Fight Aging!

A great many approaches to therapy work because they adjust the behavior of macrophage cells. These innate immune cells are found throughout the body. They are deeply involved in the fine details of tissue maintenance, in addition to being capable of mounting a defense against pathogens and malfunctioning cells when called upon to do so. Macrophages adopt different packages of behavior in response to circumstances, and one can argue that maladaptive behavior patterns in macrophages in aged tissues are responsible for some fraction of degenerative aging: chronic inflammation, disruptions to tissue structure and function, and so forth. The simple model of macrophage polarization is that M1 macrophages are inflammatory and aggressive, while M2 macrophages are anti-inflammatory and focused on tissue maintenance. This may be too simple a model, however, even given that a range of research and development efforts are focused on coercing macrophages into one or the other state - typically M1 for cancer therapies, and M2 for other age-related conditions.

Today's open access paper is an interesting tour of the issues with painting macrophage categories in broad strokes. The authors note that the reality under the hood is a great deal more complex, circumstantial, and tissue-specific. The subtypes of M1 and M2 macrophages are likely as different from another as is the case for subtypes of T cell or B cell. Still, there is more enough evidence for alterations to macrophage behavior to be beneficial in the right circumstances for the research and development communities to continue to show a great deal of interest in this line of work. Most of the clinical stage work to date has focused on encouraging macrophages to attack cancerous cells. It remains to be seen as to how and when the regenerative medicine side of the house will catch up, with novel treatments that encourage macrophages to become more involved in tissue maintenance and suppression of the chronic inflammatory signaling characteristic of aging.

Macrophage reprogramming in degenerative musculoskeletal diseases: From tissue-niche biology to therapeutic translation

Degenerative musculoskeletal diseases (DMSDs), including osteoarthritis (OA), osteoporosis (OP), intervertebral disc degeneration (IVDD), and sarcopenia (SP), impose a major burden through pain, structural deterioration, mobility loss, fracture risk, and functional decline. Although these disorders are often grouped as age-related musculoskeletal conditions, they arise from distinct tissue niches and cannot be explained by a single pathogenic mechanism. Macrophages occupy a central position at the interface between degenerative stress and tissue outcome, but their functions extend far beyond a binary M1/M2 polarization model.

This review proposes a disease-niche-adapted framework for macrophage reprogramming in DMSDs. In this framework, macrophages are interpreted according to the pathological tasks they perform within each tissue environment: inflammatory amplification and pain-related synovial crosstalk in OA, osteoimmune remodeling in OP, immune-barrier disruption and macrophage-nucleus pulposus (NP) cell feedback in IVDD, and impaired regenerative support in aging muscle in SP. We discuss how macrophage functional states are shaped by transcriptional and epigenetic regulation, immunometabolic rewiring, inflammatory signaling, autophagy and organelle quality control, and local niche-derived cues.

Therapeutic strategies are then evaluated according to whether they interrupt upstream niche stress, redirect inflammatory and metabolic decoding, restore quality-control capacity, or reshape macrophage-mediated tissue communication. Finally, we propose that macrophage-targeted therapy should be assessed through a hierarchy of evidence, progressing from marker changes to functional reprogramming, macrophage-causal validation, and disease-specific structural or functional improvement. This framework may help convert macrophage plasticity from a broad immunological concept into a more precise, testable, and disease-adapted therapeutic strategy for musculoskeletal degeneration.

Researchers here report on the development a senostatic treatment, one that reduces the pace at which cells become senescent in aged tissues. This allows the immune system to catch up on its clearance of senescent cells, and thus the overall burden of senescence is reduced over time. The big question regarding this sort of approach is whether it will still allow senescence to occur when it should occur, such as in wound healing and potentially cancerous cells. Senostatics that act through upregulated autophagy, such as rapamycin, are demonstrated to be quite safe in this regard in mice. Novel mechanisms would need the same sort of proof, but since this mechanism involves SIRT1 activity one might be optimistic that it will be beneficial.

The deacetylase SIRT1 is a critical regulator of cellular senescence, and the excessive accumulation of senescent cells can further drive the onset of organismal aging. SIRT1 activity is tightly governed by posttranslational modifications, including ubiquitination. While ubiquitination has been well documented to control SIRT1 protein stability, the precise regulatory pathway underlying SIRT1 activity remains poorly understood. Here, we identify the deubiquitinase USP25 as a central regulator of cellular senescence. Specifically, USP25 deficiency in mice mitigates age-related phenotypes and improves overall physiological function.

Mechanistically, USP25 directly interacts with SIRT1 and mediates its deubiquitylation via K63-linked polyubiquitination, specifically targeting SIRT1 lysine residues K506 and K513, which ultimately suppresses SIRT1 deacetylase activity. Reduced SIRT1 deacetylase activity, in turn, increases P53 or PGC1α acetylation, which further increases the transcriptional activation of downstream target genes and consequently accelerates cellular senescence. Furthermore, we developed a cell-penetrating peptide, pSirt1-4, that efficiently disrupts the USP25-SIRT1 interaction, increases SIRT1 deacetylase activity, and attenuates cellular senescence.

Collectively, our findings establish USP25 as a critical regulator of aging and highlight the USP25-SIRT1 axis as a promising therapeutic target for treating senescence-related diseases.

Link: https://doi.org/10.1111/acel.70786

The composition of the gut microbiome changes with age for reasons that are not fully explored, but likely involve the progressive failure of the immune system to remove problem microbes. Inflammatory microbial species grow in number while microbial species producing metabolites necessary to tissue function are reduced in number. There is considerable evidence for this change of composition to contribute to degenerative aging, but in humans that evidence is all correlational. From a scientific perspective there is thus a great deal of work yet to be accomplished to obtain a firm map of the problem and how exactly the problem contributes to specific conditions and aging more generally. Nonetheless, even prior to that point it is sensible to try to further develop and run clinical trials for approaches to rejuvenation of the gut microbiome such as flagellin immunization and fecal microbiota transplantation.

Age-related changes in gut microbiota metabolism are heterogeneous across populations and pathways, and their relationships with immunometabolism and organ phenotypes should be interpreted in the context of health status and disease. Microbial abundance or the concentration of a single metabolite does not, by itself, capture microbial production, host exposure, or effects in target tissues. This narrative review summarizes upstream influences, including gastrointestinal physiology, dietary substrates, comorbidities, and medications, and discusses the origins and host processing of major metabolites, their immunometabolic effects, and associated organ phenotypes.

Studies in some older populations report lower fecal short-chain fatty acid concentrations. Microbiota-derived indole derivatives and host-synthesized, microbiota-modified bile acids show molecule- and population-specific patterns. Circulating concentrations of some host-microbe co-metabolites are higher in selected older or disease populations, but are also shaped by host biotransformation and clearance. Human evidence is predominantly observational and links metabolic features to health status or clinical phenotypes, whereas animal and cell studies support effects on barrier function, inflammation, and cellular metabolism under specific experimental conditions. Personalized nutrition, metabolite supplementation, selective targeting of microbial enzymes, and multi-omics-based responder stratification are promising research directions; prospective evidence that these strategies improve functional outcomes in older adults remains limited.

Link: https://doi.org/10.3389/fnut.2026.1984798

A sizable number of humans have received first generation stem cell therapies, with considerable variation in protocols and sources of cells. Only a small fraction of these patients and treatments resulted in data that was robustly recorded and made available to the rest of the world, as only a small fraction of those patients were participants in clinical trials. Stem cell therapies (and, given more time, likely exosome therapies as well) have an entirely justified reputation as being unreliable in outcome. The available evidence suggests a fairly reliable reduction in chronic inflammation for a period of months, but whether or not a patient exhibits improved function in tissues, and to what degree, is a roll of the dice.

One of the reasons why the world at large, patients, clinicians, and researchers alike, continues to engage with these forms of therapy, beyond the point that reducing chronic inflammation is a highly desirable outcome, is that a broad range of animal studies do show improvements in tissue function, extension of life, and reversal of measures of disease to result from stem cell or exosome therapies. Today's open access paper is a concise review of a few dozen such studies. One might think that where there is smoke there is fire, and perhaps the unreliability in human patients is caused by an incomplete understanding how small differences in protocol and cell culture give rise to large differences in the quality of the therapy, and perhaps one can just pick the right clinic and the right technicians. Those patients with bad results thought just the same way as those with good results, of course.

Stem Cell and Exosome Treatment for Organ Health and Longevity

Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into a variety of different types of human cells, including, but not limited to, bone, cartilage, fat, muscle, and nerve. MSCs can be isolated from various tissue sources, such as umbilical cord, placenta, dental pulp, bone marrow, and fat. MSCs and exosomes have anti-inflammatory, pro-healing, and immunomodulatory effects. MSCs exert these effects by secreting growth factors and cytokines such as transforming growth factor-1 (TGF-β1), prostaglandin E2 (PGE2), and hepatocyte growth factor (HGF) which assist with modulating the body's immune response. MSCs also secrete extracellular vesicles (EVs) such as exosomes, microvesicles, and apoptotic bodies. These EVs, exosomes in particular are small vesicles, approximately 100-200 nanometers in diameter and have emerged as potential therapeutic options in various disorders, as they contain various proteins, miRNA, and DNA.

Stem cells have been shown to be effective in treating a variety of disorders. They are also often promulgated as effective in improving overall health and increasing lifespan in otherwise clinically healthy individuals. However, there are limited evidence-based studies examining the effects of stem cells and exosomes on longevity and the potential for improved health in nonpathological human organs. While there is a general agreement that stem cells and exosomes have potential to be helpful to organ aging and longevity, there has not yet been a comprehensive, evidence-based evaluation of this thought.

Through a review of the scientific literature, we sought to determine whether there is scientific evidence to support the use of MSCs and exosomes to reverse tissue and organ aging, improve function, and increase longevity and overall health in the absence of specific disease states. We chose a total of 34 different preclinical studies using stem cells and/or exosomes that were performed in mice, rats, or macaques. We believe that these 34 studies were an adequate amount for this review to showcase the anti-aging effects of MSCs, exosomes, and EVs. Stem cell treatment appears to increase longevity, and both stem cell and exosome treatments are effective in rejuvenating and improving tissue and organ function in mammalian systems. Stem cells can extend overall mammalian lifespan. Transplantation of bone-marrow derived mesenchymal stem cells can restore bone density in mice. MSCs have a regenerative effect on aging muscles in mice. Both stem cells and exosomes have a rejuvenative effect on animal organ systems. Stem cells and exosomes improve organ function in the absence of pathological states.

The present natural human lifespan is determined by an evolved balance between (a) reduced tissue maintenance that slowly leads to tissue failure, frailty, and death versus (b) continued tissue maintenance that steadily increases the risk of cancer and abrupt death. A growing burden of mutational damage throughout the body with advancing age makes the activities of cell maintenance (particularly replication in stem cell populations) ever more likely to result in cancer. That risk of cancer is lowered by reduced tissue maintenance, at the cost of a slower mortality via other causes. One of the mechanisms by which tissue maintenance is dialed down in later life is a reduction in sex hormone production. This occurs slowly over time in older men, and fairly abruptly in older women at menopause. The size of this effect can be observed in data such as that presented here, showing that women who either undergo menopause later or were using hormone therapy exhibit a reduced burden of neurodegeneration.

Women are disproportionately affected by Alzheimer's disease (AD), a vulnerability that may relate to estrogen fluctuations across the lifespan. Estrogen has neuroprotective and vasoprotective effects, suggesting that lifetime estrogen exposure may influence both AD-related neurodegeneration and cerebrovascular health. However, its association with late-life vascular and neurodegenerative brain changes remains unclear. We aimed to examine the associations of lifelong estrogen exposure - endogenous (reproductive span) and exogenous (oral contraceptives, menopausal hormone therapy) - with late-life vascular brain injury and AD-related atrophy and explore apolipoprotein-ε4 (APOE-ε4) effects.

This population-based study included cognitively unimpaired women from the Gothenburg H70-1944 Birth Cohort who underwent brain MRI at age 70 and again 5 years later. Among 352 women (mean age 70 years), longer reproductive span was associated with lower cerebral small vessel disease burden (odds ratio = 0.92). Menopausal hormone therapy use was associated with fewer perivascular space enlargements and cerebral microbleeds. Oral contraceptives and menopausal hormone therapy use were associated with greater white matter integrity, with combined use showing the highest fractional anisotropy compared with nonusers (β = 0.45). No multiplicative interaction between oral contraceptives and menopausal hormone therapy was observed, although joint exposure analyses suggested cumulative effects. Menopausal hormone therapy use was associated with greater AD-related cortical thickness among APOE-ε4 carriers only (β = 0.38). Longer estrogen exposure was associated with stable cortical thickness and white matter hyperintensity trajectories over time.

Link: https://doi.org/10.1212/WNL.0000000000218706

Senescent cells are constantly created throughout life, but accumulate in aged tissues as a result of a growing age-related failure of the immune system to promptly clear these cells. Evidence suggests that one contribution to this lack of clearance is that senescent cells in aged tissues increasingly employ immune evasion markers. The research community has already mapped a range of immune evasion markers in the context of cancer, and at least some of these are also employed by senescent cells. This suggests that some of the approaches to therapy developed in the cancer research community may also help to enable the aged immune system to better clear lingering senescent cells.

Cellular senescence arrests cell cycle progression in response to diverse stressors. When such cells persist in aging tissues, they acquire a senescence associated secretory phenotype (SASP) that promotes chronic inflammation, tissue dysfunction, and age-related pathology. This raises a key question. If senescent cells display a pro-inflammatory profile that should recruit immune cells for clearance, why do they instead evade elimination and accumulate with age? The PD-1/PD-L1 immune checkpoint is known for its role in tumor immune evasion, and recent evidence indicates that it operates similarly in senescence. Senescent cells upregulate PD-L1, engage PD-1 on cytotoxic T cells and natural killer cells, and thereby dampen their own immune clearance.

The upstream signals that drive PD-L1 upregulation in senescent cells have not been fully defined. We propose that the DNA damage response (DDR), a conserved signaling network rapidly activated by genotoxic stress, acts as a key upstream driver of PD-L1 expression in senescence through both transcriptional and post-translational mechanisms, thereby linking senescence-associated genomic instability to immune checkpoint activation. The DDR can be engaged by multiple senescence-associated stressors, including telomere dysfunction, oxidative damage, and replication stress. DDR signaling drives PD-L1 expression through two distinct routes: transcriptional induction via the cGAS-STING pathway and post-translational stabilization through p16-mediated inhibition of CDK4/CDK6. The DDR-PD-L1 axis thus forms a self-reinforcing circuit that perpetuates senescent cell accumulation and immunosenescence.

Link: https://doi.org/10.3389/fcell.2026.1974523

Few interventions have been demonstrated to slow aging or address age-related damage to a sufficient degree to extend mouse life span by 15% or more if applied starting at a late age. The requirement to start late in life cuts down the field of possibilities quite dramatically. Today's open access paper stakes a claim for inhibition of asparagine endopeptidase activity to be included in the small number of interventions capable of this sort of outcome. The researchers started treating mice at 18 months of age, roughly equivalent to 50-something in humans, and saw a four month gain in median survival, from 24 to 28 months. For comparison, this is in the same ballpark as the results of rapamycin treatment started in late life in mice.

Rapamycin is a calorie restriction mimetic, with benefits to cell function, tissue function, health and aging emerging through increased efficiency in the operation of the cellular maintenance processes of autophagy. This improves mitochondrial function by better clearing dysfunction mitochondria, helps cells resist entering a senescent state and thus reduces the burden of senescence in aged tissues, and helps ameliorate a range of other noted contributions to the aging process. Inhibition of asparagine endopeptidase activity arrives at a similar outcome via a different path; again better mitochondrial function and a reduced burden of senescence, though here this is argued to arise from a direct improvement of mitochondrial metabolism that may or may not involve improved autophagy.

Inhibition of asparagine endopeptidase extends the lifespan and improves health span during aging

Asparagine endopeptidase (AEP), alternatively referred to as legumain (LGMN), is a cysteine protease activated under acidic conditions and belongs to the C13 peptidase family. As an enzyme, AEP specifically cleaves its substrates after asparagine residues and is primarily localized to the endo-lysosomal system; however, under pathophysiological conditions, AEP is also localized in the cytoplasm or in the nucleus. Increasing evidence links aberrant AEP activation to multiple age-associated pathological processes, particularly in tissues exposed to lysosomal stress and chronic inflammation. In this state, AEP cleaves a range of target proteins, generating fragmented, often pathogenic, versions that contribute to cellular dysfunction. Aging is also associated with a decline in autophagy, the cell's recycling process. Dysregulated AEP activity may contribute to this decline by perturbing lysosomal function and proteolytic homeostasis, leading to the accumulation of damaged proteins and organelles.

Our findings support the idea that AEP is involved in multiple aging-associated pathological processes and that pharmacological inhibition of AEP may ameliorate several age-related phenotypes. In the current work, AEP inhibitor #11a alleviated multiple frailty indices in both male and female mice and was associated with attenuated age-related decline in physical and cognitive functions. In parallel, #11a reduced NAMPT cleavage and was associated with higher NAD-related readouts together with elevated SIRT1 and PGC-1α levels. #11a treatment was also associated with improved insulin sensitivity and reduced adiposity-related changes in brown adipose tissue and inguinal white adipose tissue. Furthermore, #11a reduced senescence-associated β-galactosidase staining and lowered several senescence- and inflammation-associated markers in multiple organs. Together, these observations are consistent with our recent report that administration of nicotinamide mononucleotide (NMN) or #11a ameliorates age-related disorders and extends lifespan in Thy1-C/EBPβ transgenic mice and worms, further supporting AEP as a therapeutically relevant target.

Our data support a model in which inhibition of AEP via #11a suppresses NAMPT cleavage and is associated with improved NAD-related readouts, thereby potentially contributing to reduced senescence-associated changes. Although these findings are consistent with a model in which #11a modulates the AEP-NAMPT-NAD+/SIRT1/PGC-1α pathway, the current evidence remains largely correlative in naturally aged mice. Additional causal studies will be needed to determine the extent to which this pathway is required for the survival and health span phenotypes observed here.

A cell is a bag of finely tuned molecular machinery moving at incredible speeds, pieces of that machinery ramming into one another countless times per second. Damage occurs constantly, a matter of inappropriate chemical reactions, broken proteins, misfolding of proteins, the machinery degraded and broken. Numerous different quality control mechanisms act to remove unwanted and damaged proteins, activities that are absolutely necessary to cell survival and correct operation. These include the various forms of autophagy, in which proteins are flagged and conveyed to a lysosome for recycling, the activities of proteasome complexes that directly break down proteins, and the unfolded protein response that steers the processes of protein synthesis to try to minimize the output of misfolded proteins. All of these are known to falter with age, for reasons yet to be fully explored.

Aging is a universal biological process signified by a time-dependent decline in physiological activity, driven by molecular and cellular damage, leading to greater susceptibility to diseases and fatal outcomes. Impaired proteostasis is a key aspect of cellular aging in which the cells become less efficient at folding, repairing, and recycling proteins, consequently inducing accumulation of damaged and aggregation-prone proteins. The onset of muscle loss is driven by a reduction in protein synthesis, heightened activation of proteolytic pathways, and elevated endoplasmic reticulum (ER) stress factors, collectively contributing to functional decline and increased vulnerability with aging.

Muscle atrophy, whether age-related or driven by chronic illness, represents a major role in defective health, impacting both quality of life and survival. This review explores the intricate and multidimensional nature of proteostasis network regulating protein quality control across skeletal muscles. We examined how the malfunction of components within proteostasis networks during aging contributes to the induction, progression, and chronicity of common age-related muscle wasting. Experimental and clinical studies exploring potential therapeutic strategies for better proteostasis in muscle wasting have been discussed.

In this review, we emphasized the increasing demand for effective therapeutic interventions that can slow down or mitigate age-related deterioration in muscle physiology and sustain mobility and quality of life in the elderly. We analyzed the roles of ubiquitin proteasome system, autophagy lysosomal pathway, and unfolded protein response in muscle wasting, highlighting protein loss from synthesis-degradation imbalance as a major driver of muscle atrophy under catabolic conditions. This review outlines key findings with emerging insights to help drive the development of targeted therapies against muscle wasting. Looking ahead, emerging approaches such as PROTACs, extracellular vesicle-based therapies, and artificial intelligence-driven predictive models hold promise for advancing precision interventions in muscle wasting research.

Link: https://doi.org/10.1016/j.exger.2026.113373

The supplement industry exists in its present vocal form because most people don't care about effect size at all. Or accuracy. Or truth. They hear that something has an effect, and run out to buy it. The industry marketing is tuned to take advantage of this aspect of human nature. But what are the expected effect sizes for the better end of supplement strategies? This study reports on the effects of a combination supplement that rolls in some of the more interesting compounds assessed in recent years, including glycine - though of course at much lower doses than those used in the small GlyNAC study that showed quite surprisingly large benefits in old patients. Since no-one cares about effect size, why go to the trouble of delivering doses larger than are convenient? Nonetheless, the study results provide an illustrative data point to add to others when managing expectations regarding what to expect from a sane strategy of supplementation.

A growing body of evidence suggests that specific nutritional bioactives, such as polyphenols, amino acids, and micronutrients, can beneficially modulate nitric oxide signalling, oxidative stress, autonomic balance, and endothelial health. While several compounds have shown efficacy individually, vascular ageing is driven by multiple converging mechanisms, raising the possibility that broader, multi-target approaches may provide additive or synergistic benefits. Because vascular ageing arises from several interacting mechanisms, single-compound interventions may only influence part of the underlying biology. A multi-component nutritional approach allows targeting several complementary pathways simultaneously while using lower doses of each ingredient, which may improve tolerability and minimize the risk of dose-related side effects. However, clinical evidence evaluating such combined strategies in humans remains limited.

We hypothesized that daily consumption of a multi-component nutritional supplement would improve endothelial function and related indices of vascular ageing compared with control. Accordingly, in this randomized, double-blind, controlled trial, we tested whether a formulation selected to combine ingredients with relevance to complementary biological pathways implicated in vascular ageing was associated with changes in endothelial function, arterial stiffness, haemodynamics, lipid profile, and estimated cardiovascular risk in healthy middle-aged and older adults (≥40 years).

The primary outcome was change in brachial artery flow-mediated dilation (FMD). Secondary outcomes included pulse wave velocity (PWV), peripheral and central blood pressure, augmentation index, lipid profile, and estimated 10-year cardiovascular risk (SCORE2/SCORE2-OP). Sixty-one participants (baseline SCORE2/SCORE2-OP 3.6 ± 2.9%) were randomized (33 actives; 28 controls); 43 completed both visits (24 vs. 19). Compared with control, the supplement improved endothelial function (ΔΔFMD at 6 months +2.9% ) and reduced arterial stiffness (ΔΔPWV -1.18 m/s). Peripheral systolic blood pressure (SBP) decreased (ΔΔSBP -6.1 mmHg). Lipids were unchanged. Estimated 10-year cardiovascular risk decreased (ΔΔSCORE2/SCORE2-OP -0.45%).

Link: https://doi.org/10.1093/ehjopen/oeag157

Cerebrospinal fluid flows through the brain and out into the body, particularly during sleep. One of the important functions of this drainage of cerebrospinal fluid is the removal of metabolic waste from brain tissue. This waste material includes the pathological protein aggregates implicated in the onset and progression of common neurodegenerative conditions, such as amyloid-β, α-synuclein, tau, and TDP-43. The primary paths of drainage are collectively known as the glymphatic system. Measure of glymphatic drainage decline with age, and are particularly negatively impacted in patients with Alzheimer's disease and other neurodegenerative conditions. Impaired cerebrospinal fluid drainage is coming to be seen as an important component of the aging of the brain. Initial consideration has been given to approaches to treatment, and evidence exists for a number of ways forward: intermittent CO2 exposure; small molecules capable of restoring lost lymphatic pulsatile function; small molecules that can reduce mislocalization of water channels in astrocytes; and so forth. Matters are still some years removed from the commercial development of therapies, however, even if there are things that can be tried by the knowledgeable and the adventurous.

Today's open access paper reports on an attempt to better map exactly why it is that fluid flow in the brain declines. Working with a mouse model of Alzheimer's disease, the researchers provide evidence for loss of fluid flow to occur as a result of dysfunction in specific locations in the brain's circulatory system. Their work also suggests that this dysfunction in fluid flow is a downstream consequence of dysfunctional lipid metabolism in the aging brain. It is well known that brain accumulates too much cholesterol with age, and in recent years the negative effects of excess cholesterol on microglial function contributing to chronic inflammation has become a favored line of inquiry when it comes to the question of why lipid metabolism dysfunction contributes to neurodegeneration. Here, however, quite a different set of mechanisms are proposed to explain how excess cholesterol can cause a dramatic decline in cerebrospinal fluid flow.

Brain-wide Cerebrospinal Fluid Recirculation Collapse in Alzheimer's Disease

The exchange between cerebrospinal fluid (CSF) and interstitial fluid (ISF) is fundamental for supplying nutrients from the vasculature to diverse neural cells and for clearing metabolic waste generated by brain activity, thereby maintaining central nervous system homeostasis. Beyond basic neuroprotection, the importance of this fluid dynamics - conceptually framed as the glymphatic system - has been increasingly recognized for its role in flushing out molecules ranging from small solutes to large protein aggregates through multiple paravascular, paravenous, and lymphatic routes.

Models indicate that parenchymal transit of fluid likely requires an active, yet-to-be-identified structural or packaging system to facilitate macromolecular delivery, a hypothesis that traditional diffusion-centric models fail to address. Furthermore, while previous imaging studies have largely focused on dorsal or lateral cortical surfaces, the macroscopic fluid dynamics within the ventral base of the brain - where major cerebral arteries such as the Circle of Willis (CW), middle cerebral artery (MCA), and olfactory artery (OlfA) branch and distribute - have been remarkably underexplored.

Understanding this full circulation loop is essential, particularly because the progressive failure of CSF transport and glymphatic clearance is increasingly implicated as a core pathology in neurodegenerative disorders such as Alzheimer's disease (AD). Pathological studies reveal that exposure to amyloid-beta (Aβ) induces severe neurovascular dysfunction, impairs macrophage function, and provokes the loss of perivascular AQP4 polarization, thereby suppressing periarterial CSF influx and ISF clearance. In both clinical settings and AD mouse models, advanced imaging modalities, such as dynamic contrast-enhanced magnetic resonance imaging, consistently report profound reductions and spatial rerouting in global CSF flow. Yet, these observations merely report the consequence - a global flow reduction - without pinpointing the exact anatomical and microstructural bottlenecks.

Here, we reveal that macroscopic CSF propagates dorsally via the perivascular spaces (PAS) of major ventral arteries which undergo severe structural degradation in an AD mouse model. High-resolution imaging of the dorsal cortex demonstrates that this structural collapse induces a severe influx blockade; in AD, CSF tracers form massive aggregates within the PAS, physically decoupling the gliovascular interface, while tracers entering the parenchyma are pathologically sequestered by amyloid plaques.

Furthermore, we identify an active, cholesterol-mediated clearance mechanism responding to exogenous CSF tracer infiltration. While healthy brains rapidly synthesize and efficiently clear this cholesterol via vascular efflux within 120 minutes, the AD model exhibits blunted cholesterol mobilization and a complete failure of capillary efflux. This terminal bottleneck forces uncleared cholesterol to retrogradely accumulate into pathological aggregates within perivascular pericytes and neuronal somata. Collectively, our findings demonstrate that AD dismantles the entire CSF recirculation loop - from macroscopic ventral entry to terminal microvascular efflux - highlighting pericytic and neuronal lipidosis as fundamental drivers of brain fluid stagnation.

Regulatory systems in wealthier parts of the world ensure that a great many different compounds at different doses are entered into long-term toxicology studies primarily conducted in mice. Researchers here report on the results of looking through that data in search of compounds that improved health and extended life. Hormesis is the name given to the benefits to health and longevity resulting from mild exposure to stress, whether toxicity, heat, cold, lack of nutrients, and so forth. Cells have evolved to react with increased maintenance and defenses when placed under stress, and if the stress is mild and transient, then the overall outcome is a net benefit to cell and tissue function. It is thus reasonable to think in advance of checking that some toxicology studies incorporated doses that improved health rather than damaged it.

Efforts to extend longevity and healthspan have benefited from the use of in vitro systems, short-lived model organisms and computational approaches, but translation to humans depends on demonstrating efficacy and safety in mammalian in vivo models. However, rigorously controlled rodent lifespan studies are slow, costly, and low-throughput. Hormesis, the induction of adaptive stress response pathways by low-level toxic or metabolic challenges, provides a mechanistic means for improved resilience, but testing hormetic dose-response relationships in mammals is logistically challenging.

Regulatory long-term toxicity studies, mandated for chemical authorisation, routinely generate lifespan and chronic toxicity data from large cohorts across multiple dose groups and therefore represent an underused resource for detecting unexpected survival benefits. We mined a random subset of the German Federal Institute for Risk Assessment electronic archive for long-term rodent pesticide studies in ≥ 50 animals per dose and sex. From qualifying studies with 154 substances, we identified 27 substances (18% of entries) that significantly increased survival at study termination.

Fifteen publicly disclosable substances were examined further; roughly half perturbed mitochondrial oxygen consumption rates in mammalian cells, and bromoxynil acted as a mitochondrial uncoupler. Back-translation to Caenorhabditis elegans showed bromoxynil improved multiple healthspan indicators without compromising organismal health. Regulatory toxicity archives can thus be repurposed to identify candidate compounds, targets, and mechanisms for mammalian healthy ageing research, and complement conventional screening pipelines.

Link: https://doi.org/10.1111/acel.70797

Senescent cells accumulate with age and generate inflammatory secretions that are disruptive to tissue structure and function. Targeted clearance of some fraction of these lingering senescent cells in aged tissues via senolytic therapies has been shown to reverse aspects of aging and extend life in mice. The small human clinical trials conducted to date have shown, on balance, promising results. Spurred by the very impressive animal data, the research community has been searching for novel mechanisms for selective destruction of senescent cells and novel senolytics. Interesting new approaches emerge a few times every year, some of which are low cost supplements and plant extracts, such as the candidate noted here. Unfortunately low cost therapies do not tend to lead to compelling human data, as clinical trials are expensive to run; if there is no profit to be made, finding funding is challenging. Academic institutions can and do run trials, but relatively few of them, and rarely large ones. Indeed, most of the trials of low cost senolytic treatments conducted to date were both small and run by academic institutions.

Current intervention strategies targeting senescent cells are primarily categorized into two types: senomorphics (modulation of the senescent phenotype) and senolytics (elimination of senescent cells). Senomorphics aim to mitigate the inflammatory microenvironment by using drugs (e.g., the mTOR inhibitor rapamycin, metformin) to inhibit senescence-associated secretory phenotype (SASP)-related signaling pathways without affecting cell survival. In contrast, senolytics aim to solve the problem at its source by selectively inducing apoptosis in senescent cells to completely eradicate SASP production. Representative senolytics include the BCL-2 family inhibitor navitoclax and the classic combination of dasatinib and quercetin. The latter has been shown to effectively clear senescent cells and improve various age-related functional declines in animal models and has shown promising results in clinical trials for Alzheimer's disease (Phase I), idiopathic pulmonary fibrosis and diabetic kidney disease.

However, existing senolytic compounds still have room for optimization in terms of selectivity, potency or long-term safety. This has prompted researchers to turn to natural products with diverse structures and unique mechanisms to find a new generation of lead molecules, such as PCC1, fisetin, and halophyte extracts.

Based on this, our study first established a system for the quantitative screening of senolytic small molecules and identified a potential candidate - cepharanthine (CEP) - through high-throughput screening. CEP is a bisbenzylisoquinoline alkaloid extracted from plants of the Stephania genus, possessing a wide range of anti-inflammatory, antioxidant, and anti-tumor activities. Previous research suggested its potential to intervene in inflammation, hinting at its anti-aging value. However, whether CEP possesses clear senolytic activity and the unique molecular mechanisms underlying its selective clearance effect have not yet been systematically elucidated.

CEP selectively eliminates senescent cells by cooperatively and in parallel regulating the PI3K/AKT and PERK-ATF4-CHOP pathways, differentially inducing PUMA/NOXA and triggering mitochondrial intrinsic apoptosis. In zebrafish, C. elegans, naturally aged mice, and progeroid mice, CEP clears senescent cells, reduces SASP levels, improves organ function and prolongs lifespan.

Link: https://doi.org/10.1016/j.phymed.2026.158875

Writing a succinct few page introduction to present scientific thought on the driving mechanisms of aging and the present landscape of development of means of treating aging seems quite the tall order. The field is complex, aging is complex, much is in flux and important updates to present understanding arrive every few years. Where to start, what to include, and what to leave out? Today's open access paper is, for its short length, a good attempt. It is important for those on the inside who have access to every last fine detail to be able to summarize at least the shape of the field to those on the outside. Knowledge is a set of concentric rings, from the laypeople at the outside to researchers at the cutting edge in the very center. The primary task of those in each ring, often neglected, is not to look inward and learn, but to look outward and explain well.

The authors of today's paper put forward their view on what we should take away from the data obtained to date on mechanisms of aging and their treatment, which is that the growing burden of cellular senescence in aged tissues plays a central, important role in degenerative aging. While numerous companies are developing forms of senolytic therapy to selectively destroy senescent cells, few have yet undertaken clinical trials. While novel approaches to clearing senescent cells or modulating their harmful behavior are discovered every year, the number of startup biotech and pharmaceutical companies focused on cellular senescence seems to have plateaued for now. This is a part of the field that, while well funded, could justifiably be funded to a much higher level than is presently the case. The mountain of animal data, that repeatedly, in scores of studies, demonstrates the capacity to rejuvenate tissues throughout the body and turn back the progression of age-related conditions, should be justification enough.

Biological mechanisms of ageing and potential therapeutic targets

Ageing is a natural and complex process that can be generally characterized by a slow and progressive physical and cognitive decline during adulthood, leading to impaired autonomic functioning and increased vulnerability to disease and death. It results from a series of biological changes that drive the accumulation of molecular and cellular damage over time, affecting cells, tissues, organs, and ultimately the entire organism. Thus, the classic view of ageing is linked to disease: one is the door that leads to the other, to the point that, socially, we associate both concepts and we see old people as sick and frail by default. Separating ageing from disease, and thus promote healthy ageing, is one of the biggest challenges of both science and the health systems.

Despite the growing insights into the biology of the ageing process, our current understanding on the complexity of multi-organ ageing and its dynamics is still limited. The first challenge is defining biological ageing itself. Currently, there is no consensus set of markers that can produce a list of organ-specific figures related to their actual biological age. Measurements of telomere length or epigenetic clocks are routinely used to estimate biological ageing, despite only covering one of the many facets of ageing. Moreover, although these are powerful tools to describe health associations in large populations, they are not designed for prediction of health at individual level, mostly due to their large variability. Thus, better makers of biological ageing are needed in order to have predictive tests with clinical impacts, and this will only come with a better understanding of the enormous complexity of the underlying molecular mechanisms of ageing.

Two major groups of theories to explain the mechanisms that lead to ageing have been proposed: the error-based and the program-based theories. The first consider ageing as a stochastic process caused by the accumulation of errors and damage in cells and tissues, both as a consequence of intracellular and external damages, as well as a less-effective system repair with time. This would include molecular processes like DNA damage, mitochondrial dysfunction, or telomere attrition. On the other hand, the program-based theories consider that individuals are partly genetically and developmentally quasi-programmed organisms and that healthy ageing would be the result of extending this programmed correctly functioning phase. As an example, there would be developmental pathways that keep working even past adulthood or mechanisms that are beneficial during the reproduction stage, like genes or certain hormones, that can be detrimental in the later stages.

There have been several attempts to classify the molecular mechanisms and biological processes associated with ageing. A landmark paper proposed 9 initial hallmarks of ageing, which were later expanded to 12, defined as factors that manifest with ageing and that, when aggravated or ameliorated experimentally, worsen or improve the ageing process. These hallmarks cover a wide variety of biological processes (from DNA damage to loss of stem cells or shortening of telomeres), but must of them seem to converge in what could be considered one of the most relevant hallmarks: the accumulation of senescent cells.

Most of the hallmarks related to stress (such as increased genomic instability, telomere shortening, metabolic changes, epigenetic changes, etc.) are potent inducers of senescence. In turn, senescence contributes essentially to other hallmarks, such as the alteration in intercellular communication or the depletion of stem cells. Moreover, the accumulation of senescent cells provides a clinically relevant target and is currently the hallmark that has more advanced therapeutic options in study. Although significant improvement of ageing phenotypes will undoubtedly require multimodal approaches, strategies to address the buildup of senescent cells in organs is likely to be the first pharmacological intervention to delay biological ageing that will be available to treat age-related diseases.

The dominant forms of cancer therapy, chemotherapy and radiotherapy, induce senescence in cancer cells they cannot kill, as well as in non-cancerous cells exposed to the treatment. Entering the senescent state is a response to a high level of stress and damage that isn't sufficient to kill the cell. A senescent cancer cell no longer replicates, and so promoting senescence continues to be seen as an acceptable goal to hinder the cancer. Cancer survivors are left with a high burden of cellular senescence, however, and as a result exhibit accelerated aging: higher mortality, higher risk of age-related conditions, including other cancers. Senotherapeutics such as senolytic drugs to selectively destroy senescent cells offer the possibility of dramatically reducing the consequences of an increased burden senescence induced by cancer therapies.

Therapy-induced senescence (TIS) has emerged as a central biological response to anticancer therapies, extending beyond tumor suppression to influence long-term tissue homeostasis, cardiovascular (CV) remodeling, and accelerated biological aging. Chemotherapy, radiotherapy, targeted therapies, and emerging immune-activating treatments can induce senescence not only in malignant cells, where it may initially contribute to tumor growth arrest and immune-mediated clearance, but also in non-malignant CV tissues. Persistent accumulation of senescent cells and sustained release of the senescence-associated secretory phenotype (SASP) represent a double-edged sword that may promote chronic inflammation and endothelial dysfunction while contributing to the exacerbation of multifactorial CV outcomes, including myocardial fibrosis, vascular stiffness, and progressive CV dysfunction.

Increasing evidence suggests that TIS-associated mechanisms - including persistent DNA damage response activation, p53/p21- and p16INK4a-mediated cell-cycle arrest, NF-κB-driven inflammatory signaling, mitochondrial dysfunction, oxidative stress, and metabolic rewiring - overlap with pathways involved in CV toxicity and systemic tissue remodeling. Through chronic inflammatory and immune-vascular crosstalk, TIS may contribute to a broader phenotype of inflammaging and therapy-associated premature biological aging.

Emerging senescence-targeting strategies, including senolytic and senomorphic therapies, represent promising approaches to mitigate long-term CV injury while preserving antitumor efficacy, although their clinical benefit and safety remain to be fully established. This review summarizes current knowledge regarding the dual and systemic role of TIS in cancer and CV disease, considering TIS as a candidate, non-exclusive mediator acting alongside direct therapy-related injury, and discusses its translational implications for integrated precision cardio-oncology strategies.

Link: https://doi.org/10.3389/fcvm.2026.1951892

Rentosertib is a TNIK inhibitor developed by In Silico Medicine in the course of the company's efforts to find drugs that can affect aging, shown to be anti-fibrotic, and thus recently in a phase 2 trial for the treatment of idiopathic pulmonary fibrosis. Here, the researchers provide evidence from multiple proteomic aging clocks to bolster the claim that this isn't just another anti-fibrotic drug candidate attempting to incrementally improve on what has come before, but does actually affect mechanisms of aging. There are of course already drugs that clearly affect mechanisms of aging to some degree - rapamycin and related rapalog molecules are perhaps the most robust when it comes to available data. But one can't raise the funds needed to run large trials to quantify and prove effects on aging in humans for a low-cost drug with no patent protection, as that drug cannot produce a large enough return on investment to motivate investors to fund the very expensive regulatory process. Thus the first drugs with robust data for modest effects on aging in humans will most likely be expensive, novel therapies. This is unfortunately the way the world works, or at least the way it works given the present approach to regulation of medicine.

Decades of progress in identifying mechanisms of aging and therapeutic targets to modulate them have revealed a tremendous overlap with central regulators of disease. Consequently, recent efforts in developing therapies to treat aging-related diseases often identify regulators of aging as promising disease targets. Drug repurposing efforts have highlighted the potential of treatments developed for one aging-related disease to modulate other aging-related diseases or longevity more generally, due to shared underlying pathway dysregulation coalescing around the hallmarks of aging. The aging field now faces a critical methodological question in translating biological insights into actionable clinical results: how best to measure the effects of an intervention on biological aging from data collected in clinical trials.

Proteomic clocks, by tracking the immediate effectors of biological change, may excel in providing aging biomarkers or mechanistic insight. Here we compare six proteomic clocks (ProtAge, OrganAgemortality, OrganAgechrono, PAC, ipfP3GPT and PAOPAC) on serum proteomes from a published 12-week phase 2a trial of the candidate anti-fibrotic drug rentosertib in idiopathic pulmonary fibrosis. We measure the variance between the clocks and find that all six clocks consistently predicted lower biological age in treated arms. However, proteomic clocks alone cannot deconvolute aging- and disease-specific effects. We addressed this issue indirectly through pathway analyses that identified potential anti-aging shifts in senescence and metabolic processes alongside the anti-fibrotic activity of rentosertib.

Link: https://doi.org/10.1038/s41587-026-03286-y