Fight Aging!

PAI-1 expression increases with age, and is implicated in cellular senescence, inflammation, and detrimental remodeling of tissue, such as the generation of fibrosis. These line items are all connected, as a burden of lingering senescent cells tissues has been shown to be sufficient to cause the other two, but nothing is biochemistry is ever as simple as it first appears.

PAI-1 in the context of aging has received increased research interest since the discovery of a small population of human loss-of-function mutants who live perhaps 7 years longer their their near neighbor peers. In such small samples numbers should probably be taken with a grain of salt, but the biochemistry suggests that there is something interesting going on under the hood.

In today's open access paper, researchers report on an investigating of the role of PAI-1 in muscle aging in mice. Interestingly, loss of function is only protective in female mice when it comes to age-related loss of muscle mass and bone mineral density. This is not what one might expect for a protein that has a large effect size on life span and aspects of degenerative aging in other tissues, but nothing is simple in biochemistry.

Roles of plasminogen activator inhibitor-1 in aging-related muscle and bone loss in mice

Aging-related sarcopenia and osteoporosis are musculoskeletal disorders characterized by accelerated muscle and bone loss. Plasminogen activator inhibitor-1 (PAI-1), a fibrinolysis inhibitor, is involved in various pathological conditions, including sarcopenia and osteoporosis; however, its roles in aging-related sarcopenia and osteoporosis have yet to be fully investigated. Therefore, we investigated the roles of PAI-1 in aging-related sarcopenia and osteoporosis using PAI-1-gene-deficient and wild-type mice. Aging-related changes in muscle and bone were assessed by comparing the values in 24-month-old mice to those in 6-month-old mice.

Regardless of sex, differences in muscle and bone parameters were observed between 24-month-old and 6-month-old mice. Aging increased PAI-1 expression in the gastrocnemius and soleus muscles of both female and male mice. PAI-1 deficiency significantly blunted aging-related decreases in lower limb muscle mass, muscle tissue weights, and grip strength in female mice but not in males. Moreover, PAI-1 deficiency significantly blunted aging-related cortical bone loss at the femurs and tibias of female but not male mice. These results indicate that PAI-1 is partly involved in aging-related sarcopenia and osteopenia in female mice, although the corresponding mechanisms remain unknown.

Age-related macular degeneration is a prevalent cause of progressive blindness caused by cell death and structural dysfunction in the retina and nearby tissue. The usual underlying mechanisms of aging and their consequences feature prominently in present thought on causes: aggregated metabolic waste, inflammation, vascular dysfunction, and so forth. The options for treatment are nowhere near as good as desired. Modestly slowing the progression of the condition remains the most plausible outcome, and relatively little can be done for the dry form of the disease in which the vasculature supplying the retina remains relatively intact and functional. This is well known, and a fair number of research programs and biotech startups aim at the production of novel approaches to therapy. The larger, more mainstream efforts remain focused on approaches that seem likely to produce only incremental gains, unfortunately.

Age-related macular degeneration (AMD) represents a spectrum of degenerative changes in the macula associated with aging, leading to significant central visual impairment. The World Health Organization recognizes AMD as one of the foremost causes of irreversible blindness among individuals over 50 years old worldwide. AMD can be classified into two major subtypes: dry and wet. Dry AMD accounts for approximately 85%-90% of all reported cases. Although the prevalence of wet AMD is lower, it affects more than 15 million individuals worldwide and poses a greater threat to vision than dry AMD.

The pathogenesis of AMD remains elusive and involves multiple factors such as aging, the environment, genetics, oxidative stress, lipid metabolism, and immune responses. Consequently, AMD treatment encounters numerous challenges. Two novel complement inhibitors and one novel treatment option were approved for the treatment of dry AMD by the U.S. Food and Drug Administration (FDA) in 2023 and 2024, whereas anti-vascular endothelial growth factor (VEGF) therapy remains the primary therapeutic approach for wet AMD. However, despite the availability of pharmacological interventions, their application still faces certain limitations. Consequently, research continues to explore alternative therapeutic strategies.

Numerous innovative drugs are presently under development to address these challenges. By conducting an extensive review of relevant literature and reports both domestically and internationally, we provide a comprehensive overview of the classification, pathophysiology, risk factors, and treatment strategies related to AMD. In this review, we systematically summarize the treatment approaches for various types of AMD, including the most recently approved drugs and therapeutic strategies, and provide a detailed overview of the advancements in ongoing clinical trials.

Link: https://doi.org/10.1002/mdr2.70009

Senescent cells exhibit noteworthy differences from one another. Exploring these differences has been a focus of research in recent years, in order to better understand how to selectively destroy or change the behavior of the lingering harmful senescent cell population that builds up with age in tissues throughout the body. Evidently senescence in different cell types can exhibit differences, but as researchers here demonstrate there are subpopulations of senescence even in a uniform cell population. One of the causes of these different manifestations of senescent behavior is where in the cell cycle a cell halted replication to become senescent, likely a largely random outcome based on the study results here.

Cellular senescence has been strongly linked to aging and age-related diseases. It is well established that the phenotype of senescent cells is highly heterogeneous and influenced by their cell type and senescence-inducing stimulus. Recent single-cell RNA-sequencing studies identified heterogeneity within senescent cell populations. However, proof of functional differences between such subpopulations is lacking.

To identify functionally distinct senescent cell subpopulations, we employed high-content image analysis to measure senescence marker expression in primary human endothelial cells and fibroblasts. We found that G2 phase arrested senescent cells feature higher senescence marker expression than G1 phase arrested senescent cells.

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

Link: https://doi.org/10.18632/aging.206299

The development of atherosclerotic plaque in blood vessel walls, narrowing and weakening those vessels, is a universal phenomenon in older people. It is worse in people with generally worse health, as it is driven by inflammation. Greatly reducing cholesterol carried from the liver to the rest of the body via LDL particles in the bloodstream slows the growth of plaque, but growth remains an inevitability on some time frame. Unfortunately the same can be said for reducing inflammation. Large plaques become unstable and rupture, and this kills a quarter of our species via heart attack and stroke.

Plaque growth occurs because the plaque environment is toxic, harmful to the macrophage cells that arrive from nearby tissue or the bloodstream in order to try to clean up the damage. The macrophages become overwhelmed and die, adding their mass to the plaque. Lowering LDL cholesterol slows plaque growth by reducing one of the inputs to this toxicity, but cannot on its own fix existing damage or entirely halt the process of plaque development and growth. Any true solution to atherosclerosis must function by in some way protecting macrophages from the plaque environment, or dramatically reducing the toxicity of the plaque environment. Only when macrophages can work unimpeded can plaque and a damaged vessel be repaired.

Many possible approaches to therapy to at least partially achieve these goals would become practical given a way to selectively carry a drug into atherosclerotic plaques. This is unfortunately challenging, but the most plausible class of approaches to this problem involves the development of forms of nanoparticle that selectively bind to distinctive features in plaque, or to cells in plaque, while ignoring the rest of the blood vessel wall. That would allow reasonable doses of a drug encapsulated within or attached nanoparticles to be injected intravenously.

Targeted Delivery of Nanoparticles to Blood Vessels for the Treatment of Atherosclerosis

The objective of atherosclerosis medication therapy is to enhance circulation, reduce cholesterol levels, and prevent thrombosis. Anti-inflammatory medication may have modest efficacy when combined with conventional regimens, given that inflammation is a pivotal factor in atherosclerosis. Nevertheless, it should be noted that all medication therapy has limitations in treating established plaques. Some medications, such as colchicine, rapamycin, and nucleic acid drugs, possess strong anti-inflammatory, lipid-lowering, or anti-proliferative properties, which means they have great potential in inhibiting atherosclerotic plaque growth and postoperative restenosis. Unfortunately, their utility in the therapy of atherosclerosis is limited by instability or dose-dependent toxicity. The introduction of nano drug delivery system (DDS) technologies has shed light on the utilization of these medications. By temporarily isolating the drug from the body's internal environment during delivery to reduce degradation and avoiding dose-related drug toxicity through effective targeted delivery, these use constraints of these promising drugs can be removed.

Nanoparticle carriers can be broadly divided into two groups: organic and inorganic. Polymers, liposomes, and micelles are typical examples of organic compounds, whereas inorganic compounds include silica, metals, and carbon, among others. According to some recent studies, nanoparticles showed great potential in both clinical diagnosis and therapy for atherosclerosis. Nevertheless, despite the encouraging outcomes observed in cell and animal studies, only a limited number of these designs have successfully transitioned to clinical trials and, even more rarely, to the market.

Nanoparticles have several notable applications in the diagnosis of atherosclerosis, including the identification of vulnerable plaques and the use of nanoparticles with both therapeutic and diagnostic functions. Nonetheless, even if the number of nanoparticle kinds is rapidly increasing, very few of them have gone to preclinical or clinical phases, and the majority of research has only formed conclusions from tests conducted in rodents (mice, rats) or other mammals (rabbits, pigs, dogs, and primates). Numerous nanoparticles have produced fairly acceptable results in cell or animal experiments; nonetheless, the evidence about their toxicity, biocompatibility, metabolic breakdown pathways, and efficacy is insufficient due to small sample sizes. Furthermore, the majority of the experimental research examined in this work yielded favorable outcomes, but the negative impacts or qualities of nanoparticles that need to be improved are hardly discussed.

Immunotherapy is a broad label, encompassing a range of approaches that include varieties of vaccination, selective interference in immune signaling, delivery of engineered immune cells, gene therapies capable of adjusting the behavior of immune cells, and more. An aging-focused viewpoint might also add the destruction of senescent cells or alteration of senescent cell signaling behavior, given the detrimental effect that senescent cell signaling produces on the immune system. Here, researchers review the ways in which one might turn the established technologies used in immunotherapies to target aging and age-related diseases. Evidently this shift is already well underway, given the application of immunotherapies to cancer, but will likely expand considerably.

Immunotherapy, after a century of development, has revolutionized the treatment of many diseases such as infections, cancers, and autoimmune diseases. Multidisciplinary advancements in immunology, molecular biology, biomedical engineering, and computer science have made immunotherapy more precise and specific, expanding its indications.

A recent study on mice demonstrated that immune checkpoint blockade (ICB) can enhance senescence surveillance, indicating the potential of immunotherapies for addressing aging. Senescent cells and aging-related microenvironmental features, such as DNA damage, oncogene expression, mitochondrial metabolic changes, and the production of senescence-associated secretory phenotypes (SASPs), provide targets for immunotherapy to eliminate and reshape the microenvironment.

Furthermore, immunotherapies can also reverse immunosenescence, which manifests as chronic low-grade inflammation and diminished reactivity toward pathogens and malignancies. These features highlight the potential of immunotherapy in delaying aging and related diseases with fewer side effects.

This review summarizes the latest progress in aging immunotherapy, including vaccines, adoptive cell transfer (ACT), antibody blockade, and cytokine intervention, while discussing the toxicity issues and limitations encountered in practice. Finally, it describes the prospects of aging immunotherapy, providing new targets and strategies for addressing aging and extending lifespan.

Link: https://doi.org/10.34133/research.0866

The goal of blood flow restriction training is to attempt to induce a mildly hypoxic environment in limb muscle tissue that encourages a greater response to physical activity. This approach has been assessed as a way to induce the growth of greater muscle mass in older individuals, alongside the more prevalent approach of resistance training. Here, researchers provide an overview of the literature on the topic.

In recent years, blood flow restriction training (BFRT) has garnered significant attention as an emerging therapeutic intervention. BFRT involves applying external pressure to the proximal limb using compression devices (e.g., tourniquets or inflatable cuffs) during exercise, partially restricting arterial inflow and fully occluding venous outflow. This creates an ischemic and hypoxic environment within the muscle tissue, triggering a cascade of physiological processes related to tissue adaptation. BFRT affects skeletal muscle primarily by promoting the secretion of anabolic hormones, protein synthesis, recruitment of type II muscle fibers, cellular swelling, and the generation of reactive oxygen species and their derivatives, e.g. nitric oxide (NO) and heat shock proteins (HSPs).

BFRT significantly enhances muscle strength and physical function in elderly populations by inducing muscle hypertrophy. Multiple studies confirm that BFRT achieves comparable outcomes to conventional resistance training for sarcopenia management in older adults, with superior efficacy particularly observed in strength improvement. Consequently, for elderly patients with comorbidities such as degenerative joint disorders or cardiovascular diseases, BFRT emerges as a viable alternative intervention that simultaneously mitigates injury risks associated with high-load training while achieving equivalent strength gains.

Link: https://doi.org/10.3389/fphys.2025.1616874

Reprogramming involves exposing cells to the Yamanaka factors, a set of transcription factors that are involved in the conversion of adult cells into embryonic stem cells in the earliest stages of embryogenesis. In addition to converting an adult somatic cell into a pluripotent stem cell, Yamaka factor expression also rejuvenates epigenetic control over nuclear DNA structure and gene expression and restores youthful mitochondrial function. This latter process of rejuvenation has become an area of strong research interest, and a few well funded biotech companies are attempting to build therapies to treat aging and age-related conditions based on partially reprogramming the cells of a living individual.

More than one of these programs is focused on the eye, for a number of reasons. Firstly, diseases of the aging eye represent a large market. Secondly, the eye is relatively isolated from the rest of the body, making it an easier target for novel classes of therapy, such as gene therapies, that carry unknown risks. Thirdly, treating the eye requires only small doses of a drug, making it a good target for classes of treatment where manufacture remains relatively expensive. Today's open access paper arises from one program focused on reversal of retinal aging, but the discovery reported is of broader interest, with potential applications beyond reprogramming therapies. Within the field of reprogramming, this appears to be another incremental step towards to capacity to separate change of cell state from rejuvenation of cell function - a desirable goal for the research community.

Reprogramming Factors Activate a Non-Canonical Oxidative Resilience Pathway That Can Rejuvenate RPEs and Restore Vision

Age-related macular degeneration (AMD), the leading cause of irreversible vision loss affecting over 200 million people worldwide, is a prime example of oxidative stress-driven pathology. The dry form of AMD, which accounts for 90% of cases, is driven by degeneration of the retinal pigment epithelium (RPE), a layer highly vulnerable to oxidative damage from chronic light exposure and bisretinoid lipofuscin buildup which elevates reactive oxygen species (ROS) over time. The causal role of ROS in AMD is supported by the AREDS2 study, where antioxidant supplementation slowed disease progression. The two recently approved therapies for dry AMD treatment provide only modest benefit, likely reflecting the fact that they target components of the alternative complement pathway, a cascade that is activated after oxidative stress has already injured the retina, rather than addressing that upstream damage directly. This highlights an unmet need to identify novel pathways that enhance oxidative resilience and counteract ROS-induced damage.

Over the past decade, partial epigenetic reprogramming through transient expression of all or subsets of the Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc, aka OSKM) has emerged as a promising strategy to restore youthful tissue function in vivo. Dual AAV-mediated delivery of OSK without the c-Myc oncogene has been shown to rejuvenate post-mitotic retinal ganglion cells (RGCs), promoting axon regeneration and restoring vision in either glaucomatous or aged mice, with long-term expression via AAV2 proving safe for up to 18 months. Notably, it has also shown promise in a non-human primate model of non-arteritic anterior ischemic optic neuropathy, a common optic neuropathy.

Despite its therapeutic potential, the mechanisms through which OSK(M) exerts functional rejuvenation remain poorly defined. A few mediators of partial epigenetic reprogramming, including Tet1/Tet2 and Top2a, have been identified, that facilitate chromatin and DNA modifications in cooperation with OSK. However, the broader network of OSK downstream effectors, those functional units that directly carry out the biological effects, remain less well explored. Here we explore the effect of OSK partial reprogramming in RPE cells, which operate under high oxidative load offering a robust model for probing how rejuvenation programs confer resistance to oxidative challenges.

Enabled by a functional genomics approach, our study uncovers a rejuvenation axis involving GSTA4 activation, that bypasses reprogramming-induced dedifferentiation. GSTA4 is a detoxifying enzyme that clears the lipid peroxidation byproduct 4-HNE, as a necessary and sufficient OSK effector. Dynamic GSTA4 regulation by OSK recapitulates a stem cell derived stress resilience program. GSTA4 overexpression alone enhances mitochondrial resilience, rejuvenates the aged RPE transcriptome, and reverses visual decline. GSTA4 is consistently upregulated across diverse lifespan-extending interventions suggesting a broader pro-longevity role. These findings uncover a previously unrecognized protective axis driven by Yamanaka factors that circumvents reprogramming, providing therapeutic insights for age-related diseases.

Mining human epidemiological data can only produce correlations. Mendelian randomization is a way to add data on genetic variants known to affect disease status into the mix so as to add some support for causation. The result isn't a determination of causation, but in the best case is supportive of that conclusion. Physical frailty is well known to correlate with neurodegeneration, and a range of reasonable hypotheses exist to explain why this is the case. Both emerge from chronic inflammation and other underlying dysfunctions of aging, for example. Or frailty involves significant dysfunction in the cardiovascular system, which in turn negatively affects the aging brain. In the absence of ways to eliminate the chronic inflammation of aging or reverse vascular aging, it is hard to prove any of this. Which doesn't matter! Regardless, the right course is to try to build approaches to reverse the damage and dysfunction of aging.

Physical frailty is associated with a higher risk of developing dementia, but it remains unclear whether this relationship is causal. This prospective cohort study was based on UK Biobank participants without dementia at enrollment (between 2006 and 2010). Physical frailty was defined by 5 criteria (weight loss, exhaustion, physical inactivity, slow walking speed, and low grip strength). Incident dementia was tracked through linked hospital admission records and death registries, using the International Classification of Diseases, Tenth Revision (ICD-10) codes. Cox proportional hazard regression models and bidirectional Mendelian randomization (MR) analyses were used to evaluate the causal association of physical frailty with incident dementia.

Among 489,573 participants (mean age 57.03 years, 54.4% female), 8,900 dementia cases were documented over a median follow-up of 13.58 years. Compared with nonfrail individuals, the risk of dementia was 50% higher in those with prefrailty (hazard ratio [HR]:1.50) and 182% higher in those with frailty (HR: 2.82). Participants with frailty and high genetic risk had the highest risk of dementia compared with those with low genetic risk and nonfrailty (HR: 3.87 for high polygenic risk score; HR: 8.45 for APOE-ε4 carriers). The forward MR analysis indicated a potential causal relationship between physical frailty and dementia (odds ratio [OR]:1.79) while the reverse MR suggested a null causal association (OR: 1.00). Structural equation modeling points to genetic background and neurologic and immunometabolic function as potential underlying mechanisms linking physical frailty to dementia.

Link: https://doi.org/10.1212/WNL.0000000000214199

Regular exercise is demonstrated to improve many aspects of health in a dose-dependent fashion. Aerobic exercise and resistance exercise have overlapping but subtly different effects, and are often studied distinctly. Program of resistance exercise have been demonstrated to reduce mortality in older individuals, and more generally the view of "use it or lose it" is supported by the scientific literature. Exercise produces benefits, and a sedentary life is harmful to long-term health. Here, researchers demonstrate that the benefits of exercise in older individuals include improved peripheral nerve function.

The natural progression of age can result in motor neuron degeneration, reflected by fewer functioning motor neuron axons and/or degradation of the motor axons. These outcomes result in the slower transmission of a nerve impulse supplying a target effector muscle and can have functional consequences such as slower movements or reduced mobility. Additionally, older adults exhibit varying degrees of loss in strength and muscle mass as a result of these effects and may become more susceptible to the development of sarcopenia.

Resistance training has long been prescribed to older adults as a means to long-term vitality. Individuals who remain active throughout their life have been known to have improved mobility, more independence, and greater life expectancy. Although previous studies have investigated training and nerve conduction speed in adults, few studies have focused on interventions that mitigate nerve speed loss and possible adaptations training may have.

The purpose of this study was 1) to quantify the effects of resistance training on nerve conduction velocity (NCV) and 2) to determine if age affects nerve plasticity in response to training. Forty-eight subjects (18-84 yr) completed this study (training: n = 14 younger, 14 older; control: n = 12 younger, 8 older). Median motor NCV and maximal strength were recorded before and after 4 weeks of handgrip training in both limbs. Training was conducted 3 times per week with the use of a grip training kit.

The results revealed significant increases in NCV for both the young (Cohen's d = 0.749) and older training groups (Cohen's d = 0.679), but neither in control groups (young: Cohen's d = 0.326; older: Cohen's d = -0.184). The results of this study suggest that resistance training may be a viable method to counteract age-related nerve deterioration.

Link: https://doi.org/10.1249/MSS.0000000000003767

Dietary protein refers to the intake of the nine essential amino acids that cannot be synthesized by our biochemistry: valine, isoleucine, leucine, methionine, phenylalanine, tryptophan, threonine, histidine, and lysine. The single value for "protein" that regulators such as the FDA required to be provided on food packaging is derived via a complicated process that starts with one of a number of different assays used to determine essential amino acid content of a foodstuff, all of which can produce subtly different results in different foodstuffs. Those results are massaged into a single number via reference to (a) what is thought to be the optimal balance of different essential amino acids versus the actual balance in the foodstuff, (b) what is thought to be the bioavailability of the amino acids present in the foodstuff, and (c) a few other scaling factors with empirical evidence for their use. A sizable literature of ongoing experimentation and debate underlies this present approach.

Restriction of dietary protein is an approach used to trigger the beneficial metabolic changes that take place in reaction to a lack of nutrients. It can be combined with overall calorie restriction, or the diet structured such that calorie level remains constant even as protein intake is reduced. Many nutrient sensing mechanisms evolved to react to levels of specific essential amino acids, and consequently researchers have experimented with restriction of essential amino acids one by one rather than all at once. Most such animal studies have focused on the effects of restricting dietary methionine, and have demonstrated that methionine restriction reproduces a fair-sized fraction of the benefits of overall calorie restriction. In today's open access paper, researchers instead restrict valine, and find that while it appears beneficial in both sexes, it only extends life in male mice.

Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice

Dietary protein is a key regulator of metabolic health in humans and rodents. Many of the benefits of protein restriction are mediated by reduced consumption of dietary branched-chain amino acids (BCAAs; leucine, valine and isoleucine), and restriction of the BCAAs is sufficient to extend healthspan and lifespan in mice. While the BCAAs have often been considered as a group, it has become apparent that they have distinct metabolic roles, and we recently found that restriction of isoleucine is sufficient to extend the healthspan and lifespan of male and female mice.

Here, we test the effect of lifelong restriction of the BCAA valine on healthy aging. We find that valine restriction (Val-R) improves metabolic health in C57BL/6J mice, promoting leanness and glycemic control in both sexes. To investigate the molecular mechanisms engaged by Val-R with aging, we conducted multi-tissue transcriptional profiling and gene network analysis. While Val-R had a significantly greater molecular impact in the liver, muscle, and brown adipose tissue of female mice than males, there was a stronger gene enrichment with phenotypic traits in male mice. Further, we found that phenotypic changes are associated with a multi-tissue downregulation of the longevity associated PI3K-Akt signaling pathway. Val-R reduces frailty in both sexes and extends the lifespan of male by 23%, but does not extend female lifespan, corresponding with a male-specific downregulation of PI3K-Akt signaling.

Our results demonstrate that Val-R improves multiple aspects of healthspan in mice of both sexes and extends lifespan in males, suggests that interventions that mimic Val-R may have translational potential for aging and age-related diseases.

The mechanistic (or mammalian) target of rapamycin (mTOR) is a well studied portion of cellular biochemistry. The activity of mTOR and downstream consequences of that activity form one portion of a broad regulatory system that reacts to nutrient availability in order to change growth and stress responses in cells. Inhibition of mTOR is a necessary part of the beneficial response to fasting and calorie restriction, in which an increase in the activity of cell maintenance processes acts to improve health and slow the progression of aging. Animal studies robustly demonstrate extended lifespan in response to mTOR inhibition. In recent years a number of programs have focused on the development of novel drugs targeting mTOR, while the generic mTOR inhibitor rapamycin is widely employed by anti-aging clinics, and was the subject of a community-funded clinical trial.

Aging is a highly intricate biochemical process. There is strong evidence suggesting that organismal aging, age-dependent diseases, and cellular senescence are related to the mammalian target of rapamycin (mTOR) signaling pathway. The signaling pathway of mTOR has become a prominent regulatory hub, managing crucial cellular activities that significantly affect lifespan and longevity. The mTOR is involved in controlling cell growth and metabolism in response to both internal and external energy signals as well as growth factors. The interaction between mTOR and cellular homeostasis is crucial in the aging process.

This extensive review summarizes the most recent findings on mTOR inhibitors in the context of aging, highlighting their complex interactions with cellular systems, effect on longevity, and potential as therapeutic approaches for age-related diseases. Rapamycin and rapalogs (analogs of rapamycin), which have been proven to be effective mTOR inhibitors, have the ability to reduce the aging process in several model species while also enhancing metabolic health and stress responses.

These results suggest mTOR inhibitors as potential therapies to address the complex aspects of age-related diseases. However, obstacles stand in the way of clinical translation. Further research is required to improve dosing protocols, reduce potential side effects, and target mTOR inhibitors precisely at specific tissues.

Link: https://doi.org/10.17179/excli2025-8384

Exercise has been shown to induce the synthesis of the metabolite betaine (trimethylglycine) in the kidneys. Separately, delivery of betaine was developed as a therapy for the rare disease homocystinuria due to its ability to blunt the harmful buildup of homocysteine in that condition. Here, researchers briefly review recent developments in the understanding of the ability of additional betaine delivered as a therapy to act as an exercise mimetic, triggering some of the beneficial metabolic responses to exercise.

Recently, researchers identified the renal metabolite betaine as a potent exercise mimetic through comprehensive multi-omics analysis of exercise responses, offering a promising solution for individuals unable to sustain long-term exercise. The researchers systematically characterized the differential responses to Acute exercise (AE) and Long-term exercise (LE). AE primarily induced acute metabolic and immune stress, marked by significant increases in non-esterified fatty acids, decreased total bile acids, and upregulation of inflammatory factors including IL-6 and EN-RAGE, alongside activation of the glucocorticoid receptor pathway and enhanced anaerobic glycolysis. In contrast, LE triggered sustained adaptations involving metabolic reorganization, immune remodeling, and gut microbiota restructuring. Metabolic reorganization is achieved through the coupling of fatty acid oxidation with tricarboxylic acid cycle activity, accompanied by optimized amino acid metabolism and activated antioxidant defenses. Immune remodeling is reflected by increased naive lymphocytes, reduced neutrophils, and attenuated lymphocyte aging via ETS1 downregulation. Gut microbiota restructuring is characterized by a decrease in opportunistic pathogens and suppressed lipopolysaccharide biosynthesis. Critically, LE also specifically activated methionine metabolism pathways, inducing significant enrichment of the renal metabolite betaine.

Integrated multi-omics analysis confirmed the kidney as the central organ for exercise-induced betaine metabolism, mediated by upregulation of renal choline dehydrogenase (CHDH). Mechanistic studies demonstrated betaine directly binds and inhibits the innate immune kinase TBK1, reducing lipopolysaccharide-induced release of pro-inflammatory cytokines TNF-α and IL-6 while inhibiting immune cell adhesion. Murine models further established betaine's capacity to alleviate cellular senescence, consistently reducing established aging markers including SA-β-Gal and p21. These data reveal the kidney-betaine-TBK1 axis as the core pathway coordinating exercise-mediated anti-inflammatory and anti-senescence effects.

To validate the therapeutic efficacy of betaine, researchers conducted comprehensive supplementation studies in aged murine models. They supplemented aged mice with 1% betaine daily for 8 weeks and found that betaine concentrations in the kidneys of aged mice increased to levels comparable to those induced by LE. Functional evaluation showed that aged mice had significantly improved motor coordination, muscle strength, and spatial memory ability, and significantly reduced depression-like behaviors. Histopathological analysis revealed attenuated markers of aging, reduced lipid deposition, and reduced fibrosis in the kidney, liver, lung, and skin, along with restoration of skeletal muscle morphology and epidermal architecture. Molecular analysis confirmed that betaine could inhibit the phosphorylation of TBK1/IRF3/p65 signaling pathway, down-regulate the proinflammatory cytokines TNF-α and IL-1β, and activate AMPK/SIRT1/PGC-1α signaling pathway. These collective findings support betaine as a viable exercise-mimetic intervention for counteracting age-related physiological and functional decline.

Link: https://doi.org/10.3389/fphar.2025.1672934

Why does the peripheral nervous system regenerate while the central nervous system does not? Both are composed of clusters of neurons linked by axons that can extend for as much as a few feet in the longest cases. Nerves are bundled axons. One of the approaches taken by researchers interested in applying regenerative medicine strategies to the central nervous system is to look for biochemical differences between peripheral nervous system neurons and axons versus central nervous system neurons and axons. There must exist specific differences that enable regeneration of peripheral nervous system axons or suppress regeneration of central nervous system axons. That doesn't mean those differences are easy to find, of course. Biology is exceptionally complex and present omics approaches are not well suited to capturing the full picture of a changing system that is moving through a process over time.

In today's open access paper, researchers report on what they believe to be an important component of peripheral nerve regeneration. Peripheral nervous system neurons express a specific set of short interspersed nuclear elements (SINEs) during axon regrowth, and this does not occur in central nervous system neurons. SINEs are a form of transposable element, repeated DNA sequences capable of copying themselves when activated, and currently a topic of interest for their contribution to degenerative aging when overly active in later life. Transposable elements are largely the remnants of ancient viral infections, but that doesn't rule out the evolution of useful functions for these sequences. Nothing is simple in cellular biochemistry, evolution loves reuse, and few aspects of our biology have only one purpose.

Repeat-element RNAs integrate a neuronal growth circuit

Neuronal growth and regeneration are regulated by RNA localization and local translation. We previously described an intrinsic neuronal-growth-regulating mechanism based on axonal transport of the RNA-binding protein (RBP) nucleolin and local translation of key mRNA cargos, including importin β1 and mTOR. Local translation of these and other mRNAs at the cell periphery and retrograde transport of the resulting proteins is thought to set up a length-dependent oscillatory signal that regulates neuronal growth rates. Indeed, perturbation of the mechanism by sequestering importin β1 mRNA or nucleolin away from axons significantly enhances neuronal growth.

Computational modeling of this intrinsic mechanism postulates the existence of a negative feedback loop for periodic resetting of the signal. Because the mechanism is critically dependent on RNA localization to axons, we considered how this might be regulated. RNA localization motifs are often located within 3′ UTRs, and 3′ UTR length can be regulated by alternative polyadenylation. We therefore examined the possibility that shortening of 3′ UTRs by alternative polyadenylation might regulate injury-induced growth of peripheral sensory neurons. This led to the unexpected identification of a subfamily of B2-SINE non-coding repeat-element (RE) RNAs as key regulators of a physiological growth circuit.

B2-SINEs are non-coding RNAs transcribed by RNA polymerase III (Pol III) from short interspersed nuclear elements (SINEs), which are high copy number transposable elements in the mouse genome. B2-SINEs are often polyadenylated, and although mostly transcriptionally repressed in somatic cells, they can be upregulated upon cellular stress. Our recent studies establish a subset of polyadenylated B2-SINE repeat elements, hereby termed GI-SINEs (growth-inducing B2-SINEs), as intrinsic axon growth regulators. This unique subset of B2-SINE RNAs integrates mRNA localization and translation to enhance sensory neuron growth after axon injury. Exogenous expression of B2-SINEs also enhances growth in central nervous system neurons that do not upregulate endogenous SINE elements upon nerve injury. The GI-SINEs are induced in response to retrograde injury signals via activation of AP-1 transcription factors and modulate growth and protein synthesis.

Elastin is a vital component of flexible tissues, and poorly maintained in the adult body. Deterioration of elastin is an important component of the age-related structural alterations that take place in tissues such as skin and blood vessels. Elastin is also hard to obtain or manufacture for use in engineered tissues, which is the primary roadblock motivating the research noted here. While this is useful, a robust source of elastin (or as here, elastin-like proteins that suitably mimic the behavior of elastin) would probably do relatively little to enable therapies to restore elastin structures in aged tissues, as those elastin structures are complex and the configuration of elastin molecules relative to other components of the extracellular matrix matters. It is likely that some form of reprogramming of cell behavior will be necessary to rebuild the elastin structures that were primarily laid down during development.

Our bodies contain a special protein called elastin, which has a remarkable ability to stretch like a rubber band and snap back to its original shape. This elasticity is crucial for the function of various organs, allowing the lungs to inhale and exhale, blood vessels to expand and contract with each heartbeat, and the skin to remain smooth and supple. Despite its utility, using natural elastin for medical applications is challenging. It's available in limited quantities naturally, the purification process is complex, and there's a risk of an immune reaction when administered to humans in other individuals. To address these issues, scientists developed elastin-like polypeptides (ELPs), which could be produced in large quantities but could not fully replicate the complex, precise functions of natural elastin.

Researchers have now created a new protein by selecting and reassembling the most critical parts of tropoelastin, the precursor to human elastin. They precisely combined three distinct domains - a hydrophobic domain that influences the protein's physical properties, a cross-linking domain that provides stability, and a cell-interaction domain that promotes interactions between cells. This new protein was named elastin domain-derived protein (EDDP). EDDP offers several advantages. It can be mass-produced like conventional ELPs while retaining the elasticity and resilience comparable to natural elastin. More remarkably, EDDP promotes cell adhesion and growth by transmitting signals that were lacking in conventional ELPs. This enhanced cell-interaction function directly aids cell survival and growth, making it highly effective in regenerating damaged tissues.

Link: https://www.postech.ac.kr/eng/research/research_results.do?mode=view&articleNo=35356

Blood pressure is dynamically regulated in response to circumstances and circadian rhythm. One of the issues arising with age is that this regulation is impaired, such as by the various mechanisms that stiffen blood vessels that include altered behavior of smooth muscle cells and cross-linking of the extracellular matrix. Researchers here show that dysregulation of diastolic blood pressure, in which normal variability is suppressed, can be distinctly correlated to progression of age-related cognitive decline. This is likely a reflection of shared underlying mechanisms that lead to both varied forms of vascular dysfunction in the brain and systemic dysregulation of blood pressure throughout the body.

Blood pressure variability (BPV) refers to the degree to which blood pressure fluctuates within a given time frame. Previous studies have shown a clear association between BPV and cerebral small-vessel disease (CSVD). BPV is strongly associated with the risk of developing CSVD and its severity, and systolic BPV (SBPV) has been shown to be positively associated with the incidence of cerebral white matter lesions, stroke, and cognitive decline. SBPV leads to unstable cerebral perfusion, which may result in chronic underperfusion or intermittent overperfusion, both of which can impair brain microstructure and function over time. This instability exacerbates the effects of CSVD, a key pathological substrate for vascular cognitive dysfunction, leading to lacunar infarcts, microhemorrhages, and diffuse white matter lesions, all of which are associated with cognitive impairment.

However, the above studies have focused on the effect of SBPV on CSVD, whereas the significant effect of diastolic BPV (DBPV) on CSVD is rarely reported. The interplay between DBPV and cognitive functions is multifaceted at the age where diastolic pressure is starting to decline. This complexity in variability may stem from the process of vascular aging, which is influenced by unique, individual factors not necessarily aligned with chronological age. After adjusting for multiple comparisons, it was found that a larger early and late-phase DBPV is associated with declines in attention tasks and psychomotor tasks, as well as a greater volume of white matter hyperintensities on imaging. It is generally accepted that DBPV fluctuations decrease with age, influenced by vascular aging.

A total of 383 CSVD patients were included in this study. Patients with CSVD were divided into 4 groups based on the Mini-Mental State Examination (MMSE) to compare the differences between these groups. AI = (blood total cholesterol - high-density lipoprotein cholesterol [HDL-C]) ÷ HDL-C; DBPV = standard deviation of 24-hour DBP. A logistic regression model was constructed to screen out the risk factors for cognitive dysfunction in patients with CSVD, and the model was evaluated using the receiver operating characteristic curve.

Patients with different degrees of cognitive dysfunction revealed differences in 24-hour mean diastolic blood pressure (DBP), DBPV, daytime DBP, nocturnal systolic blood pressure, and nocturnal drop in systolic blood pressure and DBP between the groups. Notably, the variability in DBP is significantly lower in the mild and moderate cognitive dysfunction groups compared to the normal cognitive function group. Additionally, the arterial stiffness index negatively correlates with cognitive decline, while showing a positive correlation with the 24-hour average DBPV. In other words, individuals with lower variability of DBP exhibited higher AI and poorer cognitive functions, emphasizing the importance of diastolic pressure stability in maintaining cognitive health. Unlike previous studies that mainly focused on the impact of systolic pressure on cognitive function, our findings suggest that variability in diastolic pressure may be an overlooked risk factor for cognitive decline.

Link: https://doi.org/10.1097/MD.0000000000044190

The Hippo pathway shows up in many areas of research into aging, regeneration, cancer, and cellular senescence. This tends to be the case for protein machinery that is involved in cell growth and cell stress responses, including programmed cell death. See the research surrounding nutrient signaling and its relationship with cell growth, centering around mTOR and its surrounding biochemistry, for example. Hippo signaling is fairly complex, but also quite well explored. Nonetheless while individual protein interactions in the pathway are well mapped, how it operates in detail to produce different outcomes in different contexts is less well understood. Its activities regulate both cell proliferation and cell death via apoptosis, both relevant to regeneration, cancer, and aging, among other topics.

In different contexts, researchers have assessed the merits of both inhibition of Hippo signaling to enhance regeneration, suppress cellular senescence and cell death, or encourage the death of cancerous cells. Here, researchers provide evidence for Hippo pathway inhibition to be a path to making the aging brain more resilient to metabolic imbalances that lead to excessive programmed cell death. Ferroptosis is one such cell death pathway, a consequence of dysregulated iron metabolism, and of late shown to be a relevant pathological mechanism in aged tissues. Inducing a lesser degree of ongoing ferroptosis may be protective in the aging brain.

Inhibition of Hippo Signaling Through Ablation of Lats1 and Lats2 Protects Against Cognitive Decline in 5xFAD Mice via Increasing Neuronal Resilience Against Ferroptosis

The Hippo signaling pathway is a key regulator of cell growth and cell survival, and hyperactivation of the Hippo pathway has been implicated in neurodegenerative diseases such as Huntington's disease. However, the role of Hippo signaling in Alzheimer's disease (AD) remains unclear. We observed that hyperactivation of Hippo signaling occurred in the AD model 5xFAD mice. To determine how inhibition of Hippo signaling might affect disease pathogenesis, we generated 5xFAD mice with conditional neuronal ablation of Lats1 and Lats2, the gatekeepers of Hippo signaling activity.

Our results indicated that 5xFAD mice with ablation of Lats1 and Lats2 were protected against cognitive decline compared with control 5xFAD mice, and this protection was correlated with a marked reduction in neurodegeneration. Interestingly, primary culture neurons with ablation of Lats1 and Lats2 had significantly increased survival following treatment with chemical inducers of ferroptosis and exhibited reduced lipid peroxidation, the driving force of ferroptotic cell death. Moreover, 5xFAD mice with ablation of Lats1 and Lats2 showed reduced lipid peroxidation, and transcriptomic analysis revealed that 5xFAD mice with ablation of Lats1 and Lats2 had enriched metabolic pathways associated with ferroptosis.

These results indicate that inhibition of Hippo signaling activity confers neural protection in 5xFAD mice by augmenting resilience against ferroptosis.

Here find an interesting review of what is known of the role of iron metabolism in osteoporosis, the progressive loss of bone mineral density that occurs with age. Bone tissue is constantly remodeled throughout life, the bone extracellular matrix deposited by osteoblast cells and broken down by osteoclast cells. The loss of strength and increasing fragility of bone in older people arises because of a growing imbalance between osteoblast and osteoclast activity, favoring the osteoclasts. Thus there are many possible ways one could in principle intervene in this problem, most of these approaches not even touching on the underlying causes of the condition, but rather trying to enhance osteoblast activity or inhibit osteoclast activity in some way. As researchers here note, aspects of iron metabolism are in this list of targets for intervention.

Osteoclast-mediated bone resorption is a tightly regulated process essential for maintaining skeletal integrity. Hyperactive osteoclasts are recognized as key contributors to excessive bone loss in conditions such as osteoporosis. Osteoclasts possess a unique ability to resorb bone matrix by releasing hydrolytic enzymes and secreting acid into a specialized extracellular compartment known as the ruffled border. This resorptive function is heavily reliant on two cellular organelles: lysosomes and mitochondria. Lysosomes create an acidic environment via a vacuolar proton pump (v-ATPase), which is essential for protease production. These acidic components, including protons and proteases, are delivered into the ruffled border to degrade the aged bone matrix. Meanwhile, this bone resorption process is highly energy demanding, in which mitochondria serve as the primary energy source. Additionally, mitochondria also provide energy to lysosomes to ensure that they are well functioned in producing and releasing acidic components.

A central player linking mitochondria and lysosomes in osteoclast-mediating bone resorption is iron. Lysosomes act as major iron uptake and recycling centers, regulating iron metabolism by controlling its trafficking, storage, and redistribution. Lysosomal acidification is essential for iron uptake, reducing ferric iron (Fe3+) to ferrous iron (Fe2+), which is then released into the cytoplasm and incorporated into the labile iron pool (LIP) for utilization, storage, or export. Subsequently, mitochondria are the primary sites for iron utilization, facilitating processes, such as oxidative phosphorylation (OXPHOS) and the electron transport chain (ETC) pathway, to generate energy and reactive oxygen species. In the context of bone homeostasis, clinical observations dating back to the early 1900s have established a connection between iron overload and excessive bone loss, underscoring the pivotal role of iron in maintaining bone homeostasis.

Building on these insights, a deeper understanding of the interactions among lysosomes, mitochondria, and iron, particularly in the context of osteoclasts and osteoporosis, is urgently needed. This review focuses on the roles of the lysosome-iron-mitochondria axis in osteoclast function and its implications for osteoporosis. We first examining the evidence supporting the pivotal function of lysosomes in regulating iron homeostasis in osteoclasts, as well as their possible involvement of iron in lysosomal biogenesis and function. Next, we summarize current knowledge on iron utilization in mitochondria and its implications for osteoclast activity. Following this, we explore emerging mechanisms underlying lysosome-mitochondria crosstalk in iron metabolism. Finally, we discuss how dysregulation of the lysosome-iron-mitochondria axis contributes to osteoclast dysfunction and highlight the potential therapeutic strategies targeting this axis for osteoporosis treatment.

Link: https://doi.org/10.34133/research.0840

Researchers here report that human neural progenitor cells derived from induced pluripotent stem cells (iPSCs) can induce some degree of recovery from stroke in mice. As expected for a cell therapy of this nature, functional recovery results from signaling provided by the transplanted cells that favorably alters the behavior of native cells. Inducing regeneration in the brain is important for more than just the damage of stroke, and so is an area of research worth keeping an eye on. In the case of stroke itself, however, more attention should be directed towards prevention: developing means of regressing atherosclerotic plaque to prevent rupture and blockage of vessels in the brain and otherwise reversing structural vascular aging to prevent breakage of vessels and consequent bleeding injury in the brain.

Stroke remains a leading cause of disability due to the brain's limited ability to regenerate damaged neural circuits. Here, we show that local transplantation of iPSC-derived neural progenitor cells (NPCs) improves brain repair and long-term functional recovery in stroke-injured mice. NPCs survive for over five weeks, differentiate primarily into mature neurons, and contribute to regeneration-associated tissue responses including angiogenesis, blood-brain barrier repair, reduced inflammation, and neurogenesis. NPC-treated mice show improved gait and fine-motor recovery, as quantified by deep learning-based analysis.

Single-nucleus RNA sequencing reveals that grafts predominantly adopt GABAergic and glutamatergic phenotypes, with GABAergic cells engaging in graft-host crosstalk via neurexin, neuregulin, neural cell adhesion molecule, and SLIT signaling pathways. Our findings provide mechanistic insight into how neural xenografts interact with host stroke tissue to drive structural and functional repair. These results support the therapeutic potential of NPC transplantation for promoting long-term recovery after stroke.

Link: https://doi.org/10.1038/s41467-025-63725-3

The evidence of recent years derived from the study of the commensal microbes dwelling in the gastrointestinal tract makes it clear that the composition of this gut microbiome is influential on long term health, likely to a similar degree as exercise and diet. Further, the balance of microbial populations shifts with age in unfavorable ways. Inflammatory populations increase, contributing to the chronic inflammation of aging, while beneficial populations decrease, reducing the supply of metabolites necessary for normal tissue function.

While today's open access paper is ostensibly focused on the connections between gut microbiome and brain, the authors do discuss direct links between age-related changes in the gut microbiome and a range of conditions in the rest of the body, including cardiovascular disease and cancer. All of this lends weight to efforts to restructure the aged gut microbiome, rebalance the distribution of population numbers to youthful levels, and thus reduce its contribution to degenerative aging.

We know that rejuvenation of the gut microbiome is possible and we know that it can last for a long time following a single intervention, as fecal microbiota transplantation from a young donor to an old recipient is fairly well studied in animal models. It does restore a more youthful microbiome, and as a consequence improves health and lengthens life. It will likely be challenging to establish the use of fecal microbiota transpantation more broadly than is presently the case in human medicine, as too many unknowns are involved in a donor microbiome, but there are other options on the table that do not suffer from those issues, such as flagellin immunization or the transplantation of synthetic microbiomes with well-vetted component microbes.

The Brain-Gut-Microbiome Axis Across the Life Continuum and the Role of Microbes in Maintaining the Balance of Health

There is a growing body of evidence that the interaction between various microbial organisms and the human host can affect various physical and even mental health conditions. Bidirectional communication occurs between the brain and the gut microbiome, referred to as the brain-gut-microbiome axis. During aging, changes occur to the gut microbiome due to various events and factors such as the mode of delivery at birth, exposure to medications (e.g., antibiotics), environmental exposures, diet, and host genetics. Connections to the brain-gut-microbiome axis through different systems also change during aging, leading to the development of chronic diseases.

Disruption of the gut microbiome, known as dysbiosis, can lead to a reduction in beneficial bacteria and a corresponding increase in more harmful or even pathogenic bacteria. This imbalance may predispose or contribute to the development of various health conditions and illnesses. Targeted treatment of the gut microbiome and the brain-gut-microbiome axis may assist in the overall management of these various ailments.

The purpose of this review is to describe the changes that occur in the gut microbiome throughout life, and to highlight the risk factors for microbial dysbiosis. We discuss the different health conditions experienced at various stages of life, and how dysbiosis may contribute to the clinical presentation of these diseases. Modulation of the gut microbiome and the brain-gut-microbiome axis may therefore be beneficial in the management of various ailments. This review also explores how various therapeutics may be used to target the gut microbiome. Gut biotics and microbial metabolites such as short chain fatty acids may serve as additional forms of treatment. Overall, the targeting of gut health may be an important strategy in the treatment of different medical conditions, with nutritional modulation of the brain-gut-microbiome axis also representing a novel strategy.

In later life atherosclerotic plaques grow in blood vessel walls to narrow and weaken those vessels. When a plaque becomes unstable and ruptures, a downstream blockage can cause a heart attack or stroke. This and the slower harmful consequences of reduced blood flow via narrowed vessels makes atherosclerosis the largest cause of human mortality. Here, researchers provide evidence for long-lasting bacterial infection to be involved in the timing of plaque instability and rupture, particularly oral bacteria that have at some point entered the bloodstream. That said, at the point at which plaque is large enough to do this, some form of catastrophe is inevitable. The bacteria are just accelerating the process.

Using a range of advanced methodologies, the research found that, in coronary artery disease, atherosclerotic plaques containing cholesterol may harbour a gelatinous, asymptomatic biofilm formed by bacteria over years or even decades. Dormant bacteria within the biofilm remain shielded from both the patient's immune system and antibiotics because they cannot penetrate the biofilm matrix. A viral infection or another external trigger may activate the biofilm, leading to the proliferation of bacteria and an inflammatory response. The inflammation can cause a rupture in the fibrous cap of the plaque, resulting in thrombus formation and ultimately myocardial infarction.

"Bacterial involvement in coronary artery disease has long been suspected, but direct and convincing evidence has been lacking. Our study demonstrated the presence of genetic material from several oral bacteria inside atherosclerotic plaques." Tissue samples were obtained from individuals who had died from sudden cardiac death, as well as from patients with atherosclerosis who were undergoing surgery to cleanse carotid and peripheral arteries. Researchers developed an antibody targeted at the discovered bacteria, which unexpectedly revealed biofilm structures in arterial tissue. Bacteria released from the biofilm were observed in cases of myocardial infarction. The body's immune system had responded to these bacteria, triggering inflammation which ruptured the cholesterol-laden plaque.

Link: https://www.tuni.fi/en/news/myocardial-infarction-may-be-infectious-disease

The epidemiological paper noted here shows that Amish life expectancy compares favorably with that of the surrounding population of the United States. While lifestyle choices for the Amish differ in many ways from the general population, their greater level of physical activity is an obvious point of focus. The dose-response curve for physical activity is fairly well characterized, and suggests that ever greater benefits to health and life expectancy continue to accrue up to twice or more the presently recommended 150 minutes per week of moderate to vigorous physical activity. The health of populations like the Amish and remaining hunter-gatherers may be examples of this effect in action.

This study examines differences in the longevity of Amish men compared to the men within the general population of the United States. Data for this analysis comes from the 1965 Ohio Amish directory, specifically the birth and death dates of men from the Holmes County settlement. Amish men's longevity is compared with the white men of Ohio based on life tables published online by the Social Security Administration.

Amish men born between 1895 and 1934 who lived past their twenty-fifth birthday had an average lifespan of 76.3 years, compared with the white men of Ohio of the same age category, who had an average lifespan of 71.3 years, for a difference of five years. When the findings are considered with published research on Amish work practices, we concluded that the remarkable longevity of Amish men might be attributed to their exceptional level of physical activity.

Link: https://doi.org/10.18061/jpac.v5i2.10378

Many classes of therapy can be robustly manufactured with little risk of issues and do not need the full cost in time, effort, and funds of Good Manufacturing Practice (GMP) specified by the FDA in order for any given batch of the drug to be demonstrated to be safe. The most frequently used AAV vector serotypes, for example, are relatively safe in this way. One can manufacture a batch of an AAV drug with any one of the very experienced manufacturers in the same way one would for research in animals, and then run all of the quality assays needed to demonstrate that the batch is safe. This costs a lot less than full GMP but should produce essentially equivalent outcomes in safety.

Medical tourism allows companies to bring drugs to the clinic in a responsible way without having to spend vast sums conforming to what the major regulators of the world, the FDA and EMA, believe is sufficient. Here I'll point out an example of a company doing this for VEGF gene therapy, a potential way to upregulate angiogenesis in order to reverse the age-related loss of capillary density that impairs function in tissues throughout the body. VEGF gene therapy in mice has been demonstrated to modestly extend life span. Forms of VEGF gene therapy have been trialed successfully in humans, and as noted here, have been approved in Russia for some years.

Keeping up with the longevity gene therapies

The recent revelation that Khloé Kardashian has received a gene therapy purported to promote tissue rejuvenation came as something of a surprise to many. The celebrity influencer received the capillary-boosting VEGF treatment from regenerative medicine specialist in Mexico. The therapy, which is claimed to help combat the age-related loss of vasculature in tissues and organs, was provided by Unlimited Bio, which operates out of Próspera, an autonomous special economic zone in Honduras designed to foster rapid biomedical innovation. The company says it is on a mission to conduct 100 clinical trials of genetic preventive therapies within 10 years, using the regulatory structures of Próspera to enable faster approvals and streamlined processes.

The founding mission of Unlimited Bio is ambitious: run 100 clinical trials within 10 years, building multiple gene therapies under one umbrella and combining them to combat the effects of aging. The first therapy to be offered by Unlimited Bio is a gene therapy delivered via plasmid, which delivers the genetic instructions for vascular endothelial growth factor (VEGF) into cells to stimulate the growth of new blood vessels (angiogenesis). "We wanted to start with a simple, well-established gene therapy. This therapy was first approved in Russia and Ukraine in 2011 for lower limb ischemia, and more than 10,000 patients have received it safely over 15 years. Of course, not everything that works for a disease will have benefits in healthy people, but VEGF is a unique case. Capillaries are essential for oxygen and nutrient delivery. With age, capillary density declines, which may contribute to sarcopenia and other age-related conditions. By enhancing capillarization, VEGF essentially upgrades our body's 'delivery system' - adding more roads for nutrients and oxygen to reach cells. That's why we believe it has strong longevity potential."

Unlimited Bio licensed the VEGF therapy for use in Prospera in preventive indications, and within six months of incorporation, had its first product on the market. While only a small number of people have received the treatment to date, the Kardashian effect is already being seen. "Since several well-known influencers received the therapy, interest has grown rapidly. I can say it is the most affordable preventive gene therapy worldwide - comparable to stem cell treatments."

Ferroptosis is a form of programmed cell death driven by iron accumulation and involving extensive lipid peroxidation as the kill mechanism. Senescent cells accumulate with age to cause tissue dysfunction and are resistant to programmed cell death. Most present approaches to the selective destruction of senescent cells as a form of therapy involve some form of sabotage of one or more programmed cell death resistance mechanisms. Here, researchers show that senescent cells both accumulate iron and resist ferroptosis, which suggests potential targets for novel forms of senolytic drug capable of selectively destroying senescent cells with minimal harm to normal cells.

Senescent cells, characterized by irreversible cell cycle arrest and inflammatory factor secretion, promote various age-related pathologies. Senescent cells exhibit resistance to ferroptosis, a form of iron-dependent cell death; however, the underlying mechanisms remain unclear. Here, we discovered that lysosomal acidity was crucial for lipid peroxidation and ferroptosis induction by cystine deprivation. In senescent cells, lysosomal alkalinization causes the aberrant retention of ferrous iron in lysosomes, resulting in resistance to ferroptosis.

Treatment with the V-ATPase activator EN6 restored lysosomal acidity and ferroptosis sensitivity in senescent cells. A similar ferroptosis resistance mechanism involving lysosomal alkalinization was observed in pancreatic cancer cell lines. EN6 treatment prevented pancreatic cancer development in xenograft and Kras mutant mouse models. Our findings reveal a link between lysosomal dysfunction and the regulation of ferroptosis, suggesting a therapeutic strategy for the treatment of age-related diseases.

Link: https://doi.org/10.1038/s41467-025-61894-9

The aging of the immune system leads to chronic inflammatory signaling, a consequence of the accumulation of forms of molecular damage and the maladative changes in cell behavior that occur in response to that damage. It is easy enough to point to the inflammation of aging and link it to accelerated onset and progression of all of the common age-related conditions, as sustained inflammation is indeed disruptive to tissue structure and function throughout the body. It is likely that there are also other, more subtle mechanisms involved in the relationship between immune aging and any specific age-related condition, however.

Osteoporosis (OP) is a systemic skeletal disorder characterized by decreased bone mineral density (BMD) and deteriorated bone microarchitecture, which leads to an increased risk of fragility fractures. Noticeably, the immune system has been recognized as a crucial regulator in bone metabolism. In recent years, osteoimmunology studies have shown that the immune system plays a key role in bone remodeling. The term "immunoporosis" was first proposed in 2018 to establish a novel field emphasizing the role of immune cells in OP pathogenesis.

Specifically, immunoporosis refers to the immunology of OP: it denotes the immune-driven mechanisms that underlie bone fragility, focusing on age-related alterations in innate and adaptive immune cells. These alterations drive chronic low-grade inflammation and enhance responsiveness to damage-associated molecular patterns (DAMPs) and other stress signals, thereby disrupting bone remodeling and resulting in increased bone resorption and reduced bone formation. For instance, activated T cells (e.g., Th17 and Treg), proinflammatory cytokines [e.g., interleukin (IL)-17, tumor necrosis factor-alpha (TNF-α), and receptor activator of nuclear factor-κB ligand (RANKL)], and innate immune cells (e.g., dendritic cells (DCs) and macrophages) may promote osteoclast formation and bone loss.

Traditional therapies for OP (e.g., bisphosphonates, denosumab, and PTH analogs) have shown immunomodulatory properties, indicating the clinical significance of this immunological pathway. Critically, aging can lead to immunosenescence, a phenomenon marked by reduced immune cell diversity, functional decline, and increased inflammatory cytokine production. It may further drive inflammaging, a state of persistent, low-grade systemic inflammation that further exacerbates bone resorption and impairs bone formation. Inflammaging and immunosenescence are now accepted as central contributors to aging-related bone loss.

Link: https://doi.org/10.1016/j.jot.2025.06.015

Many proteins can form transient aggregates, in which misfolding or chemical decoration allows solid clumps of protein to precipitate from solution and disrupt cellular biochemistry. A much smaller number of proteins can form persistent aggregates, however, and this unfortunate mechanism is an important contributing cause of a variety of age-related conditions. This is particularly the case in the brain. Consider amyloid-β, tau, and α-synuclein, for example, contributing to Alzheimer's, Parkinson's, and other neurodegenerative conditions. Meanwhile in the rest of the body, transthyretin amyloid is likely important in heart failure, while a number of other types of amyloid (such as medin) likely contribute to aging in more subtle ways.

Our biochemistry is capable of clearing protein aggregates via a form of autophagy called aggrephagy. Autophagy is the name given to a collection of processes that identify and flag unwanted molecules and structures, and in a variety of ways deliver those flagged molecules and structures into a lysosome. Once inside a lysosome, enzymes break down the material for recycling. Clearly the normal operation of aggrephagy is not sufficient to the task of keeping persistent aggregates from accumulating to cause disease, but it does have an impact. Thus the research community is interested in finding ways to meaningfully enhance the operation of aggrephagy. That in turn requires a better understanding of how exactly aggrephagy functions.

Your cells break down protein clumps to smaller pieces before taking it to the trash

A new study shows that our cells' ability to clean out old protein clumps, known as aggregates, also includes a previously unknown partnership with an engine that breaks down bigger pieces into smaller before "taking it to the trash." The process involves something called the proteasomal 19S subunit and DNAJB6-HSP70-HSP110 chaperone module, which together practically form a grinder. This is a very important key that may lead to better treatments of diseases like characterized Alzheimer's, Parkinson's, Huntington's, ALS, and other diseases that are characterized by the accumulation of clumps, in most cases formed by a specific protein

"We know that augmenting autophagy, which is one of the two major cleaning systems in our cells, can delay the onset of several of the devastating neurodegenerative diseases mentioned. Our findings suggest that a combined treatment where we enhance both the breaking down of the big protein clumps into smaller pieces to make them a better substrate for autophagy and autophagy, may be a much better therapeutic approach for these diseases. We are just starting to decipher the mechanism of this whole cell-cleaning process, and we need to deep dive into the details before we can start to work on actual treatments, but understanding how we can enhance it, will certainly help to eliminate, at least partially, those toxic protein aggregates leading to the above-mentioned lethal neurodegenerative diseases."

A chaperone-proteasome-based fragmentation machinery is essential for aggrephagy

Perturbations in protein quality control lead to the accumulation of misfolded proteins and protein aggregates, which can compromise health and lifespan. One key mechanism eliminating protein aggregates is aggrephagy, a selective type of autophagy. Here we reveal that fragmentation is required before autophagic clearance of various types of amorphous aggregates. This fragmentation requires both the 19S proteasomal regulatory particle and the DNAJB6-HSP70-HSP110 chaperone module. These two players are also essential for aggregate compaction that leads to the clustering of the selective autophagy receptors, which initiates the autophagic removal of the aggregates. We also found that the same players delay the formation of disease-associated huntingtin inclusions. This study assigns a novel function to the 19S regulatory particle and the DNAJB6-HSP70-HSP110 module, and uncovers that aggrephagy entails a piecemeal process, with relevance for proteinopathies.

The composition of the gut microbiome changes with age, and researchers have demonstrated that many of these changes correlate with worse outcomes in aging. In animal studies, altering the composition of the gut microbiome to be more youthful produces health benefits, indicating that changes in the gut microbiome contribute to aging, but similar data in humans remains sparse. Mendelian randomization is a way to use genetic differences across a study population to infer whether or not a given correlation indicates causation. The results are not conclusive, but add support for causation to the be the case. Here, researchers mine a large database of gut microbiome composition, genetics, and health outcomes in an attempt to find specific cases in which an aspect of the gut microbiome, such as increased numbers of a given microbial species or altered production of a specific metabolite, is a contributing cause of an aspect of degenerative aging.

In the past 20 years, the involvement of gut microbiome in human health has received particular attention, but its contribution to age-related diseases remains unclear. To address this, we performed a comprehensive two-sample Mendelian Randomization investigation, testing 55,130 potential causal relationships between 37 traits representing gut microbiome composition and function and age-related phenotypes, including 1,472 inflammatory and cardiometabolic circulating plasma proteins from UK Biobank Pharma Proteomic Project and 18 complex traits.

A total of 91 causal relationships remained significant after multiple testing correction and sensitivity analyses, notably two with the risk of developing age-related macular degeneration and 89 with plasma proteins. The link between purine nucleotides degradation II aerobic pathway and apolipoprotein M was further replicated using independent genome-wide association study data. Finally, by taking advantage of previously reported biological function of Faecalibacterium prausnitzii we found evidence of regulation of six proteins by its function as mucosal-A antigen utilization.

These results support the role of gut microbiome as modulator of the inflammatory and cardiometabolic circuits, that may contribute to the onset of age-related diseases, albeit future studies are needed to investigate the underlying biological mechanisms.

Link: https://doi.org/10.18632/aging.206293

The innate immune cells known as macrophages adopt different packages of behaviors (known as polarizations) depending on circumstances. Most research is focused on the difference between the pro-inflammatory M1 polarization and the anti-inflammatory M2 polarization. M2 is considered to be more regenerative, and many issues in aging are thought to involve the presence of too many M1 macrophages. Yet M1 macrophages do play a role in regeneration, as noted here, and this contribution is also disrupted with age to inhibit the ability to regrow muscle in older individuals. This is one of the aspects of macrophage behavior that illustrates the limitations of the simple M1/M2 model; the underlying reality is more of a spectrum of behaviors, and one M1-like macrophage is not necessarily undertaking the same tasks as another.

Impaired muscle regrowth in aging is underpinned by reduced pro-inflammatory macrophage function and subsequently impaired muscle cellular remodeling. The essential role of pro-inflammatory macrophages during tissue remodeling are well appreciated given that they are early responders to facilitate the clearance of tissue debris and initiate intracellular communication such as stimulation of satellite cell proliferation and regulation of the deleterious accumulation of collagen and intramuscular adipose from fibroblasts and fibro-adipogenic progenitors.

Macrophage phenotype is metabolically controlled through citric acid cycle intermediate accumulation and activation of hypoxia-inducible factor 1-alpha (HIF1A). We hypothesized that transient hypoxia following disuse in old mice would enhance macrophage metabolic inflammatory function thereby improving muscle cellular remodeling and recovery. Old (20 months) and young adult mice (4 months) were exposed to acute (24h) normobaric hypoxia immediately following 14-days of hindlimb unloading and assessed during early re-ambulation (4- and 7-days) compared to age-matched controls.

Treated aged mice had improved pro-inflammatory macrophage profiles, muscle cellular remodeling, and functional muscle recovery to the levels of young control mice. Likewise, young adult mice had enhanced muscle remodeling and functional recovery when treated with acute hypoxia. Treatment in aged mice restored the muscle molecular fingerprint and biochemical spectral patterns (Raman Spectroscopy) observed in young mice and strongly correlated to improved collagen remodeling. Finally, intramuscular delivery of hypoxia-treated macrophages recapitulated the muscle remodeling and recovery effects of whole-body hypoxic exposure in old mice. These results emphasize the role of pro-inflammatory macrophages during muscle regrowth in aging and highlight immunometabolic approaches as a route to improve muscle cellular dynamics and regrowth.

Link: https://doi.org/10.1172/jci.insight.194303

The peripheral nervous system is capable of regeneration, albeit not as much as desired. Lasting loss of function following injury is certainly possible, particularly following injury to larger nerves. The research community has long been interested in finding ways to improve this situation, some of which might be applicable to the much less regenerative central nervous system as well. Peripheral nerves are made up of bundled axons, long connections between neurons that pass signals back and forth. It is the regeneration of these axons that is the primary concern. Peripheral nervous system axons can be as much as several feet long, but even these are capable of regeneration and regrowth - at least until old age dismantles this ability along with many others.

In today's open access paper, researchers uncover an approach to improving peripheral axon regeneration that works in both young and old tissues. This appears to function at least in part by changing the behavior of the satellite glial cells that surround peripheral neurons making up nerve ganglia. The function of these glial cells is not completely understood, and therefore how this approach functions in detail is not completely understood. At the high level, it seems likely that (a) satellite glial cells regulate the environment of the ganglia in ways that are conducive to normal function, analogous to the supporting role of glial cells in the brain, (b) their ability to do this declines with age, and (c) there are ways to favorably change the behavior of satellite glial cells that have few negative consequences. The small molecule drug used in this study may or may not count as one of those ways, but more targeted approaches can be envisaged.

Endothelin B receptor inhibition rescues aging-dependent neuronal regenerative decline

Peripheral sensory neurons regenerate their axons after injury to regain function, but this ability declines with age. The mechanisms behind this decline are not fully understood. While excessive production of endothelin 1 (ET-1), a potent vasoconstrictor, is linked to many diseases that increase with age, the role of ET-1 and its receptors in axon regeneration is unknown.

Using single-cell RNA sequencing, we show that satellite glial cells (SGCs), which completely envelop the sensory neuron cell body residing in the dorsal root ganglia (DRG), express the endothelin B receptor (ETBR), while ET-1 is expressed by endothelial cells. Inhibition of ETBR ex vivo in DRG explant cultures improves axon growth in both adult and aged conditions.

In vivo, treatment with the FDA-approved compound, Bosentan, a ETBR/ETAR antagonist used to treat pulmonary hypertension, improves axon regeneration and reverses the age-dependent decrease in axonal regenerative capacity. Single-nuclei RNA sequencing and electron microscopy analyses reveal a decreased abundance of SGCs in aged mice compared to adult mice. Additionally, the decreased expression of connexin 43 (Cx43) in SGCs in aged mice after nerve injury is partially rescued by Bosentan treatment.

These results reveal that inhibiting ETBR function enhances axon regeneration and rescues the age-dependent decrease in axonal regenerative capacity, providing a potential avenue for future therapies.

The most interesting comparative biology programs aim to use the cellular biochemistry of unusually regenerative, long-lived, and cancer resistant species as a tool to better understand our vulnerabilities to aging and injury. In principle, understanding why a species is unusually long-lived could point to a basis for therapies to slow aging in humans, while understanding why species such as naked mole-rats, elephants, whales, and turtles have such low incidence rates of cancer could point to ways to shut down human cancers. This remains a hypothesis, as comparative biology research has not yet advanced to the point at which technology demonstrations of transferring biochemistry between species are commonplace, or at which any of the discoveries seem easily used as a basis for the development of therapies. It may just be a matter of time, or it may be that this is a project for a more distant future in which engineering significant changes in human biochemistry is an easier undertaking.

Turtles occupy the extremes of biology, but perhaps are best known for their longevity: even the shortest-lived species (the chicken turtle, Deirochelys reticularia) exceed 20 years, whereas others, such as Galapagos and Aldabra giant tortoises, can live well over 150 years. Turtles also exhibit remarkable variation in adult body size. Theoretically, organisms with more cells and higher lifetime cellular turnover should face greater cancer risk. Therefore, large, long-lived species must have evolved mechanisms to mitigate this increased risk. On the basis of their considerable variation in both body mass and lifespan, turtles are a promising group for studying the evolution of natural cancer resistance. However, cancer reports in turtles remain exceedingly rare - far less common than in mammals, birds, or even other reptiles.

To build on previous studies, we analyzed 290 additional necropsies from 64 turtle species across eight zoos in Europe, the United Kingdom, and the United States, representing nine taxonomic families. Despite extensive taxonomic and geographic coverage - from the tiny black-breasted leaf turtle (Geoemyda spengleri; 150 grams) to the Galapagos giant tortoise (Chelonoidis spp.; less than 300 kilograms) - we found only one case of neoplasia, in the mata mata (Chelus fimbriata), with no malignancies detected. This corresponds to neoplasia and cancer prevalence estimates of 0.34% and 0%, respectively. These values are similar to those reported by other groups. Taken together, this data reinforces the conclusion that cancer is very uncommon in turtles. When cancer does occur, it rarely metastasizes, suggesting that turtles may possess biological or evolutionary traits contributing to their low cancer prevalence.

Genomic analyses of large, long-lived species such as Galapagos and Aldabra giant tortoises, have revealed positive selection and duplications in key tumor suppressor genes, metabolic regulators, immune response genes, and pathways involved in genome maintenance. Moreover, comparative studies indicate that Galapagos tortoises exhibit enriched expression of tumor suppressors, proteostasis regulators, and metabolic pathways associated with growth control, potentially contributing to their reduced cancer susceptibility. Functional assays in Galapagos giant tortoise cell lines further suggest an enhanced ability to trigger apoptosis to mitigate endoplasmic reticulum stress, which may help clear damaged cells before tumorigenesis can occur.

Link: https://doi.org/10.1093/biosci/biaf100

Some potentially damaging molecules are produced during the normal operation of metabolism. Cells have evolved numerous mechanisms to clean up that damage, but have also evolved to treat the presence of these damaging molecules as a part of the complex systems of signaling that regulate metabolism and cell maintenance. Thus when mitochondria are altered to produce a mild increase in reactive oxygen species (ROS), the usual byproduct of their production of the chemical energy store molecule adenosine triphosphate (ATP), cells react with increased maintenance and improved function. The end result in short-lived laboratory species such as nematodes and flies is a greater resilience to the damage of aging and a modestly extended life span. Researchers would like to tie this and similar exhibitions of mild stress producing a modest slowing of aging into a more unified big picture, and examining the oxidation of cysteine present in proteins in these processes is one step along that path.

Reactive oxygen species (ROS) and hydrogen sulfide (H2S) are naturally produced during metabolic processes. At physiological levels, they act as oxidation-reduction (redox) signaling molecules and regulate a myriad of cellular processes. Redox signaling occurs largely through rapid and reversible oxidation of reactive cysteine residues in target proteins, leading to changes in protein ligand binding affinity, subcellular localization, and function. Recent studies have demonstrated that ROS and H2S play an essential role in various longevity models, and that a mild increase in ROS or H2S levels is sufficient to extend lifespan in model organisms. Meanwhile, the number of aging-related proteins that are modulated by ROS- or H2S-mediated post-translational modification is constantly growing.

In this review, we aim to summarize key results that support cysteine-based redox regulation of organismal aging and lifespan. The human proteome contains ∼210,000 cysteine residues, and mass spectrometry-based chemoproteomics analyses reveal that thousands of cysteines are oxidant-sensitive. Under physiological conditions, ROS and H2S signaling are intrinsically connected via cysteine oxidation. For example, treating HeLa cells with EGF induces a transit increase in H2O2 production and promotes global sulfenylation, followed by a wave of proteome-wide cysteine persulfidation. H2O2-mediated sulfenylation of the active site cysteine Cys797 enhances EGF receptor (EGFR) tyrosine kinase activity, which is suppressed by pretreatment with H2S. These results suggest that ROS- and H2S-mediated cysteine modifications may play antagonistic roles in growth factor signaling, and raise an important question whether the crosstalk between ROS and H2S also exists in other processes including aging.

Link: https://doi.org/10.1016/j.redox.2025.103852

Researchers studying neurodegenerative conditions have increasingly focused on the role of microglia in recent years. Microglia are innate immune cells analogous to the macrophages found in the rest of the body. They undertake a broad range of tasks including defense against pathogens, destruction of malfunctioning cells, coordination of tissue maintenance and regeneration, and assisting in alterations to the networks of synaptic connections between neurons necessary for the function of the brain. With age, some microglia become overly active and inflammatory, while others become senescent, further exaggerating those behaviors. This is disruptive and harmful to the brain.

Separately, a body of evidence suggests that cholesterol metabolism in the brain becomes dysfunctional with age. The brain is separated from the rest of the body by the blood-brain barrier and the two sides separately conduct transport, recycling, and manufacture of cholesterol. Every cell needs cholesterol, an important component in cell membranes, but too much cholesterol in any given cell is toxic. A balance of manufacture, transport, and recycling is thus important. Outside the brain cholesterol is only manufactured in the liver and distributed via the circulatory system. In the brain, cholesterol is primarily manufactured by astrocytes, a large population of cells. The brain is much more cholesterol-rich than other tissues, and cholesterol metabolism is correspondingly more important.

Linking these two topics, dysregulation of cholesterol metabolism appears to be involved in inflammatory microglial dysfunction. Excess cholesterol in the form of lipid droplets is observed in microglia in the aged brain, for example. Further, the APOE protein is involved in cholesterol transport, and one of the variant sequences, APOEε4, is associated with a greater risk of Alzheimer's disease. Researchers have shown that this variant increases the vulnerability of microglia to cholesterol excess, making microglia more inflammatory and disruptive to brain tissue. Today's open access paper expands upon this link between cholesterol, microglia, and Alzheimer's disease.

Microglial States Are Susceptible to Senescence and Cholesterol Dysregulation in Alzheimer's Disease

Cellular senescence is a major contributor to aging-related degenerative diseases, including Alzheimer's disease (AD), but much less is known about the key cell types and pathways driving senescence mechanisms in the brain. We hypothesized that dysregulated cholesterol metabolism is central to cellular senescence in AD. We analyzed single-cell RNA-seq data from the The Religious Orders Study / Memory and Aging Project (ROSMAP) and Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD) cohorts to uncover cell type-specific senescence pathologies.

In ROSMAP single nuclei RNA-seq data (982,384 nuclei from postmortem prefrontal cortex), microglia emerged as central contributors to AD-associated senescence phenotypes among non-neuronal cells. Homeostatic, inflammatory, phagocytic, lipid-processing, and neuronal-surveillance microglial states were associated with AD-related senescence in both ROSMAP (152,459 microglia nuclei from six brain regions) and SEA-AD (82,486 microglia nuclei) via integrative analysis.

We assessed top senescence-associated bioprocesses and demonstrated that senescent microglia exhibit altered cholesterol-related processes and dysregulated cholesterol metabolism. We identified three gene co-expression modules representing cholesterol-related senescence signatures in postmortem brains. To validate these findings, we applied these signatures to snRNA-seq data from induced pluripotent stem cell derived microglia（iMGs) exposed to myelin, amyloid-β, apoptotic neurons, and synaptosomes. Treatment with AD-related substrates altered cholesterol-associated senescence signatures in iMGs.

This study provides the first human evidence that dysregulated cholesterol metabolism in microglia drives cellular senescence in AD. Targeting cholesterol pathways in senescent microglia is an attractive strategy to attenuate AD progression.

High levels of the circulating amino acid homocysteine are regarded as a risk factor for the development of atherosclerosis. It can occur due to dietary deficiency, particularly in B vitamins, but since elevated levels are fairly common in later life there are clearly other contributing factors. Well established approaches based on diet and supplements do exist to attempt to lower homocysteine levels. Researchers here provide evidence in an animal model for raised homocysteine to also contribute to the stiffness of arteries. Blood vessel stiffening can induce hypertension, which in turn can accelerate the growth of atherosclerotic plaques in blood vessel walls, and also increase the risk of plaque rupture to cause a heart attack or stroke.

Hyperhomocysteinemia, an elevated level of homocysteine in the blood, is an independent risk factor for atherosclerosis and, more generally, cardiovascular disease. However, its relationship with aortic biomechanics has not been investigated yet. To better understand the influence of elevated homocysteine levels on aortic biomechanics, we propose an animal model in which hyperhomocysteinemia, hypercholesterolemia, and their combination were induced in rabbits by balloon injury of the abdominal aorta, special diets, and intravenous homocysteine injections.

The effects of a diet deficient in B vitamins and choline, which are required for homocysteine degradation, a cholesterol-rich diet, their combination, and increased homocysteine concentration are investigated in relation to abdominal aortic biomechanics in rabbits. For this purpose, equibiaxial and non-equibiaxial extension tests were carried out, and the influence of risk factors on the stress-stretch relationship, mechanical anisotropy, and tissue inelasticity is discussed. The mechanical characterization of the tissue was supported by microstructural histological analyses.

Our study reveals that deficiency of B vitamins and choline cause aortic stiffening even in the absence of hypercholesterolemia, suggesting a possible independent role in the development of atherosclerosis. Further increasing homocysteine concentration through intravenous injections in rabbits fed B vitamins and choline-deficient diet also results in a stiffer stress response and more pronounced inelastic phenomena with respect to the control group.

Link: https://doi.org/10.1016/j.actbio.2025.06.003

Parkinson's disease and Lewy body dementia are synucleinopathies, forms of neurodegeneration characterized by the misfolding and aggregation of α-synuclein. Given an initial misfolding event, this pathology can spread from cell to cell through the nervous system and brain, one misfolded molecule encouraging others to also misfold in the same way. The resulting disruption of cell biochemistry kills neurons, particularly those involved in motor control. Here, researchers report evidence for particulate air pollution, known to correlate with increased risk of neurodegenerative conditions, to contribute to synucleinopathies by encouraging α-synuclein aggregation.

Researchers have uncovered a possible molecular connection between air pollution and an increased risk of developing Lewy body dementia (LBD). The team discovered that exposing mice to fine particulate air pollution (PM2.5) triggered formation of an abnormal alpha-synuclein (αSyn) strain, PM2.5-induced preformed fibril (PM-PFF). These toxic protein clusters shared key structural and disease-related features with those found in the brains of patients with Lewy body dementia.

The researchers also analyzed hospital data from 56.5 million U.S. patients admitted between 2000 and 2014 with neurodegenerative diseases. They focused on patients hospitalized for the first time with Lewy body-related conditions, and used data from the individuals' ZIP codes to estimate their long-term exposure to PM2.5. The scientists found that each interquartile range increase in PM2.5 concentration in these ZIP code areas resulted in a 17% higher risk of Parkinson's disease dementia and a 12% higher risk of dementia with Lewy bodies.

Exploring the biological reason for this association between exposure to PM2.5 and Lewy body dementia, the researchers then exposed both normal mice and mice genetically modified to lack the alpha-synuclein protein (αSyn-/- animals) to PM2.5 pollution every other day for a period of 10 months. "In normal mice, we saw brain atrophy, cell death and cognitive decline - symptoms similar to those in Lewy body dementia. But in mice lacking alpha-synuclein, the brain didn't exhibit any significant changes. We believe we've identified a core molecular link between PM2.5 exposure and the propagation of Lewy body dementia."

Link: https://www.genengnews.com/topics/translational-medicine/possible-molecular-link-between-air-pollution-and-lewy-body-dementia-identified/

The pharmaceutical industry suffers from all of the issues that plaque heavily regulated industries that have been heavily regulated for a long time. Costs increase, restrictions increase, the ability to create new medicines declines. Everyone sees at least part of the problem, but no one person and no one group is in a position to change enough of the perverse incentives that operate during regulatory capture in order to meaningfully steer away from a collapse into mediocrity and inability to make progress. People have certainly tried! The past few decades have seen intense lobbying and patient advocacy on the part of quite well funded groups and influential insiders in regulators and industry, aiming to reduce the cost and speed up regulatory approval of new therapies. Yet this is the same period of time in which the cost of drug development has more than doubled, largely due to increased regulatory requirements.

The article I'll point out today is written largely from the perspective of investors, entrepreneurs, and other businessfolk. The author advances the idea that (a) the way out of this present industry malaise is to make drugs to treat aging, because they will have a vastly greater value than present disease-specific drugs, and (b) that nearly everyone presently involved in the aging field is going about this in the wrong way. I largely agree at the high level, and perhaps would quibble on the details. Certainly, I think that the most practiced and well funded areas of biomedical research and development are a poor fit for the treatment of aging as a medical condition, particularly the present fixation on genetics and gene variants. Aging is universal. Certainly genetic variants have some small influence on the process, but the underlying mechanisms of aging are the same for everyone. This limits the scope of the benefits that can be achieved as a result of discovering a gene variant that reduces disease risk, understanding how it works, and then building drugs to manipulate the relevant mechanism.

We only have to look as far as atherosclerotic cardiovascular disease to see this in action. Every drug class that lowers LDL cholesterol (statins, PCSK9 inhibitors, etc) emerged from the discovery of human populations with a variant gene that exhibited lifelong low LDL cholesterol and consequent reduced risk of developing sufficient atherosclerosis to cause a heart attack or stroke (by as much as 50% for some variants). Yet reducing LDL cholesterol via small molecule drugs in later life has been shown to produce only a 10% to 20% reduction in mortality risk, many people cannot tolerate the side-effects of statins, and lowering LDL cholesterol does not regress existing atherosclerotic plaque reliably or to any great degree. This is not a curative approach.

Where are all the trillion dollar biotechs?

Of the many trends people chase in biotech, the only one that proves sure and consistent is declining returns. Even after adjusting for inflation, the number of new drugs approved per $1 billion of R&D spending has halved approximately every nine years since 1950. Deloitte's forecast R&D internal rate of return (IRR) for the top 20 pharmas fell below the industry's cost of capital (~7-8%) between 2019 and 2022. In other words, while the industry remained profitable overall, the incremental economics of R&D investment were value-eroding rather than value-creating. So, while other industries have a reason to treat the current market downturn as transient, the business of developing medicine has a more fundamental problem to deal with - it is quite literally shrinking out of existence.

When was the last time the industry managed to get the IRR number to go up? It wasn't better targets, it wasn't AI, and it wasn't cheap Chinese trials. Both in the case of the 2021 and 2024 industry comebacks, the average return on investment rose because of sales of drugs for extremely large patient populations - COVID-19 vaccines and GLP-1 receptor agonists. To me, big indications almost always mean age-related indications, since aging is the only disease that affects everyone ("aging is the biggest total addressable market (TAM) on Earth"). So if you asked me to write a recipe for an industry-wide fix, I would start with age-related diseases: Alzheimer's, sarcopenia, and heart disease. Solving those would almost certainly put pharma growth back on track. Yet in 2024, of the 50 new drugs approved, only 2 targeted age-related indications (Resmetirom and Donanemab). The same trend was true in all the previous years.

I generally don't subscribe to the idea that pharma isn't solving aging because their thinking is old-school or outdated. This ignores the fact that companies like Novartis, Regeneron, and Eli Lilly have long-standing "aging" research arms, and that many pharmas are experienced with multi-morbidity and all-cause mortality trials. If aging represents a trillion-dollar market, but the field still has little traction in addressing it, it's not because people with PhDs are blind to opportunities or complacent about the lack of progress. I've written about this before, but the reality is that, despite our best efforts and billions in investments, we just aren't very good at treating age-related diseases.

Our best heuristics for drug development are just failing to work here. First, genetic targets have poor propagation to late-stage damage. I think of genetic variants as models for early prevention. Unfortunately, factors that prevent late-stage disease are, in most cases, harmful to carry as a genetic variant in youth. For example, targets that ended up being successful for reducing fibrosis in age-related lung disease, idiopathic pulmonary fibrosis - like PDGFR, FGFR, and VEGFR - are essential for tissue repair, capillary growth, and connective tissue formation. This means our standard approach to discovering treatment targets is much harder to apply here.

In alternative approaches to target discovery, aging also breaks our intuition about cause and effect. We are used to the idea that, if something seemingly causes damage, then clearing it will fix the disease. In age-related macular degeneration, for instance, accumulation of complement proteins in extracellular retinal debris was one of the most consistent clinical features observed in patients. However, when complement cascade activation was pharmaceutically halted, there was no improvement in vision decline. Similarly, one of the most obvious features of Alzheimer's is amyloid plaques in post-mortem patient brains. Multiple drugs have now cleared plaques successfully, yet they show no evidence of improved cognition. In fact, most beta-amyloid drugs shrink patients' brains. Multidimensional problems, of course, require multidimensional solutions.

Most industries have eras when progress stalls before a new paradigm unlocks scale again. Electricity needed transmission grids, computers needed operating systems, and aviation needed jet engines. For biotech, whether the shift will come from new modalities, new regulatory frameworks, or entirely new ways to validate efficacy in humans is not yet clear, but we can, perhaps, outline the boundaries within that future will exist: manufacturing and trials should get cheaper with each run, regulations should become more adaptive, approval frameworks should increase and not decrease in variance, and new therapeutic modalities should focus on unlocking new biology, not just producing slightly better iterations on problems we already know how to solve. Until those new paradigms take hold, building a trillion-dollar biotech will remain caught in Lewis Carroll's logic: running as fast as we can just to stay in place, and twice as fast to make any real progress.

Exposure to particulate matter and other air pollution is generally agreed upon to be bad for long-term health. The worse the exposure, the worse the outcome. The epidemiological data is quite convincing, particularly studies in those parts of the world where, by happenstance, very similar populations are exposed to very different degrees of air pollution. The consensus on biological mechanisms is that pollutants interact with lung and airway tissues to provoke greater systemic inflammation. That inflammation in turn accelerates the onset and progression of all of the major fatal conditions of aging. Here the focus is on dementia, but other studies have shown similar influences on cardiovascular disease.

This cohort study used data associated with autopsy cases collected from 1999 to 2022 at the Center for Neurodegenerative Disease Research Brain Bank at the University of Pennsylvania. Data were analyzed from January to June 2025. Participants included 602 cases with common forms of dementia and/or movement disorders and older controls after excluding 429 cases with missing data on neuropathologic measures, demographic factors, APOE genotype, or residential address.

One-year mean PM2.5 concentration prior to death or prior to last Clinical Dementia Rating Sum of Boxes (CDR-SB) assessment was estimated using a spatiotemporal prediction model at residential addresses. Dementia severity was measured by CDR-SB scores. Ten dementia-associated neuropathologic measures representing Alzheimer's disease, Lewy body disease, limbic-predominant age-related TDP-43 encephalopathy, and cerebrovascular disease were graded or staged.

In a total of 602 autopsy cases (median age at death, 78 years), higher PM2.5 exposure prior to death was associated with increased odds of more severe Alzheimer disease neuropathologic change (ADNC) (odds ratio 1.19). In a subset of 287 cases with CDR-SB records (median age at death, 79 years), higher PM2.5 exposure prior to CDR-SB assessment was associated with greater cognitive and functional impairment (β = 0.48). Lastly, 63% of the association between higher PM2.5 exposure and greater cognitive and functional impairment was statistically mediated by ADNC (β = 0.30).

Link: https://doi.org/10.1001/jamaneurol.2025.3316

While the first blood-based assays are entering use for the early detection and diagnosis of Alzheimer's disease, they remain expensive and are so far employed for only a limited number of patients. More work is needed to identify associations between circulating factors and disease progression, in order to produce better combinations of biomarker assays that can be more widely deployed at a lower cost. Thus expect to see more research along the lines of the paper noted here, in which the association between loss of cognitive function and circulating levels of some of the better known biomarkers are more carefully studied in a given population.

Subjective cognitive decline (SCD) may be an early indicator of Alzheimer disease and related dementias (ADRD), yet its association with plasma biomarkers remains unclear among middle-aged and older adults. his cross-sectional study used survey-weighted data from the Study of Latinos-Investigation of Neurocognitive Aging, an ancillary study of the Hispanic Community Health Study/Study of Latinos. Participants were aged 50 to 86 years and resided in 4 major US cities. Data were collected from 2016 to 2018 and analyzed between December 2024 and June 2025.

Plasma biomarkers included amyloid-beta (Aβ42/Aβ40), phosphorylated tau-181 (ptau-181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). SCD was assessed using the short-form Everyday Cognition Scale (ECog-12), evaluating global-, executive-, and memory-related SCD, and a single-item cognitive concerns question.

Among 5,712 adults (mean age 63.47 years), higher ln(ptau-181) was associated with ECog-12 memory (unstandardized β = 0.088). Higher ln(NfL) levels were associated with greater ECog-12 global (unstandardized β = 0.169), executive (unstandardized β = 0.182), and memory (unstandardized β = 0.156) domains. Higher ln(GFAP) levels were associated with greater ECog-12 global (unstandardized β = 0.109) and executive (unstandardized β = 0.121) domains. Ln(Aβ42/40) was not associated with SCD domains. Cognitive concerns significantly modified the associations between ln(NfL) and ECog-12 domains, with more pronounced associations among those reporting cognitive concerns. These findings underscore the potential utility of p-tau181, NfL, and GFAP, but not Aβ42/40, in early ADRD detection strategies.

Link: https://doi.org/10.1001/jamanetworkopen.2025.31038

Senescent cells accumulate with age in tissues throughout the body, primarily when a cell reaches the Hayflick limit on replication, but also because of damage or stress. When a cell becomes senescent it ceases to replicate and undergoes profound metabolic changes that cause it to secrete a pro-inflammatory, pro-growth set of signals known as the senescence-associated secretory phenotype (SASP). This serves a useful purpose in the context of potentially cancerous cells, attracting the immune system to destroy them, and aids in regeneration from injury. In youth, senescent cells are efficiently destroyed by the immune system, but with advancing age this clearance slows down. A growing imbalance between creation and destruction allows senescent cells to accumulate, and the inflammatory signaling that is useful in the short term becomes increasingly harmful when sustained for the long term.

One of the possible approaches to the treatment of aging is to destroy senescent cells. While appearing to be beneficial in mice, extending life span and reversing age-related dysfunction in many studies, there are some concerns that removing senescent cells could cause harm in some contexts. For example if senescent cells are supporting the structure of a sizable atherosclerotic plaque then clearing them could increase the risk of plaque rupture and a consequent heart attack or stroke. While not yet supported by a sizable body of evidence, this viewpoint has led a number of research teams to search for ways to reduce the SASP rather than destroy senescent cells. If a senescent cell just sat there and did not signal, then its contribution to degenerative aging would be largely eliminated. One might look at the senescent cells in long-lived naked mole-rats, for example, as they exhibit an attenuated SASP and do not appear to contribute to aging in way that senescent cells do in mice.

Thus one sees papers like today's open access research materials, in which researchers dig into the fine details of the mechanisms by which the senescent state triggers inflammatory signaling. Researchers are looking for potential targets for therapies that could interfere in the generation of the SASP without causing meaningful side-effects in the biochemistry of non-senescent cells.

Targeting CyclinD1-CDK6 to Mitigate Senescence-Driven Inflammation and Age-Associated Functional Decline

Cellular senescence is a stable form of cell-cycle arrest triggered by stresses such as DNA damage, oncogene activation, and telomere shortening. Senescent cells accumulate with age in many tissues and contribute to chronic inflammation, tissue dysfunction, and age-related pathologies through secretion of pro-inflammatory cytokines, chemokines, and interferon-stimulated genes (ISGs), collectively termed the senescence-associated secretory phenotype (SASP). Persistent DNA damage signaling in senescent cells promotes the formation of cytoplasmic chromatin fragments (CCFs) and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which sustains SASP and systemic inflammation. Identifying the molecular drivers that maintain this chronic inflammatory state is essential for understanding and targeting age-related dysfunction.

Cyclin D1 (CCND1), classically defined as a regulator of G1 progression through activation of CDK4/CDK6 and phosphorylation of the retinoblastoma protein (pRB), is paradoxically elevated in senescence despite proliferative arrest. The functional significance of CCND1 upregulation in non-proliferating, senescent cells remain unclear. Moreover, whether CCND1's unconventional accumulation contributes causally to persistent DNA damage signaling, cytoplasmic chromatin stress, or inflammatory gene expression has not been explored.

Here, we investigate the role of CCND1 and its associated kinase CDK6 in sustaining DNA damage, cytosolic chromatin accumulation, and inflammatory signaling in senescence. Using complementary in vitro and in vivo models, we reveal an essential role for the CCND1-CDK6 complex in promoting persistent DNA damage, CCF formation, and cGAS-STING-driven inflammation. Mechanistically, we identify previously unrecognized interactions between CCND1 and chromatin-associated kinesin proteins, such as KIF4A, which has been implicated in chromatin architecture and DNA repair. Finally, we show that genetic ablation of CCND1 in aged hepatocytes or pharmacological inhibition of CDK4/6 significantly attenuates chronic inflammatory signaling and ameliorates age-associated functional decline, suggesting broad therapeutic implications.

The category of glial cells covers all of the supporting cells of the brain, everything not a neuron, a big tent that includes immune cells such as microglia, the oligodendrocytes that manufacture myelin sheathing for axons, and the sizable astrocyte population, among others. These are very different cell populations with very different functions and behaviors, but all become dysfunctional with age. The present consensus is that glial cell dysfunction is important in aging and neurodegenerative conditions, each population contributing to loss of cognitive function in various ways. Given the size of the topic and the complexity of the brain, a review such as this one can really only skate the surface, however, even when focusing on only one region of the brain.

Among brain regions, the cerebellum (CBL) has traditionally been associated with motor control. However, increasing evidence from connectomics and functional imaging has expanded this view, revealing its involvement in a wide range of cognitive and integrative processes. Despite this emerging relevance, the CBL has received comparatively less attention in aging research, which has focused mainly on other central nervous system (CNS) regions such as the neocortex and hippocampus.

This review synthesizes the current evidence on glial cell aging across the CNS, emphasizing how cerebellar circuits follow distinct trajectories in terms of cellular remodeling, transcriptional reprogramming, and structural vulnerability. Recent findings highlight that cerebellar astrocytes and microglia exhibit specific signatures related to aging compared to their cortical counterpart, including moderate reactivity, selective immune response, and spatial reorganization. Cerebellar white matter (WM) undergoes structural alteration, suggesting that oligodendroglial cells may undergo region-specific alterations, particularly within WM tracts, although these aspects remain underexplored.

Despite the presence of glial remodeling, the CBL maintains a notable degree of structural and functional integrity during aging. This resilience may be the result of the CBL's ability to maintain synaptic adaptability and homeostatic balance, supported by its highly organized and compartmentalized architecture. A better understanding of the dynamics of cerebellar glial cells in aging may provide new insight into the mechanisms of brain maintenance and identify potential biomarkers for healthy brain aging.

Link: https://doi.org/10.3390/ijms26157553

Mouse data has consistently shown fisetin to be senolytic, capable of selectively destroying the senescent cells that accumulate in tissues with age. Doses most often used are equivalent to around 20 mg/kg in humans, but dosing strategies range from a one-time course of treatment of a few days to intermittent doses provided over months. Unfortunately, despite planned and actually undertaken human trials of fisetin supplementation, there is still no published data of its senolytic capacity in humans. The dasatinib and quercertin combination and the locally delivered senolytic developed by UNITY Biotechnology before they ran out of funds remain the only senolytics with human data for clearance of senescent cells.

Advancing age is the strongest risk factor for cardiovascular diseases (CVDs), primarily due to progressive vascular endothelial dysfunction. Cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to age-related endothelial dysfunction by promoting mitochondrial oxidative stress and inflammation, which reduce nitric oxide (NO) bioavailability. However, the molecular changes in senescent endothelial cells and their role in endothelial dysfunction with aging remain incompletely unclear. As such, in this study we sought to identify the endothelial cell senescence-related signalling pathways, endothelial-derived SASP factors, and their impact on endothelial function with aging.

Single-cell transcriptomics was performed on aortas from young (6 months) and old (27 months) mice with and without in vivo senolytic treatment with fisetin (100 mg/kg/day administered in an intermittent dosing paradigm) to characterize endothelial cell senescence and transcript expression changes. Senescent endothelial cells exhibited elevated expression of SASP factors, particularly Cxcl12, which was reversed by fisetin supplementation, with responses also reflected in circulating CXCL12 concentrations. Plasma from old mice impaired endothelial function by inducing vascular cell senescence, reducing NO, increasing mitochondrial oxidative stress, and promoting endothelial-to-mesenchymal transition-effects partially driven by CXCL12 and prevented by fisetin.

Link: https://doi.org/10.1101/2025.08.13.670216

It is difficult to overstate the importance of immune system dysfunction as a component of degenerative aging. All of the common fatal age-related diseases are strongly connected to immune dysfunctions, particularly the chronic inflammation that occurs with age. At the high level, researchers tend to divide immune aging into two components: immunosenescence is a loss of the ability of the immune system to defend against pathogens and destroy unwanted cells; inflammaging is a state of continual, unresolved inflammatory signaling, a maladaptive reaction to the altered environment and molecular damage of aged tissues. Both immunosenescence and inflammaging are just different viewpoints into one very complex bundle of dysfunctional mechanisms, signals, behaviors, and cell populations, however. One does not occur without the other, because they both arise from the same underlying issues.

Identifying the underlying issues that give rise to immune aging is an important part of building therapies to reverse the dysfunction. Some areas of focus are more promising than others. For example, attempts to fairly bluntly manipulate the signaling environment to suppress inflammation by inhibiting specific circulating proteins or their interactions with receptors are favored by the research and development communities, even though these approaches also suppress necessary inflammatory signaling and thereby inhibit the effectiveness of the immune system. Better approaches include restoration of hematopoietic stem cell function in bone marrow, regrowth of the thymus, and adjustment of the gut microbiome, where in principle there will be much less in the way of unpleasant trade-offs between benefit and side-effect.

Targeting immunosenescence and inflammaging: advancing longevity research

Aging profoundly affects the immune system, leading to two interrelated phenomena: immunosenescence and inflammaging. Immunosenescence is characterized by the immune system's functional decline, reduced immune surveillance, diminished T cell diversity and a weakened response to new infections and vaccinations. Inflammaging, on the other hand, refers to chronic, low-grade inflammation driven by factors such as senescent cells, damage-associated molecular patterns, and alterations in the gut microbiome. Together, these processes accelerate tissue degeneration, systemic dysfunction, and the development of age-related diseases while further impairing immune function.

Emerging therapeutic strategies targeting immunosenescence and inflammaging offer hope for restoring immune balance, reducing inflammation, and extending healthspan. Interventions such as thymus rejuvenation, hematopoietic stem cell modulation and senolytic therapies can potentially combat immune decline. Additionally, technologies targeting IL-11 inhibition and toll-like receptors (TLR5 or TLR7) activation have effectively reduced chronic inflammation and enhanced immune resilience. Specifically, IL-11 inhibition mitigates systemic inflammation and supports tissue regeneration, while TLR5 or TLR7 activation strengthens immune function and promotes regenerative capacity, collectively contributing to lifespan extension.

However, understanding the complexity of immunosenescence and inflammaging is critical to developing effective therapeutic interventions. While chronic inflammation is often viewed as detrimental, inflammation plays a vital role in immune defense, tissue repair, and vaccine efficacy. The challenge lies in maintaining a balance - promoting inflammation's protective effects while mitigating its chronic, maladaptive impacts during aging. Ultimately, by addressing both immune decline and chronic inflammation, these strategies can potentially transform how aging and age-related diseases are managed. Success in these endeavors could extend lifespan and meaningfully improve healthspan, ensuring healthier aging for future generations.

Cardiovascular disease correlates very well with incidence of dementia, and this is well demonstrated via analysis of epidemiological data in papers such as the one noted here. Disruption of the flow of blood to the brain is a possible causal mechanism, but one can also consider that both classes of condition are driven by the same underlying processes, such as chronic inflammation. More generally, aspects of aging correlate because aging is an accumulation of damage throughout the body and damaged systems tend to become dysfunctional and fail. The correlation between cardiovascular disease and dementia is strong enough, however, to suggest an additional bidirectional relationship of direct causation.

Cardiovascular disease (CVD) and dementia represent two of the most pressing global health challenges, particularly in low- and middle-income countries. While vascular pathology is increasingly recognized as a contributor to cognitive decline, few studies have systematically explored the global association between CVD and dementia using standardized, population-level data. This study aimed to investigate the relationship between CVD and dementia incidence across 204 countries, stratified by economic status, development level, and geographic region.

Age-standardized incidence rates for cardiovascular disease (CVD) and dementia in 2021 were sourced from the Global Burden of Disease Study. Globally, CVD incidence was significantly associated with dementia incidence (Pearson r = 0.777; Spearman ρ = 0.868). CVD explained approximately 43.0% of the variance in dementia incidence at the population level (r^2 = 0.4303), even after adjusting for key confounders. The association was notably stronger in low- and middle-income countries and developing regions. Among CVD subtypes, peripheral arterial disease (β = 0.903), cardiomyopathy (β = 0.869), and atrial fibrillation (β = 0.708) demonstrated the strongest independent associations with dementia incidence.

Link: https://doi.org/10.1002/hsr2.71179

Losing weight improves health outcomes. To put it another way, carrying excess visceral fat tissue causes ongoing harm via a range of mechanisms connected to the disrupted, inflammatory metabolism it induces. Thus a growing number of studies demonstrate that weight loss achieved through GLP-1 receptor agonist use improves outcomes in the presently largely overweight populations of the wealthier regions of the world. It is always possible that GLP1-1 receptor agonist drugs have other effects that are meaningful along the way, but losing weight is so influential on health that very robust data would have to be presented to be convincing that non-weight-loss effects are important in the context of overweight individuals.

Heart failure with preserved ejection fraction (HFpEF) is a major cause of hospitalization, often occurring in patients with cardiometabolic comorbidities such as obesity and type 2 diabetes. Although early trials of semaglutide and tirzepatide have shown promising results in improving symptoms, those findings were based on few clinical events, leaving treatment recommendations uncertain.

To evaluate the effectiveness and safety of semaglutide and tirzepatide in patients with cardiometabolic HFpEF in clinical practice, five cohort studies were assessed using national US health care claims data from 2018 to 2024. Two cohort studies emulated the STEP-HFpEF DM (semaglutide) and SUMMIT (tirzepatide) trials to benchmark results. Eligibility criteria were then expanded to evaluate treatment effects in patients typically treated in clinical practice. Finally, a head-to-head comparison of tirzepatide and semaglutide was implemented. Follow-up was up to 52 weeks.

The primary end point was a composite of hospitalization for heart failure or all-cause mortality. In analyses using expanded eligibility criteria, 58,333 patients were included in the semaglutide vs sitagliptin cohort, 11,257 for tirzepatide vs sitagliptin, and 28,100 for tirzepatide vs semaglutide. Initiators of semaglutide (hazard ratio, HR, 0.58) and tirzepatide (HR, 0.42) had substantially lower risk of the primary end point compared with sitagliptin. Tirzepatide had no meaningfully lowered risk compared with semaglutide (HR, 0.86).

Link: https://doi.org/10.1001/jama.2025.14092

Cognitive function can be measured in many different ways. It is generally considered to consist of a number of different domains that are influenced by different aspects of brain physiology and biochemistry, and which can improve and decline to different degrees over the course of a lifetime. We should expect the various forms of memory, executive function, sensory processing, and cognitive control to be capable of differing in trajectories as degenerative aging progresses, for example. Indeed, studies show this to be the case. While the story of aging writ large is a story of decline, the details have considerable latitude to vary.

The brain develops, and then the brain declines. There is thus a peak of cognitive function, distributed across some range of chronological ages for a given population. The location of that peak will likely vary for the different domains of cognitive function in any specific study population for the reasons given above. Here, researchers show that cognitive control peaks relatively early in adult life, at least relative to the usual perceptions of the character of growing old. As matters actually progress, a person may be sharply intelligent in their late 20s, then not so sharp but a great deal more experienced in their late 40s. A part of that loss of sharpness is a decline in cognitive control.

When does our brain start getting 'old'? Charting the lifespan trajectories of cognitive control

Cognitive control refers to the cognitive process through which individuals regulate attention, thought, and action to achieve specific goals, allowing them to focus on objectives while excluding distractions. For example, maintaining concentration on reading in a library where people are conversing relies heavily on the cognitive control's regulation of attention. Although the patterns of cognitive and behavioral changes related to cognitive control have been well established and serve as diagnostic criteria for development-related and aging-related diseases, systematic research on the corresponding brain activities' changes with age remains limited.

This study collected 139 neuroimaging studies related to cognitive conflict tasks, encompassing 3,765 participants aged 5 to 85 years. Through systematic meta-analysis using seed-based effect size mapping (SDM), generalized additive models (GAM), and model comparison methods, researchers were able to construct the lifespan trajectory of brain activities associated with cognitive control for the first time. The core finding revealed a significant inverted U-shaped lifespan developmental trajectory, where brain activity gradually increases during childhood and adolescence, peaks during adulthood, and slowly declines in later life. The GAM-fitted peak age was found to be between 27 and 36 years.

This period coincides with the peak of individual intellectual maturity and overall cognitive ability, providing a scientific explanation for the high social productivity and creativity exhibited by humans during this phase from a neural mechanism perspective. Notably, the gradual decline in brain function following this peak period suggests the need to prioritize the maintenance and exercise of brain function during middle adulthood to mitigate potential cognitive decline associated with aging.

The lifespan trajectories of brain activities related to conflict-driven cognitive control

Cognitive control is fundamental to human goal-directed behavior. Understanding its trajectory across the lifespan is crucial for optimizing cognitive function throughout life, particularly during periods of rapid development and decline. While existing studies have revealed an inverted U-shaped trajectory of cognitive control in both behavioral and anatomical domains, the age-related changes in functional brain activities remain poorly understood.

To bridge this gap, we conducted a comprehensive meta-analysis of 139 neuroimaging studies using conflict tasks, encompassing 3765 participants aged 5 to 85 years. We adopted the seed-based d mapping (SDM), generalized additive model (GAM), and model comparison approaches to investigate age-related changes in brain activities to characterize the lifespan trajectories of cognitive control. Our analyses revealed two key findings: (1) The predominant lifespan trajectory is inverted U-shaped, rising from childhood to peak in young adulthood (between 27 and 36 years) before declining in later adulthood; (2) Both the youth and the elderly show weaker brain activities and greater left laterality than young adults. These results collectively reveal the lifespan trajectories of cognitive control, highlighting systematic fluctuations in brain activities with age.

Researchers here describe an interesting approach to redirecting the immune system to destroy unwanted cells. The membranes of dead cells are distinctively marked and immune cells contain machinery to recognize those marks. This is an important part of the way in which immune cells are directed to engulf and destroy dead cells and cell debris, helping to keep tissue functional. If immune cells are equipped instead with an altered, engineered sensor mechanism, then in principle their well-established behavior of engulfing and destroying dead cells could be repurposed to attack any specific target live cell population. This has applications to many conditions of aging, as researchers have identified many errant, malfunctioning cell populations that contribute to age-related disease and dysfunction. Efficient and safe ways to remove these cells will provide the basis for an important class of future therapies.

During the process of engulfment, phosphatidylserine is exposed on the surface of dead cells as an 'eat-me' signal and is recognized by Protein S (ProS), a secreted factor that also binds to the Mer tyrosine kinase (MerTK) on phagocytes. Despite its robust activity, this engulfment mechanism has not been exploited for therapeutic purposes. Here we develop a synthetic protein modality called Crunch (connector for removal of unwanted cell habitat) by modifying ProS, inspired by the high engulfment capability of the ProS-MerTK pathway.

In Crunch, the phosphatidylserine-binding motif of ProS is replaced with a nanobody or single-chain variable fragment that recognizes the surface proteins of targeted cells. Green fluorescent protein nanobody-conjugated Crunch eliminates green fluorescent protein-expressing melanoma cells in transplantation mouse models. In addition, CD19+ B cells are eliminated by anti-CD19 single-chain variable fragment-conjugated Crunch, resulting in a therapeutic effect on systemic lupus erythematosus. Both mouse and human versions of Crunch are effective, establishing this synthetic ligand as a promising tool for the elimination of targeted cells.

Link: https://doi.org/10.1038/s41551-025-01483-9

The low cost of omics tools combined with the ability to distinguish the behavior of individual cells from a tissue sample allows for the creation of ever larger databases of epigenetic and transcriptional profiles of the aging brain. Creating these databases is one thing, and the results are of great interest, but comparatively little progress has been made on the leap from a mass of data describing how an aged brain differs from a young brain to an understanding of cause and effect in those observed changes. That understanding is necessary in order to build effective therapies, but establishing it is also the hard part of the problem.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, yet its epigenetic underpinnings remain elusive. Here, we generate and integrate single-cell epigenomic and transcriptomic profiles of 3.5 million cells from 384 postmortem brain samples across 6 regions in 111 AD and control individuals.

We identify over 1 million candidate cis-regulatory elements (cCREs), organized into 123 regulatory modules across 67 cell subtypes. We define large-scale epigenomic compartments and single-cell epigenomic information and delineate their dynamics in AD, revealing widespread epigenome relaxation and brain-region-specific and cell-type-specific epigenomic erosion signatures during AD progression. These epigenomic stability dynamics are closely associated with cell-type proportion changes, glial cell-state transitions, and coordinated epigenomic and transcriptomic dysregulation linked to AD pathology, cognitive impairment, and cognitive resilience.

This study provides critical insights into AD progression and cognitive resilience, presenting a comprehensive single-cell multiomic atlas to advance the understanding of AD.

Link: https://doi.org/10.1016/j.cell.2025.06.031

Alzheimer's disease is a slow progression over time and lost cognitive function, but it does kill people in the end. How exactly does the pathology of Alzheimer's disease cause the widespread death of neurons that is characteristic of the late stages of the condition and the eventual cause of death? There are many ways of building an answer to this question, as one can focus on many different parts of the chain of cause and consequence that must exist in the less well studied spaces that exist between the more well studied aspects of Alzheimer's biochemistry. On the one hand protein aggregation of amyloid-β and tau, and on the other hand disrupted metabolism and cell death in neurons, and in between a great deal of dark matter.

In today's open access paper, researchers focus on a mechanism that is closer to neuronal cell death in the chain of cause and effect than is the case for protein aggregation. Two receptors on the cell surface of neurons combine in the context of other Alzheimer's disease cellular dysfunction to cause cell death via a range of severe downstream consequences. The researchers found a way to specifically interfere in the interaction between these two receptors, a necessary approach to therapy, as both are individually essential to cell function and thus cannot be depleted. This interference appears to slow the pathology of Alzheimer's disease in a mouse model of the condition. Interestingly, it has also shown promise in other neurodegenerative conditions, such as in models of ALS.

The NMDAR/TRPM4 death complex is a major promoter of disease progression in the 5xFAD mouse model of Alzheimer's disease

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by cognitive decline and neuronal degeneration. The formation of amyloid β plaques and neurofibrillary tangles are key morphological features of AD pathology. However, the specific molecules responsible for the cell destruction triggered by amyloid β and tau proteinopathies in AD has not yet been identified.

Here we use the 5xFAD mouse model of AD to investigate the role of a recently discovered death signaling complex which consists of the extrasynaptic N-methyl-D-aspartate receptor (NMDAR) and the transient receptor potential cation channel subfamily M member 4 (TRPM4). The NMDAR/TRPM4 death complex is responsible for toxic signaling of glutamate, which has been implicated in AD pathogenesis. We detected an increase in NMDAR/TRPM4 death complex formation in the brains of 5xFAD mice. This increase was blocked by the oral application of FP802, a small molecule TwinF interface inhibitor that can disrupt and thereby detoxify the NMDAR/TRPM4 death complex.

FP802 treatment prevented the cognitive decline of 5xFAD mice assessed using a series of memory tasks. It also preserved the structural complexity of dendrites, prevented the loss of synapses, reduced amyloid β plaque formation, and protected against pathological alterations of mitochondria. These results identify the NMDAR/TRPM4 death complex as a major promoter of AD disease progression, amplifying potentially self-perpetuating pathological processes initiated by amyloid β. TwinF interface inhibitors offer a novel therapeutic avenue, serving as an alternative or complementary treatment to antibody-mediated clearing of amyloid β from AD brains.

Why do some applications of electric fields appear to enhance regeneration from injury? The study of the effects of electromagnetism on cell behavior lags far behind the study of biochemistry, the effects of proteins and small molecules. Here, researchers provide evidence for electrical stimulation to be able to shift macrophage cells into a more pro-regenerative state. Macrophages are innate immune cells resident in tissue that conduct a wide range of tasks relating to defense against pathogens, destruction of harmful cells, and coordination of tissue maintenance. Macrophages adopt packages of behaviors dependent on circumstances; the most prominent model for describing those behaviors is the distinction between M1 macrophages (aggressive, inflammatory) and M2 macrophages (regenerative, anti-inflammatory). A fair amount of research effort has been directed towards ways to encourage macrophages to adopt a specific desired state in order to treat disease, particularly inflammatory disease.

Modulation of the immune response, in particular innate immune cells such as macrophages, has emerged as a promising strategy to combat degenerative disease and promote effective tissue repair. Electrical stimulation has the potential to regulate cell function during wound healing and regeneration; however, studies to date regarding the effects of electrical stimulation on macrophages remain limited, particularly regarding primary human cells.

Here, we demonstrate that electrical stimulation exhibits an immunomodulatory effect on primary human macrophages, promoting an anti-inflammatory pro-regenerative phenotype, accompanied by decreased inflammatory macrophage marker expression and enhanced expression of angiogenic genes. Furthermore, we highlight the ability of electrically stimulated macrophages to promote angiogenic tube formation in human umbilical vein endothelial cells (HUVECs), as well as mesenchymal stem cell (MSC) migration in a wound scratch model. Collectively, these findings endorse electrical stimulation as a viable therapeutic strategy for the modulation of macrophages across multiple injury and defense microenvironments.

Link: https://doi.org/10.1016/j.xcrp.2025.102795

The research here is notable for having progressed as far as a non-human primate study, as the conventional wisdom is that delivery of bacterial genes into mammals via forms of gene therapy is a bad idea because of the potential for immunogenic reactions. It is hard to find funding for any such project, and almost impossible for it to progress far along the path of development in a biotech company. Investors are more skeptical than regulators and will be very wary even given good data. Nonetheless, this is an interesting project, even if it is a little far on the compensatory side of the house: it is better to aim at prevention of heart attacks than to aim at helping the survivors be less impacted.

Current clinical therapies for myocardial infarction (MI) and sudden cardiac death show limited efficacy. The ability to enhance amplitudes of peak sodium (Na+) current and calcium (Ca2+) transient in cardiomyocytes could uniquely prevent arrhythmias and improve the contractile function of infarcted hearts. Previously, we leveraged the small size of engineered prokaryotic voltage-gated Na+ channels (BacNav, <1 kb) to overcome the adeno-associated virus (AAV) size constraint on delivered sequences and demonstrated that BacNav expression can directly enhance cardiac excitability. Here, we investigated whether cardiomyocyte-specific BacNav expression can provide both antiarrhythmic and inotropic benefits to the injured heart.

Encouraged by the in vitro results, we tested therapeutic efficacy of BacNav delivery in a Cynomolgus macaque model of ischemia-reperfusion (I/R)-induced MI. On the I/R injury, 10^12 vector genome/kg self-complementary AAV9-MHCK7-BacNav-HA (human influenza hemagglutinin tag) or self-complementary AAV9-MHCK7-GFP (green fluorescent protein) virus was injected intramyocardially in and around the infarct. Sham-surgery animals served as control. Immunostaining for HA tag fused to BacNav 4 weeks post-AAV injection demonstrated robust transgene expression around the infarction site, with successful targeting of BacNav channels to the T-tubular sarcolemma.

Longitudinal monitoring of cardiac contractile function by transthoracic echocardiography (ECG) revealed that at 1 week post-MI, left ventricular ejection fraction was similarly decreased in BacNav- and GFP-treated animals compared with sham-injury controls. By 4 weeks post-MI, GFP-treated but not BacNav-treated animals showed further decrease in left ventricular ejection fraction and increase in left ventricular end-systolic volume, with BacNav 4-week values not being significantly different from sham animals. Simultaneously, left ventricular end-diastolic volume did not differ across groups or time points suggesting that AAV-mediated, cardiomyocyte-specific BacNav expression directly counteracted an MI-induced contractile deficit.

We also implanted loop recorders at the time of MI induction and analyzed occurrence of spontaneous arrhythmias from recorded ECG traces during the 4-week follow-up. All 6 animals in the GFP group developed arrhythmic events, whereas only 1 animal in the BacNav group and 2 animals in the sham group exhibited arrhythmias.

Link: https://doi.org/10.1161/CIRCRESAHA.125.326570

The biggest challenge facing the deployment of gene therapies for the treatment of aging and age-related disease is that delivery systems are lacking. There is no well established way to safely and robustly deliver a payload of sufficient size to most organs (or all organs) without multiple direct injections, an approach that bears an unacceptable risk when deployed across very large numbers of relatively healthy people. When delivering a gene therapy via intravenous injection, the bloodstream carries most of the payload to the liver and lungs, and this limits the amount of drug that can be introduced to any given other organ because delivery systems are toxic at higher doses. The amount that ends up in the liver dramatically limits what can be done.

A connected issue is that the options for selective expression of a transgene by tissue type are also limited. Selective expression requires introducing a transgene and an associated promoter structure either into the genome or as a plasmid into the cell nucleus; the promoter structure can usually be cleverly tailored to condition expression of the transgene to the desired cell type. The well-trodden options for vectors today are (a) viral vectors and (b) various forms of lipid nanoparticles (LNPs) delivering messenger RNA (mRNA). Viral vectors have the issue noted in the first paragraph above: while you can specify expression by cell type by tailoring the payload of the virus, if one wants sufficient amount of vector to be delivered to a specific tissue, one either risks toxicity in the liver and lungs or undertakes direct injection. LNP-mRNA vectors have two issues: firstly that selective delivery is only well solved for the liver, and secondly that mRNA cannot perform selective expression. It will express in every cell delivered to.

People are working on these problems. One of the most promising near future advances, generally agreed upon to be possible in principle, would be some form of viral vector or LNP delivering DNA plasmids rather than mRNA that more smoothly distributes to the whole body following intravenous injection. No vast buildup of vector inside liver cells or lung cells with minimal delivery to smaller organs, but a distribution that is closer to being even. In the case of LNP-DNA therapies, this hypothetical improvement would also require a novel technology to allow DNA plasmids to safely and effectively enter the cell nucleus. Clearly this also is possible in principle, as it is exactly what an adeno-associated virus (AAV) does. But engineering one of the existing widely used DNA plasmid structures to do this once dropped into the cell cytosol via uptake of an LNP remains an unsolved problem.

Today's open access paper from the Entos Pharmaceuticals team reports on their progress towards a better LNP, one that is very much less toxic than present standards, and delivers more smoothly throughout the body. To the degree that an LNP has very low toxicity, one can accept more of an excess delivery to the liver, provided that one is delivering DNA plasmids that will only express the transgene in the desired organ. Promisingly, the work reported here is relevant to both mRNA and DNA delivery. Specific optimizations of LNP composition and manufacture will differ between delivery of mRNA and DNA, but the general strategy should work in both cases.

Safe and effective in vivo delivery of DNA and RNA using proteolipid vehicles

Non-viral delivery vehicles such as lipid nanoparticles (LNPs) have been widely used for RNA-based therapeutic approaches and have cost, manufacturing, and immunogenicity advantages over viral vectors. The approval of patisiran (Onpattro) as a systemic therapy and the more recent success of LNP mRNA COVID-19 vaccines has set the stage for the development of numerous LNP-based nucleic acid therapies. LNPs are formulated with ionizable lipids, which facilitate endosomal escape. However, formulations containing ionizable lipids are also associated with tolerability challenges such as potentiation of apoptotic cell death and dose-limiting liver toxicity following systemic delivery.

Given the strengths and limitations of current viral and non-viral approaches, we developed a proteolipid vehicle (PLV) platform that incorporates an engineered viral fusion protein into a lipid-based formulation to achieve intracellular delivery of nucleic acid cargoes with low immunogenicity and high tolerability. The PLV platform utilizes fusion-associated small transmembrane (FAST) proteins derived from the non-enveloped fusogenic orthoreovirus. At 100-200 residues in length, FAST proteins are the smallest known viral fusogens. These fusion proteins are expressed inside virus-infected cells and are trafficked to the plasma membrane where they facilitate cell-cell membrane fusion, generating multinucleated syncytia to facilitate viral transmission. FAST proteins function at physiological pH and do not require specific cell receptors, allowing them to fuse almost all cell types.

We previously showed in proof-of-concept experiments that FAST protein-containing liposomes induce liposome-cell fusion and facilitate intracellular delivery of encapsulated membrane-impermeable cargo. Here, we evaluated a panel of chimeric FAST protein constructs for fusion activity to identify a high-activity FAST protein chimera that was formulated into a PLV comprised of well-tolerated lipids. We demonstrate that FAST-PLVs comprise a nucleic acid delivery platform that mediates effective delivery and expression of encapsulated mRNA and DNA in vitro and in vivo, while maintaining excellent tolerability, low immunogenicity, and favorable biodistribution in rodent and non-human primate (NHP) models.

Systemically administered FAST-PLVs showed broad biodistribution and effective mRNA and DNA delivery in mouse and non-human primate models. FAST-PLVs show low immunogenicity and maintain activity upon repeat dosing. Systemic administration of follistatin DNA gene therapy with FAST-PLVs raised circulating follistatin levels and significantly increased muscle mass and grip strength. These results demonstrate the promising potential of FAST-PLVs for redosable gene therapies and genetic medicines.

Innate immune cells, particularly monocytes and macrophages, are important to tissue function throughout the body. Like all cell populations, they become dysfunction in various ways with advancing age. A particular issue is that these cells become more inflammatory. These cells are not present in the brain to any great degree; the brain has its own population of analogous cells called microglia. Thus it is interesting to see that delivering functional, youthful monocytes and macrophages into circulation can improve function in the aging brain. There are likely many indirect mechanisms at work beyond the question of the chronic inflammation of aging, but effects on inflammation would be the first place to look.

Young blood or plasma improves cognitive function in aged animals but has limited availability. The current study generates a subtype of young blood cells from easily expandable induced pluripotent stem cells and evaluates their effects on age- and Alzheimer's disease (AD)-associated cognitive and neural decline. In aging mice, intravenous delivery of induced mononuclear phagocytes (iMPs, including monocytes and macrophages) improves performance in hippocampus-dependent cognitive tasks, increases neural health, and reduces neuroinflammation.

Hippocampal single nucleus RNA-sequencing shows that iMPs improve the health of a subpopulation of mossy cells that are critically involved in the type of cognitive task in which iMPs improve performance, and shows that iMPs decrease the transcriptional age of several hippocampal cell types. Plasma proteomic analyses reveal that iMPs can also reverse age-associated increases in serum amyloid levels. This is verified in vitro, where iMP-conditioned media is shown to protect human microglia against cell death induced by serum amyloids. Finally, iMPs improve cognition in both young and aging 5×FAD mice, highlighting their potential as a prevention as well as an intervention strategy.

Together, these findings suggest that iMPs provide a novel therapeutic strategy to target both age- and AD-related cognitive decline.

Link: https://doi.org/10.1002/advs.202417848

You might recall that one of the approaches to emerge from considerations of the differences between old blood and young blood, and why connecting the circulatory systems of an old mouse and a young mouse produces some modest degree of rejuvenation in the old mouse, is to combine a reduction in circulating TGF-β with an increase in circulating oxytocin. This is under development as a potential form of therapy, and along the way researchers are accumulating animal study data. Here find the results of a recent study in frail, aged mice that shows an interestingly large difference in the outcome for male mice versus female mice.

Important studies report acute rejuvenation of mammalian cells and tissues by blood heterochronicity, old plasma dilution, defined factors, and partial reprogramming. And extension of rodent lifespan via single-prong methods was tried in recent years. Here, we examined whether simultaneous calibration of pathways that change with aging in opposite directions would be more effective in increasing healthspan and lifespan. Moreover, we started with the challenging age group - frail 25-months-old mice that are equivalent to ~75-year-old people.

We used an Alk5 inhibitor (A5i) of the age-elevated, pro-fibrotic transforming growth factor-beta (TGF-β) pathway that regulates inflammatory factors, including IL-11, and oxytocin (OT) that is diminished with age and controls tissue homeostasis via G-protein-coupled receptor and ERK signaling. Treatment of old frail male mice with OT+A5i resulted in a remarkable 73% life extension from that time, and a 14% increase in the overall median lifespan. Further, these animals had significantly increased healthspan, with improved physical performance, endurance, short term memory, and resilience to mortality. Intriguingly, these benefits manifested only in the male and not in the female mice, yet OT+A5i had positive effects on fertility of middle-aged female mice.

Mechanistically, metabolic proteomics on the blood serum demonstrated that the acute, 7-day, treatment of the old mice with OT+A5i youthfully restored systemic signaling determinants and reduced protein noise in old mice of both sexes. However, after 4 months of OT+A5i, only old male, but not female, mice remained responsive, showing the youthful normalization of systemic proteome. These findings establish the significant health-span extension capacity of OT+A5i and emphasize the differences in aging and in response to longevity therapeutics between the sexes.

Link: https://doi.org/10.18632/aging.206304

Researchers have developed many aging clocks in recent years. Machine learning techniques are applied to large sets of biological data assessed at various ages in order to identify algorithms that predict chronological age, mortality risk, disease risk, or other measures of interest. If an individual has a predicted age higher than chronological age, this is known as accelerated biological age. A major challenge facing the use of clocks at present is that most clocks are inscrutable, in the sense that little to nothing is known of how the individual values making up the clock algorithm are linked to specific underlying mechanisms of aging or specific outcomes of age-related dysfunction and disease.

One path to making this situation better is to run as many clocks as possible in as many human studies as possible: accumulate as much data as possible and see what emerges from that data. Thus we should expect to see many publications that are similar to today's open access paper in the years ahead, in which researchers apply one or more clocks to a specific study and health context. Here, the context is age-related cognitive decline, assessed in a test conducted seven years after the collection of initial clock data. As we might expect for a good clock, accelerated biological age correlated with a greater loss of cognitive function.

Association of DNA methylation age acceleration with digital clock drawing test performance: the Framingham Heart Study

Neuropsychological (NP) tests are typically used to measure cognitive functions for individuals, focusing on one or several specific cognitive domains. For example, the long-used Clock Drawing Test (CDT) evaluates executive functioning and spatial skills. The digital Clock Drawing Test (dCDT), a digital version of the standardized CDT done with pen and paper, provides a much more robust assessment of cognitive functioning. We used linear mixed regression to evaluate the associations between epigenetic aging metrics (Horvath, Hannum, GrimAge, PhenoAge, DunedinPACE) and digital Clock Drawing Test (dCDT) scores in the Framingham Heart Study (FHS), adjusting for covariates.

Among the 1,789 FHS participants (mean age 65 ± 13, 53% women), higher epigenetic age acceleration metrics at baseline predicted lower dCDT scores approximately seven years later. The magnitude of these associations was greater in older participants (≥65 years, n = 985). The strongest association was observed between the dCDT total score and DunedinPACE in the full sample (beta = -2.1), the younger (<65 years; beta = -1.9), and older (beta = -2.2) age groups. Additionally, the dCDT total score was associated with age acceleration estimated by Horvath (beta = -1.9) and PhenoAge (beta = -2.5) in older participants, while not in the full sample or younger participants. Furthermore, higher levels of DNAm-based PAI1 (beta = -0.9) and ADM (beta = -2.9), components of GrimAge, were significantly associated with lower dCDT total scores. In analyses of cognitive subdomains, simple motor function was significantly associated with DunedinPACEin both age groups, and with GrimAge in the older age group, suggesting that deterioration in various organ systems may particularly impact this domain.

Our findings suggest that advanced biological aging, particularly as captured by DunedinPACE and GrimAge components, is significantly associated with poorer cognitive performance measured by dCDT, especially in older adults, highlighting a potential link between systemic aging processes and cognitive decline.

Researchers here analyze human genetic variants in the IL-6 gene to show that reduced IL-6 activity correlates with a lower risk of cardiovascular disease. Circulating IL-6 is generally thought of as a pro-inflammatory signal, and it is a target for the development of therapies. Chronic inflammation in later life is an important contribution to dysfunction and disease, and better control over this maladaptive inflammatory reaction to the cell and tissue damage that characterizes aging is a desirable goal.

Human genetics supports a causal involvement of IL-6 signaling in atherosclerotic cardiovascular disease, prompting the clinical development of anti-IL-6 therapies. Genetic evidence has historically focused on the IL-6 receptor (IL6R) missense variants, but emerging cardiovascular treatments target IL-6, not its receptor, questioning the translatability of genetic findings. Here we develop a genetic instrument for IL-6 signaling downregulation comprising IL-6 locus variants that mimic the effects of the anti-IL-6 antibody ziltivekimab and use it to predict the effects of IL-6 inhibition on cardiometabolic and safety endpoints.

Similar to IL6R, we found that genetically downregulated IL-6 signaling via IL-6 perturbation is associated with lower lifetime risks of coronary artery disease, peripheral artery disease, and ischemic atherosclerotic stroke in individuals of European and East Asian ancestry. Unlike IL6R missense variants linked to bacterial infections, the IL6 instrument was associated with lower risk of pneumonia hospitalization. Our data suggest that IL-6 inhibition can reduce cardiovascular risk without major unexpected safety concerns related to the response to infection.

Link: https://doi.org/10.1038/s44161-025-00700-7

Vaccinations have been shown to produce a phenomenon called trained immunity. Effects include (a) increased responsiveness to pathogens other than the one vaccinated against, and (b) reduced chronic inflammation in later life. Trained immunity is well studied for the former phenomenon, but less well studied for the latter; questions remain as to whether different forms of vaccination for the same pathogen have different effects, for example. Correlations between later life vaccination and reduced risk of age-related disease and dysfunction have been observed, but it remains an open question as to whether this reflects trained immunity effects versus late life vaccination, a voluntary process, selecting for people who tend to take better care of their health in other ways as well.

A new global systematic literature review and meta-analysis has shown that herpes zoster vaccination, used to prevent shingles, is associated with a statistically significant lower risk of heart attack and stroke. The study found that herpes zoster vaccination, with either the recombinant herpes zoster vaccine (RZV) or the live attenuated zoster vaccine (ZVL) was associated with an 18% and 16% reduction in risk of cardiovascular events in adults 18 and 50 years or older, respectively. In studies that reported on cardiovascular event absolute risk, the absolute rate difference ranged from 1.2 to 2.2 fewer events per 1,000 person-years.

The global systematic literature review was conducted using three scientific literature databases, and a meta-analysis was conducted of phase 3 randomized controlled trials and observational studies assessing the effect of herpes zoster vaccination on cardiovascular events. 19 studies were included in the review; eight observational studies and one randomized controlled trial (a pooled safety analysis of two Phase 3 randomized trials; not designed or powered to evaluate the effects of herpes zoster vaccination against cardiovascular events), met the meta-analysis inclusion criteria for herpes zoster vaccination effectiveness on cardiovascular events. Across all nine studies, 53.3% of participants were male. Seven studies reported mean ages from 53.6 years to 74.0 years.

Link: https://www.escardio.org/The-ESC/Press-Office/Press-releases/New-systematic-review-and-meta-analysis-shows-an-association-between-shingles-vaccination-and-lower-risk-of-heart-attack-and-stroke

The gut microbiome has received a great deal of attention in recent years, spurred by the ability to accurately and cheaply assess the composition of the gut microbiome, specific species and their proportions, via 16S rRNA sequencing. Researchers have demonstrated that the composition of the gut microbiome shifts with age to favor species that generate chronic inflammation at the expense of species producing beneficial metabolites needed for tissue function. Researchers are also turning these tools to the oral microbiome, a distinct set of populations that might also contribute to aspects of aging in various ways.

In today's open access review paper, the authors make the point that the oral microbiome and gut microbiome are not entirely independent of one another. Microbes and metabolites can move between the two via a number of pathways. The paper restricts its context of age-related disease to frailty and sarcopenia, but many of the points made can equally be applied to other common age-related conditions. The chronic inflammation of aging in particular is disruptive to tissue structure and function throughout the body, an important mechanism driving the pathology of many age-related conditions.

The Oral-Gut Microbiota Axis as a Mediator of Frailty and Sarcopenia

Traditionally studied in isolation, the oral and gut microbiota are now being recognized as interconnected through anatomical and physiological pathways forming a dynamic "oral-gut microbiota axis". Both oral and gut microbiota undergo changes with aging, characterized by a decline in microbial diversity and a shift toward potentially harmful species. Interactions between oral and gut microbiota occur mainly through three pathways namely the enteral, the bloodstream and the fecal-oral routes. Alterations in the oral-gut microbiota axis contribute to chronic low-grade inflammation (i.e., "inflammaging") and mitochondrial dysfunction, key mechanisms underlying frailty and sarcopenia.

Microbial metabolites, such as short-chain fatty acids and modified bile acids, appear to play an emerging role in influencing microbial homeostasis and muscle metabolism. Furthermore, poor oral health associated with microbial dysbiosis may contribute to altered eating patterns that negatively impact gut microbiota eubiosis, further exacerbating muscle decline and the degree of frailty. Strategies aimed at modulating the microbiota, such as healthy dietary patterns with reduced consumption of ultra-processed foods, refined carbohydrates and alcohol, ensuring an adequate protein intake combined with physical exercise, as well as supplementation with prebiotics, probiotics, and omega-3 polyunsaturated fatty acids, are increasingly recognized as promising interventions to improve both oral and gut microbiota health, with beneficial effects on frailty and sarcopenia.

A better understanding of the oral-gut microbiota axis offers promising insights into nutritional interventions and therapeutic strategies for the age-related muscle decline, frailty, and systemic health maintenance.

To what degree is the neurodegeneration of Alzheimer's disease driven by reduced blood flow to brain tissue? This is as compared to the contributions of the well-studied aggregation of amyloid-β and tau proteins, or the neuroinflammation driven by senescent cells, persistent viral infection, and various forms of molecular damage in and around cells. One of the challenges inherent in investigations of aging and age-related disease is that it is very hard to determine the relative importance of the range of mechanisms likely involved in producing pathology, loss of function, and eventual mortality. Here, however, the data suggests that vascular dysfunction may indeed be more important than protein aggregation, at least in the earlier stages of Alzheimer's disease.

Instead of looking at the brain's amyloid plaques, researchers focused on the way blood flow through the brain is autoregulated in order to oxygenate the brain tissue, and whether possible dysregulation may cause cognitive impairment. The study harnessed data from 200 participants over five years, investigating the intricate dynamic relationship between natural changes in arterial blood pressure, carbon dioxide (CO2) levels in the blood, and the resulting fluctuations of cerebral blood flow and cortical tissue oxygenation. "When we exert cognitive effort, we generate CO2 from the metabolism in our cerebral cells, which obviously has to be taken away by our blood to avoid acidosis. Our body is endowed with this regulatory mechanism called vasomotor reactivity, which dilates (widens) our cerebral vessels when CO2 goes up in the blood, so that more blood can go through and the excess CO2 be washed out."

Fifteen years ago, researchers made a serendipitous observation: Alzheimer's patients show impaired vasomotor reactivity. "They cannot dilate the cerebral vessels to bring more blood in and provide adequate blood perfusion to the brain. This means they don't get the oxygen, nutrients, and glucose that we need for cognition in a timely manner." In the new study, researchers tested this observation, developing a novel marker called the Cerebrovascular Dynamics Index (CDI). This non-invasive test uses non-invasive Doppler ultrasound to measure blood flow velocity in some main arteries of the brain, and near-infrared spectroscopy to measure oxygenation in the front part of the brain's cortex. This quantifies how quickly and effectively the brain's blood supply responds to subtle changes in pressure and CO2.

The research team obtained some encouraging results - The CDI showed excellent diagnostic performance, differentiating individuals with mild cognitive impairment (MCI) or Alzheimer's from cognitively normal control subjects with an Area Under the Curve (AUC) of 0.96. AUC is a common statistical measure of diagnostic performance; a value of 1.0 is perfect, and 0.5 is random chance. For context, the amyloid PET test achieved an AUC of only 0.78, while the Montreal Cognitive Assessment (MoCA) and mini-mental state examination (MMSE) cognitive tests were 0.92 and 0.91, respectively. The difference between 0.78 and 0.96 translated to a "very substantial improvement" in the test's ability to correctly identify those with and without the condition.

Link: https://viterbischool.usc.edu/news/2025/08/brains-blood-flow-could-change-how-we-understand-and-treat-alzheimers/

Arrythmia can be a precursor of later, more severe heart issues, indicative of a level of dysfunction in heart tissue arising due to aging or other causes. It can also result from electrolyte imbalances that in turn arise from lifestyle choices. Arrythmia is generally taken as a point of concern by physicians where it occurs in older patients. Here, researchers show that a low level of fitness is independently a risk factor in the development of arrythmia, distinctly from old age. There are many other well-known reasons to maintain fitness into later life, but perhaps this finding will motivate an additional segment of the population.

New research has revealed that older age and low aerobic fitness levels are strong and independent risk factors for a high burden of heartbeat irregularities, known as arrhythmias, that indicate future cardiovascular risk. 1,151 healthy individuals aged between the ages of 40 and 65, without any heart symptoms or structural heart disease, took part in the study. The mean age of participants was 52 ± 7 years and 88% were men and 12% were female. Participants' fitness and heart health were monitored during exercise stress testing using portable and continuous electrocardiography (ECG) that records the heart's electrical activity, also known as Holter monitoring.

Researchers grouped participants by their 'median ectopy daily burden' which is the average percentage of premature or early heartbeats per day. They categorised the participants into having a low or high ectopy (irregular heartbeat) burden. They found that 32% of participants had supraventricular tachycardia, 4% had atrial fibrillation and 6% had nonsustained ventriculatachycardia - all of which are complex arrhythmias.

Analysis revealed that 'high atrial ectopic burden' was associated with older age, male sex, lower fitness levels, high blood pressure, and a measure of reduced kidney health. High ventricular ectopic burden was associated with older age and a measure of reduced kidney health - but was not related to fitness levels. Multivariable analysis confirmed that older age and lower fitness levels were strong, independent risk factors for atrial ectopy burden. The researchers found that the chance of arrhythmia increased by 9% per year for atrial and 4% per year for ventricular arrhythmia. Age-stratified analysis demonstrated a marked rise in arrhythmia prevalence starting from the 50-54 age group.

Link: https://www.escardio.org/The-ESC/Press-Office/Press-releases/Older-age-and-low-fitness-levels-are-associated-with-heartbeat-abnormalities-that-increase-future-cardiovascular-risk

The market for investment in biotechnology and pharmaceutical startup companies is tough at the best of times. Executive teams have to content with the broad valley of death that lies between enthusiasm for a company with early preclinical results in mice and enthusiasm for a company with initial human clinical data. Satisfying regulators, setting up Good Manufacturing Practice (GMP) manufacture of a drug, and producing that clinical data is exceptionally expensive, and the reality is that relatively few investors fund companies in the late preclinical stage, even when the market is good. As soon as the market sours, investors pull away from preclinical companies near entirely.

The longevity industry emerged outside the established biotechnology venture capital community, and most companies were largely funded by family offices, angel investors, and other entities that do not tend to act like venture capital. They tend to make a single investment and are done, and have somewhere between no representation or very limited representation on the company board of directors, whereas venture capital funds tend to make ongoing investments as a company moves forward, make larger investments, and do tend to have board seats. They also have much more experience in manipulating terms and contracts to their favor.

The market for biotechnology and pharmaceutical investment has not been good for several years now, for the longevity industry and everyone else. Preclinical companies with acceptably good technologies have been dying through the simple mechanism of failing to find investors willing to fund their work and consequently running out of runway. So it goes for every industry when times are bad. But even the relatively successful longevity industry companies are now being forced into very unfavorable terms by later stage professional investors in order to fund their initial clinical trials and further progress towards regulatory approval.

I am aware of a number of investment deals conducted this year by ostensibly successful longevity biotechnology and pharmaceutical companies (with clinical trials in process, with Big Pharma deals, with good results for their technologies) in which the early investors were essentially wiped out, had their stake in the company dramatically reduced. There are a number of established ways in which this can happen legally, and the structure most often seen is some variant of Pay to Play with compulsory conversion of shares and a pull-through provision. Existing stock is converted into new stock under very different terms. Early investors are asked to contribute a new investment under pro rata terms, and their stock largely eliminated (cut down by 5 to 1, 100 to 1, some other large number) if they do not do this. One viewpoint is that this is simply the realization of a loss of value that has already happened due to a poor market. Another view is that it is fair to call this theft and extortion, a very uneven distribution of that loss of value. Either way, early investors typically have no leverage in this situation, and any attempt to fight the imposed terms legally would cost more than is lost.

This squeezing out of early investors as a matter of course, whenever later stage investors can get away with it, is short-sighted, I feel. The investors who typically force such provisions on a company, and the executive teams who accept in exchange for some preservation of their stake in the company, are burning long-term relationships for short-term gain. No executive who goes along with this will ever receive early stage investment again from anyone involved in one of their Pay to Play exercises. Further, people talk. At the community level, once it becomes known that early stage biotech investors in the longevity industry are often eliminated in later rounds by predatory institutional investors, there will be little early stage investment. Who funds the preclinical work? Not the later stage investors. Where will their future deal flow come from? Who knows. This is not good for the industry, and not good for anyone involved.

Greater educational achievement is well established to correlate with greater life expectancy. It is one of a web of correlations linking longevity, intelligence, education, wealth, and socioeconomic status. Untangling the causes of these correlations remains a work in progress, and this will likely continue to be the case for the foreseeable future. Here, researchers use an aging clock based on clinical parameters to produce biological age estimates from past epidemiological study data to show how the correlation between education and biological age has changed over time. They find that educational achievement correlated with a greater slowing of biological age ten years ago than was the case thirty years ago.

It is interesting to speculate as to why this might be the case. We might start with the hypothesis that more approaches to intervention in aging, and more knowledge of those approaches, have become available over time. Equally, this could simply be a consequence of a general improvement in medicine and approaches to health, that have the side-effect of modest gains in life expectancy. Then consider that people with a greater degree of educational achievement tend to be better placed to make use of those improvements.

Educational inequality in health has been increasing in the United States. The growth in health inequality has not been limited to specific conditions but has been observed across a wide range of outcomes, including disability, multimorbidity, self-rated health, and mortality. This study used data for adults aged 50-79 from the National Health and Nutrition Examination Survey to assess changes in biological aging across education groups over a 25-year period.

We found that while biological aging slowed for each education group, educational inequality increased owing to greater improvements among those with the highest education levels. Specifically, biological age differences between adults with 0-11 years of schooling and adults with 16+ years of schooling grew from one year in 1988-1994 to almost two years in 2015-2018. Growing inequality in biological aging was not attenuated by changes in smoking, obesity, or medication use. Overall, these results point to an increasing difference in physiological dysregulation by education among U.S. older adults, which might remain a source of greater and growing inequality in morbidity, disability, and mortality in the near future.

Link: https://doi.org/10.1215/00703370-12175545

Lysosomes are recycling systems inside a cell, organelles that contain enzymes capable of breaking down proteins and cell structures into raw materials for reuse. The cell maintenance processes of autophagy are responsible for identifying proteins and structures that should be recycled and deliver them to a lysosome. Lysosomal dysfunction is a feature of aging in long-lived cells, as the lysosomes become filled with persistent metabolic waste that they struggle to break down. Enlargement of lysosomes is observed in this situation, and researchers here explore this phenomenon with an eye to find ways to manipulate lysosomal state to improve cell function.

A vacuole is a membrane-bound compartment inside cells, like a water balloon, that stores water, molecules, or waste. In plant cells, the central vacuole is large and helps store nutrients, regulate pressure and maintain structural rigidity. Animal cells don't usually have vacuoles, but they contain related compartments called lysosomes. Lysosomal vacuolation refers to a condition in which lysosomes become abnormally enlarged like overinflated balloons, resembling plant vacuoles.

Lysosomes are essential for cell health. Like a waste disposal system, they digest damaged proteins, worn-out parts, and invading microbes. By degrading a broad range of macromolecules, lysosomes preserve cellular function and longevity. Lysosomal vacuolation is thought to be an indication of stress or dysfunction of lysosomes, and these vacuoles are found in a large spectrum of medical conditions, including lysosomal storage disorders, aging, infection, chemotherapy, cataracts, cadmium toxicity, prion diseases, and other neurodegenerative conditions, such as Parkinson's and Alzheimer's disease.

"Lysosomal vacuolation has been observed in many diseases and has puzzled scientists for decades. However, we still don't know whether it is harmful or beneficial, largely because the mechanisms behind vacuole formation remain poorly understood. We found that cells have a well-developed system to drive lysosomal vacuolation. In response to many different types of stress, lysosomes become filled up with solutes, which draws in water and stretches the lysosomal membrane - like inflating a balloon. The potential risk of lysosomal rupture is detected by a protein we named LYVAC, or lysosomal vacuolator. LYVAC attaches to these stressed lysosomes, where it delivers lipids, which serve as membrane building blocks to allow lysosomal expansion in a controlled way."

"This process of lysosomal vacuolation is a natural, highly regulated response. LYVAC plays a central role in this process, helping cells adapt to stress and maintain lysosomal stability. By targeting LYVAC, we can begin to understand the exact roles that lysosomal vacuoles play in different diseases. If vacuole formation turns out to be a key driver of disease, then blocking LYVAC could offer a promising new treatment strategy."

Link: https://www.medschool.pitt.edu/news/overinflated-balloons-study-reveals-how-cellular-waste-disposal-system-deals-stress

The transport protein transthyretin is one of the few proteins in the body capable of misfolding or otherwise becoming altered in ways that allow formation of solid deposits of aggregated proteins. These aggregates and their surrounding biochemistry are toxic, a contributing cause of age-related dysfunction and disease. Transthyretin amyloidosis may be near universal in older people, but only a tiny fraction develop this form of amyloidosis to the exaggerated level required for it to be identified and diagnosed. The more likely outcome for any given individual is that amyloidosis goes undiagnosed while nonetheless contributing to, for example, cardiovascular mortality.

Thus while therapies to treat transthyretin amyloidosis now exist, regulators and industry treat it as a rare disease, focused only on very severe instances of the condition, whether or not caused by mutation. This ensures that therapies are sold at the very high prices that characterize the rare disease industry, and in turn makes it hard to take the important next step, which is to greatly expand the detection of lesser degrees of amyloidosis and more widely deploy the best of the existing treatments for the condition, those lacking severe side-effects, into the broader aged population.

Advances in the treatment of transthyretin amyloidosis

Transthyretin (TTR) is a tetrameric plasma protein primarily synthesised by hepatocytes in the liver. It plays a key role in the transport of thyroxine (T4) and retinol-binding protein bound to vitamin A. More than 220 mutations in the TTR gene have been identified, many of which are associated with hereditary forms of amyloidosis. TTR amyloidosis occurs when the TTR tetramer dissociates into monomers, which then misfold and aggregate into insoluble amyloid fibrils. These oligomers eventually aggregate into amyloid fibrils that deposit extracellularly in tissues such as the peripheral nerves, myocardium, gastrointestinal tract, kidneys and eyes. These deposits disrupt tissue architecture and function, leading to organ dysfunction and clinical symptoms. Mutations in the TTR gene destabilise the tetramer structure, accelerating the aggregation process. However, even wild type TTR can form amyloid fibrils with ageing, leading to the non-hereditary form of the disease.

Once considered rare, transthyretin amyloidosis (ATTR) is now recognised as more prevalent, largely due to improved diagnostic methods. Wild type transthyretin amyloidosis (ATTRwt) occurs sporadically and primarily affects older men. Autopsy studies reveal that over 25% of men above age 80 years have cardiac ATTR deposits, most of which go unrecognised during life. Prospective imaging studies suggest that up to 13% of patients with heart failure with preserved ejection fraction (HFpEF) and 12% of those undergoing transcatheter aortic valve replacement have cardiac ATTR. These findings highlight the extent of underdiagnosis in elderly populations with cardiac symptoms.

In recent years, substantial progress has been achieved in the treatment of ATTR, fundamentally transforming the clinical outlook for affected individuals. The introduction of TTR stabilisers, gene-silencing therapies, and emerging disease-modifying approaches - including monoclonal antibodies and CRISPR-based genome editing - has enabled a more comprehensive and multifaceted approach to disease management. These therapeutic advancements, in combination with innovations in non-invasive diagnostic techniques such as scintigraphy and advanced cardiac imaging, have significantly improved the potential for early detection, which is crucial for optimising treatment outcomes.

Despite these remarkable developments, several important challenges and unanswered questions persist. One major gap is the absence of head-to-head clinical trials comparing the efficacy and safety of different therapeutic classes. Additionally, while multiple treatment modalities are now available or in late-stage development, the optimal sequencing of therapies - or whether combination treatments may confer additive or synergistic benefits - remains unclear. Another concern is the high cost and variable accessibility of novel therapies, particularly gene-based treatments and biologics. There is a pressing need for real-world data on cost-effectiveness and long-term clinical benefit, as well as strategies to ensure equitable access across diverse healthcare settings.

You might recall past research efforts to understand whether proteins found alongside amyloid-β aggregates in the aging brain were causing pathology, and possibly causing more pathology than the amyloid-β itself. One of those proteins is midkine, and here researchers present evidence for the presence of midkine close to amyloid-β to be a protective response that in fact hinders amyloid-β aggregation.

Proteomic profiling of Alzheimer's disease (AD) brains has identified numerous understudied proteins, including midkine (MDK), that are highly upregulated and correlated with amyloid-β (Aβ) from the early disease stage but their roles in disease progression are not fully understood. Here, we present that MDK attenuates Aβ assembly and influences amyloid formation in the 5xFAD amyloidosis mouse model.

MDK protein mitigates fibril formation of both Aβ40 and Aβ42 peptides according to thioflavin T fluorescence, circular dichroism, negative-stain electron microscopy, and nuclear magnetic resonance analyses. Knockout of the Mdk gene in 5xFAD increased amyloid formation and microglial activation in the brain. Further comprehensive mass-spectrometry-based profiling of the whole proteome in these mouse models indicated significant accumulation of Aβ and Aβ-correlated proteins, along with microglial components. Thus, our structural and mouse model studies reveal a protective role of MDK in counteracting amyloid pathology in AD.

Link: https://doi.org/10.1038/s41594-025-01657-8

Continual, unresolved inflammation is a feature of all of the common age-related conditions, and particularly so in the brain. When sustained for the long-term, inflammatory signaling is disruptive to tissue structure and function, and thus contributes to dysfunction and eventual mortality. Here, researchers focus on the role of the chronic inflammation of aging in Alzheimer's disease specifically, though most of what is said can be applied to the etiology of other neurodegenerative conditions as well.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder and the most common cause of dementia. While the amyloid cascade hypothesis has long dominated AD research, emerging evidence suggests that neuroinflammation may play a more central role in disease onset and progression. Increasingly, AD is recognized as a multifactorial disorder influenced by systemic inflammation and immune dysregulation, shifting focus toward peripheral immune mechanisms as potential contributors to neurodegeneration.

This review explores the hypothesis that inflammaging, the age-related increase in pro-inflammatory mediators, combined with lifelong exposure to infections, injuries, metabolic changes, and chronic diseases, among others, may prime the immune system, amplifying neuroinflammation and influencing the progression and exacerbation of AD pathology. To this end, we examined how systemic immune disturbances, including chronic pain, post-operative cognitive dysfunction, viral and bacterial infections, gut microbiome dysregulation, and cardiovascular disease, may act as risk factors for AD. Overall, evidence suggests that modulating peripheral inflammation, accompanied by early diagnosis, could significantly reduce the risk of developing AD.

Furthermore, we highlight key immune signaling pathways involved in both central and peripheral immune responses, such as the NLRP3 inflammasome and TREM2, which represent promising therapeutic targets for modulating inflammation while preserving protective immune functions. Strategies aimed at reducing systemic inflammation, identifying early biomarkers, and intervening before significant neurodegeneration occurs may provide novel approaches to delay or prevent AD onset.

Link: https://doi.org/10.1186/s12979-025-00529-5

Calorie restriction is the practice of eating fewer calories, as much as a 40% reduction from the usual ad libitum calorie intake, while still obtaining an adequate level of micronutrients. Various forms of intermittent fasting also act as calorie restriction; the important factor is likely the length of time spent in a state of hunger. In a variety of animal species, calorie restriction has been shown to slow aging and extend life span, as well as produce sweeping positive changes to the operation of cellular metabolism in tissues throughout the body.

Human studies of mild long-term calorie restriction have reproduced the short-term changes, but there is no data on effects on life expectancy. Researchers expect calorie restriction to produce smaller changes in long-lived species such as our own than it does in short-lived species such as mice. The reasoning here is that the calorie restriction response evolved because of seasonal famine, a way for the individuals of short-lived species to increase the odds of later reproduction in a period of relative plenty. A season is a large fraction of a mouse life span, but not of a human life span - so only short-lived species exhibit large gains in life span via calorie restriction. Further, we might expect that long-lived species become long-lived in part because some of the beneficial changes produced by calorie restriction in short-lived species become enabled by default, throughout life.

Today's open access paper is illustrative of many similar efforts to investigate the fine details of the calorie restriction response in one specific organ. Here, the cell populations of the brain were the focus, and researchers profiled gene expression for hundreds of thousands of distinct cells in different brain regions. The results are quite interesting.

Spatiotemporal profiling reveals the impact of caloric restriction in the aging mammalian brain

Aging induces functional decline in the mammalian brain, increasing its vulnerability to cognitive impairments and neurodegenerative disorders. Among the various interventions to slow aging and delay age-related diseases, caloric restriction (CR) is particularly notable for its consistency in extending lifespan across species, including worms, flies, rats, and mice. Importantly, CR has demonstrated beneficial effects on brain function, enhancing learning and memory and increasing resilience against neurodegenerative diseases. However, established methods such as bulk transcriptomics yield little insight into how CR acts on highly heterogeneous brain cell populations and regions to mitigate the molecular and cellular changes of aging.

Recent advances in single-cell transcriptomics and spatial transcriptomics have enabled the precise measurement of gene expression changes across distinct cell populations and brain regions. However, the low throughput of standard approaches remains a challenge, impeding the study of how hundreds of different brain cell states respond to anti-aging treatments, particularly for rare yet critical aging-associated cell populations (e.g., neurogenic cells and activated microglia). To improve throughput, we recently developed two scalable approaches, EasySci and IRISeq, which enable comprehensive single-cell and spatial transcriptomic analysis of the mammalian brain across ages and conditions.

In this study, we profiled more than 500,000 cells from 36 control and CR mouse brains across three age groups with EasySci single-nucleus transcriptomics and performed imaging-free IRISeq spatial transcriptomics on twelve brain sections from CR and control aged mice. We thereby explored the impact of CR in more than 300 cellular states and 11 brain regions. CR delayed expansion of inflammatory cell populations, preserved neural precursor cells, and broadly reduced the expression of aging-associated genes involved in cellular stress, senescence, inflammation, and DNA damage. CR restored the expression of region-specific genes linked to cognitive function, myelin maintenance, and circadian rhythm. In summary, we provide a high-resolution spatiotemporal map of the aging mouse brain's response to CR, detailing precise cellular and molecular mechanisms behind its neuroprotective effects.

The near term path to verifying the utility of aging clocks is for the research community to accumulate as much data as possible for as many different clocks as possible, and then sift through it in search of correlations, problems, and reliability. Hence one should expect to see a great many studies in the years ahead that are similar to the one noted here. Some early clocks are known to have unexpected quirks in their sensitivity to interventions known to affect aging and incidence of age-related disease, which might make us suspicious of trusting their output when assessing a novel form of therapy aimed at slowing or reversing aspects of aging. Even clocks that are as well exercised as those used here will require some form of validation for the use of a given form of anti-aging therapy before the results can be taken at face value, and that validation will be a slow and costly process.

Osteoporosis is a major age-related musculoskeletal condition, yet chronological age does not fully capture individual risk. Biological age acceleration (BAA), as a biomarker of systemic aging, may offer greater predictive value for osteoporosis and lifespan loss. We analyzed data from 293,224 participants in the UK Biobank cohort who were free of osteoporosis at baseline. BAA was estimated using two validated models - Klemera-Doubal Method Biological Age (KDM-BA) and PhenoAge. Polygenic risk scores (PRS) were used to account for genetic susceptibility. Multivariable Cox models examined associations of BAA and PRS with incident osteoporosis and all-cause mortality.

Over a median follow-up of 8.5 years, 9,780 participants developed osteoporosis. Each one standard deviation (SD) increase in KDM-BA and PhenoAge acceleration was associated with a 22.6% and 19.3% higher risk of osteoporosis, respectively. Participants in the highest tertile of BAA had a 38-43% increased risk compared to those in the lowest tertile. Individuals with both high BAA and high PRS had nearly threefold higher osteoporosis risk, indicating a strong additive effect. Accelerated aging was also linked to a 1.3-1.8-year reduction in life expectancy at age 45, independent of osteoporosis status.

Link: https://doi.org/10.1016/j.bone.2025.117609

Physical activity is influential on long-term health. The correlation with health and longevity is well documented in many large human data sets, while animal studies of exercise and fitness demonstrates causation. One might also look at the epidemiology of hunter-gatherer populations that engage in considerably more physical activity than is the case for most humans, and observe the much reduced incidence of common age-related conditions in those individuals, relative to the sedate inhabitants of wealthier regions of the world. Here find yet another paper in which the authors report that a sizable human study population exhibits the expected relationship between physical activity and mortality. This is one of many.

We used data from the 2005-2018 waves of the Chinese Longitudinal Healthy Longevity Survey (CLHLS), including participants aged 60 years and older. Healthy Lifestyle Index (HLI) was constructed based on five modifiable factors: body mass index (BMI), smoking status, alcohol consumption, physical activity, and dietary intake. Multimorbidity was defined as the presence of two or more chronic conditions. Cox proportional hazards regression was employed to assess the associations between healthy lifestyle, multimorbidity, and all-cause mortality, with stratified analyses by age, sex, and urban-rural residence.

A total of 21,418 participants were included, with 15,113 deaths recorded over a median follow-up of 3.44 years. The age- and sex-adjusted mortality rate was 149.19 per 1,000 person-years. Among the lifestyle factors, physical activity showed the strongest association with reduced mortality (hazard ratio, HR=0.68). Participants with a healthy lifestyle had significantly lower all-cause mortality risk compared to those with an unhealthy lifestyle (HR=0.65). Notably, the protective effect was more pronounced among those with multimorbidity (HR=0.58) than those without (HR=0.65).

Link: https://doi.org/10.1186/s12877-025-06246-4