Fight Aging!

Microglia are innate immune cells resident in the brain. They are broadly similar in behavior to the macrophages found elsewhere in the body, with an added portfolio of duties relating to maintenance of the synaptic connections that link neurons to form neural networks. Researchers have provided evidence for microglia to both harm and help the aging brain, with various subpopulations of microglia either acting to cause damage and dysfunction or attempting to resist that damage and dysfunction. One of the most studied aspects of microglial aging is the increase in inflammatory signaling, as microglia react to the age-damaged environment and their own internal age-related dysfunctions with maladaptive patterns of behavior. Chronic inflammation in aged brain tissue contributes to neurodegeneration, and is driven in part by microglia.

In today's open access paper, the authors expand on recent research that points to PU.1 as a gene of interest in the regulation of microglial inflammation. A few research groups have set their sights on selective PU.1 inhibition in microglia as a potential basis for therapy, as it appears to reduce inflammation in animal studies. In this new paper, the authors report that this feature of PU.1 inhibition is actually driven by a small subpopulation of microglia that are in some way acting to regulate the behavior of other microglia. This sort of behavior is well described in the adaptive immune system - consider regulatory T cells, for example. It is interesting to see innate immune cells specializing into the regulators and the regulated in response to circumstances.

Lymphoid gene expression supports neuroprotective microglia function

Microglia, the innate immune cells of the brain, play a defining role in the progression of Alzheimer's disease (AD). The microglial response to amyloid plaques in AD can range from neuroprotective to neurotoxic. Here we show that the protective function of microglia is governed by the transcription factor PU.1, which becomes downregulated following microglial contact with amyloid plaques.

Lowering PU.1 expression in microglia reduces the severity of amyloid disease pathology in mice and is linked to the expression of immunoregulatory lymphoid receptor proteins, particularly CD28, a surface receptor that is critical for T cell activation. Microglia-specific deficiency in CD28, which is expressed by a small subset of plaque-associated low PU.1 expression microglia, promotes a broad inflammatory microglial state that is associated with increased amyloid plaque load.

Our findings indicate that low-PU.1 CD28-expressing microglia may operate as suppressive microglia that mitigate the progression of AD by reducing the severity of neuroinflammation. This role of CD28 and potentially other lymphoid co-stimulatory and co-inhibitory receptor proteins in governing microglial responses in AD points to possible immunotherapy approaches for treating the disease by promoting protective microglial functions.

Epidemiological research has consistently demonstrated a sizable difference in outcomes between those who are sedentary and those who conduct even a modest, low level of physical activity. More exercise is better, of course, but some researchers have have nonetheless focused on the degree to which small amounts of activity can be beneficial in older individuals. Here, for example, researchers show that relatively low levels of physical activity slow the progression towards outright Alzheimer's disease in patients with high levels of amyloid-β aggregation. The amyloid-β in and of itself causes only minor loss of cognitive function, but sets the stage for a later environment of inflammation and tau aggregation that causes much more severe damage to the brain and its function.

Physical inactivity is a recognized modifiable risk factor for Alzheimer's disease (AD), yet its relationship with progression of AD pathology in humans remains unclear, limiting the effective translation into prevention trials. Using pedometer-measured step counts in cognitively unimpaired older adults, we demonstrated an association between higher physical activity and slower cognitive and functional decline in individuals with elevated baseline amyloid.

Importantly, this beneficial association was not related to lower amyloid burden at baseline or longitudinally. Instead, higher physical activity was associated with slower amyloid-related inferior temporal tau accumulation, which significantly mediated the association with slower cognitive decline. Dose-response analyses further revealed a curvilinear relationship, where the associations with slower tau accumulation and cognitive decline reached a plateau at a moderate level of physical activity (5,001-7,500 steps per day), potentially offering a more approachable goal for older sedentary individuals.

Collectively, our findings support targeting physical inactivity as an intervention to modify the trajectory of preclinical AD in future prevention trials, and further suggest that preferentially enrolling sedentary individuals with elevated amyloid may maximize the likelihood of demonstrating a protective effect of physical activity on tau accumulation and cognitive and functional decline in early AD.

Link: https://doi.org/10.1038/s41591-025-03955-6

Researchers here demonstrate a novel way of delivering stem cells as a therapy for bone fractures that occur in the context of osteoporosis, by forming spheroids of stem cells combined with a bone mineral scaffolding material. The approach appears to encourage the survival of a larger fraction of transplanted cells, producing a greater regeneration of bone tissue. More usually near all of the transplanted cells die shortly after a transplantation procedure, and whatever benefits are obtained are derived from the signaling generated by the stem cells prior to that point.

Osteoporotic vertebral fractures substantially contribute to disability and often require surgical intervention. However, some challenges, such as implant failure and suboptimal bone regeneration, limit current treatments. Adipose-derived stem cells are promising for regenerative therapy because they are easily obtained, highly proliferative, and resistant to osteoporosis-related symptoms. This study aimed to evaluate the combined effects of osteogenic adipose-derived stem cell spheroids and β-tricalcium phosphate on vertebral bone regeneration in a rat osteoporotic vertebral fracture model.

Osteoporosis was induced in 33 rats (11 per group) by ovariectomy, and defects were created in the L4 and L5 vertebrae. Adipose-derived stem cells were spheroidized and mixed with β-tricalcium phosphate scaffolds. Groups included osteogenic spheroids, undifferentiated spheroids, and β-tricalcium phosphate alone. Bone regeneration was assessed using micro-CT, histology, and biomechanical testing at four and eight weeks. Further in vitro analyses were conducted.

The osteogenic spheroid group showed significantly higher bone mass, fusion score, and mechanical strength than the control group did. Histological analysis revealed enhanced new bone formation and β-tricalcium phosphate integration. Gene expression analysis revealed osteogenic marker (ALP, osteocalcin, and Runx2) and regenerative factor (BMP-7, IGF-1, HGF-1, and Oct4) upregulation, along with reduced apoptosis. Further, adipose-derived stem cell survival was confirmed at the repair site. These results indicate that adipose-derived stem cells contribute to both paracrine and direct osteogenesis.

Link: https://doi.org/10.1302/2046-3758.1410.BJR-2025-0092.R1

Stem cell therapies have existed for a few decades now, and over that time have moved from experimental use for many conditions in the medical tourism industry to a much more formulaic, controlled use for some conditions in the more regulated markets such as the US and Europe. More experimental use in medical tourism never went away, however. It became a larger industry, more varied, the body of knowledge more widespread, but the existence of a very formalized, robust set of procedures adopted by clinics and companies in more regulated markets where every therapy and its method of manufacture is reviewed in great detail (and consequently at great expense) doesn't make the earlier, less costly, less certain approach go away. Well informed patients continue to have the choice over how they proceed.

The trajectory of the stem cell therapy field is presently to replace the use of cells with the use of extracellular vesicles harvested from those cells. Extracellular vesicles are more cost-effective as a basis for therapy, as they can be manufactured centrally, frozen, shipped, and stored indefinitely with minimal loss of efficacy. In practice, as this move from cells to vesicles is at a fairly early stage in the grand scheme of things, there isn't yet all that much centralization of manufacture. There is certainly very little standardization of manufacture; it is a rerun of the early years of stem cell therapies, but for vesicles this time. This will change. As happened for stem cell therapies, there will be more regulated, more expensive extracellular vesicle therapies, manufactured more robustly, and approved by regulators to treat only some conditions. Meanwhile, the medical tourism industry will continue much as it is at the moment, only more so. Check back in a decade, and this will likely be the state of the field.

Efficacy of extracellular vesicles derived from mesenchymal stromal cells in regulating senescence: In vitro and in vivo insights

Researchers have pointed to stem cell depletion as a key mechanism contributing to cellular senescence in aging. Thus, stem cell-based therapy, especially treatment with mesenchymal stromal cells (MSCs), has become an innovative anti-aging approach. A phase I/II double-blind and placebo-controlled study showed that the application of intravenous exogenous allogenic MSCs can reverse the symptoms of frailty in elderly individuals, significantly improving quality of life, physical performance, and reducing chronic inflammation. However, using MSCs in therapeutic applications poses several challenges, including the risk of cellular rejection, tumorigenesis, and problems related to cell delivery and engraftment. These concerns have led researchers to assess alternative strategies for using MSCs for treatment while mitigating the risks related to their application. One such promising strategy involves using extracellular vesicles (EVs) derived from MSCs (MSC-EVs).

The cargo of MSC-EVs consists of various cytokines, growth factors, bioactive lipids, and regulatory microRNAs (miRNAs) that can participate in cell-to-cell communication and cell signaling and alter the metabolism of cells or tissues at short or long distances in vivo. These vesicles have the therapeutic ability of MSCs and can influence tissue response to injury, infection, and disease. Researchers showed that EVs derived from umbilical cord-derived MSCs (UC-MSCs) can delay the aging of naturally aged mice throughout the body and significantly alter the degenerative functions of various tissues and organs.

Many preclinical studies have shown that multiple sources of EVs, especially those derived from UC-MSCs, are prospective cell-free therapeutic agents for aging therapy. However, key parameters, including quality, reproducibility, and potency, determine the development of therapies based on EVs. Large-scale production of EVs faces multiple challenges, including low yield, heterogeneity, targeted delivery, storage stability, and the lack of standardized protocols to ensure quality, safety, and consistency. Current isolation techniques, such as ultracentrifugation and density gradient methods, suffer from limited yield and insufficient purity, making them inadequate for clinical-scale applications.

This study established a highly efficient technique for extracting and characterizing MSC-EVs. Additionally, we identified and implemented crucial quality control checkpoints for MSC-EVs. These measures were taken to ensure consistent yield, quality, and reproducibility of the MSC-EVs, rendering them suitable for clinical use. Next, we conducted several experiments to determine the effects of MSC-EVs on senescence in senescent cells and aged murine models. We found that MSC-EVs inhibited the aging-related secretory phenotype at the cellular level and reduced the attenuation of age-associated degenerative changes in multiple organs. Moreover, integrated metabolomics and transcriptomics analyses were performed, and the results confirmed the anti-aging mechanism of MSC-EVs.

Macular degeneration is a progressive blindness caused by forms of age-related damage that disable and destroy cells of the retina, such as the accumulation of persistent forms of metabolic waste. The dry variant of macular degeneration, in which there is no great degree of inappropriate blood vessel growth in the retina, has no effective treatment at the present time - and treatments for the wet form typically only slow progression. The materials noted here discuss progress towards a precision heat therapy that uses a laser to induce mild cell stress and consequently greater cell maintenance activities in retinal tissue. If used in the early stages of the condition, animal studies suggest it can significantly postpone the onset of more severe degeneration.

The new heat treatment involves heating the retinal pigment epithelium at the back of the eye (at the fundus) with near-infrared laser and precise temperature control. The objective is to halt the development of the condition in its early stages and to prevent it from progressing to the dry or wet form. Heat treatment of the fundus is not a new invention, but until now, it has not been possible to monitor the temperature of the retinal pigment epithelium while the treatment is administered. This is essential in order to avoid damage to the tissues being treated.

The causes of macular degeneration include oxidative stress and the resulting protein misfolding and aggregation. A heat treatment for the back of the eye strengthens the defence mechanisms of retinal cells. These mechanisms help proteins refold back into their correct forms, and at the same time stimulate the natural healing process. In the new heat treatment, the temperature elevation of the fundus is determined from the acceleration of electrical signalling of retinal nerve cells in response to light stimuli and the signals can be registered in real-time from the surface of the eye using electroretinography. With this method, the voltage change caused by light flashes is measured using electrodes placed on the surface of the eye and the skin near the eye.

The temperature determination method has been shown to work in tissue research on mice and pigs, and preclinical tests for the heat treatment have begun. The goal of the commercialisation project is to enable the use of heat treatment in humans, and the design and construction of the treatment device is currently under way.

Link: https://www.aalto.fi/en/news/new-laser-therapy-seeks-to-halt-the-progression-of-age-related-vision-loss

Brown adipose tissue conducts thermogenesis and its activities have been found to be beneficial to the operation of metabolism. Thus a greater proportion of brown adipose tissue versus other types of fat tissue is protective in the context of aging. Unfortunately brown adipose tissue function declines with age, and here researchers provide evidence for this form of fat tissue aging to be caused by a decline in the efficacy of chaperone mediated autophagy, also a feature of aging. This form of autophagy uses chaperone proteins to shuttle damaged or otherwise unwanted molecules into a lysosome for recycling. Like all forms of autophagy the efficiency of its operation is connected to the pace of aging in animal studies; all of the varied processes that help to clear cells of damaged molecules appears beneficial in this context.

Brown adipose tissue (BAT) protects against obesity, diabetes, and cardiovascular disease. During BAT activation, macroautophagy is inhibited, while chaperone-mediated autophagy (CMA) is induced, promoting thermogenic gene expression, adipokine release, oxidative activity, and lipolysis. Aging reduces BAT function and lowers levels of LAMP2A, the rate-limiting CMA component. Pharmacological CMA activation restores BAT activity in aged mice.

To explore the CMA's role in BAT, we generated LAMP2A-deficient brown adipocytes and found that CMA regulates proteins essential for thermogenesis and metabolism. Blocking CMA in BAT reduced energy expenditure, raised blood triglycerides, impaired secretion, and led to an increase of thermogenesis repressors. These findings show that CMA is essential for maintaining BAT function, especially during adaptive thermogenesis. By degrading repressors of thermogenesis, CMA supports BAT activity under cold or metabolic stress.

This work highlights CMA as a key regulator of BAT plasticity and a promising therapeutic target for treating age-related metabolic disorders.

Link: https://doi.org/10.1126/sciadv.ady0415

The broad category of glial cell includes all of the cells making up the nervous system that are not neurons. This includes the innate immune cells known as microglia, the astrocytes that manage brain metabolism and make up much of the brain's structure, the oligodendrocytes that maintain the myelin sheathing necessary for nerves to conduct electrical impulses, and a few other smaller or more localized populations. These are all very different cell types with very different functions, so one can't really talk about them in sweeping terms. Nonetheless, they all become dysfunctional with advancing age for the same underlying reasons, each population contributing to the complexities of brain aging, and in turn being negatively affected by other aspects of aging.

In today's open access review paper, the authors take a tour of what is known of both the ways in which glial cells contribute to the aging of the brain, and the ways in which the aging of the brain harms glial cell function. Aging is sufficiently complex that it is challenging to fully map all of the ways in which the various known changes and dysfunctions interact with one another. Robustly identifying cause and consequence is difficult when the consequence can in turn interact with the cause, and it isn't just one cause and one consequence, but rather an interacting network of effects and their outcomes, all of which can influence one another.

Interplay Between Aging and Glial Cell Dysfunction: Implications for Central Nervous System Health

At the molecular level, aging induces extensive reprogramming of glial cell gene expression, driven by the cumulative impact of epigenetic drift (defined as stochastic alterations in the epigenome that accumulate over time) encompassing changes in DNA methylation patterns, histone modifications, and chromatin remodeling. In aging glial cells, chromatin accessibility is often reduced at loci associated with neuroprotective and metabolic genes, while pro-inflammatory and stress-response genes might become more accessible, driving a maladaptive transcriptional shift. Mitochondrial dysfunction, a well-established hallmark of aging, plays a central role in this process. In glial cells, compromised electron transport chain efficiency reduces ATP production, impairing the high-energy-demanding functions of those cells. This inefficiency also leads to excessive production of reactive oxygen species (ROS), which induce oxidative damage on lipids, proteins, and nucleic acids.

Astrocytes, which play essential roles in maintaining central nervous system (CNS) homeostasis, supporting neuronal function, and regulating the blood-brain barrier (BBB), undergo a shift toward a reactive phenotype in response to aforementioned insults. Their reactive state is characterized by hypertrophy, increased expression of intermediate filament proteins like GFAP and vimentin, and the secretion of several pro-inflammatory mediators, such as IL-1β, TNF-α, and CCL2. Sustained activation of the NF-κB signaling pathway locks astrocytes into an inflammatory state, further impairing their neuroprotective roles. One functional consequence is the reduction in glutamate clearance due to decreased expression of excitatory amino acid transporters EAAT1 and EAAT2, creating conditions favorable for excitotoxic neuronal damage.

Microglia, the resident immune sentinels of the CNS, undergo a parallel but distinct aging trajectory, a process often known as microglial priming. With aging process, pattern recognition receptor pathways, particularly TLR4 signaling, become dysregulated, making microglia hyperresponsive to secondary insults including infections or trauma. Primed microglia exhibit amplified and sustained inflammatory responses, but paradoxically show reduced phagocytic efficiency, compromising the clearance of myelin debris, apoptotic cells, and aggregated proteins such as amyloid-β. Dysfunction in purinergic signaling, especially through P2X7 and P2Y12 receptors, further disrupts microglial chemotaxis and injury sensing. Autophagic flux declines with age, leading to lysosomal dysfunction, which traps damaged organelles and undigested materials inside the cell. This failure of clearance mechanisms sustains the presence of damage-associated molecular patterns (DAMPs) in the CNS microenvironment, perpetuating a self-reinforcing cycle of inflammation and neuronal stress.

Oligodendrocyte precursor cells (OPCs), the main source of new myelinating oligodendrocytes in the adult CNS, also exhibit significant age-related decline. Aging OPCs show impaired proliferation and differentiation capacity, largely driven by epigenetic repression of the genes implied in myelin synthesis, such as MBP and PLP1. Furthermore, OPCs become less responsive to mitogenic growth factors, including PDGF-A and FGF2, which usually promote OPC expansion and maturation. The loss of regenerative capacity impairs remyelination efficiency and contributes to the progressive degradation of white matter integrity, a crucial substrate for cognitive processing speed and executive function.

These issues are exacerbated by systemic aging factors, including chronic low-grade inflammation (known as inflammaging), characterized by increased levels of circulating pro-inflammatory cytokines, as well as alterations in metabolic hormones such as insulin and IGF-1. These systemic molecules facilitate glial senescence via activation of the cell cycle inhibitors p16 and p21, inducing an irreversible growth arrest that further impairs the CNS reparative and adaptive capacity. Over time, these converging cellular and molecular deficits create a CNS environment more susceptible to neurodegenerative processes. Furthermore, these glial modifications do not occur in isolation but rather within a complex and bidirectional interplay with aging neurons, vascular elements, and the immune system.

Aging begins long before evident loss of function arises. As researchers point out here, efforts to better map and intervene in the progression of these pre-symptomatic changes are not the primary focus of medical research and development. But attaining any degree of control over aging also implies the same degree of prevention of aging, meaning the ability to intervene early with therapies that repair the damage that would otherwise lead to greater dysfunction. Any rejuvenation therapy that shows efficacy in late stage disease should be even better as a way to prevent emergency of disease. Nonetheless, the historical focus on late stage disease in aging has already successful misdirected medical research and clinical practice into less beneficial approaches, and may continue to do so absent a cultural shift to focus more on prevention.

Aging is a multifactorial process that progressively disrupts cellular and tissue homeostasis, affecting all organ systems at distinct rates and predisposing individuals to chronic diseases such as cancer, type II diabetes, and sarcopenia. Among these systems, skeletal muscle plays a central role in healthspan decline, yet the precise onset of its deterioration remains unclear. Most studies emphasize late-life models, overlooking the transitional phase of middle age, when initial alterations emerge. Evidence indicates that middle-aged muscle exhibits aberrant metabolism, impaired insulin sensitivity, and an early, gradual reduction in mass, suggesting that decline begins long before overt sarcopenia, a pathologic loss of muscle mass and functionality after middle age.

Indeed, most of the in vivo research about skeletal muscle aging focuses on comparisons between old and young organisms, creating a gap in the field regarding mid-age alterations. This creates two problems: (i) it overlooks non-linear biomarkers that return to basal values in old age after an organism initiates compensatory response mechanisms, and (ii) it presents treatment mainly as a damage-control strategy after molecular and morphological alterations are already established. These "palliative" treatments may partially promote lifespan but have a limited impact on healthspan.

Therefore, we seek to summarize and identify biomarkers indicative of the onset of skeletal muscle aging from in vivo studies on young adults and middle-aged humans and rodents in an attempt to identify some of the chronological alterations. This review aims to contribute insights for future research seeking to prevent or delay the onset of sarcopenia.

Link: https://doi.org/10.3390/ijms262010145

Researchers here find a potential way to induce greater regeneration in injured heart muscle, normally a tissue that regenerates only poorly following damage, and particularly so in older individuals. Inducing CCNA2 expression appears to promote replication of the cardiomyocyte cells making up heart muscle. Still, a great deal of work remains in order to build a viable gene therapy based on this finding and assess it in a clinical trial. The direct delivery of a gene therapy to heart muscle is perhaps more viable than is the case for other internal organs given the range of established minimally invasive surgical procedures developed for use in the cardiovascular field. One can envisage a therapy that is delivered alongside the procedures normally carried out for patients following a heart attack.

When someone has a heart attack or heart failure, heart muscle cells are lost and the heart cannot replace them. There is no current way to grow new heart muscle cells after damage. Researchers wanted to know if they could reawaken the heart's ability to regenerate itself by using a naturally occurring pathway that enables cardiomyocyte (heart muscle) cell division in utero. They focused on CCNA2 - a gene that is normally silenced after birth - and turned it back on in adults to see if this would help grow new heart cells and help the heart heal.

The research team built a replication-deficient human-compatible virus that carries the CCNA2 gene and delivered it to heart muscle cells. They tested it directly in living adult human heart cells in culture from healthy donor hearts. Researchers used time-lapse imaging to analyze the heart cells with CCNA2 and saw these cells divide successfully, while still keeping their normal structure and function.

More specifically, researchers looked at three healthy hearts from donors who were 21, 41, and 55-years-old. Cyclin A2 therapy triggered these adult human heart cells to divide in the 41- and 55-year-old hearts. Conversely, cells from hearts belonging to a 21-year-old showed no change when given the CCNA2 therapy. This latter finding aligns with previous studies that show younger hearts do have regenerative potential and that their cells are capable of dividing without the stimulus provided by CCNA2.

Link: https://www.eurekalert.org/news-releases/1103140

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