.73 for the CT biological age model, and increased to 24.79 after excluding cancer diagnoses within 5 years of CT. Muscle density, aortic plaque burden, visceral fat density, and bone density contributed the most.

Link: https://doi.org/10.1038/s41467-025-56741-w

The various aging clocks only become truly useful to the degree that there is enough existing data on their performance to understand whether or not one can trust their outputs for a given novel intervention targeting aging. A way to rapidly assess effects on biological age will steer the development of therapies towards the most effective approaches much more rapidly than is presently the case. Even through the clocks have issues, the largest of which being that the research community cannot link clock components to specific mechanisms of aging via a clear chain of cause and effect, using them broadly in as many human trials as possible is a good idea, including lifestyle interventions and supplements thought to have only modest effects. In this study, for example, researchers found that a few of these interventions slowed the increase of biological age over time in older people by something like 10%, on average.

While observational studies and small pilot trials suggest that vitamin D, omega-3, and exercise may slow biological aging, larger clinical trials testing these treatments individually or in combination are lacking. Here, we report the results of a post hoc analysis among 777 participants aged 70 years and older of the DO-HEALTH trial on the effect of vitamin D (2,000 IU per day) and/or omega-3 (1 g per day) and/or a home exercise program on four next-generation DNA methylation (DNAm) measures of biological aging (PhenoAge, GrimAge, GrimAge2 and DunedinPACE) over 3 years.

Omega-3 alone slowed the DNAm clocks PhenoAge, GrimAge2 and DunedinPACE, and all three treatments had additive benefits on PhenoAge. Overall, from baseline to year 3, standardized effects ranged from 0.16 to 0.32 units (2.9-3.8 months). In summary, our trial indicates a small protective effect of omega-3 treatment on slowing biological aging over 3 years across several clocks, with an additive protective effect of omega-3, vitamin D and exercise based on PhenoAge.

Link: https://doi.org/10.1038/s43587-024-00793-y

Today's open access paper is a good introduction to what makes the Rho-GTPase family an important area of study in molecular biochemistry: it is relevant to efforts to suppress cancer metastasis. If metastasis could be eliminated, the majority of cancer mortality would evaporate, even if no further advances occurred in the field. Surgical techniques would be sufficient to remove most tumors even at later stages. Cancer would become a localized problem in the body, much less of a threat.

Unfortunately, while the biochemistry of metastasis is quite well understood, satisfactory efforts to interfere have yet to emerge. As is so often the case in cell biology, the runaway mechanisms involved in the migration and attachment of cancer cells are also essential to normal tissue function. One can't just break the mechanism for benefit, as that generates serious side-effects, too serious for even cancer patients. So, as illustrated by this paper, one has to approach the target mechanism in a better, more indirectly.

An allosteric inhibitor of RhoGAP class-IX myosins suppresses the metastatic features of cancer cells

Tumour cells disseminate by migration, either collectively as sheets and clusters, or individually, where single cells transition through a mesenchymal- and/or amoeboid type of migration to escape from the primary tumour and invade target organs to establish new connective attachments, followed by unrestrained growth and proliferation. Single and collective cell migration, both share common pathways of receptor-mediated stimulation that are tightly regulated via signalling cascades involving members of the Ras homologous (Rho) family of small guanosine triphosphatases (GTPases), including Rho, Rac, and Cdc42.

Aberrant RhoGTPase signalling is considered a dominant driving force of metastasis and cancer progression. Particularly, oncogenic mutations in RhoGTPases and their regulators, excessive receptor signalling, and altered effector activity patterns, are factors that stimulate cells to gain pro-migratory capabilities and acquire highly invasive, proliferative phenotypes that promote dissemination and metastasis formation. Thus, targeted interference of Rho-associated signalling cues has become a viable and increasingly investigated strategy for suppressing cancer metastasis. Lack of target selectivity, side effects, and development of resistances have yet prevented positive responses to treatments and therapeutic breakthroughs.

A promising, yet elusively explored approach to target the metastatic properties of cancer cells, particularly those related to enhanced migration and invasiveness, is to gain control over the activity of GTPase-activating proteins (GAPs), the negative regulators of RhoGTPases. Drugs that are capable of enhancing and/or locally controlling RhoGAP activity provide a means to suppress the adhesive and migratory properties of cancer cells, and thus metastasis.

Here, we report the identification and characterization of adhibin, a synthetic allosteric inhibitor of RhoGAP class-IX myosins that abrogates ATPase and motor function, suppressing RhoGTPase-mediated modes of cancer cell metastasis. In human and murine adenocarcinoma and melanoma cell models, including three-dimensional spheroid cultures, we reveal anti-migratory and anti-adhesive properties of adhibin, affecting actin-dynamics and actomyosin-based cell-contractility. Adhibin blocks membrane protrusion formation, disturbs remodelling of cell-matrix adhesions, affects contractile ring formation, and disrupts epithelial junction stability; processes severely impairing single/collective cell migration and cytokinesis.

That immune cells in an inflammatory environment produce a much greater amount of oxidizing molecules is one of the reasons why increased levels of chronic inflammation and oxidative stress tend to be linked in older individuals. Researchers here review this mechanism in the context of Alzheimer's disease, as a way in which inflammation can drive detrimental epigenetic changes in cell populations in the brain, as those changes are in a part a reaction to an environment of greater oxidative stress.

It is widely accepted that chronic neuroinflammation plays a role in the development of Alzheimer's disease (AD), although the specific mechanisms remain elusive. Chronic low-grade inflammation is a characteristic of ageing and systemic inflammation is associated with AD onset, and we have presented a multitude of studies that suggest an effector role for immune cells in AD pathology. The extent to which peripheral immune cells, such as neutrophils, can enter the brain remains unclear and is difficult to measure temporally, however signs of oxidative stress are evident and clearly contribute to the aetiology of AD. Sources of oxidative stress are abundant in AD and include dysfunctional mitochondria, neurons, and endothelial cells, but immune cells are emerging as an abundant and potentially modifiable source.

Microglia are specialised immune cells of myeloid lineage that reside chiefly in the central nervous system and comprise up to 15% of all cell types found in the brain. Their main function is surveillance and maintenance of the central nervous system through clearance of dead and dying cells, as well as plaques. Microglia express NOX, an enzyme that produces superoxide and results in the formation of a range of oxidant species. Immune cell-derived oxidants differ greatly in their specificity and reactivities and produce a range of radical and non-radical species that can influence a variety of cellular and molecular processes, but can also cause tissue injury.

Oxidative stress can alter neuronal health both by directly damaging the DNA and causing cell death but also in more subtle ways, through the manipulation of key cellular enzymes and cofactors that have the potential to modify the epigenetic regulation of the genes associated with Alzheimer's disease onset and progression. Further studies are required to explore the impact of immune-derived oxidants on DNA methylation profiles in the ageing brain with the aim of uncovering targeted immunomodulatory, epigenetic, or mitochondrial therapeutic agents in the treatment of AD. As the world's population ages, it will become increasingly important to find reliable biomarkers of oxidative stress in middle-aged humans, before the onset of age-related disease such as AD, with the ultimate goal of prolonging the health span of individuals as they age.

Link: https://doi.org/10.1080/13510002.2024.2428152

Engineering the growth of new adult teeth has been a work in progress for some years now. As noted here, researchers have moved on from small mammals such as rats and are attempting regrowth of teeth in pigs. The process involves implanting a artificial tooth bud into the jaw, made of a suitable mix of cells seeded into a scaffold material. In this case, the researchers used decellularized tooth bud extracellular matrix as the scaffold, ensuring the correct chemical cues are present. The challenge in all of this lies in controlling the shape and structure of the resulting tooth; a tooth bud implanted in the jaw in this way does not naturally result in a correctly shaped tooth, so something is still missing from the recipe.

The use of dental implants to replace lost or damaged teeth has become increasingly widespread due to their reported high survival and success rates. In reality, the long-term survival of dental implants remains a health concern, based on their short-term predicted survival of ~15 years, significant potential for jawbone resorption, and risk of peri-implantitis. The ability to create functional bioengineered teeth, composed of living tissues with properties similar to those of natural teeth, would be a significant improvement over currently used synthetic titanium implants.

To address this possibility, our research has focused on creating biological tooth substitutes. The study presented here validates a potentially clinically relevant bioengineered tooth replacement therapy for eventual use in humans. We created bioengineered tooth buds by seeding decellularized tooth bud (dTB) extracellular matrix (ECM) scaffolds with human dental pulp cells, porcine tooth bud-derived dental epithelial cells, and human umbilical vein endothelial cells. The resulting bioengineered tooth bud constructs were implanted in the mandibles of adult Yucatan minipigs and grown for 2 or 4 months. We observed the formation of tooth-like tissues, including tooth-supporting periodontal ligament tissues, in cell-seeded dTB ECM constructs.

Link: https://doi.org/10.1093/stcltm/szae076

Cells are state machines, more or less, their behavior largely driven by the specific pattern of gene expression they adopt. With age other factors can enter play, such as the presence of molecular waste (lipofuscin and so forth) that is very hard for cells to break down or eject, and changes in the exterior environment that produce corresponding reactions within the cell, including cross-linking of the extracellular matrix, inflammatory signaling, and the like. Even so, the potential offered by any means of reliably controlling gene expression is the ability to selectively reset the behavior of cells, to override their unfortunate reactions to the aged environment, and to restore behaviors that result in improved tissue function. Control of cell behavior implies a sizable degree of control over disease, dysfunction, aging.

Much of the cell reprogramming space is focused on treatment of aging, reversing at least some of the characteristic age-related changes in gene expression that alter cell function for the worse. Much of that work centers around application of the Yamanaka factors that are involved in transforming adult germline cells into embryonic stem cells in early embryogenesis. But this is just one form of reprogramming. There are many others. Why not, for example, reprogram a cancerous cell to stop being a cancerous cell? That is the topic of today's research materials, narrowly focused on colon cancer as a first application of a platform for discovering ways to revert specific cancerous changes in specific tissues. This line of work is now under development at a new biotech company, Biorevert.

A Molecular Switch that Reverses Cancerous Transformation at the Critical Moment of Transition​

A research team has succeeded in developing a fundamental technology to capture the critical transition phenomenon at the moment when normal cells change into cancer cells and analyze it to discover a molecular switch that can revert cancer cells back into normal cells. A critical transition is a phenomenon in which a sudden change in state occurs at a specific point in time. The research team discovered that normal cells can enter an unstable critical transition state where normal cells and cancer cells coexist just before they change into cancer cells during tumorigenesis, the production or development of tumors, and analyzed this critical transition state using a systems biology method to develop a cancer reversal molecular switch identification technology that can reverse the cancerization process. They then applied this to colon cancer cells and confirmed through molecular cell experiments that cancer cells can recover the characteristics of normal cells.

This is an original technology that automatically infers a computer model of the genetic network that controls the critical transition of cancer development from single-cell RNA sequencing data, and systematically finds molecular switches for cancer reversion by simulation analysis. Among the common target genes of the discovered transcription factor combinations, researchers identified cancer reversing molecular switches that were predicted to suppress cancer cell proliferation and restore the characteristics of normal colon cells. When inhibitors for the molecular switches were provided to organoids derived from colon cancer patients, it was confirmed that cancer cell proliferation was suppressed and the expression of key genes related to cancer development was inhibited, and a group of genes related to normal colon epithelium was activated and transformed into a state similar to normal colon cells.

Attractor Landscape Analysis Reveals a Reversion Switch in the Transition of Colorectal Tumorigenesis

Cell fate changes often involve abrupt transition, called "critical transition," at key points, superimposed on a background of more gradual changes. In particular, it has been well known that tumorigenesis incurs such critical transition. So, questions arise as to what the core molecular regulatory network underlying the critical transition is and whether we can reverse it by controlling a master regulator of the core network.

A number of intriguing studies have been followed to the present reporting the possibility of reverting cancer cell states to phenotypically healthy cell states under various experimental settings. However, these approaches often relied on trial-and-error experiments or comparative analyses mostly that focus on static network properties, limiting their ability to capture dynamic transitions.

Here a systems framework, REVERT, is presented with which can reconstruct the core molecular regulatory network model and a reversion switch based on single-cell transcriptome data over the transition process is identified. The usefulness of REVERT is demonstrated by applying it to single-cell transcriptome of patient-derived matched organoids of colon cancer and normal colon. REVERT is a generic framework that can be applied to investigate various cell fate transition phenomena.

Atrial fibrillation is a dysfunction arising in the aging heart that is associated with later cardiovascular disease; in this context it might be taken as an advance warning of the consequences of a growing burden of cell and tissue damage. As for many age-related conditions, there is a correlation with the chronic inflammation of aging. Lasting, unresolved inflammatory signaling changes the behavior of cells for the worse and is disruptive to tissue structure and function. Here, researchers identify the starting point of one specific pathway by which which inflammation disrupts the regulation of heart rhythm.

Chronic inflammation is a common denominator in many conditions associated with atrial fibrillation (AF). However, the exact mechanisms linking inflammation to arrhythmia have remained elusive. Interleukin-1 beta (IL-1β) - a molecule of the immune system involved in regulating inflammation - can directly influence the heart's electrical activity, creating a predisposition to AF. "The present work marks a key scientific milestone in the field of knowledge. Many review papers had already suggested that IL-1β could play a vital role in atrial fibrillation. We were able to demonstrate that this actually happens."

The research team began by analyzing the immunological profiles of 92 patients, including 30 healthy controls and 62 individuals diagnosed with AF. To delve deeper, the researchers used mice to investigate the effects of IL-1β. By administering controlled doses of IL-1β over 15 days, they simulated prolonged systemic inflammation. During observation, the rodents developed cardiac alterations that made them more susceptible to AF. Additionally, the team employed genetically modified mice lacking IL-1β receptors in macrophages - immune cells found throughout the body, including the heart. These animals did not develop AF, demonstrating that IL-1β triggers the condition by activating its receptors on macrophages.

The study also opens new avenues for treatment. Medications that inhibit IL-1β or caspase-1 - the enzyme that activates IL-1β production - are promising candidates to prevent AF in at-risk patients, particularly those with chronic inflammatory conditions.

Link: https://www.eurekalert.org/news-releases/1072499

Here find a discussion of the relevance of age-related changes in the epigenetic regulation of gene expression to memory function. The behavior of a cell is determined by the structure of nuclear DNA, which regions are accessible to the transcription machinery responsible for producing RNA molecules, and thus which RNAs and proteins are produced. That structure is shaped by epigenetic mechanisms such as the addition of methyl groups to specific sites on the genome and the addition of acetyl groups to the histone proteins that DNA is spooled around.

Memory formation is associated with constant modifications of neuronal networks and synaptic plasticity gene expression in response to different environmental stimuli and experiences. Dysregulation of synaptic plasticity gene expression affects memory during aging and neurodegenerative diseases. Covalent modifications such as methylation on DNA and acetylation on histones regulate the transcription of synaptic plasticity genes. Changes in these epigenetic marks correlated with alteration of synaptic plasticity gene expression and memory formation during aging.

These epigenetic modifications, in turn, are regulated by physiology and metabolism. Steroid hormone estrogen and metabolites such as S-adenosyl methionine and acetyl CoA directly impact DNA and histones' methylation and acetylation levels. Thus, the decline of estrogen levels or imbalance of these metabolites affects gene expression and underlying brain functions.

In the present review, we discussed the importance of DNA methylation and histone acetylation on chromatin modifications, regulation of synaptic plasticity gene expression and memory consolidation, and modulation of these epigenetic marks by epigenetic modifiers such as phytochemicals and vitamins. Further, understanding the molecular mechanisms that modulate these epigenetic modifications will help develop recovery approaches.

Link: https://doi.org/10.3389/fragi.2024.1480932

The protein α-synuclein can misfold in ways that encourage other α-synuclein molecules to also misfold in the same way. These misfolded proteins spread slowly from cell to cell through the nervous system, clumping together to form aggregates surrounded by a toxic biochemistry that stresses and kills neurons. This gives rise to the age-related neurodegenerative conditions known as synucleinopathies, characterized by the formation of Lewy bodies, aggregates of α-synuclein that form inside neurons. Parkinson's disease is the synucleinopathy that receives the most attention; motor neurons are the most vulnerable to disease pathology, and motor function is affected as these vital cells die, giving rise to the most evident symptoms of the condition.

An association between gastrointestinal dysfunction and Parkinson's disease was noted long before the advent of modern biotechnology. Now, given the means to study the biochemistry and microbial populations of the gastrointestinal tract in fine detail, researchers have found that in many cases misfolded α-synuclein appears to originate in the intestines and then spread to the brain. Associations exist between specific differences in the gut microbiome and Parkinson's disease. It remains to be seen as to what will emerge from all of this work; the best way forward may be to develop efficient ways to clear misfolded α-synuclein, and in that case the mechanisms of origin and spread will become irrelevant.

Lewy body diseases and the gut

Gastrointestinal (GI) involvement in Lewy body diseases (LBDs) has been observed since the initial descriptions of patients by James Parkinson. Recent experimental and human observational studies raise the possibility that pathogenic alpha-synuclein (⍺-syn) might develop in the GI tract and subsequently spread to susceptible brain regions. The cellular and mechanistic origins of ⍺-syn propagation in disease are under intense investigation. Experimental LBD models have implicated important contributions from the intrinsic gut microbiome, the intestinal immune system, and environmental toxicants, acting as triggers and modifiers to GI pathologies.

Here, we review the primary clinical observations that link GI dysfunctions to LBDs. We first provide an overview of GI anatomy and the cellular repertoire relevant for disease, with a focus on luminal-sensing cells of the intestinal epithelium including enteroendocrine cells that express ⍺-syn and make direct contact with nerves. We describe interactions within the GI tract with resident microbes and exogenous toxicants, and how these may directly contribute to ⍺-syn pathology along with related metabolic and immunological responses. Finally, critical knowledge gaps in the field are highlighted, focusing on pivotal questions that remain some 200 years after the first descriptions of GI tract dysfunction in LBDs.

We predict that a better understanding of how pathophysiologies in the gut influence disease risk and progression will accelerate discoveries that will lead to a deeper overall mechanistic understanding of disease and potential therapeutic strategies targeting the gut-brain axis to delay, arrest, or prevent disease progression.

Mild stresses are observed to slow aging in short-lived species, sometimes dramatically. Low nutrient intake, heat, cold, toxins, and anything else that makes cells react by upregulating maintenance processes tends to produce sweeping improvements in metabolism, reduced inflammation, and a range of other benefits. This results in extended healthy life span. Unfortunately, long-lived species such as our own do not exhibit anywhere near the same degree of extended life, even while the cellular biochemistry of the response to mild stress looks very similar. The underlying reasons for this difference have yet to be established.

Although the longevity benefits of low temperatures were documented over a century ago, the precise mechanisms by which cold influences lifespan and healthspan are not fully understood. The prevailing hypothesis suggests that cold-induced longevity is mainly attributed to a slowdown in the rate of biochemical reactions and metabolic processes, leading to reduced energy expenditure and a decelerated pace of physiological activities. Recent research, however, has uncovered more intricate mechanisms through which cold exposure can extend lifespan and improve health.

Cold exposure has been shown to impact several key physiological processes related to aging. One of the major mechanisms is its ability to reduce chronic inflammation, a condition often referred to as "inflammaging". Chronic, low-grade inflammation is a hallmark of aging and is associated with the development of various age-related diseases, including cardiovascular diseases, diabetes, and neurodegenerative disorders. It has been reported that cold exposure can mitigate inflammation by modulating immune responses and reducing the production of pro-inflammatory cytokines in healthy individuals as well as patients with inflammatory diseases. These cytokines are typically elevated in chronic inflammation and are associated with various age-related diseases. By lowering their production, cold exposure may help decrease systemic inflammation.

Another significant aspect of aging is oxidative stress, which results from the accumulation of reactive oxygen species (ROS) that causes damage to cellular components and contributes to cellular aging and various diseases. The free radical theory of aging posits that oxidative stress is a major driver of the aging process. Cold exposure has been shown to reduce oxidative stress and enhance the body's antioxidant defenses, thereby reducing inflammation and protecting cells from damage.

Metabolic regulation is also profoundly affected by cold exposure by increasing energy expenditure and altering metabolic pathways. Activating brown adipose tissue (BAT) through cold exposure increases energy expenditure and improves metabolic health. This process enhances insulin sensitivity, promotes lipid metabolism, and helps to regulate glucose metabolism, thereby mitigating inflammatory responses associated with metabolic dysfunction. These metabolic pathways play a crucial role in maintaining overall health and longevity. Additionally, recent studies have also revealed that cold exposure can activate proteasomes through PA28γ/PSME3 pathway, enhancing protein degradation and reducing disease-related protein aggregation.

Despite the promising short-term benefits of cold exposure, the long-term effects remain unclear. Epidemiological studies present a paradox: while short-term cold exposure seems to offer health benefits, populations living in high-altitude cold environments face an increased health risks, including higher mortality rates and a greater incidence of cardiovascular diseases. This complexity underscores the need for further research to fully understand the relationship between cold exposure and aging.

Link: https://doi.org/10.1016/j.lfs.2025.123431

In this meta-analysis, researchers review epidemiological studies that employed a simple classification system to assess both how healthy a diet is and how vegan it is, the plant-based diet index. It is perfectly possible to eat an unhealthy vegan diet: just consume a lot of sugar and processed grains. The result is much as one might expect, in that those adhering to a more vegan diet exhibit lower mortality provided that the diet is healthy. There is some debate regarding which of the possible mechanisms are important in producing this outcome, such as levels of inflammation, a modestly lower overall calorie and protein intake, and so forth.

The adherence to plant-based diets has been shown to positively impact longevity by reducing the incidence and severity of lifestyle-related diseases. Previous studies on the association of plant-based dietary pattern, as evaluated by plant-based dietary index (PDI), healthy plant-based dietary index (hPDI) and unhealthy plant-based dietary index (uPDI), with mortality risk have reported inconsistent results. We performed the present meta-analysis to summarize evidence on this association and to quantify the potential dose-response relationship based on all available cohort studies.

A total of 11 eligible cohort studies (13 datasets) were eventually included in this meta-analysis. Participants in the highest quintile of both the PDI and hPDI had a significantly decreased risk of all-cause mortality (pooled hazard ratio for PDI = 0.85; pooled hazard ratio for hPDI = 0.86) compared to participants in the lowest quintile. In contrast, the highest uPDI was associated with an increased risk of mortality (pooled hazard ratio for uPDI = 1.20). In conclusion, greater adherence to PDI or hPDI dietary pattern was associated with a lower risk of mortality, whereas uPDI dietary pattern was positively associated with mortality risk.

Link: https://doi.org/10.3389/fnut.2025.1518519

Myelin structures form an insulating sheath coating the axons that connect neurons, and are essential for proper electrical function of an axon, the conduction of nerve impulses along the axon structure. Dramatic loss of myelin, as occurs in conditions such as multiple sclerosis, results in severe symptoms and eventual death. A lesser degree of loss of myelin occurs more broadly with age throughout the population, and is thought to provide some contribution to declining cognitive function and conditions such as mild cognitive impairment. In this second case, how exactly the mechanisms cause myelin loss are less well understood. One can look at the state of the oligodendrocyte population responsible for maintaining myelin and see changes in size or changes in activity, but connections to specific molecular biochemistry is ever a challenge.

As researchers note in today's open access paper, there is no FDA-approved therapy to enhance remyelination. This isn't for lack of trying in the usual small molecule development space, where much of the work is focused on trying to find existing drugs and targets that have some modest beneficial effect and few enough side-effects to make it worth the effort. One of the small molecules tested in the paper here was in clinical trials for multiple sclerosis, the antihistamine clemastine, but prevalent inflammatory side-effects caused that line of development to be halted. The other, LL-341070, is in clinical trials for the treatment of depression.

The primary thrust of the paper is an examination of the way in which mild deymelination spurs a response from oligodendrocytes to repair the problem, and the threshold at which that response is insufficient. Drugs that boost oligodendrocyte activity might in principle be able to make a dent in demyelination conditions by shifting this threshold. Interestingly, even drugs and doses that have too small an effect to matter for multiple sclerosis, and have thus been discarded by the development community, could be useful in the treatment of age-related demyelination more generally. Though they are unlikely to be rigorously tested for this use in the present regulatory environment!

Incomplete remyelination via therapeutically enhanced oligodendrogenesis is sufficient to recover visual cortical function

Demyelination is typically followed by a period of heightened new myelin formation known as remyelination, which can restore action potential propagation and prevent neurodegeneration. Remyelination is carried out primarily by newly formed oligodendrocytes differentiating from parenchymal and germinal zone derived oligodendrocyte precursor cells (OPCs) as well as - in some instances - by oligodendrocytes that survive the demyelinating injury. However, the endogenous remyelination response is often incomplete, resulting in chronic demyelination and limited functional recovery. Thus, understanding the drivers and limitations of endogenous remyelination and developing methods to enhance it are clinical imperatives for many demyelinating conditions. Despite substantial progress in identifying compounds that improve remyelination in recent years, there is still no FDA-approved remyelination therapy. Furthermore, independent of specific therapeutic strategies, we require a deeper understanding of fundamental aspects of therapeutic-induced remyelination, such as the dynamics and constraints of therapeutic action, and the magnitude and timing of remyelination required to recover neuronal function.

The afferent visual pathway is well-suited to investigate the relationship between myelin and neuronal function throughout de/remyelination. The circuits of primary visual cortex (V1) are sensitive to input spike precision and contain precise and reliable sensory-evoked activity, important for action potential transmission and visual coding. Moreover, perturbations in the timing of sensory-evoked activity in V1 have previously been observed in patients and animal models during de/remyelination. Here, we used longitudinal in vivo two-photon imaging of oligodendrocytes and high-density electrical recordings with single neuron resolution in V1 to study the dynamics of endogenous and therapeutic-induced neocortical remyelination and the relationship between remyelination and functional recovery. Demyelination was induced with cuprizone, and mice were treated with two remyelination drugs: a new thyroid hormone mimetic (thyromimetic), LL-341070, and a clinically validated therapeutic, clemastine.

Cuprizone treatment induced oligodendrocyte loss and a concomitant increase in visual response latency. This was followed by a rapid and robust endogenous remyelination response that was driven by recent oligodendrocyte loss. Endogenous remyelination was highly efficacious at mild demyelination levels, but when moderate or severe demyelination occurred quickly, endogenous remyelination failed to restore the oligodendrocyte population after seven weeks. Treatment with a high dose of LL-341070 substantially increased regenerative oligodendrogenesis during remyelination, acting more quickly and robustly than clemastine, and hastened neuron functional recovery. The therapeutic benefit of LL-341070 was loss-dependent, exclusively impacting remyelination after moderate or severe demyelination. Consequently, LL-341070 eliminated the endogenous remyelination deficit after seven weeks of remyelination, restoring oligodendrocyte numbers to original levels and myelin to levels comparable to those of age-matched healthy mice. However, full restoration of oligodendrocytes and myelin to these levels was not necessary to recover neuronal function.

The heart is one of the least regenerative organs in the mammalian body, and the scarring that follows injuries such as that sustained during a heart attack impairs function. Transplantation of cardiomyocyte cells to produce regeneration of scarred heart tissue has been a work in progress for going on twenty years now. It is possible to produce patient-matched cardiomyocytes from induced pluripotent stem cells, but such cells exhibit minimal survival and perform poorly when transplanted. The development of artificial tissues using nanoscale scaffolds, enabling the production of thin patches of heart muscle made up of cardiomyocytes, has improved matters. More cells survive following transplantation, and functional improvements are observed in animal models of heart injury. The latest concerns have revolved around whether heart electrical function remains disrupted by the introduction of new cells, causing arrhythmia or worse, but as noted here even that problem seems to be yielding to the latest state of the art.

Cardiomyocytes can be implanted to remuscularize the failing heart. Challenges include sufficient cardiomyocyte retention for a sustainable therapeutic impact without intolerable side effects, such as arrhythmia and tumour growth. We investigated the hypothesis that epicardial engineered heart muscle (EHM) allografts from induced pluripotent stem cell-derived cardiomyocytes and stromal cells structurally and functionally remuscularize the chronically failing heart without limiting side effects in rhesus macaques.

After confirmation of in vitro and in vivo (nude rat model) equivalence of the newly developed rhesus macaque EHM model with a previously established Good Manufacturing Practice-compatible human EHM formulation, long-term retention (up to 6 months) and dose-dependent enhancement of the target heart wall by EHM grafts constructed from 40 to 200 million cardiomyocytes/stromal cells were demonstrated in macaques with and without myocardial infarction-induced heart failure. In the heart failure model, evidence for EHM allograft-enhanced target heart wall contractility and ejection fraction, which are measures for local and global heart support, was obtained. Histopathological and gadolinium-based perfusion magnetic resonance imaging analyses confirmed cell retention and functional vascularization. Arrhythmia and tumour growth were not observed.

The obtained feasibility, safety and efficacy data provided the pivotal underpinnings for the approval of a first-in-human clinical trial on tissue-engineered heart repair. Our clinical data confirmed remuscularization by EHM implantation in a patient with advanced heart failure.

Link: https://doi.org/10.1038/s41586-024-08463-0

Researchers here provide some initial evidence for declining expression of a network of natural antioxidant molecules known as selenoproteins to contribute to the aging of hematopoietic stem cells, responsible for generating red blood cells and immune cells. Note that the researchers impaired selenoprotein expression and observed impaired function, which is nowhere near as convincing as restoring lost expression to observe improved function. There are any number of ways to break cell function and produce results that look similar to aging, even though the specific breakage isn't all that relevant to normal aging. The next step for this line of research is to find a way to restore selenoprotein expression in aged mice, and look for improvement in hematopoiesis.

Human cells have 25 different selenoproteins. These antioxidant enzymes help convert dangerous reactive oxygen species (ROS), such as lipid peroxides, into a safer form. Buildup of lipid peroxides can affect critical cells called hematopoietic stem cells (HSCs), a phenomenon observed in aging diseases. "We observed that aged HSCs frequently display impaired selenoprotein synthesis, but it was unclear how this could contribute to cell aging and if it could be reversed. We hypothesized that selenoproteins are a critical part of the antioxidant system that fights age-related changes in HSCs."

To investigate this, the team used a mouse model with tRNAsec knocked out, leading to disrupted selenoprotein production. They then examined how this affected different cell types, finding that the knockout negatively impacted HSCs and immune cells with B cell lineage (types of white blood cells) but had few effects on myeloid cells (a different family of immune cells). These observations, along with increased expression levels of aging-related genes in these cell types, were consistent with what is frequently seen in age-related diseases. Further investigation indicated that the effects were driven by lipid peroxidation. Additionally, experiments with cells from the mouse model revealed that the disruption in selenoprotein synthesis could support B progenitors switching to the myeloid cell family.

Link: https://www.eurekalert.org/news-releases/1072381

It took twenty years of work and enormous expenditure, but the most recent immunotherapies targeting amyloid-β are capable of clearing most of this form of amyloid from the brain. Unfortunately, this class of therapy produces very little gain for patients in the later stages of Alzheimer's disease. This may be because the amyloid cascade hypothesis should be interpreted to mean that amyloid-β plays no great role in the pathology of the later stages of Alzheimer's disease, it only sets the stage for neuroinflammation and tau aggregation, and it is those mechanisms that destroy the brain and kill patients. It remains to be seen as to whether these therapies can produce even modest gains in the early stages of the condition, acting in a more preventative mode to stop the development of later pathology.

The poor results for technically successful immunotherapies are spurring a greater interest in alternative mechanisms in the research community, continuing the trend started by frustration with the slow progress towards effective amyloid clearance. There are many programs, hypotheses, and mechanistic targets in search of support for the development of potential new therapies. They tend to keep a focus on the known molecular biochemistry surrounding amyloid-β, but bring new interpretations to the table. Today's research materials are an example of the type, reintepreting the role of γ-secretase in the production of amyloid-β as a crucial part of disease progression. As with all of the other novel ideas, the only real way to determine the importance of this mechanism is to build therapies and try them in patients. The mouse models of Alzheimer's disease have historically told us little about whether any given mechanism is actually important in our own species.

Study suggests stalled amyloid protein production drives Alzheimer's disease

For several decades, researchers studying Alzheimer's disease have been working to understand the 'amyloid cascade hypothesis', which proposes that a buildup of amyloid-β (Aβ) proteins kickstarts a cascade of events that leads to neurodegeneration and dementia. Despite advances in understanding the mutations that lead to Aβ aggregation, uncertainties about the assembly of neurotoxic Aβ proteins remain. Moreover, clinical trials of treatments targeting Aβ protein or its aggregates have only been modestly effective, prompting a re-evaluation of Aβ as the primary driver of the Alzheimer's disease process.

Increasing focus is now being placed on the production of Aβ - a process called proteolysis, during which a precursor protein called amyloid precursor protein (APP) is trimmed by an enzyme called gamma-secretase (γ-secretase). Researchers have previously shown that mutations found in early-onset familial Alzheimer's disease (FAD) prevent γ-secretase from trimming APP effectively, leading to a build-up of lengthy forms of APP/Aβ intermediates. During proteolysis, the γ-secretase enzyme binds together in a complex initially with APP and then with subsequent intermediate forms of the protein as it is trimmed. Researchers have now further assessed mutations in γ-secretase, showing that they increase the stability of enzyme-substrate complexes. This result makes sense alongside initial proteolysis analysis, which suggests the proteolytic process had stalled.

"We've shown that these mutations lead to stalled proteolysis and stabilize the enzyme with its substrate in an intermediate form. These findings are in keeping with our 'stalled complex' hypothesis, where it is these enzyme-substrate complexes that trigger neurodegeneration even in the absence of amyloid beta-protein production. We propose that γ-secretase activators that can rescue stalled proteolysis could complement treatments targeting other Alzheimer's-associated pathways."

The brain is a relatively fatty organ, and has its own complex lipid metabolism. A range of evidence suggests that detrimental shifts in this lipid metabolism accompany aging and neurodegenerative conditions. Some inroads have been made into linking specific lipid mechanisms to specific aspects of neurodegeneration, such as increased inflammatory activity on the part of microglia. Here, researchers review what is known of the role of lipids in the pathologies exhibited by patients with Alzheimer's disease. As noted, there is much left to understand, and what is known today is just a small step into a large dark room.

Lipid homeostasis is crucial for the physiological function of organisms. In the central nervous system (CNS), altered lipid homeostasis and disrupted lipid metabolism signaling pathways are often seen in aging and neurodegeneration. A plethora of genome-wide association studies (GWAS) have identified variants in genes involved in lipid-modifying processes such as transportation, synthesis, and conversion, suggesting altered lipid metabolism may serve as key drivers of late onset Alzhemer's disease (LOAD). However, the chemical diversity and functional heterogeneity of lipids have long posed challenges in characterizing lipid alterations and understanding their biological implications in Alzheimer's disease (AD).

In this review, we provided an overview of recent advancements in lipidomics techniques and their applications in AD research. Current findings strongly support the involvement of specific lipid classes, including sphingolipids, cholesterol, and phospholipids, in AD pathology. This is further underscored by numerous studies elucidating the molecular mechanisms by which lipids influence multiple pathological aspects of AD. These insights lay a solid foundation for the identification of diagnostic lipid biomarkers and the development of lipid-related therapies.

The crosstalk of lipids and AD pathologies such as amyloid-β, tau, and neuroinflammation plays a significant role in modulating neurodegeneration. As essential intracellular bioactive molecules and key components of cell membranes, lipids also influence cellular functions by participating in oxidative stress responses and mediating synaptic activities among other mechanisms. Further understanding of these connections will provide guidance for leveraging lipidomics information during targeted therapy of these disease mechanisms. Moreover, integrating lipidomics into the evaluation of the diagnostic and treatment efficacy will broaden our options for developing personalized treatment strategies and identifying new biomarkers for AD. Ongoing research aimed at uncovering novel mechanisms of lipid involvement in AD is poised to provide valuable insights that will guide future data-driven clinical investigations.

Link: https://doi.org/10.1186/s13024-025-00803-6

There are researchers who consider declining levels of nicotinamide adenine dinucleotide (NAD) in mitochondria to be important in aging. The inability to produce sizable effects on longevity and age-related disease by upregulating NAD levels (or SIRT1 for that matter) argues against this view. Like very many other measures, NAD reduction is not all that important in and of itself, and fixing it in isolation isn't all that useful. Still, a fair number of researchers continue to explore the biochemistry surrounding the role of NAD in mitochondrial function. As yet, ways to meaningfully influence the progression of aging have yet to emerge from this part of the space. Looking at the decades of work put into IGF-1 signaling with a similar lack of tangible results when it comes to the treatment of aging, we might expect this state of affairs to continue for research into NAD.

The very first attempt to have such a meaningful image for the regulation of aging and longevity resulted in the introduction of a concept named the "NAD World" in 2009. The NAD World is a systemic regulatory network that connects NAD+ metabolism, biological rhythm, and aging and longevity control in mammals. In the original NAD World concept, two critical components were proposed to drive the NAD World: The mammalian NAD+-dependent protein deacetylase SIRT1 and the key NAD+-biosynthetic enzyme NAMPT. While NAMPT generates a circadian oscillation of NAD+ production in multiple tissues, SIRT1 responds to NAD+ availability and regulates many fundamental cellular and physiological processes, including transcription, DNA repair, stress response, metabolism, circadian rhythm, and aging. Through these coordinated functions, SIRT1 and NAMPT control the system dynamics of the NAD World and determine the process of aging and eventually, lifespan. The most important prediction from the concept of the NAD World was that the driving force of aging is the systemic decline in NAD+ levels.

The concept of the NAD World was then reformulated as the NAD World 2.0 in 2016, based on significant progress in the field over seven years. In the NAD World 2.0, three key tissues have been identified: The hypothalamus as the control center of aging, skeletal muscle as a mediator, and adipose tissue as a modulator. The details of the NAD World 2.0 were described previously6. Among several predictions from the NAD World 2.0, the most critical one is that the secretion of extracellular NAMPT (eNAMPT) from adipose tissue is a key inter-tissue communication between the hypothalamus and adipose tissue in mammalian aging and longevity control. A related prediction is the importance of nicotinamide mononucleotide (NMN), a key NAD+ intermediate and the product of the NAMPT enzymatic reaction, in the maintenance of biological robustness. With these exciting developments, the further reformulated version of the concept, the NAD World 3.0, is now proposed, featuring multi-layered feedback loops mediated by NMN and eNAMPT for mammalian aging and longevity control.

Link: https://doi.org/10.1038/s41514-025-00192-6

The thymus is a small but vital internal organ. Thymocytes generated in the bone marrow migrate to the thymus where they mature into T cells of the adaptive immune system. One of the important contributions to the aging of the immune system is that the thymus steadily atrophies with advancing age, losing active tissue that is replaced with fat. This reduces the ongoing supply of replacement T cells to a fraction of the youthful numbers, leading to a adaptive immune system that is ever more populated by malfunctioning, exhausted, and senescent cells that should have been replaced - and ever more dysfunctional as a result. In most individuals, little thymic tissue is left by age 50, starting a slow countdown to the prevalent immunosenescence exhibited by people in their 70s.

A number of research groups and companies are now delving more deeply into the mechanisms governing atrophy of the thymus, tissue maintenance in the thymus, and regeneration of the thymus following injury. The hope is to find a cost-effective way to spur the atrophied, aged thymus into regrowth, and thus rejuvenate some aspects of the aged immune system. Sadly, much of the roadblock remains one of challenges in delivery and side-effects. There are demonstrated means of provoking thymus regeneration, but it is a small organ, and the only ways to bring materials to it efficiently remain direct injection and use of cells that home to the thymus. The former will never be approved for widespread use, because it carries a small but significant risk of severe side-effects in older people, and the latter will be too expensive for widespread use. Thus one needs a therapy that the rest of the body can tolerate or ignore, and so far the only viable means with evidence for modest thymic regrowth are (a) calorie restriction and (b) long-term growth hormone treatment combined with other drugs to blunt the side-effects of growth hormone.

Today's open access research is an interesting example of ongoing work on the mechanisms of thymic regeneration from injury. It remains unclear whether mechanisms identified in this context will also be useful in the context of normal tissue maintenance, however. The way to find out is to try, of course, and this work does at least point to one quite specific mechanism as a target.

Recirculating regulatory T cells mediate thymic regeneration through amphiregulin following damage

Robust thymic function produces a diverse T cell pool and is essential for a competent immune response. Decreased thymic output of T cells, resulting from age-associated thymic involution or thymic injury, increases the risk of malignancies, autoimmunity, mortality, and morbidity. There is an unmet clinical need to identify strategies to boost thymic function, particularly for patients undergoing cancer therapies and for older adults. The regenerative capacity of the thymus involves a complex interplay of stromal cells, innate immune cells, and immigrating bone-marrow-derived progenitor cells. The role of mature recirculating T cells in this process is poorly understood. However, recirculating regulatory T cells (Treg cells) have been identified as drivers of regeneration in specific compartments, such as lung, visceral adipose tissue, muscles, aorta, hair follicle, and skin - in addition to their classically understood roles in regulating adaptive and innate immune responses.

The cytokine amphiregulin (Areg) is specially implicated in the regenerative function of Treg cells at epithelial surfaces. In the thymus, a population of recirculating Treg cells that migrates between the periphery and the thymus coexists with newly generated Treg cells during negative selection. Here, we examined the role of Treg cells in the regeneration of the thymus after injury. We identified a unique population of Rag2GFP-CD4+Foxp3+ Treg cells that accumulate in the thymus after acute injury. Depletion and adoptive transfer of this cell population impaired and promoted, respectively, thymic repair in mice. Single-cell transcriptome analyses of this Treg cell population throughout aging highlighted variation in the expression of Areg, and Treg cell-specific deletion of Areg-impaired thymic regeneration. Analyses of human thymi identified a similar recirculating population of Treg cells. Our findings provide insight into the mechanisms of thymic regeneration and repair, with implications for therapeutic approaches aimed at boosting thymic function in the elderly and in cancer patients.

Stem cell therapies produce beneficial effects largely via the signaling produced by transplanted cells for the short time that they survive. Much of this signaling is carried between cells by extracellular vesicles, such as exosomes. Exosomes can be harvested from cells in culture, and this is a less costly and logistically easier approach to the production of therapies. Researchers here demonstrate that exosomes from ovarian follicle cells can be used to restore some of the ovarian function lost with aging, at least in mice.

Ovarian aging is mainly characterized by a progressive decline in oocyte quantity and quality, which ultimately leads to female infertility. Various therapies have been established to cope with ovarian aging, among which exosome-based therapy is considered a promising strategy that can benefit ovarian functions via multiple pathways. Here, we isolated and characterized exosomes derived from ovarian follicular fluid and profiled the differential expression patterns of exosomal noncoding RNAs in young and aged women.

Treatment with young mouse-derived exosomes efficiently rescued ovarian function in aged mice. The follicular fluid exosomes from young mice and miR-320-3p can also promote the proliferation of ovarian granulosa cells and improve mitochondrial function from old mice in vitro. The mechanism may be involve that exosomes transfer miR-320-3p to granulosa cells, and inhibit the expression of FOXQ1. Exosomes also can increase the number of primordial and growing follicles, and improve the developmental ability of oocytes in the old mice in vivo. And hnRNPA2B1 controls miR-320-3p entry into exosomes.

This work provides insights into the antiaging potential of follicular fluid-derived exosomes and the underlying molecular mechanisms, which may facilitate prevention of ovarian aging and an improvement in female fertility.

Link: https://doi.org/10.1093/lifemedi/lnae013

Researchers here show that a form of ultrasound stimulation can be used to provoke lingering senescent cells into behavior that increases the pace of immune clearance of these unwanted cells. The change in markers of the burden of senescence in skin tissue, a reduction of about a third, is similar to the levels of clearance produced in other organs by first generation senolytic drugs. It is worth noting that the researchers used young mice in their study, and a course of irradiation to produce senescent cells. There are differences in the senescent state resulting from irradiation versus other causes of senescence. Further, the immune system becomes less capable of clearing senescent cells in later life. It is unclear whether this approach would work as well on the natural burden of senescence in old mice.

As emerging therapeutic strategies for aging and age-associated diseases, various biochemical approaches have been developed to selectively remove senescent cells, but how physical stimulus influences senescent cells and its possible application in senolytic therapy has not been reported yet. Here we developed a physical method to selectively stimulate senescent cells via low-intensity pulsed ultrasound (LIPUS) treatment. LIPUS stimulation did not affect the cell cycle, but selectively enhanced secretion of specific cytokines in senescent cells, known as the senescence-associated secretory phenotype (SASP), resulting in enhanced migration of monocytes/macrophages and upregulation of phagocytosis of senescent cells by M1 macrophages.

We found that LIPUS stimulation selectively perturbed the cellular membrane structure in senescent cells, which led to activation of the intracellular reactive oxygen species-dependent p38-NF-κB signaling pathway. Using a UV-induced skin aging mouse model, we confirmed enhanced macrophage infiltration followed by reduced senescent cells after LIPUS treatment. Due to the advantages of ultrasound treatment, such as non-invasiveness, deep penetration capability, and easy application in clinical settings, we expect that our method can be applied to treat various senescence-associated diseases or combined with other established biochemical therapies to enhance efficacy.

Link: https://doi.org/10.1111/acel.14486

Telomeres are caps of repeated DNA sequences at the ends of chromosomes. A little telomere length is lost with each cell division, and cells with very short telomeres become senescent or undergo programmed cell death. This is one part of the mechanisms making up the Hayflick limit on the number of times a somatic cell can divide, ensuring turnover of somatic cells making up tissues. New cells with long telomeres are generated by adult stem cell populations. Average telomere length decreases with age, but only when considering large study populations. It is a very blurry measure of declining stem cell function and increased replication stress on cells resulting from the causative mechanisms of aging.

In particular, it is worth noting that telomere length is usually measured in white blood cells from a blood sample, not a tissue sample. Immune cells are subject to a dynamic characteristic of replication and replacement that is quite different from that of cells in tissue. Average telomere length in a sample of immune cells can vary from day to day, by burden of infectious disease, by psychological stress, and everything else that might adjust the behavior of the immune system distinctly from the behavior of tissues. This is one of the reasons why it is a poor biomarker of aging, of little use for planning on the part of any one individual. One does still see correlations in large study populations, however.

Biomarker tied to premature cell aging may signal stroke, dementia, late-life depression

Leukocyte telomere length, which reflects the length of the telomeres within white blood cells (leukocytes), is a known marker of biological aging. Telomeres gradually shorten with age, reducing their ability to protect the chromosomes' genetic material, leading to cellular aging and increased susceptibility to age-related diseases. The length of telomeres is affected by unchangeable factors such as genetics, ancestry, and gender, as well as modifiable factors such as lifestyle choices and environmental stressors, including pollution.

The current study uses data from more than 356,000 participants in the large UK Biobank to address three questions. When participants were recruited for the study between 2006 and 2010, they provided blood samples to analyze leukocyte telomere length. Additionally, they underwent a Brain Care Score assessment, a tool designed to quantify modifiable factors such as physical factors, lifestyle choices, and social interactions. Participants were followed for a median duration of 12 years to monitor the onset of stroke, dementia, or late-life depression.

Compared to participants with longer leukocyte telomeres, people with the shortest leukocyte telomere length had an 8% higher risk of stroke, a 19% higher risk of dementia, and a 14% higher risk of late-life depression. Overall, compared to participants with longer leukocyte telomeres, people with the shortest leukocyte telomere length had an 11% higher risk of developing at least one of the age-related brain diseases studied.

The state of chronic inflammatory signaling in aging is complex, employing many different signaling pathways to regulate the immune system and many different provocations to stimulate those pathways. Hematopoietic stem cells in the bone marrow are responsible for generating immune cells and red blood cells, and their function changes and declines with aging in ways that are similarly complex, driven by many different factors. Here, researchers take a look at one small portion of the intersection between these two complex phenomena, focusing in on the one inflammatory regulator NFκB.

Hematopoietic aging is characterized by chronic inflammation associated with myeloid bias, hematopoietic stem cell (HSC) accumulation, and functional HSC impairment. Yet it remains unclear how inflammation promotes these aging phenotypes. NFκB both responds to and directs inflammation, and we present an experimental model of elevated NFκB activity ("IκB-") to dissect its role in hematopoietic aging phenotypes.

We found that while elevated NFκB activity is not sufficient for HSC accumulation, HSC-autonomous NFκB activity impairs their functionality, leading to reduced bone marrow reconstitution. In contrast, myeloid bias is driven by the IκB- proinflammatory bone marrow milieu as observed functionally, epigenomically, and transcriptomically. A new single cell RNA sequencing framework enabled comparisons with aged murine and human HSC datasets, documenting an association between HSC-intrinsic NFκB activity and quiescence, but not myeloid bias.

These findings delineate separate regulatory mechanisms that underlie the three hallmarks of hematopoietic aging, suggesting that they are specifically and independently therapeutically targetable.

Link: https://doi.org/10.1101/2025.01.14.632900

Variation in lifestyle choice clearly affects life expectancy. A sizable body of evidence exists to connect a slower pace of degenerative aging to both forms of calorie restriction and the various means of maintenance of physical fitness into later life. Immune system aging is an important component of aging considered more broadly, and here researchers discuss the relationship between lifestyle choice and immune aging, including a review of what is known of the mechanisms driving this association.

Immunosenescence, the age-related decline in immune function, is a complex biological process with profound implications for health and longevity. This phenomenon, characterized by alterations in both innate and adaptive immunity, increases susceptibility to infections, reduces vaccine efficacy, and contributes to the development of age-related diseases. At the cellular level, immunosenescence manifests as decreased production of naive T cells and naive B cells, accumulation of memory and senescent cells, thymic involution, and dysregulated cytokine production.

Recent advances in molecular biology have shed light on the underlying mechanisms of immunosenescence, including telomere attrition, epigenetic alterations, mitochondrial dysfunction, and changes in key signaling pathways such as NF-κB and mTOR. These molecular changes lead to functional impairments in various immune cell types, altering their proliferative capacity, differentiation, and effector functions. Emerging research suggests that lifestyle factors may modulate the rate and extent of immunosenescence at both cellular and molecular levels. Physical activity, nutrition, stress management, and sleep patterns have been shown to influence immune cell function, inflammatory markers, and oxidative stress in older adults.

This review provides a comprehensive analysis of the molecular and cellular mechanisms underlying immunosenescence and explores how lifestyle interventions may impact these processes. We will examine the current understanding of immunosenescence at the genomic, epigenomic, and proteomic levels, and discuss how various lifestyle factors can potentially mitigate or partially reverse aspects of immune aging. By integrating recent findings from immunology, gerontology, and molecular biology, we aim to elucidate the intricate interplay between lifestyle and immune aging at the molecular level, potentially informing future strategies for maintaining immune competence in aging populations.

Link: https://doi.org/10.3390/biology14010017

Mitochondria are the power plants of the cell, producing the chemical energy store molecule adenosine triphosphate (ATP). Every cell contains hundreds of mitochondria, evolved from the symbiotic bacteria that took up residence inside the ancestors of today's eukaryotes. Mitochondria replicate like bacteria, can fuse together or pass around component parts, while damaged mitochondria are culled by mitophagy, a quality control mechanism. Mitochondrial function declines with aging, and this is associated with reduced mitophagy and changes in mitochondrial dynamics. This is an area of active and extensive study, but a complete and concrete understanding of how and why mitochondria become less effective in the cells of old tissues remains to be established.

A number of projects have focused on improving the efficiency of mitophagy in order to slow the age-related decline in mitochondrial function. How exactly the various drugs and supplements used in these programs act to improve mitophagy is largely understood only in outline, if at all. Some drugs are discovered by screening, and their mechanism of action only uncovered later. Others are developed to target a particular mechanism, but a full understanding of why that mechanism is important is only later established. As noted in today's open access paper, another approach is to try to alter mitochondrial dynamics in favorable ways, adjusting the pace of fission or fusion of mitochondria to alter average size or other structural and functional aspects. Mitophagy and mitochondrial dynamics are clearly closely connected, but again, a full understanding of why this is the case remains a work in progress.

Tuning mitochondrial dynamics for aging intervention

The mitochondrion is a double membrane structure within the cytoplasm that contains its own genome and generates the majority of the cell's energy via aerobic respiration. Mitochondria naturally eliminate pathogenic mitochondrial DNA (mtDNA) mutations and repair dynamic architectures by controlling organelle division and fusion via guanosine triphosphatase (GTPase) dependent signaling. In this process, fusion compensates partially damaged mitochondria, whereas fission generates new mitochondria and dilutes the fraction that is dysfunctional. It is known that defects in GTPase-driven biogenesis cause dysfunctional oxidative phosphorylation and this is associated with mammalian aging and organ failure. Therefore, effectively targeting mitochondrial quality has the potential to rejuvenate cellular biology and ameliorate aging-associated disease.

The GTPases Mitofusins 1 and 2 (MFN1 and MFN2) represent important targets in mitochondrial disease as they initiate mitochondrial membrane fusion. Indeed, a hallmark of myocardial aging is the accumulation of dysfunctional mitochondria due to non-redundant functions of MFN1 and 2. To target MFN1 fusion activity, a small molecule agonist was recently developed. Termed S89, it rescued mitochondrial fragmentation and swelling following ischemia/reperfusion injury by interacting with the GTPase domain of MFN1, thus delayed aging-derived senescence resulting from mitochondrial DNA mutations. To modulate MFN2's fusogenic activity, a further peptidomimetic small molecule, MASM7, was recently discovered. MASM7 activates MFN2 pro-tethering conformation and enables mitochondrial fusion resulting in increased membrane potential, mitochondrial respiration, and subsequent ATP production, providing promise to reduce age-related degenerative metabolic disease.

The regulation of mitochondrial fission in human aging has also been studied. The GTPase dynamin-related protein 1 (Drp1) uniquely triggers mitochondrial fission by chemoenzymatically constricting the mitochondrial surface to divide the organelle leading to mitophagy. Uncontrollable Drp1 activation leads to hyper-fragmentation, sustained opening of mitochondrial permeability transition pores and eventually apoptosis, which is commonly detected during aging. The most successful Drp1 inhibitor is Mdivi-1, a derivative of quinazolinone, which has been widely reported to mitigate disease, from myocardial failure to abnormal neurodegeneration. Most recently, a new covalent molecule named MIDI was discovered. MIDI interacts with Drp1 cysteines and effectively blocks Drp1 recruitment instead of directly targeting its tetramerization and GTPase activity. This provides a fresh angle to further establish Drp1 inhibitors that target age-related diseases.

Oxidative stress and inflammation tend to go hand in hand in aging, one causing the other. Cells naturally produce oxidizing molecules, such as via mitochondrial activities, and have evolved a range of antioxidant mechanisms to defend themselves. Upregulation of some of these mechanisms has been shown to suppress age-related chronic inflammation, improve tissue function, and even modestly extend life span in animal studies using short-lived species. The paper noted here is an example of this sort of work, targeting NRF2 as a regulator of antioxidant activities in the cell.

Hematopoietic stem cells (HSCs) possess the remarkable capability for self-renewal and multilineage differentiation, giving rise to a spectrum of mature blood and immune cells essential for physiological functions. Oxidative stress, a critical cellular stressor, is characterized by an elevation in reactive oxygen species (ROS) levels and the consequent accumulation of oxidative stress byproducts. This surge in ROS and oxidative damage can precipitate a cascade of detrimental cellular responses, including DNA damage, cell cycle dysregulation, premature cell senescence, and, ultimately, the impairment of HSC function.

DDO1002, a potent inhibitor of the NRF2-KEAP1 pathway, modulates the expression of antioxidant genes. Yet, the extent to which it mitigates hematopoietic decline post-total body irradiation (TBI) or in the context of aging remains to be elucidated. Our study has elucidated the role of DDO1002 in modulating NRF2 activity, which, in turn, activates the NRF2-driven antioxidant response element (ARE) signaling cascade. This activation can diminish intracellular levels of ROS, thereby attenuating cellular senescence. In addition, DDO1002 has been demonstrated to ameliorate DNA damage and avert HSC apoptosis, underscoring its potential to mitigate hematopoietic injury precipitated by TBI.

Competitive transplantation assay revealed that the administration of DDO1002 can improve the reconstitution and self-renewal capacity of HSCs in aged mice. Single-cell sequencing analysis elucidated that DDO1002 treatment attenuated intracellular inflammatory signaling pathways and mitigated ROS pathway in aged HSCs, suggesting its potential to restore the viability of these cells. Consequently, DDO1002 effectively activated the NRF2-ARE pathway, delaying cellular senescence and ameliorating impaired hematopoiesis, thereby demonstrating its potential as a therapeutic agent for age-related hematopoietic disorders.

Link: https://doi.org/10.1093/lifemedi/lnae043

Researchers here review the evidence for age-related changes in heart rate variability to be usefully reflective of age-related disruption to oxidative metabolism, the well-known oxidative stress observed in the tissues of older individuals. The presence of excessive oxidizing molecules in and around cells is harmful to cell function, and thus to tissue function and health. Oxidative stress is also linked to excessive inflammatory signaling, as one can cause the other. Unfortunately the mechanisms are sufficiently complex for suppressing oxidative stress to be a harder problem than simply consuming known antioxidants. Suppression of inflammation or engineering antioxidants to target specific cell structures has been more promising, but none of the existing solutions are all that great in terms of size of effect.

It is increasingly recognized that mild-to-moderate upregulation in the production of free radicals plays an important physiological role in cellular signaling and can trigger the mechanisms of antioxidant defense, supporting an adaptive response to various stressors. This so-called hormetic response results in the improvement of the functional metabolic reserves and is related to healthy aging as well as to the effects of anti-aging interventions. On the other hand, excessive production of free radicals contributes to the development of oxidative stress and leads to aging. Therefore, the search for biomarkers that would allow efficient assessment of redox homeostasis is of great importance in the monitoring of healthy aging.

We hypothesize that heart rate variability (HRV), which measures the changes in the time between successive R waves in an electrocardiogram (ECG), is largely defined by the activity of the redox homeostasis and, therefore, can be used as a biomarker of aging. Such reasoning is based on several lines of experimental evidence suggesting mechanistic links between the autonomic regulation and oxidative load. In this paper, the modulatory effect of well-characterized oxygen sensor H2S on cardiovascular function and pacemaker activity of the sinus node, the studies on the direct effects of free radicals on the functionality of adrenergic and cholinergic receptors, and demonstrated bidirectional interactions between the activity of the autonomic nervous system and immune response were introduced to support the hypothesis about the close interactions between the production of ROS and autonomic regulation and, thus, HRV. At the same time, further studies are needed to improve our understanding of the crosstalk between mitochondrial function and autonomic regulation.

Link: https://doi.org/10.3390/biomedicines13010161

There remains a great deal yet to be learned of the fine details of cellular biochemistry and the interactions between cells and their environments. Even just one cell remains a fantastically complex, incompletely understood collection of mechanisms. As a general rule, given further study, any aspect of cellular biology will turn out to be more complex than the present understanding suggests it to be. This is one of the reasons to advocate for approaches to aging that try to repair known forms of cell and tissue damage rather than adjust cell behavior. To use an analogy, it is a lot easier to periodically remove rust than it is to build and experimentally validate a computational model of how rust progresses to structural failure in a complex arrangement of pipes, and then use the model to test ways to alter the biochemistry of rust or the form of the structure in order to slow the corrosion.

So to today's example of newly understood complexity in cellular biochemistry. It hasn't been all that long since researchers established that cells are capable of using mitochondria as signals, secreting them and taking them up, or exchanging them via short-lived nanotubes established between cells for this purpose. Any mechanism employed by normal cells is on the table for exploitation by cancerous cells, and this is the case for transport of mitochondria. It turns out that tumor cells will feed dysfunctional mitochondria to nearby immune cells, suppressing their normal tendency to attack the cancerous cells. Numerous other immunosuppression techniques are employed by cancer cells; in principle, finding ways to disable any one of them might give some advantage to cancer patients.

Immune evasion through mitochondrial transfer in the tumour microenvironment

Cancer cells in the tumour microenvironment use various mechanisms to evade the immune system, particularly T cell attack. For example, metabolic reprogramming in the tumour microenvironment and mitochondrial dysfunction in tumour-infiltrating lymphocytes (TILs) impair antitumour immune responses. However, detailed mechanisms of such processes remain unclear. Here we analyse clinical specimens and identify mitochondrial DNA (mtDNA) mutations in TILs that are shared with cancer cells. Moreover, mitochondria with mtDNA mutations from cancer cells are able to transfer to TILs.

Typically, mitochondria in TILs readily undergo mitophagy through reactive oxygen species. However, mitochondria transferred from cancer cells do not undergo mitophagy, which we find is due to mitophagy-inhibitory molecules. These molecules attach to mitochondria and together are transferred to TILs, which results in homoplasmic replacement. T cells that acquire mtDNA mutations from cancer cells exhibit metabolic abnormalities and senescence, with defects in effector functions and memory formation. This in turn leads to impaired antitumour immunity both in vitro and in vivo.

Accordingly, the presence of an mtDNA mutation in tumour tissue is a poor prognostic factor for immune checkpoint inhibitors in patients with melanoma or non-small-cell lung cancer. These findings reveal a previously unknown mechanism of cancer immune evasion through mitochondrial transfer and can contribute to the development of future cancer immunotherapies.

The relative proportions of various microbial species making up the gut microbiome changes with age, in ways that provoke greater chronic inflammation and reduce the generation of beneficial metabolites such as butyrate. This likely contributes to many different age-related diseases, but producing the data to firmly support that hypothesis remains a work in progress. Papers such as the one noted here are being published at a fair pace these days, building out an understanding of the correlation between specific changes in the gut microbiome and specific age-related conditions. Even as this body of knowledge is established, it already seems clear that interventions capable of restoring a more youthful gut microbiome must be brought to the clinic and widely deployed.

Sarcopenia is an age-related muscle disorder that increases risks of adverse clinical outcomes, but its treatments are still limited. Gut microbiota is potentially associated with sarcopenia, and its role is still unclear. To investigate the role of gut microbiota in sarcopenia, we first compared gut microbiota and metabolites composition in old participants with or without sarcopenia. Fecal microbiota transplantation (FMT) from human donors to antibiotic-treated recipient mice was then performed. Specific probiotics and their mechanisms to treat aged mice were identified.

Old people with sarcopenia had different microbial composition and metabolites, including Paraprevotella, Lachnospira, short-chain fatty acids, and purine. After FMT, mice receiving microbes from people with sarcopenia displayed lower muscle mass and strength compared with those receiving microbes from non-sarcopenic donors. Lacticaseibacillus rhamnosus (LR) and Faecalibacterium prausnitzii (FP) were positively related to muscle health of old people, and enhanced muscle mass and function of aged mice.

Transcriptomics showed that genes related to tricarboxylic acid cycle (TCA) were enriched after treatments. Metabolic analysis showed increased substrates of TCA cycle in both LR and FP supernatants. Muscle mitochondria density, ATP content, NAD+/NADH, mitochondrial dynamics and biogenesis proteins, as well as colon tight junction proteins of aged mice were improved by both probiotics. LR and the combination of two probiotics also benefit intestinal immune health by reducing CD8+ IFNγ+ T cells.

Link: https://doi.org/10.1111/acel.14485

Researchers here show that long term exposure to reprogramming factors in the hypothalamus of rats slows ovarian aging. It is an interesting result to add to a range of existing studies demonstrating that cell reprogramming can be conducted safely in the central nervous system. Bringing forms of reprogramming to human medicine still looks like a long, slow process, even given the sizable amounts of funding dedicated to this project at Altos Labs and other organizations.

In middle-aged (MA) female rats, we have demonstrated that intrahypothalamic gene therapy for insulin-like growth factor-I (IGF-I) extends the regular cyclicity of the animals beyond 10 months (the age at which MA rats stop ovulating). Here, we implemented long-term Oct4, Sox2, Klf4, c-Myc (OSKM) gene therapy in the hypothalamus of young female rats. The main goal was to extend fertility in the treated animals. We constructed an adenovector that harbors the green fluorescent protein (GFP) gene as well as 4 Yamanaka genes. An adenovector that only carries the gene for GFP or DsRed was used as control. At 4 months of age 12 female rats received an intrahypothalamic injection of our OSKM vector (treated rats); 12 control rats received a vector expressing a marker gene (control rats).

At 9.3 months of age control and treated rats were mated with young males. A group of 12 young intact female rats was also mated. The rate of pregnancy recorded was 83%, 8.3% and 25% for young, MA control, and MA treated animals, respectively. Pup body weight (BW) at weaning was significantly higher in the MA OSKM rats than in MA controls. At the age of estropause (10 months), OSKM treated females still showed regular estrous cycles. The particular significance of the present results is that, for the first time, it is shown that long-term OSKM gene therapy in the hypothalamus is able to extend the functionality of such a complex system as the hypothalamo-pituitary-ovarian axis.

Link: https://doi.org/10.18632/aging.206191

It is once again time to suggest possible areas of focus for new startups intending to develop means to treat aspects of degenerative aging, or accelerate that development. We live in the formative decades of a barnstorming era of endless possibility when it comes to biotechnology and the manipulation of cellular biochemistry. Sadly, this is joined at the hip to a risk-averse regulatory environment determined to bury every new idea beneath an ever-expanding sea of costs and requirements, most of which are unnecessary. Of the realm of the possible in biotechnology and pharmaceuticals, very little emerges from laboratories and successful animal studies to successfully make the leap into human medicine, and the vast costs force much of that progress to focus on unambitious incremental steps forward, rather than more rapid, radical progress.

Still, even within this dire state of affairs it is possible to build ambitious new medicine. The best approaches can still obtain backing. There are many, many dire unmet needs in the patient population. Aging corrodes the bodies and minds of the entire population, imposing a vast cost on individuals, governments, medical systems. Every potential therapy capable of repairing some of the cell and tissue damage of aging in order to produce rejuvenation has a potentially vast market at the end of the day. That motivates investors even given the daunting hurdle of regulatory costs that lies between a promising preclinical therapy and its adoption in the clinic.

Better Approaches to the Chronic Inflammation of Aging

The present dominant approach to chronic inflammation characteristic of aging and many age-related conditions is a broken record: identify a signal molecule or molecular interaction involved in the inflammatory response, and find a way to suppress it. Small molecules, siRNAs, and monoclonal antibodies are all excellent tools to achieve this sort of result. The identification of targets and attempts to interfere in these targets represents much of modern medical development. The problem here is that the immune system makes use of exactly the same signals and pathways for unwanted chronic inflammation as it does for necessary short-term inflammation. Well established TNF inhibitor therapeutics in use for more than 20 years illustrate the problems facing every future therapy based on this identify-and-interfere approach, in that all such treatments degrade the effectiveness of the immune system as a side-effect of reducing inflammation. There must be a better way forward.

Reversal of Cellular Senescence

Considerable skepticism has attended efforts to reverse cellular senescence, to force such cells back into the cell cycle and change their behavior back to that of an ordinary somatic cell. Senescent cells exhibit a lot of DNA damage as a result of entering the senescent state, and further, many senescent cells are senescent for good reasons - such as potentially cancerous DNA damage. All this said, recent data demonstrates that reversal of senescence throughout the body of an aged mouse is in fact beneficial, producing improved health and extended life. Thus it seems a good time to work towards novel means of allowing cells to escape senescence, expanding on the existing small portfolio of approaches, and better assessing the long term results of doing this in larger mammalian species.

Build a Gut Microbiome in a Capsule

The composition of the gut microbiome changes with age in ways that provoke harm: more inflammation, and the generation of fewer beneficial metabolites. How to address this? Fecal microbiota transplantation enables permanent alteration of the gut microbiome. In animal studies, transplanting a young microbiome into old individuals produces lasting rejuvenation of the gut microbiome, and consequent improvements in health and extension of life span. Unfortunately, there is something like a 1% risk per year in young adults of developing one of the number of chronic pain or autoimmune-like idiopathic conditions, such as fibromyalgia, that may be caused by as yet unmapped microbial activities in the gut microbiomes of patients. If a donor who is otherwise screened as clear of pathogens goes on to develop such a condition, the recipient may do so also. This is a risk that cannot presently be quantified, too little is known.

The solution is to produce artificial gut microbiomes with known constituents, building up to the scores of microbial species known to change in prevalence with age in suitable bioreactors. Delivery could involve, say, use of a handful of enteric-coated capsules to delivery a few ounces of material via oral administration rather than an enema as is presently the case. This goal requires a considerable advance over the present state of the art for culturing commensal microbes at scale. It is, however, the most likely endpoint for this end of the industry. Those developers who are first to market with pseudo-natural youthful mixes of gut microbiota capable of producing lasting change with a single administration will likely do well.

More Initiatives Aimed at Repairing the Aged Extracellular Matrix

The extracellular matrix changes in many ways over the course of aging. Some of this is the result of altered behavior in the cells responsible for maintaining the matrix. Perhaps the most well understood of these situations is the path to osteoporosis, where the activity of cells breaking down bone extracellular matrix progressively outweighs the activity of cells building up bone extracellular matrix. But more generally, all too little is understood of the ways in which maintenance of the extracellular matrix changes with age, how these changes cause further harm, and how best to intervene somewhere close to the causes of these problems.

Further, beyond the question of cell maintenance of the extracellular matrix, matrix molecules become altered and damaged in ways that provoke harm, such as through altered cell behavior in reaction to matrix changes, or altering the physical properties of the tissue, such as elasticity. Cross-linking of molecules is one of the better known issues, but while considerable effort has been devoted towards expanding the size of the research community involved in studying cross-linking, there is a long way to go yet. Few efforts have made the leap to for-profit development. More initiatives here would be welcome, particularly in areas beyond cross-linking where comparatively little work has been carried out on harmful matrix alterations, their characterization, causes, and possible remediation.

An Infrastructure for Cheaper, Faster Clinical Trials

Clinical trials are far too expensive. This dramatically slows the pace of development, and leads to a situation in which a whole range of interventions are never rigorously assessed because it would be impossible for investors to recoup the cost of a clinical trial. Small initiatives have nibbled away at the edges of this problem for years, largely with only small gains to show for it. They range from crowdfunding trials for off-patent drugs such as rapamycin to attempts to establish parallel clinical trial infrastructures outside the US and EU. That latter path has on the one hand given rise to the Australian clinical trial industry which enables early stage trials to run at something like half the cost of the US, by greatly reducing the requirements for GMP manufacturing, and devolving most of the regulation of trials to competing institutional review boards rather than a centralized government agency. At the other end of the spectrum, initiatives such as Próspera attempted to build an even cheaper solution with a far more libertarian regulatory framework. In between these two extremes, one finds countries such as the Bahamas or Eastern European nations trying to attract a clinical trial industry by offering lower regulatory burdens, tax incentives, and cheaper costs.

The existing US and EU pharmaceutical industry, deeply embedded in regulatory capture, is hostile to most of the efforts made to escape the regulatory costs of clinical trials, as it wields those costs as a defense against upstart competitors. The biggest challenge facing any novel effort to reduce costs and streamline trials beyond the line in the sand set by Australia is that companies taking advantage of the lower costs and regulatory burden will suffer attacks on their reputation, informal censure and hindrance by regulators, and other consequences should they try to proceed with clinical development in heavily regulated markets such as the US and EU. Most biotech startup entrepreneurs look at what that would do to their ability to obtain future funding and avoid this path. A solution to this problem is very much needed, one that provides the right incentives to build a sizable parallel clinical trial infrastructure that can operate at a fraction of the present cost.

Fix Medical Tourism, Free the Data

Medical tourism is an extremely messy industry. Discovery of and comparison between the clinics scattered between jurisdictions is extremely difficult, next to no clinic publishes any data beyond a few carefully cherry-picked case studies, and there is little development of an industry of guidance and review to assist with these problems. Nonetheless, enormous amounts of data are being generated for forms of stem cell therapy, to pick one example, and then essentially thrown into the void. There is no incentive for any given clinic to submit to rating and review, or to publish data. There is no incentive for clinics with particularly successful protocols to share those protocols or their data. Too little is known of how to optimize protocols around cell therapy and exosome therapy, a very data-driven endeavor. In principle, there is a vast mine of valuable data out there waiting to be tapped, to accelerate progress and improve widely used therapies. In practice the incentives all line up against that outcome. Somewhere out there is a way to do better than this.

Here find an interview with the founder of Rubedo, a senolytic drug discovery company, also one of the co-founders of Turn Bio, one of the first cellular reprogramming companies. Of note, Rubedo recently released more information on their lead program. The senolytic space is expanding considerably in terms of potential target mechanisms. It begins to resemble the cancer research community, which pioneered development of many of the early senolytic drugs, and indeed one might expect this to continue. The two fields share a similar goal, meaning the selective destruction of specific cells that exhibit complex, incompletely mapped characteristics, where those characteristics likely differ in important ways by tissue type, and will naturally tend to proceed along analogous paths to one another.

We just announced our target: it's GPX4. Our compound RLS1496 is a proprietary GPX4 modulator. We developed a molecule that can modulate GPX4 and target vulnerabilities in senescent cells while sparing healthy cells, and its effects extend beyond skin. GPX4 is central to ferroptosis, a distinct form of cell death different from apoptosis or necroptosis. Though this pathway was only discovered about ten years ago, it's generating a lot of interest.

This target has been studied mostly in the context of oncology so far. Now, people are looking at cardiovascular conditions, inflammation, and fibrosis. Our own next step will be systemic applications targeting inflammation and metabolic disorders. We also have other programs with different targets - for instance, our lung interstitial disease program, supported by the California Institute for Regenerative Medicine (CIRM), targets lung stem cells that become senescent. These cells trigger a cascade leading to fibrosis as in idiopathic pulmonary fibrosis, and tissue degeneration leading to COPD or pulmonary hypertension. We'll start with lung fibrosis before expanding to other indications.

In oncology, ferroptosis has been explored as a therapeutic opportunity studying aggressive cancer cells that resist traditional treatments. Researchers are trying to use synthetic lethality approaches to sensitize treatment-resistant cancer cells to ferroptosis, with GPX4 as a target. This presents challenges because cancer cells proliferate rapidly, develop resistance, and require carefully engineered synthetic lethality. What we discovered is that certain senescent cells are naturally vulnerable to ferroptosis. But senescent cells have an advantage over cancer cells - they don't divide or grow. This means we can use more flexible dosing schedules and don't need to eliminate every single cell immediately. We can gradually reduce their population over time.

We've found that by modulating GPX4 in specific ways, we can trigger ferroptosis in senescent cells while sparing healthy cells, giving us a therapeutic window. Our compound, RLS1496, is a potent GPX4 modulator that can achieve this effect at single-digit nanomolar concentrations. Studies have shown that reducing GPX4 levels throughout life in mice (not completely removing it, which is lethal at birth) increases lifespan by 7-10%, and these mice develop fewer tumors and are generally healthier. While this suggests a broader role in longevity, we're currently focusing on targeting specific pathological senescent cell populations.

Link: https://www.lifespan.io/news/marco-quarta-on-cellular-senescence-in-aging/

The concept of "healthy aging" is well-intentioned but pernicious. By definition, aging is a loss of health, the rise of mortality risk due to failure of vital biological systems in the body. Aging less rapidly is better than aging more rapidly, and advocacy for greater physical activity to slow the progression aging is a good thing, but painting any state of aging as "healthy" is the road to acceptance of decline, the road to minimizing the need for rejuvenation therapies, the road to painting a slowing of aging as the only possibility worth talking about. Rejuvenation is clearly possible, as demonstrated by many animal studies of senolytics, reprogramming, fecal microbiota transplantation, and other approaches. Some of the well-established patient advocacy rhetoric relating to later life health needs to change as a result.

Canada's population is aging, with at least 1 in 5 people aged 65 years or older in 2025, and the number of people older than age 85 years is expected to triple in the next 20 years. However, for many people, these added years do not mean healthy years. More than 80% of adults do not meet the recommendations for physical activity. "Physical activity is one of the most important ways to preserve or improve functional independence, including among older adults who are frail or deemed to be at increased risk of falling. Higher levels of physical activity in older age are associated with improvements in cognition, mental health, and quality of life."

A meta-analysis of several large studies found that 150 minutes of moderate physical activity every week reduced risk of death from all causes by 31%. Physical activity is essential for aging well and can help prevent or reduce disease in more than 30 chronic conditions, such as coronary artery disease, heart failure, type 2 diabetes mellitus, chronic obstructive pulmonary disease, osteoporosis, depression, dementia, and cancer. Benefits of activity include the following: protection against risk of death from any cause; falls prevention through increased muscle strength and better balance; bone and joint health, including improved bone density and alleviation of some osteoarthritis symptoms; improved cognitive function, and better mood and mental health; ability to engage in daily activities and improved quality of life.

Link: https://www.eurekalert.org/news-releases/1071172