Fight Aging!

The most common metabolic diseases, such as type 2 diabetes or fatty liver disease leading to metabolic dysfunction-associated steatohepatitis (MASH), a fibrotic condition of the liver, are consequences of the dysfunctional state of metabolism that results from being overweight and sedentary. These conditions are rare in thin, fit people, even in later life when the damage of aging makes metabolism more vulnerable and inflammatory. Excess visceral fat tissue is known to promote the accumulation of senescent cells. While cells become senescent throughout life, in youth they are promptly cleared by the immune system. That clearance falters with age, allowing senescent cells to linger and accumulate. The metabolic dysfunction produced as a consequence of being overweight accelerates this process.

In today's open access paper researchers review what is known of the bidirectional relationship between metabolic dysfunction and the burden of senescent cells. Metabolic dysfunction promotes senescence, and in turn the inflammatory secretions of senescent cells further disrupt the operation of metabolically active tissues such as the liver. While a fair number of companies are presently developing senolytic drugs capable of clearing a meaningful fraction of senescent cells from the body, and while cheap first generation senolytic treatments, such as the dasatinib and quercetin combination, are readily available for anyone willing to put in a little effort to obtain them, metabolic disease is fairly low on the research and development communities' priority list. It seems unlikely that clinical trials will take place any time soon, but an increasing number of people are choosing to use senolytics off-label, an option that unfortunately generates very little solid data on whether or not a therapy is effective in any given use case.

Metabolically Active but Dysfunctional: The Impact of Senescent Cells and SASP

Cellular senescence and its secretory phenotype (SASP) have emerged as important contributors to chronic inflammation and metabolic dysfunction across multiple tissues. In adipose tissue, a combination of telomere attrition, oxidative stress, and pro-inflammatory signals pushes preadipocytes and mature adipocytes into premature senescence. These senescent adipocytes secrete a complex SASP, rich in cytokines, chemokines, and matrix-remodeling enzymes, that perpetuates local "metaflammation," impairs insulin signaling, and promotes systemic lipotoxicity.

In the liver, hepatocyte and stellate cell senescence similarly contribute to the progression of steatosis to MASH and cirrhosis, as SASP factors drive fibrosis, immune cell infiltration, and metabolic reprogramming. In the pancreas and skeletal muscle, senescence undermines β-cell function and glucose uptake, respectively, further exacerbating insulin resistance and hyperglycemia. Collectively, the cumulative burden of senescence and chronic SASP underscores a feed-forward cycle: metabolic stress induces senescence, and persistent SASP amplifies tissue dysfunction and accelerates disease progression.

Despite the protective role that acute, transient senescence can play in wound healing and tumor suppression, the accumulation of senescent cells in aged or obese individuals creates a pathogenic SASP milieu, often termed "inflammaging", that underlies obesity, type 2 diabetes, MASLD/MASH, and related cardiometabolic disorders. In rodent models, reducing senescent-cell marker burden has been associated with improved metabolic parameters, reduced fibrosis, and improved insulin sensitivity. These findings suggest translational potential for senotherapy in metabolic disease, although whether it can delay or reverse disease onset in humans remains to be established.

The research community remains very interested in finding novel ways to promote muscle growth with minimal side effects. Therapies that inhibit myostatin or upregulate follistatin signaling are under development, and follistatin gene therapies have been available via medical tourism for some years. But most of the research community is focused on pharmacology, the use of small molecules to influence muscle metabolism. As an example of this type of work, researchers here report on a small molecule that mimics adiponectin signaling to promote muscle growth in rats.

Skeletal muscle atrophy is a hallmark of ageing and chronic diseases, yet effective pharmacotherapies remain unavailable. Adiponectin signalling through receptors AdipoR1 and AdipoR2 regulates skeletal muscle metabolism, regeneration and oxidative capacity, but the therapeutic use of adiponectin is limited by its large size and complex multimeric structure. Small-molecule AdipoR agonists, therefore, represent an attractive therapeutic strategy.

Here, we report the discovery and pharmacological characterization of medicarpin, a previously described osteogenic phytoalexin and its water-soluble sodium salt (Med), as dual AdipoR1/R2 agonists, and demonstrate the efficacy of Med in vitro and in rodent models of skeletal muscle atrophy. Med enhanced myogenic differentiation, evidenced by increasing myotube formation and expression of MyoD, myogenin and MyHC. Med also enhanced oxidative capacity by increasing fatty acid oxidation and Med-treated cells showed elevated oxidative fibre markers.

Oral administration of Med significantly attenuated muscle atrophy in both rat models, evidenced by improved muscle morphology, suppressed atrogenes, enhanced myogenic markers and increased muscle adiponectin expression and corresponding downstream signalling. Med markedly improved muscle function, including grip strength, wire hanging, rotarod performance, and toe-spread ability of denervated limbs.

Link: https://doi.org/10.1002/jcsm.70364

Parkinson's disease and Lewy body dementia are synucleinopathies, characterized by the spread of misfolded α-synuclein through the central nervous system. The presence of misfolded α-synuclein provokes harmful changes in cell behavior and ultimately cell death in important populations of neurons. Researchers here explore differences in the vulnerability of different parts of the brain to the pathology produced by misfolded α-synuclein. They conclude that more complex parts of the brain, characterized by increased mitochondrial activity and greater connectivity between neurons, are more fragile in the face of the pathological mechanisms of syncleinopathy.

A total of 89 patients with dementia with Lewy bodies and 89 matched controls underwent T1-weighted brain MRI. Scans were processed to generate surface-based cortical thickness maps. Regional cortical thickness estimates, after slice-by-slice manual correction, were mapped to gene expression data from healthy postmortem human brains to identify transcriptomic signatures associated with decreased thickness in dementia with Lewy bodies. We assessed whether genes whose expression was increased with regional thinning converged onto established Parkinson's disease- and Alzheimer's disease-related pathways and identified genes uniquely implicated in dementia with Lewy bodies. Spatial annotation mapping was then used to test whether patterns of cortical thinning overlapped with in vivo neurotransmitter system distributions and whether the observed thickness pattern was constrained by large-scale structural connectivity, consistent with a network-based propagation process.

Cortical thinning predominated in regions that, in the healthy brain, show higher expression of genes involved in mitochondrial function and synaptic transmission. The transcriptomic profile associated with thinning significantly overlapped with genes belonging to Parkinson's disease and Alzheimer's disease pathways, supporting shared pathogenic mechanisms across Lewy body- and Alzheimer-type neurodegeneration. However, 90 genes associated with cortical thinning did not overlap with Parkinson's disease or Alzheimer's disease pathways and were enriched for GABAergic signalling. Spatial mapping analyses showed that regions with greatest thickness reductions colocalized with GABAA, serotoninergic 5-HT1A, 5-HT1B, 5-HT4, and dopaminergic D2 receptor distributions, and that the thickness pattern followed structural connectivity.

In conclusion, MRI-derived cortical thickness changes in dementia with Lewy bodies reflect selective molecular and network vulnerabilities rather than a non-specific degenerative process. Mitochondrial and synaptic genes, together with a distinct GABAergic association and connectivity constraints, delineate mechanisms explaining why some cortical territories are more affected in dementia with Lewy bodies.

Link: https://doi.org/10.1186/s12929-026-01267-6

Atherosclerosis is universal; everyone develops fatty atherosclerotic plaques in their arteries at some point, and to some degree. Plaques narrow blood vessels to impede blood flow, and rupture of unstable plaque causes heart attack, stroke, and embolism. It is the largest cause of human mortality, and at present the best that the medical community can do is to slow down plaque growth. Established therapies based on reducing the amount of cholesterol carried outward from the liver on low-density lipoprotein (LDL) particles produce something like a 15% mortality risk reduction at best, and do not regress plaque to any meaningful degree. Interestingly, the drivers of atherosclerosis are sufficiently complex and varied for there to be a few lucky people who exhibit 10% or more plaque regression in response to some combination of lifestyle change and medication. The flip side of that point is the majority of people who show up in a hospital in the immediate aftermath of a first heart attack or stroke do not in fact exhibit elevated LDL cholesterol, and probably benefit very little from the relentless clinical focus on LDL cholesterol.

It isn't all that easy to assess the degree of plaque present in the early stages of atherosclerosis. Imaging approaches have improved greatly over the past ten to fifteen years, but still struggle to distinguish small amounts of plaque. Little to no assessment takes place in the early stages of the condition. Many people have no idea as to whether or not they are in a high risk group until it is far too late. Simple risk factors are well understood, such as chronic inflammation, being overweight, suffering metabolic disease, and so forth. But as the discovery and continued research into the role of Lp(a) in atherosclerosis risk illustrates, there is a great deal yet to be catalogued of how exactly specific differences in metabolism yield differences in the pace at which atherosclerotic lesions emerge. It remains largely a mystery as to why any given person exhibits a given degree of atherosclerosis.

It does seem plausible that differences in atherosclerosis risk, onset, and progression, could correlate usefully well from specific differences in the configuration of the immune system, some of which are more likely (but not guaranteed) to exist in overweight, chronically inflamed, or metabolically dysfunctional people. Fundamentally, an atherosclerotic lesion is a consequence of macrophage dysfunction. Macrophages are innate immune cells responsible for clearing up excess cholesterol in blood vessel walls, and otherwise repairing damage. A lesion is a macrophage graveyard, perpetually calling in more macrophages, driving them into an inflammatory state, and killing them with its toxic mix of excess cholesterol and other lipids. Macrophages do not operate in a vacuum, however, and are strongly influenced by the activities of cells in other immune compartments. There is plenty of evidence for T cells of the adaptive immune system to affect plaque growth in animal studies, for example.

CD8+ effector memory and regulatory T cell dynamics predict subclinical atherosclerotic plaque formation in healthy aging

Age-related structural and functional changes in the arterial wall promote endothelial dysfunction and accelerate atherosclerosis development. Importantly, this process begins long before clinical symptoms appear. During this silent phase, early vascular damage and subclinical atherosclerotic plaque (SAP) formation may already occur but remain undetected. Detecting such early alterations is therefore crucial for improving prevention and enabling timely intervention. Immunological mechanisms and inflammation are increasingly recognized as central drivers of atherogenesis. T cells play a pivotal role in maintaining chronic vascular inflammation. Both CD4+ and CD8+ T-cell subsets modulate plaque biology through pro- and anti-inflammatory effects, whereas regulatory T cells (Tregs) exert protective effects by limiting immune activation and stabilizing plaque. Reduced Treg activity has been linked to accelerated vascular damage. In addition, a broad network of mediators, including cytokines such as Interleukin (I)L-1β, IL-6, IL-18, and tumor necrosis factor-alpha (TNF-α), contributes to endothelial activation, arterial remodeling, and plaque progression. Together with circulating proteins such as growth differentiation factor-15 (GDF-15) and osteoprotegerin (OPG), these immune-related pathways form a complex regulatory network that may provide early insight into emerging vascular vulnerability.

Previous cross-sectional work in a carefully characterized cohort of healthy, medication-free older adults with high cardiorespiratory fitness demonstrated that SAP were accompanied by distinct cellular and molecular immune signatures. Individuals with SAP exhibited hallmarks of immunosenescence, including reduced proportions of naïve CD4+ T cells, expansion of differentiated subsets such as CD4+ and CD8+ central memory cells, elevated inflammatory mediators, molecular features of cellular senescence, and alterations within Treg subpopulations. These findings underscored the pivotal role of immune system alterations in early plaque formation and suggested that immunological profiling may help identify individuals at increased vascular risk before clinical manifestation.

In a three-year longitudinal study, 49 healthy older adults (63.8 ± 3.8 years) underwent carotid ultrasound, T cell phenotyping, serum protein profiling, body composition assessment, and fitness testing at baseline and follow-up. At follow-up, participants were classified as no SAP, new SAP or persistent SAP. We analyzed baseline determinants and within-person changes to predict incident plaque formation. New SAP occurred in 30.3% of those initially plaque-free. At baseline, lower frequencies of CD8+ effector memory (EM) T cells and higher frequencies of CD8+ effector memory re-expressing CD45RA (EMRA) T cells and regulatory T cells (Tregs) were associated with higher odds of new SAP. Over time, expansion of CD8+ EM T cells was the most consistently associated independent variable of new SAP, accompanied by declines in Tregs and in the Treg/Teff ratio. Vascular cell adhesion molecule-1 (VCAM-1) at baseline was an additional independent predictor. Increases in visceral fat and declines in VO2peak were linked to new SAP, but immune markers were more robust than metabolic variables or serum cytokines.

Oligodendrocytes resident in the brain are responsible for maintaining the insulating myelin sheaths around axons that are required for the effective transmission of electrical impulses between neurons. Loss of myelin integrity is the cause of a number of debilitating conditions, but also occurs to some degree with aging. It has been an open question as to how large a contribution this makes to age-related cognitive decline. Researchers here provide evidence for age-related changes in oligodendrocyte behavior and myelin structures to be more complicated than the simple concept of reduced remyelination and loss of myelin integrity, and to correlate with meaningful differences in the trajectory of cognitive decline in mice.

The underlying mechanisms driving cognitive decline in aging remain unclear. Learning in humans in youth and adulthood is associated with increased central nervous system (CNS) myelin, the insulating membrane produced by oligodendrocytes that surrounds neuronal axons to facilitate rapid electrical impulse conduction and provide metabolic support. Furthermore, it is now well established that, in mice, learning requires an increase in oligodendrocytes through de novo generation. Cognitive impairment in aged mice and non-human primates is associated with reduced oligodendrocytes and myelin; however, the white matter pathologies driving human cognitive decline remain unclear. Indeed, although magnetic resonance imaging studies associate white matter abnormalities with cognitive decline in aged humans, the underpinning oligodendrocyte and myelin changes are unknown.

Here we uncover a role for oligodendrocytes in explaining the variance of cognitive decline with aging. By investigating neuropathological and transcriptomic changes in human white matter associated with individual rates of cognitive decline in aging, we find that worse cognitive trajectories unexpectedly associate with smaller myelinated axon size, thicker myelin and more oligodendrocytes with downregulation of NRF2. Aged oligodendrocyte-specific NRF2-knockout mice showed attenuated cognitive improvement over time and mirrored the white matter pathology of human cognitive decline in aging. These findings place the oligodendrocyte as a contributor to cognitive decline and highlight the NRF2 pathway as a therapeutic target to preserve cognition in human aging.

Link: https://doi.org/10.1038/s41591-026-04608-y

Blood tests to assess Alzheimer's disease risk and progression exist, for example based on the presence of circulating varieties of tau protein, but there is a great deal of room for improvement. Researchers here provide evidence for an approach to the measurement of very small amounts of misfolded amyloid-β in blood to work reasonably well in patients. The amyloid cascade hypothesis continues to steer much of the field of research and development for Alzheimer's disease; misfolded amyloid-β spreads slowly in the brain over years, and eventually causes sufficient dysfunction to promote a subsequent disease stage characterized by a feedback loop between chronic inflammation and tau aggregation. Tracking this growth in misfolded amyloid-β make sense as an approach to assessing risk and progression of the early stages of Alzheimer's disease.

A hallmark of Alzheimer's disease (AD) pathophysiology is the misfolding and aggregation of β-amyloid (Aβ) protein in the brain, which results in tau pathology, neuroinflammation, synaptic loss, neurodegeneration, and cognitive decline. The misfolded Aβ aggregates, or "seeds", range from small, soluble oligomers to large, insoluble fibrils that have a rich β-sheet secondary structure and are generally stable. Because of its specific structure, Aβ seeds corrupt natively folded Aβ and promote the aggregation and formation of pathogenic assemblies, which is a process similar to prion-like aggregation. Such a process follows a secondary nucleation mechanism in which new aggregates generate at a rate dependent on the concentration of existing seeds.

Based on this seeding nucleation mechanism, protein misfolding cyclic amplification (PMCA) has been developed to amplify trace amounts of misfolded proteins to a detectable level in biological samples. It uses repeated cycles of incubation and amplification for seed multiplication. However, the application of these techniques to AD diagnosis is relatively limited. In the present study, we detected plasma Aβ aggregation seeding activity using a real-time sonication-based PMCA method. A total of 549 participants were recruited between December 2020 and May 2024. Plasma Aβ aggregation seeding activity was measured using a real-time sonication-based protein misfolding cyclic amplification assay. The diagnostic performance of plasma Aβ aggregation seeding activity as a biomarker was assessed.

In the validation stage, plasma Aβ aggregation seeding activity exhibited high diagnostic accuracy with optimal cutoff values of 42.91 for distinguishing AD from cognitively unimpaired (area under the curve [AUC] = 0.93), 42.02 for AD from non-AD dementia, and 43.24 for mild cognitive impairment due to AD from non-AD dementia. Plasma Aβ seeding activity significantly correlated with cognitive functions (Mini-Mental State Examination [MMSE] scores: rs = -0.68; Clinical Dementia Rating [CDR] scores: rs = 0.71).

These findings indicate that plasma Aβ aggregation seeding activity could serve as a promising minimally invasive biomarker for identifying both AD and MCI due to AD. This biomarker potentially facilitates early detection and differential diagnosis of AD at different clinical stages.

Link: https://doi.org/10.1097/CM9.0000000000004142

Aging clocks can be readily produced by using what are by now well established machine learning techniques on any body of biological data that changes with age. Omics data is favored, as there are a great many databases of such data for large study populations, but clocks have been made using clinical chemistry results from simple blood tests, imaging data, and many other items. A clock is calibrated to predict age in the reference population, and when used on people outside that reference populations, most clocks tend to predict a higher age for people more greatly impacted by aging. Thus a higher clock age than chronological age tends to correlate with increased mortality risk, presence of age-related conditions, and so forth, at least over populations.

The most important goal for the development of aging clocks is to prove that one or more of them can be used to assess the quality of novel interventions in aging. Having a way to quickly assess whether or not a potential rejuvenation therapy is any good would transform the field, allowing researchers to rapidly focus on the best ways forward and optimize them. Unfortunately, there is no way to trust that a clock will be reliable in such circumstances other than to calibrate it against the intervention by running slow and expensive life span studies - which defeats the purpose. Unfortunately, there remains no well mapped direct connection between the data used to derive clocks and the underlying mechanisms of aging. Any given clock might underestimate or overestimate the effects of any given approach to treating aging, and whether that is the case or not is presently unknowable in advance.

The approach to this challenge taken by the research community is to gather as much data as possible on the behavior of as many different clocks as possible, both in animal studies and in human clinical trials. The hope is that out of this growing body of data, patterns and understanding will emerge as to which forms of clock, and which measures making up clocks, can be trusted. Today's open access paper is illustrative of progress on this front, an assessment of much of the human clinical trial data gathered to date for interventions that are known or hoped to affect late life health and life expectancy. Obviously, the catalog of interventions rigorously assessed in humans since the advent of aging clocks is at the present time largely modest in effect: exercise, diet (including calorie restriction), metformin, therapeutic plasma exchange, and so forth. Nonetheless, there is still something to be learned, even at the present state of progress.

Responsiveness of epigenetic aging biomarkers to longevity interventions in humans

Aging biomarkers can potentially allow researchers to rapidly monitor the impact of an aging intervention without the need for decade-spanning trials. However, before the use of aging biomarkers, such as epigenetic clocks, as surrogate endpoints, their responsiveness to interventions that target aging must be tested. Here we curate TranslAGE, a harmonized database of 51 public and private longitudinal interventional studies, and calculate a consistent set of 16 prominent epigenetic clocks for each study, along with 94 other DNA methylation (DNAm) biomarkers that can help explain the changes observed for each clock.

Using this database, we discover patterns of responsiveness across a variety of interventions and DNAm biomarkers. For example, clocks trained to predict mortality or pace of aging show the strongest responses across all interventions and show consistent results with one another; pharmacological and lifestyle interventions drive the strongest responses from DNAm biomarkers; and the characteristics of the study population and study duration are key factors in determining the responsiveness of DNAm biomarkers to an intervention. Moreover, clocks with multiple subscores (that is 'explainable clocks') provide specificity and greater mechanistic insight into the responsiveness of interventions than single-score clocks.

These findings can help to design future clinical trials by guiding the choice of interventions and of specific subsets of DNAm biomarkers to minimize multiple testing, study duration, study population and sample size, with the eventual aim of uncovering DNAm biomarkers that can be used as surrogate aging endpoints.

Here, researchers report on their investigation of gene therapy to introduce a bacterial enzyme, lipoic acid protein ligase A (LplA), into mammals in order to improve mitochondrial metabolism. LplA undertakes lipoylation of proteins, attaching lipoic acid to the protein, and does so somewhat more efficiently than the analogous enzymes in mammals. Lipoylation is known to be involved in the regulation of metabolism, and is largely researched in the context of conditions exhibiting lipoylation deficiency. Here, however, the focus is on enhancement of metabolism in healthy individuals over the course of aging. This is interesting work, but at the present time it would be very hard to convince investors to fund and regulators to approve the introduction of a bacterial protein into humans as a basis for therapy; there is a strong assumption that a negative immune reaction would result, and a consequently high bar set for proof that it doesn't.

As primary energy producers, mitochondria generate adenosine 5′-triphosphate (ATP) through efficient oxidative phosphorylation, but this process inevitably produces reactive oxygen species (ROS), which act as crucial signaling mediators at physiological levels yet become drivers of cellular aging and functional decline when accumulated excessively. Thus, an essential challenge involves maintaining an optimal balance between energy production and ROS management to achieve truly efficient and clean energy metabolism. This biochemical context raises the core question of whether interventions can be developed that enhance energy metabolism while simultaneously minimizing oxidative damage, thereby combining the benefits of both vitality and longevity.

Lipoylation is an essential posttranslational modification that directly influence the enzyme activity, and its substrates including enzymes serve as strategic metabolic gatekeepers. In higher eukaryotes, lipoylation is sequentially coordinated by multiple enzymes, whereas in Escherichia coli, a single enzyme, LplA, is sufficient to complete the entire process with remarkable efficiency. Our recent studies demonstrated that this bacterial enzyme not only rescues lipoylation deficiencies but also functions as a metabolic enhancer that significantly boosts energy production.

We conducted cross-species expression studies in Caenorhabditis elegans and mouse models and comprehensive physiological assessments across their life stages. The results demonstrate that this enzymatic intervention effectively enhances lipoylation and energy metabolism while lowering ROS level. The favorable metabolic state translates to broad physiological benefits, including enhanced motility and stress resistance in early life, and delayed age-related decline with extended health span when intervention begins later in life.

Link: https://doi.org/10.1126/sciadv.aef3262

One might think that an alteration to the machinery of gene expression that systemically changes the amino acid components of proteins, in effect giving all proteins the possibility of multiple single nucleotide polymorphisms, would be quite harmful. But some forms of mistranslation of RNA into protein actually extend life span, as demonstrated in flies. The reason why this happens is unknown at the present time. It is suspected that this is a hormetic effect of some sort, mistranslation triggering stress responses that clean up the cell for an overall benefit. The evidence presented here argues against a meaningful role for stress and stress response in mistranslation induced longevity, however.

Accurate translation of genes into proteins is critical to organism fitness, and errors in this process are usually detrimental and cause proteotoxic stress. Mistranslation occurs when the amino acid that is incorporated into the nascent polypeptide chain does not match what is dictated by the genetic code. Valine-to-serine (V→S) and threonine-to-serine (T→S) mistranslating models of the fruit fly Drosophila melanogaster have demonstrated a surprising, sex-specific increase in virgin female longevity. We predict that the added stressor of reproduction would eliminate this mistranslation-induced lifespan increase since females prioritize reproductive tissues over somatic tissues, and proteotoxic stress would therefore lead to higher protein damage and cell death in the somatic tissues of mated females.

We measured the impact of reproduction on V→S and T→S mistranslating D. melanogaster by measuring longevity, egg laying, and fecundity. Counter to our prediction, both V→S and T→S mistranslation led to a sex-specific increase in mated female longevity compared with nonmistranslating controls. Additionally, the risk of death decreased for mated females with mistranslation, beyond the pure additive benefits of mistranslation alone. These effects could not be explained by reduced egg laying or fertilization rates in mistranslating females. Thus, we find that the added proteotoxic stress caused by mistranslation does not exacerbate the detrimental effects of reproduction and instead can ameliorate lifespan decreases due to female reproduction.

Link: https://doi.org/10.1093/g3journal/jkag216

Osteoporosis results from the slow loss of bone mineral density that occurs with advancing age, eventually leaving bones dangerously weak and prone to fracture. Bone extracellular matrix is constantly remodeled throughout life: osteoblast cells build up the matrix while osteoclast cells break it down. With age, a variety of mechanisms tip the balance to favor osteoclasts and a slow loss of bone mineral density over time. A wide variety of drugs have been developed to reduce this imbalance, but the problem is far from solved, and none of the available therapies address underlying causes. Thus a sizable research community continues to work on the mechanisms driving osteoblast and osteoclast activity, in search of a better approach to the problem.

In today's open access paper, researchers investigate one of the mechanisms by which exercise improves bone mineral density. It is well established in human epidemiological studies that physical activity correlates with a slower pace of declining bone mineral density. That physical activity tends to reduce inflammation is one of the first places to look if seeking a deeper understanding, as chronic inflammation is strongly linked to osteoporosis, both in the epidemiology and in the present understanding of the underlying biochemistry. Beyond specifics relating to inflammation, this study implicates the gut microbiome and levels of TMAO in circulation in the body resulting from its activities as a contributing cause of metabolic changes leading to reduced bone mineral density.

Exercise is associated with attenuated aging-related osteoporosis through TMAO alpha Klotho inflammasome signaling

Osteoporosis is characterized by trabecular deterioration and loss of bone mass. The core pathology is an imbalance between osteoblast and osteoclast activity, driven by hormonal changes, low-grade inflammation, oxidative stress, and abnormalities of the bone marrow microenvironment. Regular exercise improves bone quantity and strength, yet the molecular pathways by which it acts in skeletal aging remain insufficiently defined. Trimethylamine N-oxide (TMAO) is generated from trimethylamine produced by gut microbial metabolism of dietary choline, phosphatidylcholine, and L-carnitine. Elevated TMAO has been linked to chronic low-grade inflammation, oxidative stress, and multisystem aging. Mechanistically, TMAO reportedly suppresses osteogenic differentiation, enhances osteoclast activity, and thereby promotes unbalanced remodeling and bone loss.

TMAO may also intensify inflammation by activating the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, a cytosolic multiprotein complex composed of NLRP3, the adaptor apoptosis-associated speck-like protein containing a CARD (ASC), and caspase-1. Activated NLRP3 promotes maturation and release of interleukin-1β (IL-1β) and interleukin-18 (IL-18), amplifying sterile inflammation and impairing osteoblast function. Conversely, the α-Klotho-TXNIP/NLRP3 signaling axis represents a critical nexus regulating oxidative stress and inflammation. α-Klotho functions as an anti-aging protein with antioxidant properties that restrain pathological signaling. TXNIP acts as a stress-responsive mediator that facilitates NLRP3 assembly and activation when protective regulation fails. We therefore hypothesized that exercise attenuates aging-related bone loss, at least in part, by reducing TMAO-associated stress and preserving α-Klotho-dependent restraint of the TXNIP/NLRP3 axis.

We combined an exploratory clinical comparison in adults aged 65 years and older with a D-galactose aging rat model and osteoblast-like cell experiments to examine exercise-associated changes in TMAO and inflammasome signaling. Higher habitual activity in older adults was associated with higher hip bone density T scores, lower serum and fecal TMAO, reduced IL-18 and IL-1β, and a turnover profile favoring bone formation. In aged rats, exercise lowered circulating and femoral marrow TMAO, preserved trabecular architecture, improved maximal load, and restrained TXNIP-NLRP3 signaling while maintaining α-Klotho. In osteoblast-like cells, TMAO promoted senescence and inflammasome assembly, whereas pathway modulation reduced these effects. These data support a gut bone inflammatory framework for exercise-associated skeletal protection in aging.

Researchers here show that a few different senolytic approaches improve the state of the population of microglia in the white matter of the brain in aged mice. This is much as one might expect, given past work into the effects of clearing senescent cells on cognitive function and neurodegeneration in various mouse models. Microglia are innate immune cells of the brain. The presence of senescent and inflammatory microglia is important in the age-related disruption of normal function in the brain, and removing them is beneficial. Sadly, little progress has been made to date in assessing established low-cost senolytic drugs in patients with neurodegenerative conditions; one small clinical trial was conducted for Alzheimer's disease, and that is about it.

Brain white matter undergoes structural and functional alterations linked to late-life cognitive decline, but the cellular and molecular basis of its selective vulnerability remains incompletely defined. Here, in naturally aged mice, we demonstrate that senescent and disease-associated microglia (DAM) phenotypes converge in hippocampal-adjacent white matter, particularly in the fimbria. Using regional gene expression profiling, GeoMx immunolabeling, digital spatial profiling and CosMx spatial molecular imaging, we identify an aged brain-exclusive microglial population concentrated in white matter that expresses DAM genes together with a 'SenBrain' senescence gene signature, including galectin-3 (GAL3/Lgals3).

Single-cell spatial trajectory analyses suggest that multiple cell fate transitions may give rise to this aged, proinflammatory, senescent- and DAM-linked state. Pharmacogenetic or pharmacological senotherapeutic interventions reduced white matter GAL3+ DAM abundance and restored a more youthful microglial organization in aged fimbria. These findings identify a senescence- and DAM-enriched microglial state as a prominent and partially reversible feature of aged brain white matter.

Link: https://doi.org/10.1038/s43587-026-01154-7

Amyotrophic lateral sclerosis (ALS) is characterized by the loss of motor neurons. Aggregation of TDP-43 is thought to be involved in producing cell death in the brain. Here researchers present evidence in a mouse model of ALS for microglia to destroy motor neurons, and identify key cell surface features that enable this activity. Whether the model is good and this will also be the case in human tissues is the usual question when considering mouse models of neurodegenerative conditions. These models tend to embody assumptions about the cause of disease, using genetic and other techniques to force the existence of specific mechanisms, as mice normally do not develop the feature of brain aging found in humans. Thus one can end up with an artificial mouse condition that resembles the natural human condition, but is not the same in important aspects.

Activation of microglia is a prominent feature of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease that leads to the death of motor neurons. A key component of this activation is elevated expression of the TAM receptor tyrosine kinases Axl and Mer (gene name Mertk). Here we show that germline and microglial-restricted inactivation of the Axl and Mertk genes in the SOD1G93A mouse model of ALS leads to an extension of lifespan, which is tied to the preservation of cholinergic motor neurons and neuromuscular synapses.

Also elevated on SOD1G93A neuronal surfaces is the essential TAM co-ligand phosphatidylserine, a potent 'eat-me' signal through which apoptotic cells are engulfed by microglia. Correspondingly, we find that microglial lysosomes are filled with the remains of cholinergic neurons in the SOD1G93A spinal cord, whereas this accumulation is markedly reduced in the SOD1G93A cord when Axl and Merkt are deleted. Together, these results suggest that microglia phagocytically kill living neurons, and thereby hasten death in ALS.

Link: https://doi.org/10.1038/s41467-026-76728-5

Glaucoma is a condition of progressive blindness driven by the death of retinal cells and degeneration of the optic nerve. It is driven by increased pressure in the aqueous humor, which fills a fluid compartment behind the cornea and also flows into the rest of the interior of the eye. Aqueous humor is produced at some pace in the ciliary processes of the interior of the eye, and drains at some pace through structures known as the trabecular meshwork at the front of the eye. Creation and drainage must be balanced to maintain pressure, but with age, drainage can become significantly impaired because of structural changes in the trabecular meshwork, causing pressure in the eye to increase. That increased pressure places stress on the structures of the back of the eye, ultimately leading to retinal cell death and blindness.

In today's open access paper, researchers investigate how exactly retinal cells die in the environment of excessive intraocular pressure. They provide evidence for high pressure to be disruptive to mitochondrial function in retinal cells, an effect that appears to arise because high pressure sabotages the processes of autophagy that help to maintain mitochondrial function by selectively destroying worn and malfunctioning mitochondria. When this mitochondrial quality control is significantly impaired, cells become overtaken by poorly functioning mitochondria and eventually die. The researchers show that pharmacological restoration of autophagy to more helpful levels via a small molecule mTOR inhibitor reduces the harm done to retinal cells by excess intraocular pressure, preserving mitochondrial function and cell function in the retina.

Pharmacological restoration of impaired autophagy in retinal ganglion cells prevents abnormal mitochondrial accumulation and glaucomatous neurodegeneration

Progressive loss of retinal ganglion cells (RGCs) and degeneration of optic nerve (ON) axons are the key pathological hallmarks of glaucoma, the leading cause of irreversible blindness. Elevated intraocular pressure (IOP), primarily due to dysfunction of the trabecular meshwork (TM), remains the most significant and only known modifiable risk factor. However, vision loss persists in some patients despite effective IOP control, highlighting the critical need to elucidate the mechanisms driving glaucomatous neurodegeneration. Emerging evidence links mitochondrial dysfunction to glaucomatous neurodegeneration, yet the precise mechanisms remain poorly defined. Here, we investigate whether defective autophagy/mitophagy, which removes damaged mitochondria, contributes to mitochondrial accumulation, oxidative stress, and neurodegeneration in glaucoma.

Glucocorticoid (GC)-induced and myocilin (MYOC)-associated glaucoma mouse models were used to assess the expression of mitochondrial markers in retinal tissues. Transmission electron microscopy (TEM) was employed to analyze mitochondrial accumulation. Chronic IOP elevation led to increased mitochondrial accumulation, oxidative DNA damage, and impaired mitophagy/autophagy in glaucomatous retina. TEM analysis further confirmed the accumulation of structurally abnormal mitochondria in glaucomatous ON. In mice, chronic IOP elevation significantly reduced mitophagy flux prior to RGC loss, indicating that mitophagy impairment precedes neurodegeneration.

Interestingly, enhancing autophagy using the pharmacological mTOR inhibitor Torin 2 restored mitochondrial health and prevented glaucomatous neurodegeneration in both mouse model of glaucoma and ex vivo cultured human retinal explants. Our results demonstrate that impaired autophagy and mitochondrial turnover drive glaucomatous neurodegeneration, while enhancing autophagy restores mitochondrial function and promotes neuroprotection.

Properties of the extracellular matrix that supports cells change with age. Increased stiffness is common in many tissues as a result of chemical cross-linking and other changes. Researchers here report on a proof of concept in vitro study in which increased stiffness of the local matrix is shown to promote gene expression changes in cells characteristic of aging. Reducing the stiffness reverses those changes. So one might argue that ways to repair the extracellular matrix in living tissues could rejuvenate cell behavior and tissue function to some degree.

While the development of ever more sophisticated artificial extracellular matrix materials is a notable part of the field of tissue engineering, efforts to modify the natural extracellular matrix in living tissues are not well funded, and little progress has been made in those areas in which benefits are thought likely, such as finding ways to remove age-related accumulation of cross-links. Indeed, many aspects of the chemistry of the aged extracellular matrix are not well understood, and it is far from clear as to which of the many possible approaches will yield the most useful results if successful.

Aging involves the accumulation of molecular alterations within cells and the extracellular matrix, resulting in cellular senescence and declining physiological functions. This study investigates the correlation between the biophysical environment and cellular aging, specifically examining how mechanical and biochemical cues affect cellular senescence and tissue degeneration. Cells were cultured on acrylamide hydrogels of different stiffnesses (4 and 19 kPa), and their mechanical properties were characterized by measuring Young's modulus via compression tests. Cell proliferation, morphology, gene and protein expression, and autophagy activity were assessed using multiple assays and imaging techniques.

Cells cultured on stiff hydrogels exhibited elongated morphologies, whereas cells on soft hydrogels formed spherical clusters. Notably, longevity-associated genes were upregulated in cells cultured on softer substrates. Reversibility experiments demonstrated that the aging phenotype could be reversed by modulating mechanical culture conditions, with softer environments enhancing autophagic activity. In summary, hydrogel stiffness significantly impacts aging-related cellular behavior. These findings suggest biomechanical cues as a promising strategy to promote cellular rejuvenation and combat aging.

Link: https://doi.org/10.3390/cells15151380

The composition of the gut microbiome, the population size of each bacterial species, changes with age. Microbes that provoke inflammation increase in number, while microbes producing a range of metabolites necessary for tissue function diminish in number. Animal studies have demonstrated that restoring a youthful composition of the gut microbiome in old animals, such as via fecal microbiota transplantation from young donors, improves health and extends life. Here researchers take a systems view of the role of the gut microbiome in degenerative aging. Nothing changes in isolation, all tissues in the body interact with one another, and that includes the commensal microbial populations we live with.

Symbiotic relationships are the basis of biological complexity. It can be traced back from ancient mitochondrial acquisition to modern host-microbiota interactions. In this review, we explore aging and disease susceptibility through the lens of a diet-microbiota-host gene triad, a dynamic symbiotic network in which dietary inputs, the gut microbiota, and the host genome co-regulate physiological equilibrium. The symbiotic triad evolved as nutrition was outsourced, with dietary and microbial components internalized by the host. Dietary components modulate microbial composition and metabolic activity. In contrast, microbial fermentation of nutrients produces short-chain fatty acids, vitamins, bile acids, and neuroactive compounds, which, in turn, influence host gene expression, immune responses, barrier integrity, nutrient preferences, and health.

Host genes have also co-evolved as critical modulators of this triad, encoding nutrient sensors, immune effectors, and proteins that maintain microbial balance and prevent dysbiosis. Polymorphisms in key metabolic and immune genes fine-tune responses to dietary and microbial adaptations, building resilience across different contexts. As organisms age, this triadic equilibrium destabilizes, leading to reduced microbial diversity, compromised barrier integrity and function, and chronic inflammation that accelerates age-related pathologies. Therefore, understanding dietary, microbial, and genetic interdependencies and viewing aging and disease from this perspective offers a blueprint for developing personalized nutrition- and microbiome-targeted therapies to combat age-associated diseases and promote health and longevity.

Link: https://doi.org/10.3389/frmbi.2026.1872481