Fight Aging!

A number of approaches to inducing muscle growth or improving muscle strength have been demonstrated in laboratory animals, in early human clinical trials, and in recent years employed in medical tourism clinics. These approaches are compensatory in the context of aging, they do not address any of the underlying issues that lead to loss of muscle mass and strength per se. An adjustment of the regulation of muscle growth to favor more growth will produce larger, stronger muscles at any age, which may help to generate greater attention and use of such therapies as they are developed.

These varied approaches directly interfere in cell signaling in some way, as it is easier to adjust the levels of circulating proteins and other molecules, or their ability to interact with cell surface receptors, then it is to adjust mechanisms that operate inside cells. Inhibition of myostatin signaling and upregulation of follistatin signaling are the presently dominant approaches. The use of antibodies targeting myostatin has been assessed, but more effort is now put toward upregulation of circulating follistatin via forms of gene therapy.

In today's open access paper, researchers discuss upregulation of a different signaling protein, FGF19. This does appear to have the effect of reducing myostatin levels, but that it only increases muscle strength rather than muscle mass suggests that other mechanisms are driving the outcome. Some indication has been given in recent years that these various strategies to grow muscle or improve muscle strength may also have a positive impact on bone mineral density. Unfortunately that doesn't seem to the be the case for FGF19.

Therapeutic potential of FGF19 in combatting osteosarcopenia: effects on muscle strength and bone health in aged male mice

Osteosarcopenia, characterized by the coexistence of osteopenia/osteoporosis and sarcopenia, represents a significant health concern in geriatrics, with an increased risk of falls and fractures. The enterokine fibroblast growth factor 19 (FGF19) was recently shown to prevent muscle weakness in preclinical models. This study investigated the therapeutic potential of FGF19 in mitigating bone and muscle deterioration in aged male mice. Twenty-one-month-old C57BL/6 male mice received daily injections of human recombinant FGF19 (0.1 mg/kg) for 21 days.

Histological and functional analyses revealed a shift toward larger muscle fibers in FGF19-treated mice as well as an increased muscle strength, without affecting muscle mass. In parallel, X-ray microtomography showed that FGF19 had no overt negative impact on bone, with a range of modest, site-specific, and opposing effects. In the distal femur metaphysis FGF19, it reduced cortical thickness, but significantly increased bone cross-sectional area, with an overall increased polar moment of inertia, a geometrical parameter linked to favorable mechanical properties. It also elevated cortical bone porosity in the same region. There were no significant effects on trabecular bone or cortical bone parameters in the proximal femur side. In the L2 vertebra, cortical porosity decreased. Histomorphometry of trabecular bone and analysis of transcriptional output of selected genes in femurs revealed only minor changes in bone cellular activities and gene expression after three weeks of treatment.

In conclusion, FGF19 treatment increased muscle strength in aged male mice, without negatively impacting aging bone.

The raised blood pressure of hypertension is damaging to sensitive tissues throughout the body, but particularly the brain. Alongside many other issues in the health and function of the vascular system, hypertension increases the pace of rupture of tiny blood vessels in the brain, each such event destroying a small volume of brain tissue. Over time this adds up to degrade cognitive function and contribute to the development of outright dementia. Thus high blood pressure is harmful, and the longer the period of time in which blood pressure is elevated, the more harm is done. Here, researchers assess cumulative blood pressure over time and find a correlation between high, sustained blood pressure and a large increase in the risk of dementia.

Cumulative blood pressure (BP), which takes into account both the magnitude and duration of BP exposure, is linked to cognitive impairment. The Chinese Longitudinal Healthy Longevity Survey (CLHLS) over 16 years was divided into two consecutive sub-cohorts, namely the 2002 sub-cohort from 2002 to 2011 and the 2008 sub-cohort from 2008 to 2018. Cumulative BP exposures were calculated as the area under the curve derived from two consequence BP measurements and their corresponding time intervals.

A total of 2,142 and 1,920 cognitively healthy older adults participants from the two sub-cohorts were included in the analysis, respectively. Over a median follow-up of 6.2 years and 7.0 years, 542 and 347 older adults experienced cognitive impairment in the two sub-cohorts, respectively. Higher cumulative systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) were significantly associated with a higher risk of cognitive impairment. Compared to the lowest quartile in the two sub-cohorts, the hazard ratios for cognitive impairment risk in the highest quartile were 1.85 and 2.64 for cumulative SBP, 2.00 and 2.20 for cumulative DBP, and 1.59 and 2.10 for cumulative PP, respectively.

Link: https://doi.org/10.1186/s12877-025-06465-9

Provoking regrowth of tooth enamel by mimicking some of its structure appears to be a going concern in dental research, if judging from this paper and another similar approach using keratin. At the high level, the idea is to coat damaged enamel with material that encourages the chemical mineralization process that takes place during enamel formation. Interestingly, the specific molecular structures demonstrated here allow this process to take place even when applied to exposed dentin. We can hope that cavities and fillings will soon enough be a thing of the past.

Tooth enamel is characterised by an intricate hierarchical organization of apatite nanocrystals that bestows high stiffness, hardness, and fracture toughness. However, enamel does not possess the ability to regenerate, and achieving the artificial restoration of its microstructure and mechanical properties in clinical settings has proven challenging.

To tackle this issue, we engineer a tuneable and resilient supramolecular matrix based on elastin-like recombinamers (ELRs) that imitates the structure and function of the enamel-developing matrix. When applied as a coating on the surface of teeth exhibiting different levels of erosion, the matrix is stable and can trigger epitaxial growth of apatite nanocrystals, recreating the microarchitecture of the different anatomical regions of enamel and restoring the mechanical properties.

The study demonstrates the translational potential of our mineralising technology for treating loss of enamel in clinical settings such as the treatment of enamel erosion and dental hypersensitivity.

Link: https://doi.org/10.1038/s41467-025-64982-y

The aging of the blood vessels supplying the brain into a state of dysfunction provides an important contribution to the onset and progression of neurodegenerative conditions. There are many aspects to this vascular aging, including: loss of capillary density over time that reduces the ability of the vasculature to deliver sufficient nutrients to cells in brain tissue; the atherosclerosis that narrows and weakens major vessels with fatty deposits; the disruption of normal function of the endothelium, the inner layer of blood vessels; disruption of the normal function of the smooth muscle that controls contraction and dilation of vessels; leakage of the blood-brain barrier, the specialized cells that line blood vessels in the brain and control which molecules are allowed to pass; and so forth. Aging is a disruption of all normal functions, in one way or another.

In today's open access review, researchers take at look at the phenomenon of endothelial-to-mesenchymal transition, a feature of aging in which endothelial cells change their state and behavior to take on the characteristics of mesenchymal cells. This is detrimental to the function of surrounding tissue, which depends on cells of a specific type continuing to act as that type. As the authors note, while the causes of endothelial-to-mesenchymal transition are only partially understood, there is evidence to link its occurrence to mechanisms of aging, and particularly to the chronic inflammatory signaling that is a feature of aged tissues. There are many ways in which continual, unresolved inflammation changes cell behavior for the worse, making it an important target for future medical control over aging.

Endothelial-to-mesenchymal transition in the central nervous system: A potential therapeutic target to combat age-related vascular fragility

Age-related dysfunction of the central nervous system, including cognitive impairment and visual disorders, is a major concern for the aging population, affecting health span and quality of life. Age-related vascular dysfunction in the central nervous system includes an increase in blood-brain or blood-retina barrier permeability, an increase in vascular fragility, and impaired neurovascular coupling, contributing to cognitive impairment and vision loss. While these pathologies occur in the brain and eye with age, gaps remain in our understanding of the underlying cellular mechanisms.

During the process of endothelial-to-mesenchymal transition (EndMT), endothelial cells lose their characteristic endothelial phenotypes, which are critical for vascular function, such as barrier integrity, and transition to a mesenchymal-like phenotype. Too little is understood regarding the interplay between triggers associated with physiological aging and the process of EndMT in both non-disease and disease-related contexts in the central nervous system. This highlights a field ripe for exploration, as many age-related processes have also been shown to be triggers of EndMT. For example, many of the inflammatory factors found in the senescence-associated secretory phenotype generated by senescent cells are triggers of EndMT.

Here, we review what is known about the role of EndMT in vascular fragility in the aging brain and eye, explore the mechanistic links between endothelial cell transdifferentiation and age-associated vascular pathologies of the central nervous system, and identify potential therapeutic targets ripe for future exploration with the goal of preserving vascular function with aging by regulating EndMT.

Nicotinamide adenine dinucleotide phosphate (NADP) has a different portfolio of functions in the cell to the better known nicotinamide adenine dinucleotide (NAD) that has been a focus for parts of the research community in recent years. NADP is thought to be primarily important as a defense against oxidative stress. Here, researchers discuss the role played by insufficient levels of NADP in vascular aging, finding that it encourages greater cellular senescence in the vascular endothelium, thus promoting endothelial dysfunction as a contribution to cardiovascular disease. Thus strategies to increase NADP levels may act to usefully improve the state of the aged vasculature, better protecting it from dysfunction.

Age-related cardiovascular diseases are featured by changes in arterial function or phenotype. Moreover, microcirculation possesses a unique ability to influence the microenvironment of majority of the organs. Thus, understanding the molecular mechanisms of vascular aging is central to tackle age-related cardiovascular disease. The vascular endothelium is a single layer of cells covering the lumen of vascular vessels and plays an important role in maintaining vascular homeostasis. Numerous studies suggest that senescence of vascular endothelial cells leads to initiation and progression of cardiovascular diseases.

Nicotinamide adenine dinucleotide phosphate (NADP, oxidized form: NADP+, reduced form: NADPH) has long been recognized as a key cofactor for redox defense and reductive biosynthesis. Intracellular NADPH consumption and production in different compartments of the cell are independently regulated. While traditional enzymatic cycling assays, mass spectrometry, and chromatography have been used to monitor whole-cell NADPH pool, they require cell homogenization and cannot differentiate compartmental NADPH pools, where it regulates distinct functions. Here, we employed a highly responsive and genetically encoded NADPH sensor and revealed that cytosolic NADPH was elevated during endothelial cell senescence.

Decreased nitric oxide concentration promoted G6PD activity leading to elevated NADPH levels. G6PD overexpression significantly elevated NADPH level, inhibited glutathione oxidation and HDAC3 activity, and suppressed endothelial cell senescence and vascular aging. These results suggest that G6PD/NADPH pathway is upregulated by stimulators of vascular aging, and it plays a casual role in limiting endothelial cell aging. Furthermore, high-throughput metabolic screening of 1419 drugs approved by the Food and Drug Administration found that folic acid significantly elevated NADPH content via MTHFD1 and augmented vascular activity in naturally aged mice. These findings highlight a beneficial role of endothelial NADPH metabolism in vascular aging.

Link: https://doi.org/10.1038/s41467-025-64652-z

Thin sheets of engineered artificial tissue can be readily manufactured because they do not require a vasculature, perfusion of fluids is sufficient to support the cells. For some years now, researchers have developed the capability to manufacture thin heart tissue patches. A number of preclinical studies in various animal models have demonstrated that applying these patches to an injured heart promotes greater regeneration and restoration of function than normally takes place. Here, the technique is combined with a minimally invasive form of surgery as a proof of concept, and used in rats following heart attack to promote greater regeneration.

For years, scientists have been working on ways to replace damaged tissue with healthy heart cells derived from stem cells. Early efforts showed promise, but most required open-heart surgery - a procedure too risky for many patients already struggling with severe heart failure. Scientists have long hoped that stem cells could provide a way to rebuild what the body cannot. By reprogramming ordinary adult cells such as skin or blood cells into induced pluripotent stem cells (iPSCs), researchers can coax them into becoming replacement heart cells. But safely and effectively delivering engineered heart tissues made from these cells has remained a major challenge.

With this in mind, researchers developed a flexible, paper-thin patch made of nano- and microfibers coated with gelatin. This hybrid scaffold supports a blend of human heart muscle cells, blood vessel cells, and fibroblasts - cells that form the tissue's structural framework - to create a living, beating piece of heart tissue. Before transplantation, the tissue is infused with bioactive factors such as fibroblast growth factor 1 and CHIR99021 that encourage the growth of new blood vessels and help the cells survive once they are in place.

"The beauty of this design is that it can be folded like a piece of paper, loaded into a slender tube, and delivered precisely where it's needed through a small incision in the chest. Once in place, it unfolds and adheres naturally to the heart's surface." Testing in preclinical rat models showed that the minimally invasive method improved heart function, reduced scarring, enhanced vascular growth, and lessened inflammation compared with conventional approaches.

Link: https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-researchers-identify-a-new-stem-cell-patch-to-gently-heal-damaged-hearts/

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