Fight Aging!

The use of electromagnetic fields to manipulate cellular biochemistry in favorable ways is a field very much in its infancy in comparison to the well established use of small molecule drugs. At the high level, it is quite similar to exploration with small molecules, in that there is a great deal of freedom to experiment with parameters: intensity, frequency, duration, dosing, a focus on primarily electrical versus primarily magnetic fields, equipment differences, and so forth. Within that vast parameter space, only some combinations will be useful. In general this part of the field is characterized by results that fail to replicate and incomplete information on all of the parameters needed to recreate the exact protocol used. Nonetheless, there are some areas of promise where multiple research groups have achieved positive results, and even brought the work into human trials. The use of electric fields to stimulate more rapid regeneration from injury is one example.

Today's open access paper reports on the use of magnetic fields to stimulate beneficial changes in mitochondrial function that are similar to those that occur following exercise. The authors term it magnetic mitohormesis, and one might take a look at an earlier review paper that discusses the mechanisms thought to be involved. The hundreds of bacteria-like mitochondria present in every cell are vital to cell function, primarily by producing adenosine triphosphate (ATP), a chemical energy store molecule. A vast body of evidence indicates that mitochondrial function declines with age, while the various strategies available to modestly improve mitochondrial function, including exercise, are beneficial to health and slow aging to some degree, at least in animal studies, in part because they improve mitochondrial function.

Investigating the Metabolic Benefits of Magnetic Mitohormesis in Patients with Type 2 Diabetes Mellitus

We, and others, have shown that brief exposures to pulsed electromagnetic fields (PEMF) stimulate mitochondrial respiration via a calcium-mitochondrial axis upstream to PGC-1α transcriptional regulation and recreate biological and metabolic adaptations similar to endurance exercise but without physical stress or strain.

In pre-clinical murine studies, PEMF exposure was shown to activate muscle mitochondrial respiration to induce exercise-related muscle adaptation and mitochondrial biogenesis. These responses resulted in the manifestation of typically exercise-associated positive metabolic adaptations, including improved insulin sensitivity, reduced resting insulin levels, enhanced fatty acid oxidation, and enhanced oxidative muscle expression downstream of the well-established pro-metabolic health pathways largely governed by PGC-1α co-transcriptional regulation.

Related benefits have also been observed in several published human studies employing this same PEMF exposure paradigm. In elderly patients, brief 10-min weekly PEMF treatment for 12 weeks increased skeletal mass and reduced total and visceral adiposity. More recently, it was found that PEMF treatment improved knee muscle strength and reduced pain in elderly patients with end-stage osteoarthritis of the knees. In another example, weekly treatment with PEMF for 16 weeks improved markers of muscle mitochondrial functioning and lowered systemic lipotoxicity in patients who underwent anterior cruciate ligament reconstruction compared to placebo.

Collectively, these data support the ability of PEMF treatment to replicate the metabolic benefits of endurance exercise. However, it is unknown whether low-dose PEMF treatment, which we will refer to as magnetic mitohormesis (MM), improves diabetes control. In this open-labeled exploratory study, we investigated the impact of MM on metabolic control in patients with suboptimally-controlled type 2 diabetes mellitus (T2DM). In addition, because PEMF treatment has been shown to reduce visceral fat, we examined whether patients with central obesity (defined as waist-to-hip ratio, WHR of ≥1.0) exhibit a greater propensity to benefit more from this treatment.

The 40 participants had a mean age of 59.4 years and HbA1c of 8.1%. MM treatment was well tolerated with no adverse events, and 77.5% of patients completed all 12 sessions. There were no significant changes in HbA1c, fasting glucose, or HOMA-IR for the overall cohort. However, in patients with central obesity, 88.9% showed a reduction in HbA1c post-treatment compared to 32.3% without central obesity, and mean HbA1c decreased from 7.5% to 7.1%. Our findings suggest that MM is safe and well-tolerated in T2DM patients and may confer a preferential benefit for individuals with greater central obesity.

There is considerable debate over the degree to which persistent viral infections contribute to neurodegenerative conditions such as Alzheimer's disease. If persistent viral infection causes generalized pathology over time, such as via increased chronic inflammation in later life, one would expect it to increase the incidence and severity of most age-related conditions. With that in mind, researchers here analyze a sizable body of study data to quantify the correlations between viral infection and cardiovascular disease. As one might expect, the results suggest that better control of viral infection could improve late life health.

It is well recognized that human papillomavirus (HPV), hepatitis B virus and other viruses can cause cancer; however, the link between viral infections and other non-communicable diseases, such as cardiovascular disease, is less well understood. Thus researchers set out to systematically review all published studies that investigated the association between any viral infection and the risk of stroke and heart attack, initially screening more than 52,000 publications and identifying 155 as appropriately designed and of high quality allowing for meta-analysis of the combined data.

In studies comparing long-term risk (average of more than 5 years) of cardiovascular events in people with certain chronic viral infections versus similar people without the infection, the researchers found: (a) a 60% higher risk of heart attack and 45% higher risk of stroke in people with HIV infection; (b) a 27% higher risk of heart attack and 23% higher risk of stroke in people with hepatitis C infection, and (c) a 12% higher risk of heart attack and 18% higher risk of stroke in people had shingles.

The findings also suggest that increased vaccination rates for influenza, COVID, and shingles have the potential to reduce the overall rate of heart attacks and strokes. As an example, the researchers cite a 2022 review of available science that found a 34% lower risk of major cardiovascular events among participants receiving a flu shot in randomized clinical trials vs. participants in the same trials who were randomly selected to receive a placebo instead.

Link: https://newsroom.heart.org/news/some-acute-and-chronic-viral-infections-may-increase-the-risk-of-cardiovascular-disease

Fibrosis is a feature of aging, in which the normal processes of tissue maintenance run awry and scar-like structures form to disrupt tissue structure and function. The proximate cause is altered behavior on the part of fibroblast cells that largely responsible for maintenance of the extracellular matrix. After than, one can point to the continual inflammatory signaling that takes place in aged tissue, and disrupts many forms of cell activity, not just this one. As is usually the case in matters relating to aging, a more comprehensive picture of causes and consequences leading to inflammation and altered fibroblast behavior, one that encompasses all of the mechanisms involved and their various layers and interactions, has yet to emerge. Biochemistry is exceedingly complex.

Cardiovascular aging is a multifactorial and systemic process that contributes significantly to the global burden of cardiovascular disease, particularly in older populations. This review explores the molecular and cellular mechanisms underlying cardiovascular remodeling in age-related conditions such as hypertension, atrial fibrillation, atherosclerosis, and heart failure. Central to this process are chronic low-grade inflammation (inflammaging), oxidative stress, cellular senescence, and maladaptive extracellular matrix (ECM) remodeling.

The ECM is a complex and dynamic network composed of proteins, proteoglycans, polysaccharides, and biologically active factors. It plays a crucial role in maintaining tissue integrity and function by undergoing remodeling in response to inflammation or injury, adapting its structure and composition to maintain tissue integrity and function. However, a persistent expansion of the ECM may evolve into maladaptive fibrosis and organ dysfunction. This pathological remodeling can be triggered by various factors such as hypoxia, inflammation, biomechanical stress, and excessive neurohormonal activation.

Inflammation contributes to ECM remodeling by releasing cytokines that activate fibroblasts, increasing the production of ECM components. It also upregulates matrix metalloproteinases (MMPs) that degrade ECM proteins. This dual action can lead to pathological ECM remodeling, contributing to fibrosis and tissue dysfunction. Senescence, on the other hand, leads to the accumulation of senescent cells that secrete pro-inflammatory factors known as the SASP. SASP factors, including cytokines, chemokines, growth factors, and proteases, further alter the ECM by promoting degradation, impairing its turnover, and reshaping its composition.

Emerging molecular therapies offer promising strategies to reverse or halt maladaptive remodeling. These include senescence-targeting agents (senolytics), Nrf2 activators, RNA-based drugs, and ECM-modulating compounds such as MMP inhibitors. Additionally, statins and anti-inflammatory biologics (e.g., IL-1β inhibitors) exhibit pleiotropic effects that extend beyond traditional risk factor control. Understanding the molecular basis of remodeling is essential for guiding future research and improving outcomes in older adults at risk of cardiovascular disease.

Link: https://doi.org/10.3390/biom15101452

A growing body of literature is associated with the debate over whether persistent viral infection provides a significant contribution to Alzheimer's disease and other neurodegenerative conditions. Some viruses, such as varieties of herpes simplex virus (HSV), cannot be effectively cleared by the immune system. They linger in the body to continually provoke immune reactions. The contribution of viral infection is clearly not reliable and sizable, however, as the epidemiological evidence is mixed. Some study populations show a correlation between infection status or use of antiviral therapies, while some do not. Some researchers have proposed that significant contributions to neurodegenerative disease require the interacting presence of several viral infections, which if true would explain why studies assessing infection status for a single virus produce mixed results.

If looking at only biological mechanisms, such as HSV-1 driving greater accumulation of amyloid-β in the aging brain, or the disruptions to immune function generated by cytomegalovirus, it all sounds quite compelling. But at the end of the day, researchers have be to able to demonstrate a robust association in epidemiological data for the viral contribution to Alzheimer's disease and other neurodegenerative conditions to be taken seriously. At the moment researchers are still in search of that robust correlation, and as a consequence this remains an exploratory part of the field.

HSV-1 as a Potential Driver of Alzheimer's Disease

Globally, approximately 4 billion people, or 64% of the population under the age of 50, are infected with herpes simplex virus type 1 (HSV-1). Antiviral medications such as acyclovir, famciclovir, and valacyclovir are prescribed to symptomatic patients. A complete cure for HSV-1 remains elusive in 2025, as these medicines do not eliminate the virus. After an initial infection, HSV-1 often enters a latent state, which can be reactivated, causing recurrent outbreaks, symptomatic or asymptomatic. Emerging evidence suggests that HSV-1 may contribute to neurodegeneration, particularly in Alzheimer's disease (AD), potentially through mechanisms such as chronic neuroinflammation, amyloid-beta (Aβ) and hyperphosphorylated Tau accumulation, oxidative stress, and synaptic dysfunction. Moreover, HSV-1 proteins have been detected in the hippocampus and thalamus, both of which are affected in AD. However, the role of HSV-1 in dementia remains unclear.

In this review, we examine current evidence on the potential role of HSV-1 in the pathogenesis of dementia and consider whether targeting HSV-1 could be a viable strategy for preventing progressive neurodegeneration. Although many studies have demonstrated an association between HSV-1 and AD, further exploration is needed to determine whether HSV-1 infection is a cause or a consequence of AD degeneration. Because HSV-1 is latent in the trigeminal ganglion and travels to the brain during reactivation, an animal model that can physiologically mimic human-brain conditions remains a challenge. Thus, future studies should examine possible experimental models in order to determine the causality between HSV-1 and AD.

AD is characterized by progressive memory impairment, executive dysfunction, and visuospatial impairment. Several studies have shown that neurotropic viral infections serve as a risk factor for AD onset and progression. Regarding the contribution of HSV-1 infection to AD onset, the studies started with the observation demonstrating the association between HSV-1 DNA and amyloid plaques. 72% of HSV-1 DNA was associated with plaques, whereas only 24% of HSV-1 DNA was associated with plaques in normal brains. Furthermore, HSV-1 DNA and proteins were found in the central nervous system, particularly in the hippocampus and thalamus, which are predominantly affected in AD, supporting the association between HSV-1 infection and AD.

In an epidemiological study, a meta-analysis revealed a positive correlation between anti-HSV-1 acyclovir treatment and the potential reduction in the risk of AD development or slowing down the progression of AD symptoms. However, the analysis may be limited by the lack of data from prospective randomized controlled clinical trials. A Phase II randomized, double-blind, placebo-controlled trial of valacyclovir in patients with mild AD and evidence of HSV-1/2 infection was recently completed (NCT03282916). After 78 weeks of treatment, valacyclovir did not slow disease progression. However, it remains unclear whether a longer treatment duration or intervention at an earlier disease stage might be required to observe therapeutic effects.

Overall, the mechanisms underlying HSV-1 in regulating AD progression are unclear, and further experimental studies are needed to confirm the epidemiological association between HSV-1 and AD. In addition, it remains unclear whether the increased presence of HSV-1 DNA and proteins in brain regions is a consequence of AD-associated immune dysfunction, making the brain more susceptible to infection.

Sirtuins are involved in the regulation of metabolism in various ways, and are clearly quite important to cell function as their structure is very similar in species as divergent as yeast, flies, and humans. Sirtuin 1 as a target for interventions in aging was intensely overhyped and likely not actually very useful in a practical sense. Sirtuin 3 is more interesting, based on research suggesting that it could have calorie restriction mimetic effects, and is involved in mitochondrial function, well known to have a role in aging. Sirtuin 6 is also interesting, as it slows aging in mice, but the mechanisms involved are less well understood. A company is presently working on gene therapies based on sirtuin 6 upregulation. Here, researchers report on their production of profile of these sirtuins in a small population of people at various ages, which might be of interest in the context of growing efforts to modestly slow aging by targeting sirtuins 3 and 6.

While modulation of SIRT1, SIRT3 and SIRT6 extends lifespan in model organisms, evidence in extreme-age humans is scarce. We quantified protein and mRNA levels, and protein-to-mRNA ratios for SIRT1, SIRT3 and SIRT6 in buccal epithelial cells obtained from healthy young adults, middle/late-aged individuals and nonagenarians/centenarians residing in a longevity-enriched region of south-eastern Azerbaijan. The cohort comprised 23 participants, stratified by sex and cardiovascular disease (CVD) status (5 per sex/CVD subgroup).

Our study has shown that although SIRT1, SIRT3 and SIRT6 levels predictably fell with age, the magnitude of these declines was significantly influenced by both sex and baseline cardiovascular health. Women retained higher absolute pools of SIRT1 and SIRT3 and exhibited a smaller loss of SIRT6 than men; their protein-to-mRNA ratios - our proxy for translational efficiency - rose by ≈30% for SIRT3 and SIRT6, whereas the male increase was modest. This pattern is consistent with hormone-dependent regulation: estrogens acting through estrogen receptor (ER)-α/β up-regulate SIRT1 transcription in endothelial and cardiac cells, via the estradiol-ERα interaction boost SIRT3 expression and mitochondrial targeting, enhancing oxidative phosphorylation, antioxidant defenses, and mitophagy for improved mitochondrial health and enhance SIRT6 activity by shielding critical acetyl-lysine residues, whereas androgens are neutral or even suppressive.

Our findings likewise showed that the presence of cardiovascular disease (CVD) reshapes the sirtuin axis far more dramatically than chronological aging and sex. We observed a decline in SIRT1, SIRT3, and SIRT6 levels, broadly consistent with a ~50% reduction in SIRT1 reported in ischemic heart disease cohorts and a ~35% decline in SIRT3 under pressure-overload conditions. In contrast, SIRT6 behaves differently: although its absolute protein level fell by ~73%, the protein-to-mRNA ratio remained virtually unchanged This pattern exemplifies translational buffering whereby cells upregulate translation of selected proteins to maintain critical functions despite drops in mRNA levels. This is more accurately framed as an emergency protective buffer, rather than a pathological driver.

This pilot study is the first to profile SIRT1, SIRT3 and SIRT6 across sex, age and cardiovascular health, defining a unified "sirtuin phenotype" that integrates nuclear energy sensing, mitochondrial integrity and chromatin maintenance as axes of cellular resilience. Although based on a small, cross-sectional cohort, the large and internally consistent effect sizes pave the way for longitudinal studies to validate sirtuin translational efficiency as a predictive biomarker of healthy ageing and cardiovascular resilience across sexes and as a target for sirtuin-modulating interventions aimed at extending healthspan.

Link: https://doi.org/10.3390/biology14101353

Here find a review of what is known of the ways in which age-related changes in the gut microbiome can contribute to the chronic inflammation of aging and development of neurodegenerative conditions. The ability to accurately map the composition of the gut microbiome by sequencing microbial DNA, in particular species-specific variations in the 16S rRNA gene, has produced a vast and growing body of data. Researchers have linked specific microbial populations to specific age-related conditions, and shown that the balance of populations shifts with age to favor those that provoke the immune system at the expense of those producing beneficial metabolites. This is the first step on the road to creating interventions capable of the lasting restoration of a more youthful gut microbiome, a goal that we know is possible because it can be achieved via fecal microbiota transplantation from a young donor to an old recipient, and approach that improves health and slows aging in animal studies.

Neurodegenerative diseases (NDs) represent a major global health challenge in aging populations, with their incidence continuing to rise worldwide. Although substantial progress has been made in elucidating the clinical features and molecular underpinnings of these disorders, the precise mechanisms driving neurodegeneration remain incompletely understood. This review examines the increasing significance of the gut-brain-immune triad in the pathogenesis of NDs, with particular attention to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. It explores how disruptions in gut microbiota composition and function influence neuroinflammation, blood-brain barrier integrity, and immune modulation through microbial-derived metabolites, including short-chain fatty acids, lipopolysaccharides, and bacterial amyloids.

In both Alzheimer's and Parkinson's diseases, a reduced abundance of short-chain fatty acid-producing bacterial taxa has been consistently associated with heightened pro-inflammatory signaling, thereby facilitating disease progression. Although detailed mechanistic understanding remains limited, experimental evidence - primarily from rodent models - indicates that microbial metabolites derived from a dysbiotic gut may initiate or aggravate central nervous system dysfunctions, such as neuroinflammation, synaptic dysregulation, neuronal degeneration, and disruptions in neurotransmitter signaling via vagal, humoral, and immune-mediated pathways.

The review further highlights how gut microbiota alterations in amyotrophic lateral sclerosis and multiple sclerosis contribute to dysregulated T cell polarization, glial cell activation, and central nervous system inflammation, implicating microbial factors in disease pathophysiology. A major limitation in the field remains the difficulty of establishing causality, as clinical manifestations often arise after extended preclinical phases - lasting years or decades - during which aging, dietary patterns, pharmacological exposures, environmental factors, and comorbidities collectively modulate the gut microbiome. Finally, the review discusses how microbial influences on host epigenetic regulation may offer innovative avenues for modulating neuroimmune dynamics, underscoring the therapeutic potential of targeted microbiome-based interventions in neurodegenerative diseases.

Link: http://dx.doi.org/10.14218/JTG.2025.00027

Heart failure is the name given to a category of dysfunctions in which the heart cannot pump enough blood to sustain the body. It is characterized by structural changes in heart muscle, some of which are maladaptive, some of which are compensatory, and a range of increasingly unpleasant consequences throughout the body and brain as the condition progresses in severity. The most prevalent cause of heart failure is the narrowing of important blood vessels by atherosclerotic plaque. The rupture of plaque to cause a transient blockage and heart attack can also sufficiently injure and weaken the heart in survivors to cross the threshold into heart failure. Hypertension is another common cause, as long-term disruption of the feedback mechanisms controlling blood pressure and heart activity causes enlargement and weakening of heart muscle, and thereby heart failure. There are other common contributing causes of heart failure that can in principle be sufficient on their own, such as severe atrial fibrillation and pulmonary hypertension, but in older people these issues are more usually coincident with atherosclerosis and hypertension.

In today's open access paper, researchers identify a harmful population of fibroblasts resident in heart tissue that only emerges in the state of heart failure. Fibroblasts are primarily responsible for generating extracellular matrix structures, and in an aged or damaged heart they also produce the scarring of fibrosis that reduces function. Fibroblasts have other capabilities, however, and the particular population of harmful fibroblasts engages in signaling that detrimentally changes the behavior of cardiomyocyte cells making up heart muscle. Interfering in this signaling may be a basis for therapies to reduce the progression of heart failure, preventing some fraction of the maladaptive changes in cell function that contribute to the condition.

Heart failure-specific cardiac fibroblasts contribute to cardiac dysfunction via the MYC-CXCL1-CXCR2 axis

Heart failure (HF) is a growing global health issue. While most studies focus on cardiomyocytes, here we highlight the role of cardiac fibroblasts (CFs) in HF. Although CFs are thought to maintain cardiac homeostasis primarily by producing extracellular matrices, CFs communicate with other cell types, including cardiomyocytes, via direct interactions and paracrine signaling. In response to diverse stresses under pathological conditions, CFs dynamically alter their phenotype, transitioning from resident fibroblasts to myofibroblasts and eventually matrifibrocytes after myocardial infarction (MI).

Single-cell RNA sequencing of mouse hearts under pressure overload identified heterogeneity in CFs across sham hearts, pressure-overload-induced hypertrophic hearts, and failing hearts, revealing an HF-specific subpopulation of fibroblasts, here designated as HF-Fibro. HF-Fibro expressed Postn, which is expressed in fibroblasts activated by MI, but not Acta2 or the osteochondral gene Chad, suggesting that HF-Fibro are different from myofibroblasts or matrifibrocytes that appear in MI hearts.

The HF-Fibro population also highly expresses the transcription factor Myc. Deleting Myc in CFs improves cardiac function without reducing fibrosis. MYC directly regulates the expression of the chemokine CXCL1, which is elevated in HF-Fibro CFs and downregulated in Myc-deficient CFs. The CXCL1 receptor, CXCR2, is expressed in cardiomyocytes and blocking the CXCL1-CXCR2 axis mitigates HF. Additionally, CXCL1 impairs contractility in neonatal rat and human iPSC-derived cardiomyocytes. Human CFs from failing hearts also express MYC and CXCL1, unlike those from controls.

These findings reveal that HF-Fibro cells contribute to HF via the MYC-CXCL1-CXCR2 pathway, offering a promising therapeutic target beyond cardiomyocytes.

A major trend in the world of stem cell therapies is the replacement of stem cell transplantation with the use of extracellular vesicles derived from those stem cells. Extracellular vesicles are much more easily managed as a basis for therapy, they are more easily stored and transported, and their production can be more centralized. Since stem cell therapies produce their benefits largely via the signals generated by the transplanted cells in the short period before they die, the use of stem cell derived extracellar vesicles appears a good substitute. The availability of extracellular vesicle therapies is spreading in the medical tourism community, where good data on outcomes is very hard to come by, and the more mainstream medical development community has started towards clinical trials and robust manufacturing approaches. One should probably expect to see a rerun of the trajectory of stem cell transplants over the past twenty years, slowly moving from initially widespread use in clinics in less regulated regions of the world to more codified and narrower uses within the heavily regulated clinical systems of Europe and the US.

Neuroaging is a complex biological process in which the brain undergoes progressive functional decline marked by synaptic loss, neuroinflammation, and cognitive decline. At the molecular and cellular level, aging is driven by multiple interconnected hallmarks, including genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Among these, cellular senescence, a state of irreversible cell cycle arrest, has emerged as a critical contributor to brain aging. Senescent cells accumulate with age, driven by the p53-p21 and p16-pRb pathways, and secrete pro-inflammatory factors via senescence-associated secretory phenotype (SASP), thereby exacerbating neurodegeneration, vascular dysfunction, and cognitive decline.

Extracellular vesicles (EVs) are natural nanocarriers of proteins, lipids, and nucleic acids, and have emerged as key mediators of intercellular communication and therapeutics for aging and age-related conditions. EVs derived from various cell types, such as mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs), can modulate senescence-related pathways, reduce inflammation, and promote tissue repair. Preclinical studies demonstrate that stem-cell-derived EVs can improve cognitive performance, enhance neurogenesis, reduce senescence phenotype, improve neuronal survival through neuroprotective miRNAs (miR-181a-2-3p), suppress neuroinflammation via inhibition of NLRP3 inflammasome, and support synaptic plasticity. Stem cell EVs possess natural biocompatibility, the ability to cross the blood-brain barrier (BBB), and targeted delivery mechanisms, making them promising candidates for anti-aging interventions.

Link: https://doi.org/10.20517/evcna.2025.65

That offspring inherit epigenetic patterns of modifications to gene expression that reflect the environmental exposures of their parents was a relatively recent discovery. The evolutionary world is just a little bit Lamarkian, in that the ability to steer the metabolic reactions of immediate descendants provides greater resilience to stressful environments. Short-lived species respond to mild stresses with extension of life span, presumably because this increases the odds of reaching a better environment in which offspring are more likely to survive. As shown here, that extension of life span fades for descendants if the stress is maintained over generations. There is at that point a different set of cost-benefit considerations when it comes to balancing the fitness advantage of a metabolism that ages more slowly versus the fitness advantage of a metabolism geared for early life reproductive success at the expense of faster aging. Evolution has clearly produced a complex set of transgenerational reactions to common stresses in the environment a species finds itself in.

Epigenetic inheritance alerts naïve descendants to prepare for stresses that could still be present, whereas distant descendants return to a basal state after several generations without stress. However, organisms are frequently exposed to stresses successively across generations. We found that parental hypoxia exposure increased parental longevity, caused intergenerational lipid reduction, and elicited transgenerational fertility reduction that was dependent on generationally transmitted small RNAs.

Here, we find that Caenorhabditis elegans adapt to repeated generational stresses. We show that, upon two repeated generational hypoxia exposures, the life-span extension is eliminated, and after four repeated generational hypoxia exposures, the reduced fertility is eliminated. Transgenerational adaptation also occurred in response to changes in glucose availability. Transgenerational hypoxia adaptation is dependent on the H3K27 trimethyltransferase PRC2 complex, and we identified transgenerationally adapted genes. Our findings reveal that transgenerational adaptation occurs and suggest that H3K27me3 is a critical modification for adapting to repeated generational stresses.

Link: https://doi.org/10.1126/sciadv.adv9451

Osteoarthritis is a prevalent degenerative joint disorder, in which cartilage and underlying bone becomes worn and damaged, while the normal processes of repair (even limited as they are in cartilage tissue) are impaired by aging. Neurodegenerative conditions in the brain are a much more complex range of dysfunctions with many different contributing causes, and a less complete understanding of how various mechanisms of aging and measured pathological changes relate to one another. How are these two aspects of aging linked to one another? The first clue is that both are inflammatory conditions, characterized by excessive immune activation and continuous, unresolved inflammatory signaling. The normal short-term processes of inflammation, necessary and helpful in the context of injury and infection, become harmful and disruptive when sustained over the long term.

In today's open access paper, researchers explore the ways in which osteoarthritis and neurodegenerative pathologies may influence one another. Interestingly this isn't just a matter of inflammatory signaling, though that is front and center. There are other, more subtle interactions. Whether these other interactions are important in the bigger picture remains an open question. One of the characteristics of age-related disease is that the causes are multifaceted and complex in their interactions with one another, and it is very hard to assign relative importance to any one cause in the absence of a way to specifically eliminate only that one contributing factor of interest.

The brain-joint axis: links between osteoarthritis and neurodegenerative disorders in aging

Growing evidence suggest a strong epidemiological and pathological link between osteoarthritis (OA) and neurodegenerative diseases. Studies indicate an association between OA with Alzheimer's disease (AD) and Parkinson's disease (PD), driven by common mechanisms such as chronic systemic inflammation, metabolic dysfunction, and bidirectional communication along the brain-joint axis. These overlapping pathways may accelerate neurodegeneration, with meta-analyses indicating that OA patients face a 25% higher risk of developing neurological conditions compared with non-OA individuals.

In longitudinal analyses, OA was significantly linked to changes in hippocampal volume (HpVR) over time among individuals with normal cognition. Individuals with OA exhibited a more rapid decline in HpVR over time compared with those without OA. Furthermore, OA patients, especially those experiencing pain, are more likely to develop memory impairments and AD. Additionally, OA-induced chronic pain was associated with declines in multiple cognitive domains, including memory, attention, processing speed, and executive function, underscoring its critical role in worsening AD-related symptoms. Patients with knee OA show significant abnormalities in grey matter volume and functional brain activity compared with healthy individuals. Moreover, structural changes, such as cortical thinning, and functional disruptions, including altered cerebral blood flow and impaired functional connectivity in pain-related networks, were observed, particularly in the right anterior insula, highlighting an association between brain alterations and knee OA.

OA and neurodegenerative disorders, though clinically distinct, share converging age-related pathophysiological mechanisms, including chronic inflammation, oxidative stress, and mitochondrial dysfunction. We propose that OA is not merely a localized musculoskeletal disorder but part of a broader systemic neuro-immuno-endocrine network whose dysfunction contributes to neurodegeneration. Emerging evidence highlights a bidirectional brain-joint axis, whereby systemic and local inflammatory cascades may reciprocally exacerbate both joint degeneration and neuronal injury, creating a self-perpetuating cycle that accelerates age-related decline.

In OA, a chronic low-grade inflammation leads to the sustained release of proinflammatory cytokines (e.g., IL-1β, IL-6, and TNF-α). Systemic inflammation may increase blood brain barrier permeability and alter tight-junction integrity, as inferred by the reduced expression of tight junction proteins in the brain observed in animal models. This allows inflammatory mediators to infiltrate the central nervous system (CNS), triggering neuroinflammation, microglial activation, oxidative stress, and synaptic dysfunction as key drivers of neurodegeneration. Neurodegenerative processes may also impair endogenous pain modulation, worsening central sensitization and OA-related symptoms. This model underscores that inhibition of peripherial inflammation may attenuate neuronal loss and neurodegeneration.

One of the ways in which the immune cells known as neutrophils attack pathogens is to release structures called neutrophil extracellular traps into the intracellular environment. These traps can disable pathogens, but like much of the activity of the immune system, too much of a good thing becomes harmful. Excessive neutrophil generation of traps in the aged tissue environment promotes chronic inflammation, and here researchers focus specific on the consequences of this activity in the vasculature, where it promotes the onset of cardiovascular disease. While relatively little work has been carried out on approaches to clear traps or reduce the pace of their creation, a range of evidence suggests that this might be a viable strategy to improve the state of the aged vasculature.

Blood vessels are critical in systemic aging with arteries stiffening and calcifying due to chronic inflammation and oxidative stress, driving age-related cardiovascular and cerebrovascular diseases. In this review, neutrophil extracellular traps (NETs) - web-like structures composed of decondensed chromatin, histones, and antimicrobial proteins released by neutrophils - are explored as therapeutic targets in vascular aging.

NETs are vital for pathogen defense, but their excessive activation leads to inflammation and vascular pathologies, promoting endothelial dysfunction, inflammatory aging, and vascular remodeling in diseases such as hypertension, atherosclerosis, myocardial infarction, heart failure, atrial fibrillation, ischemic stroke, and Alzheimer's disease. Increasing evidence supports that modulating NETs through inhibitors or scavengers can reduce inflammatory responses, preserve endothelial integrity, and improve prognosis. As a potential therapeutic target, growing attention has been directed toward exploring the balance between NET induction, inhibition, and degradation.

Link: https://doi.org/10.3389/fimmu.2025.1657938

Researchers here report on a novel approach to slow aging and extend life in mice by interfering in the activity of a protein involved in the regulation of metabolism. The researchers find that SAPS3 expression increases with age, and deletion of this gene slows metabolic aging. SAPS3 is a component of a protein complex that reduces levels of AMPK. Upregulation of AMPK is known to slow aging, and here that is achieved by disabling the SAPS3-related process that acts to reduce AMPK levels. The size of the effect on life span in mice is modest, as one might expect given past work on AMPK and aging. This illustrates the point that biochemistry is complex, and for any given target there are many different ways (upstream and downstream in networks of protein interactions) in which one can intervene to achieve a given result.

Aging is characterized by disruptions in metabolic homeostasis, yet the mechanisms that regulate these metabolic changes remain poorly understood. We show that the serine/threonine-protein phosphatase 6 (PP6) regulatory subunit 3, SAPS3, is a critical regulator of metabolism during aging. SAPS3 deletion significantly extends lifespan in mice and counteracts age-related impairments in metabolic health. SAPS3 deficiency improves the effects of aging on the affective behaviors, cognition, and motor functions in aged mice.

We find that SAPS3 expression is increased during aging to inhibit adenosine monophosphate-activated kinase (AMPK) activity. Deletion of SAPS3 leads to AMPK activation and reverses cellular senescence and aging-induced metabolic alterations. Using in vivo U-13C6-D-glucose tracing and metabolomic analysis, we find that SAPS3 deficiency restores metabolic homeostasis with increased glycolysis, tricarboxylic acid (TCA) cycle, and decreased fatty acid synthesis in aged mice. These findings highlight a critical role of the SAPS3/PP6 phosphatase complex in aging and suggest that strategies targeting SAPS3 may promote longevity and healthy aging.

Link: https://doi.org/10.1126/sciadv.adt3879

Proteins are largely quite delicate structures dependent on being manufactured and correctly folded and localized inside a cell. Thus no-one tries to make recombinant proteins or deliver them as a therapy for the vast majority of proteins. The exceptions are those proteins robust enough to be secreted by a cell and circulate in blood and other fluids in the body. In that case one can develop means of manufacture and build a recombinant protein that can be injected as a basis for therapy, assuming that more of that protein is a desirable goal. So far as I am aware it is unusual to find a protein that can survive oral administration and the harsh environment of the gastrointestinal tract, and then enter circulation to produce the same beneficial effects that the natively manufactured protein is capable of achieving. An energetic portion of the research community is actively engaged in trying to find ways to enable proteins to survive oral administration.

A fair amount has been written on the topic of BPIFB4 and its effects on life span and cardiovascular disease in recent years. The longevity-associated variant of the protein both reduces inflammation and reduces the impact of aging on the ability of blood vessels to contract and dilate. Exploration continues to try to fully understand its effects on the complex regulation of the vascular system. While the longevity-associated variant of BPIFB4 was discovered in humans, researchers have demonstrated in a number of studies that it produces benefits in aged mice. Today's open access paper on this topic is largely interesting because the authors used oral administration of a recombinant longevity-associated variant of BPIFB4. This is not the expected next step after earlier success in mice with BPIFB4 gene therapies, precisely because, as mentioned above, very few proteins can be delivered orally.

In vivo evidence supports the effectiveness of the longevity-associated protein LAV-BPIFB4 in reducing adipose tissue-derived mediators of systemic inflammation to prevent vascular insult and atheromatous change

Obesity triggers chronic low-grade inflammation contributing to cardiovascular and metabolic diseases. Over-release of adipokines and pro-inflammatory mediators by white adipose tissue (WAT) enhances inflammation through a feedforward loop involving endothelial and immune cells, promoting atherosclerosis. Our previous studies showed that in vivo gene transfer of the longevity-associated variant (LAV) of BPIFB4 restores endothelial and cardiac function and reduces systemic inflammation in mouse models.

Here we investigated the anti-inflammatory potential of orally administered recombinant rhLAV-BPIFB4 in ApoE-/- mice fed a high-fat diet to elucidate its role in modulating endothelial dysfunction primed by adipose tissue inflammation. We studied n = 5 ApoE-/- mice on standard diet (SD), n = 5 (VEH-HFD) and n = 6 (LAV-HFD) ApoE-/- mice fed high-fat diet without or with rhLAV-BPIFB4 protein. Primary pre-adipocyte cultures were established from epididymal WAT to evaluate CD45+CD38+ leukocyte infiltration, inflammatory profile of pre-adipocytes, and ex vivo effects of conditioned media on vessels.

Oral administration of rhLAV-BPIFB4 in ApoE-/- mice fed high-fat diet dampens atherosclerosis by preserving endothelial integrity and reducing ICAM+ and CD68+ cell infiltration. Despite unchanged adiposity, systemically rhLAV-BPIFB4 reduces pro-inflammatory cytokines (IL-1α/β, TNF-α, IL-6) while mildly increasing IL-10 levels. Supernatants from pre-adipocytes treated with rhLAV-BPIFB4 demonstrate similar anti-inflammatory cytokine profiles. Conditioned media from rhLAV-treated eWAT ex vivo restores endothelial function in dysfunctional arteries. Collectively our data show that targeting adipocyte-associated inflammation, LAV-BPIFB4 emerges as a promising therapeutic strategy to counteract endothelial dysfunction in obesity.

Researchers here demonstrate that diluting calorie intake with non-digestible fiber produces similar outcomes in the health and longevity of mice as does moderate calorie restriction. The researchers also combined this intervention with exome matching of amino acid composition of dietary protein. Exome matching implies that the amino acid composition of proteins in the body is matched to that of the diet; interestingly, mice prefer such exome matched chow over other options. The degree to which either of these approaches can be implemented on a practical basis in a human diet is an interesting question, certainly some discussion and research would be needed. Adding cellulose starch as non-digestible fiber to the diet is certainly possible, but at 30% of all food intake by weight, the amount used here, that may produce complications, logistical and otherwise.

Caloric restriction (CR) is the most extensively studied dietary approach for delaying ageing and extending lifespan across many taxa. In vertebrates such as mice, rats and nonhuman primates, CR is typically implemented by restricting food intake to 50%-80% of ad libitum-fed consumption, provided as a single daily portion with micronutrient supplementation. This feeding regimen induces both energy restriction and extended fasting periods because animals usually consume all available food within a few hours and then fast until the next feeding cycle.

In our previous work with ad libitum-fed mice, we applied this framework and demonstrated that the ratio of dietary protein to carbohydrates influences lifespan. In that study, we incorporated non-digestible cellulose into certain diets to simulate the effects of CR in ad libitum-fed animals. This marked the first instance of CR achieved by dietary dilution in mice. As anticipated, mice consuming the high-cellulose diets increased their food intake as a compensatory response to nutrient dilution, yet their overall energy intake decreased. However, that previous study did not include a comparison to a conventional CR-treated group.

A recent nutritional intervention that may influence growth and longevity is exome-matching. This involves manipulating dietary protein so that dietary amino acids are at a ratio matched with the exome, thereby meeting (without excess) the predicted requirements for protein translation under physiological conditions. Here, we compared longevity and ageing in mice on three diets: an ad libitum-fed control diet (Con); a conventional 20% CR diet; and a low-protein, high-carbohydrate (LPHC) ad libitum-fed diet, which caused caloric restriction through dilution with non-digestible fibre. The amino acid composition of dietary protein in all diets was exome-matched to reduce variation in food intake caused by an imbalance of amino acids.

Survival curves show that the LPHC and CR diets had similar effects on lifespan compared with the ad libitum control diet. LPHC and CR diets significantly increased median lifespan by 17% and 11%, respectively, compared to the control diet. There was no statistically significant difference between median lifespans of the CR versus LPHC. Maximum lifespans were 1008 days for controls, 1179 days for CR, and 1115 days for LPHC diets. Sex was not a significant effect modifier.

Link: https://doi.org/10.1111/acel.70269

A fair sized body of evidence shows that circadian rhythm, the daily cycle of changed gene expression and behavior in cells, is important to tissue function but becomes disrupted with age and age-related disease. The regulation of circadian rhythm is complex and occurs distinctly the central nervous system and periphery of the body, and so one of the ways in which problems arise is when different cell types and tissues fall out of synchronization of rhythm. Here, researchers show that the aggregation of misfolded amyloid-β thought to be the initiating cause of Alzheimer's disease causes disruption of circadian rhythm in supporting cells in the brain, yet another view of the complex pathology of the condition.

While circadian rhythm disruption may promote neurodegenerative disease, the impact of aging and neurodegenerative pathology on circadian gene expression patterns in different brain cell types remains unknown. Here we used a translating ribosome affinity purification to identify the circadian translatomes of astrocytes, microglia and bulk tissue in healthy mouse cortex and in the settings of amyloid-β plaque pathology or aging.

Our data reveal that astrocytes and microglia have robust and unique circadian translatomes, that circadian gene expression patterns reprogram dramatically in the setting of amyloid pathology or aging, and that changes are cell-type specific and context dependent. The core circadian clock was generally robust in the setting of amyloid plaque pathology in bulk cortex, astrocytes and microglia, although downstream rhythms in AD-relevant gene expression underwent dramatic circadian reprogramming. However, aging caused blunting of core clock gene rhythms in microglia, but not in astrocytes.

Our findings illustrate that circadian rhythms in gene expression are highly dependent on cell type and are reprogrammed in a context-dependent manner, in some cases despite robust core clock oscillation. We find that many transcripts related to metabolism, proteostasis, and AD show rhythmic expression that can be altered by pathology, emphasizing the importance of circadian regulation of gene expression and cellular function in aging and neurodegenerative conditions.

Link: https://doi.org/10.1038/s41593-025-02067-1