Fight Aging!

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

The immune system is very complex, and immune cells exist in a continuum of states rather than being separated into clearly demarcated pigeonholes of behavior. Many of the categorizations applied to immune cells, largely based on cell surface marker differences, are conceptually useful, but also greatly oversimplify a complex reality. Sometimes one has little need of the deeper details, and it is certainly true that modern medicine has come a long way on a very incomplete map of immune system details, but equally sometimes the deeper details are critical to understanding how the immune system behaves and can be manipulated for benefit in a given situation.

Today's open access paper provides an example of one nice, neat category of immune cells fraying at the edges because the reality is somewhat more complicated than a simple categorization can account for. T cells of the adaptive immune system that bear the CD4 marker are viewed as regulators that control immune responses via signaling, while their CD8+ T cell peers take on the actual work of killing malfunctioning cells and infectious pathogens. In today's open access paper, however, researchers note the evidence for some CD4+ T cells to be quite capable of killing cells and pathogens, and argue for this subpopulation of CD4+ T cells to be important in the progression of aging, in ways both helpful and harmful.

Cytotoxic CD4+ T cells across aging: a conceptual framework for health, protection, pathology, and age-associated diseases

T cells are broadly classified into CD4+ and CD8+ subsets, with CD4+ T cells traditionally regarded as helpers that orchestrate immune responses through cytokine production, e.g. by Th1, Th2, Th17, follicular helper T (Tfh), and regulatory T (Treg) cell subsets. In contrast, direct cytotoxic activity has long been attributed primarily to CD8+ T cells. However, accumulating evidence has revealed the existence of cytotoxic CD4+ T cells (CD4 CTLs) that express cytotoxic granules, including perforin and granzymes, resembling the effector machinery of CD8+ T cells and natural killer (NK) cells.

CD4 CTLs arise under conditions of repeated or prolonged antigen exposure, such as chronic viral infections and the tumor microenvironment, where they provide an additional layer of immune surveillance against targets that may evade CD8+ T-cell-mediated immunity. More recently, senescent cells have been identified as previously unrecognized cytotoxic targets of CD4 CTLs, suggesting a role for these cells in limiting senescent-cell accumulation. Conversely, aberrant CD4 CTL programs have also been implicated in pathogenic processes, including autoimmune and neurodegenerative diseases, as well as severe COVID-19.

In this review, we use the term CD4 CTLs operationally to refer to CD4+ T cells that display a bona fide cytotoxic effector program, ideally supported by perforin/granzyme expression together with clonality, antigen experience, and/or direct killing activity; CD4+ T-cell subsets that express only partial cytotoxic modules or overlapping markers are discussed as related but not automatically equivalent states. Given the age-associated surge in susceptibility to infection, cancer, autoimmunity, and neurodegeneration, understanding the dual roles of age-expanded CD4 CTLs is of critical importance. These cells represent a double-edged sword: while they can contribute to host protection by recognizing viruses, malignant cells, and senescent cells as nonself, their loss of self-tolerance or inappropriate deployment may drive tissue destruction. Importantly, these beneficial and pathological functions may in some settings reflect integrated responses shaped by the aged tissue microenvironment and chronic antigenic burden, although this relationship is not yet established uniformly across diseases.

A precise understanding of CD4 CTL biology-including antigen recognition, tissue localization, and effector programs within aged tissues-is expected to provide critical insights and may offer new therapeutic avenues across a broad spectrum of aging-associated diseases. In this review, we provide a comprehensive overview of the emerging biology of CD4 CTLs, highlighting their differentiation, phenotypic characteristics, and dual roles in host protection and pathology. Beyond summarizing current knowledge, we propose a conceptual perspective in which the age-associated expansion of CD4 CTLs may contribute to the convergence of aging and age-related diseases, including cancer, chronic infections, autoimmunity, and neurodegeneration.

This popular science article discusses recent research that categorizes age-related changes a few thousand different cell populations in the body, distinguished by transcriptional behavior. This big picture view of aging shows a wide variety of responses to aging between cell types that occur in a staged progression throughout life, which the researchers characterize as a grand remodeling of the society of cells. The principle scientist in question favors a programmed aging viewpoint, but as is always the case, whether one thinks aging is a program like development that is under evolutionary selection or instead an accumulation of damage that occurs because health and fitness in later life is not under strong evolutionary pressure, the actual observations can be made to fit any theory of aging.

In one set of studies, we extracted more than 20 million cells from various organs from mice of different ages: 3, 6, 12, 16, and 23 months - roughly equivalent to 20, 30, 50, 60, and 75 years in humans. We analyzed the expression of 20,000 genes per cell and used this information to define the cell types. Then we tracked their population dynamics. We found that not every cell type gets changed in aging. We identified 536 main cell types and 1,828 subtypes. Only about one-quarter of these subtypes show a strong shift in aging. Others remain stable across the lifespan. It is surprising to find that changes in aging are not universal across all the cells, that there are specific cell populations that are more vulnerable.

We found that aging can be separated into distinct time windows. In each window, specific groups of cells show coordinated dynamics. In the early phase, for example, we see that some cell types are rapidly depleted. This is followed by another phase, in which other cells are greatly expanded. In the first stage, 3 to 6 months in a mouse [about 20 to 30 years in a human], there is a loss of certain fat and muscle cells, and of two immature cell types in the brain that have the capacity to regenerate different types of brain tissue.

Between 6 and 12 months in a mouse [equivalent to a person in their 30s and 40s], we see dramatic depletion of cells needed to maintain the body's tissues. These include tenocytes [the primary component of tendons]; the cells that wrap around blood vessels and stabilize the circulatory system; the smooth muscle cells of the colon; and kidney epithelial cells, which filter toxins from the blood. Also in decline are some immune cells that protect specific tissues such as the intestine.

At around 12 months in mice [roughly 40 to 50 years in humans], there is a shift from cell depletion to cell expansion. The first expansion wave is dominated by immune cells, but also includes select cells in the lungs, kidneys, and other organs whose properties have changed as a result of stress or inflammation. At around 16 months in mice [late 50s and beyond in humans], specialized aging-associated immune cells expand. When these selfish, uncontrolled cells emerge, they will eventually proliferate and destroy the system. In the meantime, they may contribute to the increased risk with age of inflammatory conditions such as heart disease, arthritis, cancer, and chronic respiratory illnesses.

Previously, people saw aging as a linear accumulation of damage to molecules such as proteins and DNA. But we found that aging is not a linear process. It's more like a developmental process, in which there are distinct stages that involve coordinated changes in specific cell types across different organs. Our claim is that aging is not so much molecular damage as a remodeling of the entire cell society.

Link: https://www.quantamagazine.org/why-aging-may-be-a-program-not-a-breakdown-20260814/

Circadian rhythm becomes disrupted with age, and a growing body of evidence points to this form of dysfunction as a contribution to many aspects of aging. The fine details of how and why circadian regulation of cell and tissue activity runs awry are complex and incompletely understood. Different circadian clocks operate in different parts of the body, communicate with one another, but fall out of synchronization in old individuals. Then cell types also change in different ways in their response to circadian signaling. While there is considerable interest in manipulating circadian mechanisms to restore better function in later life, little progress has been made towards working therapies. This paper is illustrative of present work; arguments are made as to which directions to take in the development of therapies to restore circadian activity, but a great deal remains to be accomplished.

Sarcopenia, characterized by the age-related decline in skeletal muscle mass, strength, and function, is associated with high healthcare costs and significant health risks, including falls, fractures, functional decline, and mortality. Despite its prevalence and extensive research, there are currently no Food and Drug Administration (FDA)-approved drugs to modify its course, likely due to an incomplete understanding of its underlying mechanisms. Recent evidence highlights two key factors in sarcopenia development: (1) Disrupted circadian rhythms affecting pathways such as protein remodeling, insulin resistance, and mitochondrial function; (2) systemic chronic low-grade inflammation (SCLGI).

This review focuses on circadian rhythm regulators implicated in skeletal muscle deterioration, examining their roles, potential interactions, and the impact of circadian disruption on sarcopenia progression. Additionally, we explore how clock genes reciprocally influence the inflammatory profile, which is crucial for developing treatment strategies to mitigate the detrimental effects of sarcopenia. We also examine factors that influence the clock and have the potential to restore circadian rhythm mechanisms that are deregulated in sarcopenia. Drawing from these insights, strategies aimed at restoring circadian synchrony and resolving inflammation are proposed as a novel therapeutic approach to effectively mitigate the manifestations of sarcopenia.

Link: https://doi.org/10.1097/CM9.0000000000004087

You might recall the paper published late last year, in which researchers reported that dietary supplementation with the L-form enantiomer of β-aminoisobutyric acid (L-BAIBA) enhanced the response of muscle and bone tissue to exercise in aged mice. L-BAIBA is one of many molecules both secreted by muscle cells during exercise, and which interact with muscle cells to produce benefits following exercise. Muscle tissue is metabolically active, and changes in muscle cell activity during exercise produce downstream effects on tissues throughout the body via signaling of this sort. That list of responsive tissues includes the muscle itself.

Last year's paper didn't discuss mechanisms, but fortunately the more recent open access publication noted here delves into the biochemistry that enables the level of L-BAIBA to determine the degree to which exercise produces benefits in muscle growth and function. L-BAIBA is an intermediary linking the activity of proteins that are more familiar to the research community in the context of muscle and aging, and indeed aging more broadly. It links the activity of PGC-1α, well investigated for its role in muscle tissue and exercise, to the effects of PPARα and PPARδ in various tissues important to energy metabolism. When there is too little L-BAIBA, the chain of cause and effect falters and the response to exercise is muted. But metabolism doesn't normally operate at peak efficiency, and it turns out that adding more L-BAIBA can improve the response to exercise.

The metabokine β-aminoisobutyric acid mediates exercise performance and skeletal muscle adaptation through a PGC1α-BAIBA-PPARδ axis

The repeated contraction, coordination, and transfer of force by skeletal muscle is central to physical activity. Skeletal muscle acts as both a source and target of the systemic signals which contribute to the adaptive remodelling and beneficial effects of exercise. The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) controls the expression of metabolic genes within skeletal muscle and is a key regulator of the skeletal muscle adaptive response to exercise. Mice with muscle-specific PGC-1α expression exhibit enhanced endurance exercise performance. Exercise training enhances expression of PGC-1α in skeletal muscle, which stimulates mitochondrial biogenesis, fatty acid β-oxidation, glucose transport, as well as an induction of muscular fiber-type remodelling from glycolytic fast-twitch type IIX muscle fibers to intermediate type IIA and oxidative type I slow-twitch muscle fibers. These adaptations in muscle physiology contribute to improved aerobic and endurance exercise performance.

The production and secretion of exercise-responsive myokines, muscle-derived endocrine signals, contributes to interorgan coordination and the systemic adaptation to exercise. We demonstrated that exercise training-induced PGC-1α expression in skeletal muscle drives the biosynthesis and secretion of the non-protein β-amino acid, β-aminoisobutyric acid (BAIBA). BAIBA functions as an exercise and PGC-1α regulated myokine-like metabokine, which induces hepatic β-oxidation and subcutaneous adipose tissue browning through PPARα, with subsequent protective effects against markers of cardiometabolic disease. BAIBA is also a bone-protective factor that prevents osteocyte cell death and reduces insulin resistance and inflammation. However, the contribution of BAIBA to exercise-mediated skeletal muscle adaptation and exercise performance is not understood.

Here, we demonstrate that BAIBA regulates muscle metabolism, morphology, and function via peroxisome proliferator-activated receptor delta (PPARδ) to determine exercise performance in mice. BAIBA mitigates muscle dysfunction in a mouse model of diabetes. Physiologically, BAIBA exists as D- and L- enantiomers. We identify L-BAIBA as the primary mediator of muscular effects. Knockdown of L-BAIBA's biosynthetic enzyme, 4-aminobutyrate aminotransferase, in mouse hindlimb muscle impairs exercise-induced adaptations and performance gains. L-BAIBA regulates human myotube fibertype and differentiation markers through Mas-related G-protein coupled receptor D. In humans, plasma L-BAIBA correlates with aerobic fitness and increases with endurance exercise training. BAIBA acts through the PGC1α-BAIBA-PPARδ axis to facilitate muscle adaptation and exercise performance.

One way of looking at human longevity is that it results from a greater resilience to the damage and dysfunction of aging, whether that resilience emerges from lifestyle choice or genetic differences. The research community spends a great deal of effort in attempting to understand how centenarians survive to old age, which of the many differences that can be catalogued are relevant in the sense of producing greater resilience. There is some question as to whether this is a useful way forward for the field; after all, centenarians are frail and exhibit a high mortality rate. It is not a state to aim at. It may be the case that studies will help to determine which of the mechanisms of aging are more versus less important, but the goal of aging research should not be to produce therapies that let people aging slightly more slowly, it should be to produce outright rejuvenation.

Aging represents an intrinsic biological process of all organisms that are affected by time-dependent changes from birth throughout the lifespan. Although the rate and phenotypic expression of aging are known to considerably vary among individuals and species, the process itself is biologically conserved. However, the dynamic of aging is not linearly related to the natural proceeding of time, but it is characterized by a complex and multifactorial nature, a process that is described as biological age. Biological age is indeed a multidimensional measure of the functional and physiological state of an individual that reflects the cumulative effects of genetic background, environmental, and lifestyle factors on the aging process. Unlike chronological age, which is defined by the passage of time since birth, biological age aims to capture the rate of aging and is considered a more accurate indicator of health status, functional capacity, and the risk of age-related diseases and mortality.

From a biomedical perspective, a wealth of determinants, mechanisms, and processes, including genomic instability, epigenetic alterations, mitochondrial dysfunction, cellular senescence, and chronic low-grade inflammation, significantly contribute to the aging-related decline in function and homeostasis. The persistent nature of these stressors leads to the accumulation of molecular damage and functional decline across multiple cellular systems. Consequently, aging represents a long-term imbalance between damage generation and resistance/repair mechanisms, ultimately driving the progressive deterioration of cellular and tissue function.

In this review, we conceptually organize the broad range of processes underlying aging into hierarchical levels of complexity, highlighting the convergence of multiple damage, antagonistic, and adaptive mechanisms in the multifaceted loss of resilience. In this context, centenarians can be considered a paradigm of exceptional biological adaptation. Accordingly, we explore this field from a physiological point of view by reviewing the genetic, epigenetic, molecular, and systems-level traits of centenarian populations and animal models, highlighting potential drivers of a favorable balance between damage and repair mechanisms associated with their remarkable longevity.

Link: https://doi.org/10.1016/j.mad.2026.112236

Aging is so very complex that almost every research project, limited in time and resources, is by necessity restricted to just examining one tiny part of the whole process. That leads to papers like this one, in which the effects of changing expression of a single gene in a single organ are considered. It is relatively straightforward to expand the map of mechanisms in cellular biochemistry, and to make an argument for the relevance of a newly explored mechanism in the progression of degenerative aging, but it is relatively hard to establish the importance of any given mechanism in comparison to all of the others involved. Relatedly, it is also challenging to demonstrate where a mechanism sits in the web of cause and consequence. In consequence, there are many failed attempts at the production of therapies, because the mechanism targeted turns out to be of lesser importance to aging and age-related disease.

Aging is a complex biological process. The corticotropin-releasing factor (CRF) signaling pathway has gained increasing attention for its potential role in regulating aging, acting as a key bridge connecting neuroendocrine stress mechanisms with both central and peripheral aging processes. As a core neuropeptide of the stress response, CRF primarily mediates downstream effects through its type 1 receptor (CRFR1), while its type 2 receptor (CRFR2) may play a modulatory, often opposing, role. Evidence from preclinical models indicates that excessive CRF signaling is associated with mitochondrial dynamics imbalance and biogenesis defects, leading to overproduction of reactive oxygen species (ROS) and mitochondrial DNA damage. These damaged mitochondria can subsequently release damage-associated molecular patterns (DAMPs), which activate innate immune pathways and may trigger a chronic low-grade inflammatory state, ultimately contributing to cellular senescence.

Elucidating the cascading mechanisms by which CRF signaling could drive aging - from mitochondrial dysfunction to chronic inflammation - is essential for understanding the molecular basis of stress-accelerated aging. This review aims to systematically integrate research advances at the intersection of the CRF signaling pathway and aging hallmarks, focusing on a proposed "CRF-mitochondrial dysfunction-inflammation-aging" axis. We explore this regulatory network and its clinical translational potential to provide a theoretical foundation for unraveling the molecular mechanisms of stress-driven aging and identifying novel intervention targets.

Link: https://doi.org/10.3389/fnagi.2026.1880569

Senescent cells accumulate with age throughout the body, either in response to forms of damage and stress or on reaching the Hayflick limit on replication. A senescent cell ceases to replicate, grows in size, and secretes a potent mix of pro-growth, pro-inflammatory signals. In youth, the immune system efficiently clears senescent cells, but with age this clearance falters. Like most of the progression of degenerative aging, the accumulation of senescent cells with age is nonlinear. This is in part because the decline of the immune system accelerates in later life, but it is also the case that the signaling generated by senescent cells can induce nearby cells to also become senescent. Thus senescent cells emerge at an accelerating pace as their numbers grow.

In today's open access paper, researchers report on an investigation of the specific details as to how senescence spreads between cells in the aging brain: which signals are involved, and which cells propagate senescence most aggressively. As one might expect, as nothing is simple in biology, there is quite a variety between cell types in the fine details of the inflammatory signaling generated and in the response to those signals. This characterization of senescent cell signaling is a necessary groundwork for later efforts to take present day approaches to interfering in unwanted inflammation and adapt them to target the harmful effects of senescent cells. While most drug development in the field of cellular senescence is presently aimed at selectively destroying senescent cells, there is growing interest in instead finding ways to suppress senescent cell signaling or its consequences while leaving the cells themselves intact.

Characterizing the SASP-Dependent Paracrine Spreading of Senescence Between Human Brain Cell Types

One of the defining phenotypes of a senescent cell is the senescence-associated secretory phenotype (SASP), which can propagate senescence in neighboring cells both in vitro and in vivo. Importantly, this paracrine spreading of senescence can act in a cell non-autonomous manner, influencing neighboring cell populations and contributing to immune cell recruitment. As cellular senescence has recently been linked to both age-related neurodegenerative phenotypes and local inflammation and is more clearly defined across brain cell types in a cell-type-dependent manner, an urgent question remains regarding how a cell-type-specific paracrine spreading of senescence occurs in the brain.

Here, we sought to unravel the relationship between key brain cell types (astrocytes, endothelial cells, microglia, oligodendrocytes, and neurons) in the context of a paracrine spreading of senescence via the SASP. We utilized our previously established in vitro DNA damage-induced human brain cell line senescence model and conditioned media experiments to profile the cell-type-dependent SASP, characterize the directionality of a paracrine spreading of senescence between the relevant cell types, identify key SASP ligands and receptors that mediate the cell-type-specific spread, and target these factors using various inhibitors in an attempt to prevent the paracrine spreading of senescence.

We demonstrate that a cell-type-specific SASP profile of each brain cell type drives differential induction of secondary senescence, where some cell types can induce senescence in themselves as well as in other cell types, while other cell types are only capable of receiving secondary senescence induction, but cannot spread. Importantly, we identified both cell-type-specific and common SASP ligands and receptors, which we successfully targeted to prevent the induction of select secondary senescence hallmarks depending on the cell types communicating with one another. Taken together, this work gives key insights into the mechanisms of paracrine spreading of senescence between brain cell types in vitro and offers potential therapeutic targets to prevent this spreading, which may in turn help to alleviate age-related tissue decline and inflammaging.

The various mitochondrial protein complexes are the building blocks of the electron transport chain, the complicated mechanism inside mitochondria that generates adenosine triphosphate (ATP), the chemical energy store molecule used to power cell activities. Nothing in a cell is simple, and the mitochondrial complexes do not operate neatly in isolation from one another. They drift in and out of supercomplex arrangements of multiple complexes, and it turns out that this supercomplex activity is important to mitochondrial function, and thus to the pace of aging. Researchers recently demonstrated that aging in mice can be slowed by inducing more supercomplex formation, for example. Here, find a review that covers what is known of the role of supercomplexes in aging and longevity.

One of the hallmarks of aging is mitochondrial dysfunction. Mitochondria are multifunctional organelles, a central function of which is the generation of cellular energy ATP through oxidative phosphorylation (OXPHOS). The OXPHOS system consists of five complexes I-V, with complexes I-IV forming the electron transport chain that transfers electrons from NADH and FADH2 to oxygen while generating a proton gradient across the inner mitochondrial membrane (IMM). This gradient drives ATP synthesis by complex V.

The abundance and activity of OXPHOS components likely decline during aging, such as reduced levels and activity of complex I, and a declining trend in complex III and complex IV. Consistently, animal models with OXPHOS defects exhibit shorter lifespans than wild type controls. Age-associated deterioration of mitochondrial OXPHOS is assumed to arise through multiple mechanisms, including the accumulation of mitochondrial DNA (mtDNA) mutations, which contributes to increased ROS production and the promotion of cellular damage.

Mitochondrial complexes organize into higher-order assemblies known as supercomplexes (SCs), which enable to efficient energy or ATP production with repressed reactive oxygen species (ROS) generation. Notably, the assembly and stability of these SCs likely decline in aged mammals. In addition, factors such as COX7RP/SCAF1 and mitochondrial lipid cardiolipin have emerged as key regulators of SC assembly. In this review, we summarize the molecular assembly, physiological roles, and longevity implications of SC in healthy mammals. We further discuss emerging evidence supporting SC modulation as a potential strategy for promoting healthy aging.

Link: https://doi.org/10.3389/fragi.2026.1876149

Old fruit flies generally die from intestinal dysfunction; intestinal aging is the most important aspect of aging in this species. INDY is a longevity associated gene that has been shown to have important effects on intestinal health in flies. Upregulation of INDY expression extends life in flies. Here, researchers show that a part of this effect results from a reduction in harmful age-related changes in the composition of the gut microbiome. A growing body of evidence shows that the gut microbiome is influential on long-term health and the pace of aging, particularly via its contribution to the chronic inflammation of aging. With age, beneficial microbial species are reduced in number while inflammatory microbial species grow in number. At the same time, the intestinal barrier becomes leaky, allowing more unwanted cells and metabolites into the body. This is detrimental to tissue function in all organs, and a contribution to degenerative aging.

Reduction in the Indy ("I'm not dead yet") gene, a plasma membrane citrate transporter, in Drosophila and its homolog in worms extends lifespan by promoting metabolic homeostasis. Indy reduction delays the onset of aging-associated pathology in the fly midgut, including preservation of intestinal barrier integrity and intestinal stem cell homeostasis. Gut microbiota has broad impacts on host metabolism, health, and aging. Age-related dysbiosis impairs intestinal barrier function and drives mortality. However, the underlying mechanisms that link increased microbial load to frailty and negative effects on health remain mostly unclear.

Here we show that Indy heterozygote flies have significantly lower bacterial load and increased diversity during aging compared to controls. However, the presence of the microbiota was not required for Indy lifespan extension, though removal of microbes did enhance the effects of Indy reduction on longevity, suggesting potential interactions between the microbiota and Indy. Indy down-regulation was linked to reduced expression of Upd3 and Upd2 in the midgut of young flies and Stat92E in old Indy flies, while no change in other members of the JAK/STAT signaling pathway observed. Furthermore, flies double heterozygous for Indy206/+ and upd3Delta/+ alleles lived longer than single heterozygous flies, suggesting synergistic effects on longevity of Indy and upd3 pathways.

Altogether, our results suggest that Indy reduction impacts microbiota load and composition, which together with effects of Indy on midgut metabolism contributes to preserved gut homeostasis and extended lifespan.

Link: https://doi.org/10.18632/aging.206408

The central nervous system is relatively isolated from the rest of the body; the blood-brain barrier ensures that only certain cells and molecules are permitted to pass between the body and brain. Many cell populations are specific to the brain, and even the immune systems in brain and body are relatively isolated and different from one another. Microglia are innate immune cells of the central nervous system, analogous to macrophages elsewhere in the body. They can destroy pathogens and malfunctioning cells, clear up metabolic waste such as protein aggregates and cell debris, and also participate in the intricate processes of tissue regeneration. Further, microglia assist in the maintenance and function of neural networks in the nervous system.

Unfortunately microglia become ever more inflammatory with age, a maladaptive reaction to internal age-related changes such as mitochondrial dysfunction, combined with interactions between microglia and age-related changes in their environment, such as rising levels of protein aggregates and the inflammatory signals generated by senescent cells. As is a common story in aging, an aspect of cell behavior that is necessary and helpful in youth becomes harmful and maladaptive in old age. In today's open access paper, researchers investigate one of the regulatory signal proteins involved in suppressing microglial inflammatory behavior, and demonstrate that (a) the presence of this signal declines with age, worsening microglial inflammation and (b) introducing more of the signal protein into the aged tissue environment improves microglial function.

Youth-associated protein TIMP2 regulates microglial state and function in healthy and aged mice

There is little understanding of how aging serves as the strongest risk factor for several neurodegenerative diseases. Microglia undergo age-related maladaptive changes, including increased inflammation, impaired debris clearance, and cellular senescence, yet specific mediators that regulate these processes remain unclear. The aged brain is rejuvenated by youth-associated plasma factors, including tissue inhibitor of metalloproteinases 2 (TIMP2), which we have shown acts on the extracellular matrix (ECM) to regulate synaptic plasticity. Given emerging roles for microglia in these processes, we examined the impact of TIMP2 on microglial function.

We show that TIMP2 deletion in mice exacerbates microglial phenotypes associated with aging, including transcriptomic changes in cell activation, changes in lysosomal-associated markers and phagocytosis, and elevated levels of stress and inflammatory proteins in the brain extracellular space measured by in vivo microdialysis. Deleting specific cellular pools of TIMP2 in vivo increases microglial CD68 and alters myelin phagocytosis. Treating aged mice with TIMP2 reverses several phenotypes observed in our deletion models, resulting in decreased microglial activation, reduced proportions of proinflammatory microglia, and enhanced phagocytosis of physiological substrates. Our results identify TIMP2 as a modulator of age-associated microglia dysfunction. Harnessing its activity may mitigate detrimental effects of age-associated insults on microglia function.

The retina is a part of the central nervous system, and as such is subject to a variety of forms of age-related neurodegeneration, culminating in conditions such as macular degeneration. The chronic inflammation characteristic of old age is just as important to neurodegeneration in the retina just as it is in the brain. Inflammatory signaling, necessary and useful in the short term, becomes disruptive to cell and tissue function when sustained over the long term. The causes of chronic inflammation are manifold, a list of much of what goes wrong in cellular biochemistry with age, but most research is focused instead on how this maladaptive inflammatory response is regulated. Development of anti-inflammatory therapies does not focus on removing the cause of inflammatory signaling - which at the end of the day will probably require achieving actual rejuvenation, repair of the cell and tissue damage that causes aging - but instead aims to sabotage the controlling mechanisms of the inflammatory response. This works, but as existing therapies demonstrate, it is hard to sabotage unwanted inflammation without also sabotaging necessary inflammation. Whether there are as yet unexplored approaches that can achieve that goal remains to be seen.

Age-related macular degeneration (AMD) is a fundus oculi disease that progressively impairs the central vision of patients. To date, its pathogenesis has not been fully elucidated, and therapeutic options for dry AMD remain limited. Recently, chronic low-grade inflammation has been recognized as an important pathogenic factor in various neurodegenerative diseases, including AMD. The NLRP3 inflammasome, a key component of the innate immune system, has emerged as a critical integrator of retinal stress signals. This review first delineates the molecular architecture and activation modalities of the NLRP3 inflammasome, encompassing canonical, noncanonical, and alternative pathways, as well as its downstream cell death programs, with a particular focus on pyroptosis and PANoptosis.

We describe how AMD-associated danger signals converge on NLRP3 inflammasome activation within distinct retinal cell populations and discuss how cell-type-specific NLRP3 responses differently shape retinal homeostasis, degeneration, and neovascularization. We further summarize current evidence indicating that the pathological consequences of NLRP3 activation vary across AMD progression, from amplification of chronic inflammation in early and intermediate AMD to promotion of retinal atrophy in geographic atrophy and angiogenic signaling in neovascular AMD. Finally, we evaluate emerging therapeutic strategies targeting the NLRP3 pathway and discuss the major translational challenges related to cell-type and disease-stage specificity, retinal delivery, and long-term safety.

By integrating retinal triggers, cellular responses, senescence-associated inflammation, inflammatory cell death, disease phenotypes, and therapeutic opportunities into a unified framework, this review provides a comprehensive perspective on the role of NLRP3 inflammasome signaling in AMD pathogenesis and treatment.

Link: https://doi.org/10.3389/fnagi.2026.1817987

Histological studies investigate the fine structure of tissues, usually thinly sliced and mounted on slides, stained in ways that emphasis specific features, and imaged via a microscope. Here, researchers demonstrate that the characteristic age-related changes in the cell and tissue features present in histological images can form the basis for development of aging clocks for research use. Any sufficiently complex set of biological data can serve as raw material for the machine learning approaches used to generate an aging clock that reflects biological rather than chronological age, the accumulation of damage and dysfunction. In this case the clock is really only suitable for research use; a way to gain more insight into aging from large databases of post-mortem human tissue analysis.

Aging is the primary risk factor for chronic disease and is characterized by profound structural and architectural remodeling of human tissues. Here, we present a comprehensive assessment of these changes using 25,712 whole-slide histopathological images from 40 tissue types across 983 individuals in the Genotype-Tissue Expression cohort. By leveraging deep learning, we quantified nuanced morphological alterations to develop 'tissue clocks', predictors of biological age that reflect tissue structural integrity and physiological fitness. These clocks correlate with established aging markers, such as telomere attrition, subclinical pathologies, and comorbidities.

Through a systematic evaluation of biological aging rates across organs, we identified associations of tissue-specific age acceleration with demographic, lifestyle, and medical factors, highlighting potentially modifiable risk factors that affect tissue aging. Furthermore, by integrating paired histology and transcriptomic data, we developed a strategy to predict tissue-specific age gaps directly from blood samples. We validated this approach by identifying disease-relevant organ aging across independent cohorts for eight prevalent diseases, including Alzheimer's disease, stroke, and Crohn's disease. This work positions tissue architecture as a critical integrator of molecular and cellular changes over the course of aging, demonstrates that histopathological imaging provides a robust framework for monitoring tissue-specific aging and offers a scalable foundation for understanding organ-level physiological decline in health and disease.

Link: https://doi.org/10.1038/s41591-026-04566-5

RANKL is best studied in the context of bone remodeling. Its activity, binding to the cell surface receptor RANK, is necessary for the function of the osteoclast cells that break down bone extracellular matrix. Bone tissue is in a constant state of remodeling, built up by osteoblast cells and broken down by osteoclast cells. The loss of bone mineral density that leads to osteoporosis arises from a growing age-related imbalance between osteoblast and osteoclast activity, favoring the osteoclasts. The various established therapies used to slow the progression of osteoporosis attempt to tilt that balance away from loss of bone mineral density, such as via monoclonal antibodies targeting RANKL to suppress osteoclast activity.

In today's open access paper, researchers note that RANKL inhibition extends life in progeroid mice. The details are interesting, adding to other data suggesting that RANKL has roles in aging that go beyond issues with bone tissue, such as influence on muscle aging. One would want to see a study in normally aged mice to confirm that this is the case, of course. In the broader context, it might be worth noting that another class of drug that inhibits osteoclast activity in a different way, bisphosphonates, may also act to slow aging. There is evidence for bisphosphonates to be senolytic, for example, and human data showing a survival advantage of five years in people using bisphosphonates versus the general population.

Targeting RANKL Prevents Bone Loss, Improves Muscle Function and Extends Lifespan in Progeroid Mice

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by the early development of pathological features associated with aging, ultimately leading to premature death. HGPS primarily affects tissues of mesenchymal origin, as evidenced by the clinical manifestations characteristic of this premature aging disorder, including, but not limited to, osteoporosis, muscle wasting, lipodystrophy, and cardiovascular disease.

In this study, we used preclinical mouse models and both genetic and translational approaches to investigate whether an antiresorptive strategy, based on RANKL targeting, ameliorated the bone loss phenotype of progeroid mice. Here we show that osteocyte-derived RANKL deletion in the Zmpste24-/- mouse model of HGPS reverted bone loss in both long bones and vertebrae. These mice also exhibited increased grip strength and improved endurance capacity. Furthermore, Zmpste24-/- mice showed increased survival upon osteocyte-specific RANKL deletion. Notably, the use of a translational approach based on the administration of a neutralizing antibody against RANKL also restored bone mass, reduced muscle fibrosis, and extended the lifespan of Zmpste24-/- mice.

Altogether, these findings support that targeting RANKL exerts a beneficial effect on both osseous and extra-osseous phenotypes of HGPS, suggesting the potential of this therapeutic approach to explore in the treatment of this disease.

In recent years, an increasing level of attention has been given to microglia as an important contribution to neurodegeneration in the aging brain. Microglia are innate immune cells resident in the central nervous system, analogous to the macrophages found elsewhere in the body. They are deeply involved in the complex processes of normal tissue function and maintenance, not just a defense against pathogens and malfunctioning cells. With age, microglia become more inflammatory at the expense of tissue function. Here, researchers look at this harmful change in the behavior of microglia through the lens of cellular metabolism: what are the alterations in metabolism that accompany and perhaps cause unwanted inflammatory activities in this cell population? Finding ways to adjust the behavior of microglia is becoming a priority in the development of therapies to treat neurodegenerative conditions, and a greater understanding of how these cells change with age is a first step on that path.

Microglia, the resident macrophages of the central nervous system (CNS), are key players in maintaining brain and spinal cord homeostasis and protecting the CNS from damage and disease. During aging, the brain undergoes profound changes-including chronic low-grade inflammation, synaptic dysfunction, and increased vulnerability to neurodegenerative diseases - all of which are closely related to alterations in microglial function. One emerging theme is that microglial metabolism is a crucial determinant of their immune and homeostatic activity.

In this mini-review, we explore how metabolic programs shape brain microglial behavior and how these processes change during aging and in neurodegenerative diseases. We first highlight the link between specific metabolic pathways and key microglial functions, including phagocytosis, cytokine production, and the oxidative stress response. We then discuss how microglial metabolism is reprogrammed during healthy aging and in Alzheimer's disease and Parkinson's disease, including sex-specific differences. Finally, we examine regulators that influence microglial metabolic states and discuss how these pathways contribute to disease susceptibility and progression.

Collectively, recent findings highlight the central role of metabolic reprogramming in shaping microglial responses during aging and in neurodegenerative diseases. We emphasize the need for integrative studies that consider microglial subsets, sex differences, disease context, and upstream molecular regulators to better understand how microglial metabolism contributes to brain health and pathology. A deeper understanding of these pathways may offer new opportunities for therapeutic strategies aimed at restoring microglial homeostasis and mitigating harmful neuroinflammatory processes.

Link: https://doi.org/10.1111/acel.70660

Researchers here review the present state of research and use of metformin as a geroprotective drug, intended to modestly slow aging. They are largely on point, if somewhat too accepting of the quality of the existing human data. While effective as a treatment for metabolic syndrome and type 2 diabetes, metformin is nowhere near as good a choice as rapamycin if forced to pick a geroprotective drug with modest effects on aging. For one, the animal data for effects on aging is very mixed, and there are sizeable methodological and other concerns regarding the human clinical trial evidence for reduced mortality and increased life expectancy. More recent human data tends to show little to no effect on that front.

Metformin is a biguanide and first line drug for type 2 diabetes (T2D) mellitus that is being recognized as a geroprotective agent capable of influencing important hallmarks of aging. Apart from its primary role in lowering blood glucose levels, metformin has been shown to have several effects at the molecular level. It acts by activating the AMPK, which leads to a cascade of downstream events such as the inhibition of mTOR, increased mitochondrial biogenesis, and autophagy, as well as epigenetic modifications. Current findings also showed its capacity to alter the gut microbiota by increasing short-chain fatty acid producing bacteria, indicating the involvement of other systemic pathways that aid in lowering inflammation, increasing metabolic fitness, and keeping epigenetic stability.

The Targeting Aging with Metformin (TAME) trial represents a landmark effort to evaluate metformin's efficacy in delaying the onset of chronic age-related diseases in non-diabetic individuals [28]. Designed as a multi-center, randomized, placebo-controlled trial, TAME seeks to enroll 3,000 individuals between the ages of 65 and 79 years and follow them for four years. By assessing biomarkers of aging and clinical endpoints across multiple age-related conditions such as cardiovascular events, cancer, cognitive decline, and all-cause mortality, TAME aims to validate metformin as a gerotherapeutic. However, since its start in 2017, no results have been published yet which make many to speculate that the trial may be on hold due to financial issues. In a 2025 interview, Dr. Nir Barzilai clarified that TAME is now handled by ARPA-H and could lead to two major trials with similar design but focused on GLP-1 agonist drugs.

The Metformin and Dietary Restriction to Prevent Age-Related Morbid Events in People with Metabolic Syndrome (MeMeMe) trial on the other hand evaluated the effects of metformin with or without dietary restriction on the development of major age-related diseases in over 1,400 participants aged 50-79 with metabolic syndromes. The trial found that 1700 mg/day of metformin was effective in preventing diabetes in people with metabolic syndromes. They reported an 80% and 92% reduction of type two diabetes in the metformin and the metformin and Mediterranean diet groups compared to the placebo group. However, no preventive effect was seen for cancer, cardiovascular diseases, and mortality.

Link: https://doi.org/10.18632/aging.206407

Most forms of air pollution (with a particular focus on fine particles) are now well established to contribute to age-related conditions at the level of exposure that is experienced in much of the industrialized world. Typically matters are worse in less wealthy regions, particularly those using solid fuel for domestic cooking and heating. Nonetheless, there is enough of a contribution even in wealthier regions for studies to show meaningful differences to health depending on varying levels of exposure. A study in the Puget Sound region, for example, found that greater exposure increased dementia risk.

The specific mechanisms by which air pollution accelerates the onset and progression of common age-related conditions are largely linked to chronic inflammation. Unresolved inflammatory signaling is disruptive to tissue structure and function, and the interaction of pollutants with cells in the lungs and airways promotes inflammatory signaling that affects the whole body.

Today's open access paper reviews what is known of these mechanisms in the context of a specific condition, Parkinson's disease. This neurodegenerative condition has a strong connection to the aging of the gut microbiome and intestines, as that is where the misfolded α-synuclein that drives the condition can originate. It then spreads through the nervous system to the brain, where it produces the first evident symptoms of Parkinson's disease, and eventually dementia and death. The greater the burden of inflammation placed upon body and brain, the faster this will happen.

Air Pollution and Parkinson's Disease Pathology: Clinical Evidence and the Molecular Mechanisms Linking Airborne Toxicants to Neuroinflammation and Neurodegeneration

Studies have reported positive correlations between exposure to particulate matter (PM), nitrogen oxide (NOx), ozone (O3), and an increased risk of Parkinson's disease (PD). Beyond the incidence of PD, studies have examined the linkage between long-term air pollution contact and the risk of hospitalization, mortality, and disease progression among PD patients, suggesting that air pollution may not only lead to the development of PD but also aggravate the clinical course and outcomes of the disorder.

Several pathways have been proposed to involve the biological processes underpinning the connection between air pollution and PD. Extensive research in animal models and human studies has reported that PD is interrelated with significant modifications in gut microbial structure, including the reduction of anti-inflammatory short-chain fatty acid (SCFA)-producing bacteria and the enrichment of opportunistic pathogens. Exposure to air pollution has been shown to disrupt the gut microbiome, potentially resulting in increased gut permeability, the propagation of pathogenic processes, and inflammation that may contribute to the development and progression of PD.

It has been demonstrated that interaction with air pollutants can also motivate α-synuclein to misfold and accumulate, as well as the impairment of other key proteins involved in neuronal function and homeostasis. Air pollution has been linked to oxidative stress and neuroinflammation, which can lead to the induction of multiple transcription factors, NRF2, NF-κB, and MAPK, forcing dopaminergic neurons to malfunction and degenerate. Furthermore, the incorporation of ultrafine PM in the brain, particularly in the olfactory bulb and other vulnerable zones, has been associated with excitotoxicity, mitochondrial dysfunction, and the propagation of neuroinflammatory processes that may be responsible for the pathophysiology of PD.

Despite progress in investigating the association between air pollution and PD, findings remain inconsistent. Some studies have recognized positive links between exposure to pollutants such as PM, NOx, and O3 and an increased risk of PD, whereas other studies have not found statistically important associations. These discrepancies underscore the complexity of the interactions between environmental exposures, genetic predisposition, and any other modifiable risk factors in the pathogenesis of PD. Mechanistic studies have offered useful insights into the biological pathways linking air pollution to PD. However, the precise mediators and dose-response relationships remain unclear. Furthermore, regional differences in pollution levels, exposure assessment methods, and population characteristics may contribute to the variability in findings across epidemiological studies. There is a growing need for well-designed, large-scale longitudinal studies with standardized exposure assessment methods to more accurately quantify the long-term effects of specific air pollutants on PD risk and progression.

The state of the cardiovascular system has a strong impact on the aging of the brain. The brain requires an sizable supply of energy, delivered via the bloodflow, and suffers when that supply is reduced. With age, the vascular system loses smaller vessels, while larger vessels become damaged. Loss of physical fitness also reduces blood supply. Additionally, damaged blood vessels allow leakage of unwanted cells and molecules into the brain to produce inflammation, while blood vessel walls can be a source of inflammatory signaling themselves. Increased blood pressure can be avoided or controlled, but where hypertension is present, it is harmful to vessels in the brain, causing a toll of small ruptures that damage brain tissue over time. All of this adds up. The study here is one of many to link vascular health with cognitive decline leading to dementia.

Midlife vascular risk factors are associated with both dementia and premature death; however, their combined association with dementia-free survival years remains unclear. We conducted a prospective cohort study (Atherosclerosis Risk in Communities study) with participants from 4 US communities. Participants were alive and dementia-free at age 55 years and had visit 2 (1990-1992) measurements of diabetes (self-report, medication use, or HbA1c ≥ 6.5%), hypertension (blood pressure ≥ 140/90 mm Hg or medication use), and current smoking. Vascular risk burden was defined as the count of these risk factors (0-3).

Among 12,409 participants (mean age 56.2 ± 5.2 years), over a median follow-up of 26.3 years, 3,008 developed dementia and 5,238 died dementia-free. Compared with 0 risk factors, 3 risk factors were associated with higher hazards of dementia (hazard ratio [HR] 2.69) and death without dementia (HR 5.61). Higher vascular burden was associated with fewer dementia-free survival years, declining from 30.1 years for 0 risk factors to 17.5 years for 3 risk factors. In conclusion, maintaining optimal midlife vascular health was associated with up to 12.6 additional dementia-free survival years, reflecting both higher dementia hazard and markedly higher competing mortality.

Link: https://doi.org/10.1212/WN9.0000000000000152

From one perspective, the XPRIZE Healthspan research prize is a way to encourage what should be happening to a far greater extent in the development of means to treat aging as a medical condition, which is to assess which approaches are better than others. The field spends too much time on approaches that cannot improve on lifestyle choices, for example. Ideally this competitive assessment requires some useful consensus definition of aging and age-related degeneration to work against - which is presently lacking; aging clocks are a step in that direction, but cannot be trusted to provide useful results for any given novel intervention targeting mechanisms of aging. Thus the XPRIZE Healthspan leadership chose to go with benchmarking competing approaches against narrow definitions of function in a few areas where fairly standardized methodologies exist: muscle, cognition, immune capacity.

Launched in 2023, the seven-year, $101 million XPRIZE Healthspan competition is the first incentive health competition of its kind dedicated to accelerating the development and clinical testing of proactive, accessible interventions that target the biology of aging itself. Rather than treating age-related diseases after they occur, the competition challenges teams to restore muscle, cognitive, and immune function by at least 10 years - with an ambitious target of 20 years - in adults ages 50 to 90, all within one year or less of treatment. If successful, these breakthroughs have the potential to help millions of people live longer, healthier, and more independent lives.

Today, XPRIZE announced the 20 Finalist teams advancing to the next stage of the competition, marking a major milestone in the global race to transform how we age. Among the finalists, 10 teams from the United States, South Korea, Japan, and China were selected as Milestone 2 awardees and will each receive a $1 million award, totaling $10 million in milestone funding, to accelerate the development and clinical testing of innovative therapies designed to extend healthy years of life. In addition to funding, the teams will gain access to key clinical testing resources to support the next phase of their work.

Together, the finalist teams represent a diverse range of approaches targeting the biology of aging, including: novel medicines and biologics designed to improve metabolism, reduce inflammation, protect neurons, and repair damaged cells; regenerative approaches, including stem cell and gene-based therapies, that support cellular repair, energy production, and tissue health; extracellular vesicles and other next-generation delivery technologies that harness the body's natural processes to promote rejuvenation; AI-enabled precision health and personalized care models that combine data, existing medicines, nutraceuticals, and lifestyle interventions to optimize healthy aging.

Link: https://www.xprize.org/news/20-healthspan-finalist-teams-advance-in-the-race-to-extend-healthy-aging

The composition of the gut microbiome is influential on long term health and the progression of aging. Unfortunately, this composition changes with age for a range of reasons yet to be fully explored, but which include the decline of the immune system and growing leakage of the intestinal barrier. With age, populations of inflammatory microbial species grow at the expense of microbial species that produce metabolites necessary for tissue function. Studies in short-lived animals suggest that the composition of the gut microbiome is at least as important as lifestyle choices such as level of physical activity when it comes to pace of aging and level of dysfunction in later life.

The means available to manipulate the composition of the gut microbiome are largely not that effective in the grand scheme of things. We know the scope of benefits that arise from a better diet and otherwise better lifestyle choices. Like probiotics, dietary choice can only produce lasting changes in the gut microbiome to some degree, and only if kept up over time. There are one-time treatments that can produce a lasting change in the gut microbiome, however. Flagellin immunization has been explored in animal studies, and provokes the immune system into a lasting campaign to eliminate exactly the sort of undesirable microbial species that increase in number with age. Fecal microbiota transplantation from a young donor into an old recipient resets the composition of the gut microbiome, and in animal studies this improves health and extends life.

In both of these one-time treatments, it is hard to predict exact outcomes. This hinders the development of these therapies for a more widespread use as treatments to reduce the impact of aging by resetting the gut microbiome. More attention is given to fecal microbiota transplantation, with clinical trials accumulating and planned. Nonetheless, the challenges in terms of controlling the inputs and the outcomes of this therapy make it likely that the path ahead will involved the development of artificial gut microbiomes that can be completely controlled and specified. These will form the basis for the next generation of probiotic therapy, capable of replicating some fraction of the effects of fecal microbiota transplantation, and in particular to be capable of producing lasting change in composition.

Gut Microbiota and Ageing: Mechanisms, Age-Related Diseases, and Therapeutic Perspectives

This narrative review synthesised a substantial body of peer-reviewed evidence demonstrating that the gut microbiota undergoes progressive, context-dependent remodelling with advancing age, characterised by reduced taxonomic and functional diversity, depletion of short-chain fatty acid (SCFA)-producing taxa, and relative expansion of pathobionts. These changes are increasingly recognised as likely contributors to inflammaging and several hallmarks of ageing, although causal relationships remain incompletely established in humans and likely promote or exacerbate prevalent age-related diseases including neurodegenerative disorders, cardiovascular disease, type 2 diabetes, sarcopenia, osteoporosis, and frailty. Conversely, the distinct microbial configurations observed in centenarians and individuals exhibiting healthy ageing trajectories suggest that maintenance of specific metabolic functionalities (particularly robust SCFA and secondary bile acid pathways) may constitute a feature of successful longevity rather than mere survival bias.

Evidence-based strategies targeting the microbiota, ranging from Mediterranean-style dietary patterns and exercise to precision probiotics, synbiotics, postbiotics, and carefully screened fecal microbiota transplantation (FMT), show genuine potential to restore microbial homeostasis, attenuate inflammaging, improve clinical phenotypes, and extend healthspan. Nevertheless, substantial methodological, causal, and translational gaps remain. Overcoming these will require concerted investment in longitudinal multi-omics cohorts, rigorously designed personalised intervention trials, advanced experimental models, and equitable implementation frameworks.

Ultimately, the gut microbiota should be viewed not as a separate entity but as an integral component of the ageing human superorganism. By nurturing microbial ecology throughout life and deploying targeted restoration strategies in later decades, it may become possible to compress morbidity, preserve functional independence, and enable more individuals to reach extreme old age in good health. While the journey from associative observation to causal, personalised, clinically validated interventions remains incomplete, the trajectory is clear: microbiome research represents one of the most promising and rapidly evolving areas within contemporary geroscience. Realising its full potential for human longevity will demand the same rigorous, collaborative, and innovative spirit that has characterised the field's rapid evolution since the advent of high-throughput sequencing.

The next generation of geroscience will increasingly depend on integrating microbial ecology with complementary molecular regulatory systems governing the ageing process, including epigenetic, metabolic, immunological, and post-transcriptional mechanisms. Such multidimensional approaches have the potential to transform microbiome research from a predominantly associative discipline into a mechanistically grounded framework capable of supporting personalised interventions for healthy ageing and longevity.

Senescent cells accumulate with age, and actively secrete pro-inflammatory signals. The present understanding of senescent cell biochemistry and animal studies of senescent cell clearance strongly suggest that senescent cells in aged tissues provide a major contribution to the characteristic chronic inflammation of old age, disruptive to tissue structure and function. As researchers here note, finding biomarkers to quantify this contribution in a usefully robust and specific way is a work in progress, however. While one might think that the medical field could forge ahead with therapies targeting senescent cells for clearance, based on being able to evidently reverse age-related pathology in animal studies, in practice regulators place a strong emphasis on the availability of simple biomarkers that can measure the direct engagement of a drug with its target, not just indirect outcomes. Drugs that lack such biomarkers will struggle to progress though the regulatory system, and thus creating these biomarkers is a major concern for researchers and companies.

Cellular senescence is the process in which cells lose their ability to proliferate irreversibly. While the process is needed for performing different functions, accumulation of senescent cells over time leads to the secretion of senescence-associated secretory phenotype (SASP). Senescence and SASP have now been known, defined and quantified in the last couple of decades. Both senescence and inflammaging are known to contribute towards several age-related diseases (ARDs), with inflammaging being a more recent concept than the former. They appear bi-directional in their cause and effects with respect to ARDs, resulting in immunosenescence, which is the age-related decline in the functioning of the immune system, but senescence is currently more quantifiable due to specific markers and known senescent cellular features.

With the increasing interest in the field, several scientists and research groups have contributed to the growing body of evidence towards cellular senescence and inflammaging in ARDs. Existing evidence indicates that senescence might be the key to tracking diseases (and thus targeting senescence for treatment), healthy aging and longevity; however, this knowledge is yet to be translated to the 'bedside' for clinical applications. This review aims to outline and simplify our current understanding of the complex links between aging, senescence and inflammaging in ARDs, classify and list the biomarkers of aging, and discuss the knowns and the unknowns of the field.

Link: https://doi.org/10.3390/biomedicines14071486

It is well established that physical fitness (and the level of activity and other lifestyle choices required to sustain it) correlate with a lower risk of mortality and longer life expectancy. Human data largely cannot provide evidence for causation, but that greater activity and fitness slow aging and extend life is robustly demonstrated in animal studies. Many large epidemiological studies have quantified the reduction in mortality risk provided by exercise or physical fitness, usually with a specific focus on some narrow aspect of the relationship, and here find yet another example of the type. The data in this study shows that old people at the low end of the range of fitness experience something like twice the late life mortality risk of those at the high end of fitness.

Regular physical activity promotes healthy aging, yet clinical risk stratification in older adults relies largely on comorbidity burden, often overlooking functional capacity. Objective fitness assessment may serve as a clinically relevant indicator of physiological reserve, but evidence from large cohorts evaluating multiple fitness domains remains limited. This nationwide cohort study included community-dwelling adults aged 65 years or older who completed standardized fitness assessments in Taiwan between January 11, 2015, and November 25, 2016. Participant data were linked to National Health Insurance records, with follow-up through December 31, 2022. The main outcome was all-cause mortality.

Of 13,423 participants (mean age, 72.9 ± 6.1] years;), 1,631 (12.2%) died during a median follow-up of 7.0 years. Compared with the lowest performance quintile, participants in the highest performance quintile had lower all-cause mortality across 4 physical fitness assessments: 8-foot up-and-go (adjusted hazard ratio, AHR, 0.41), 1-leg stance (AHR 0.50), 30-second chair stand (AHR 0.55), and 2-minute step test (AHR 0.58). The composite fitness index showed the lowest risk of all-cause mortality (AHR 0.39).

To conclude, in this cohort study of older adults, objectively measured physical fitness - particularly balance and agility, lower-body strength, and cardiorespiratory fitness - was associated with lower all-cause mortality in a graded manner.

Link: https://doi.org/10.1001/jamanetworkopen.2026.28227

Rehabilitation following a stroke that causes significant loss of function is a slow, painful, and uncertain process. The concept underlying these efforts is that the brain will attempt to rebuild neural connections given sufficient efforts to use lost and diminished function. This does happen to some degree, but far less so in aged patients. Changes in brain circuitry require neuroplasticity: the creation of new neurons that integrate into existing neural networks, and the creation of new synaptic connections between neurons. Neuroplasticity is well demonstrated to decline with age, though there is some debate over which of the contributing factors are more versus less important. Stem cells decline in their activity, and the aged tissue environment is more inflammatory and less conducive to regeneration.

In today's open access paper, researchers report on a demonstration of improved rehabilitation in mice following stroke via reprogramming. Reprogramming involves exposing cells to some or all of the Yamanaka factors; if kept up for long enough, cells undergo rejuvenation of their patterns of gene expression and a change of state into pluripotent stem cells. Ideally in a therapeutic use, the exposure lasts long enough to produce epigenetic rejuvenation but not so long as to produce change in cell state. It is worth noting that for the purposes of a mouse study, in which the mice will be sacrificed and examined at the end of the assessment, it isn't necessary to be as careful about crossing the line into the creation of pluripotent stem cells that can generate cancers as one would have to be in human medicine.

Here, researchers used a viral vector to introduce plasmids encoding the Yamanaka factors Oct4, Sox2, and Klf4 into neurons in the corticospinal tract of mice, which links the cortex to the spinal cord and carries the signaling necessary for control of limbs. Expression of the Yamanaka factors was transiently induced by treatment with doxycycline, a necessary limit on the process of reprogramming. After inducing a stroke in the animals, those mice with reprogrammed neurons exhibited greater neuroplasticity and functional recovery. This is one of a number of interesting demonstrations of the capabilities of cellular reprogramming, but questions on safety, and how to ensure it in various different therapeutic contexts, will no doubt slow down the field for some years yet.

Rejuvenation of corticospinal neurons enhances rehabilitation-associated corticospinal tract axon sprouting and functional recovery post photothrombotic ischemic stroke in mice

Rehabilitative training is widely adopted in the clinic to achieve functional recovery following stroke. The rationale of rehabilitative training is based on the Hebb theory, which predicts simultaneous pre- and post-synaptic activities that will facilitate synaptogenesis and ultimately lead to the formation of new circuits. However, the effectiveness of rehabilitative training is highly dependent on the level of neuroplasticity and, consequently, is limited in aged patients. Thus, a logical strategy to improve outcomes of rehabilitative training is to identify avenues that are capable of rejuvenating adult neurons in the central nervous system (CNS).

Epigenetic changes are well recognized as hallmarks of ageing. The transcription factor-based cellular reprogramming can refresh the epigenetic landscape and thus presents an innovative method for the rejuvenation of aging cells. Recent studies have shown that overexpression of Oct4, Sox2, and Klf4 (referred to as OSKTFs) reverses epigenetic changes in aged retinal ganglion cells and enables them to regrow their injured axons, a process typically absent in the mature mammalian CNS.

In the current study, we first showed that unilateral photothrombotic stroke ablated corticospinal neurons, leading to severe impairments in skilled but not gross motor function. We further demonstrated that expression of OSKTFs in corticospinal neurons partially rescued the developmental decline of major epigenetic regulators. Ectopic expression of OSKTFs in corticospinal neurons had minimal impact on corticospinal tract (CST) axons' spinal termination and function in intact animals but moderately promoted the collateral outgrowth of the CST axons in the cervical spinal cord and skilled motor recovery in animals with photothrombotic stroke.

OSKTFs expression synergized with rehabilitative training through enhanced mTOR activity, producing additive benefits on CST collateral sprouting and skilled locomotion recovery. Mechanistically, the observed axon sprouting and functional recovery depend on mTOR activation and are driven by newly formed CST collaterals. Taken together, our study revealed an effective avenue to rejuvenate corticospinal neurons, thereby providing new thoughts to optimize the otherwise modest effects of rehabilitative training that is widely used for treating patients with traumatic CNS injuries.

Cells become senescent constantly throughout life, in response to damage, stress, or reaching the Hayflick limit on replication. A senescent cell ceases to replicate, grows in size, and begins to secrete a potent mix of pro-inflammatory signals. In youth, the immune system efficiently clears senescent cells. Clearance falters in later life, however, and this failure of the immune system to keep up with the pace at which senescent cells are created enables the steady accumulation of senescent cells over time. The inflammatory signaling becomes increasingly disruptive to tissue structure and function, an important contribution to degenerative aging. A number of research groups and companies are focused on ways to restore the ability of the aged immune system to clear senescent cells, and time will tell as to whether this sort of approach becomes favored versus senolytic small molecule drugs that selectively stress senescent cells to cause programmed cell death.

Aging involves molecular changes that can give rise to different cell fates, one of those being cellular senescence. Senescent cells stably arrest in the cell cycle and play important roles in physiological processes and can act in a tumor-suppressive manner. However, senescent cells accumulate throughout the body with both chronological and biological aging, promoting chronic inflammation and tissue dysfunction. One of the features of senescent cells is their ability to adopt a secretory phenotype, which can act as a chemotactic gradient to attract immune cells. These infiltrating immune cells are capable of recognizing senescent cells and targeting them for destruction, thus maintaining a balance between senescent cell generation and elimination.

Unfortunately, with age, the immune system undergoes changes that alter functional capacity, referred to as immunosenescence. Immunosenescence impacts both innate and adaptive immune cells, impairing their protective functions, like immunosurveillance, or causing them to adopt a hyperinflammatory phenotype, which may further enhance senescent cell burden. These age-related changes in immune function can compromise immunosurveillance, further exacerbating senescent cell burden and its effects. Additionally, senescent cells themselves can modulate markers on their cell surface that make detection by immune cells more difficult and allow them to escape immune clearance. The role of the immune system in limiting senescent cell burden to maintain homeostasis and how immunosurveillance is compromised with age is explored. Furthermore, mechanisms by which senescent cells evade immunosurveillance and potential strategies to restore age-related deficits in immune cell-mediated clearance of senescent cells are also discussed.

Link: https://doi.org/10.3389/fgene.2026.1882818

First generation stem cell therapies that use a variety of cell sources and protocols are widely used in the medical tourism industry. A more limited set of such therapies are used in more regulated medical systems. The aspirational goal in the field of stem cell medicine is to induce regeneration of aged and damaged tissues to improve function, but this outcome remains unreliable. Stem cell therapies can fairly reliably produce a reduction in chronic inflammation for a period of months, however. Even so, results vary widely from patient to patient and clinic to clinic; standardization remains a challenge, perhaps in large part due to the sensitivity of cells to small differences in how they are cultured. The degree to which stem cells in culture become senescent, and thus detrimental to the treatment, can vary widely.

Stem cell therapy has emerged as one of the most promising strategies in regenerative medicine due to its potential to repair, replace, or regenerate damaged tissues and organs. Over the past several decades, advances in stem cell biology, biomaterials, and translational medicine have significantly expanded the therapeutic landscape, enabling applications across a wide range of diseases, including neurological, cardiovascular, ophthalmological, orthopedic, and oncological conditions

Despite substantial progress in stem cell biology, biomaterials, and regenerative medicine, several important clinical challenges continue to limit the successful translation of stem cell-based therapies into routine medical practice. Although numerous preclinical studies have demonstrated encouraging therapeutic outcomes, reproducibility across clinical studies remains inconsistent. Differences in patient populations, disease stage, genetic background, age, and underlying pathological conditions may contribute to substantial variability in treatment responses.

Link: https://doi.org/10.3390/biomedicines14071443

Myesthenia gravis is a rare autoimmune condition in which a specific receptor needed for nerve impulses to pass through the neuromuscular junction to active muscle fibers is blocked or destroyed by immune activity. This leads to muscle weakness that varies over time, and can progress to be life-threatening in a minority of cases. The prognosis is good for the majority of patients, however. While distressing, the condition affects only parts of the body, and doesn't cause pathology (such as chronic inflammation) that directly contributes to other conditions or the pace of aging. The existing therapies are helpful for most patients, and are improving over time. If forced to choose one presently incurable neuromuscular autoimmune condition to suffer, this would be strong contender. The others tend towards being much worse.

A very interesting paper was published recently. Researchers set out to compare the epidemiology of patients with myesthenia gravis and multiple sclerosis using data in four US state databases. Both are incurable autoimmune conditions that affect muscle function, the second being far worse than the first in terms of loss of vital function and patient outcomes. Along the way, the researchers made the unexpected discovery that myesthenia gravis patients live five years longer than the general population, noting that "this observation should be interpreted as hypothesis-generating." Meaning that there is no obvious reason as to why this would be the case.

How long can sizable differences in life expectancy between groups hide from the attention of those who seek to understand why exactly it happens? There are analogous examples, such as the clinical trial showing a five year survival advantage over the general population in osteoporosis patients who took bisphosphonate drugs, for example. It later turned out that those drugs may be senolytic, reducing the burden of senescent cells, but the topic is by no means closed, nor even really all that widely known or eagerly investigated.

But on with the hypothesizing on the matter of myesthenia gravis related longevity. Firstly, we might propose that there was some form of error on the part of one or more groups within the chain that leads from gathering to warehousing to analysis of epidemiological data. This seems unlikely, given the incentives of those involved, and the effort to use distinct sources of data, but this is why replication is necessary: someone will have to repeat the analysis using databases for another population.

Secondly, we might think that one or more of the common treatments used by the majority of myesthenia gravis patients have a positive effect on late life mortality risk. These treatments are acetylcholinesterase inhibitors and various immunosuppressive therapies. It would be surprising to find that any immunosuppressive therapy reduces mortality risk in late life in any scenario other than inflammatory autoimmune disease; the consensus is that suppression of necessary immune functions is harmful, and only an acceptable trade-off for conditions such as rheumatoid arthritis and worse autoimmunities. As noted above, myesthenia gravis isn't an inflammatory condition. Acetylcholinesterase inhibition is a more interesting thread to pull on; acetylcholine is an important neurotransmitter, these drugs block its degradation, and are primarily used in Alzheimer's patients where they are shown to slow cognitive decline. Do they produce other meaningful benefits that start in the brain and percolate out into the body or that result directly from actions outside the brain? The answer to that question seems largely unclear, but there are supportive studies in aged mice, such as one showing improved lung function.

Thirdly, myesthenia gravis patients, once diagnosed, tend to have a close relationship with physicians and are quite actively monitored, as is the case for many rare diseases. One outcome of this is that patients are strongly encouraged to exercise and improve their lifestyle. Does this five year difference in life expectancy result from being closely monitored by physicians, and thus other age-related issues are identified earlier and treated more effectively as a result, combined with being constantly encouraged and motivated to improve lifestyle choices? One has to imagine that the threat of severe muscle weakness should the condition advance, to the point of needing mechanical ventilation, is quite motivating, even setting aside the effects of a great deal more support and direction from the medical community than most people receive.

Unexpected longevity in myasthenia gravis: a multi-state population-based comparison with multiple sclerosis and the U.S. population

We examined death records from four US states in the years 2000, 2005, 2010, and 2015. We compared the age at death for people with myasthenia gravis (MG) and multiple sclerosis (MS) to life expectancy in the general US population. During this period, many of today's newer high-efficacy treatments were not yet available, which allowed us to examine mortality patterns before the introduction of more recent therapies. MS is widely known to shorten life expectancy, but less is understood about long-term survival in MG. In clinical practice, we observed that many patients with MG were living into their 80s and 90s, while this was uncommon in MS. Understanding whether these observations reflect broader patterns can help clinicians, patients, and researchers better understand the long-term impact of these conditions.

This population-based analysis across four U.S. states demonstrates a consistent and substantial difference in age at death between individuals with MG and those with MS. Age at death of MS patients was significantly lower than the general population (-12.4 years). In contrast, MG patients showed a higher mean age at time of death compared with the general population (+4.8 years) and died significantly later than MS patients (+15.5 years, adjusted for sex and year). These patterns were consistent across datasets. Despite a higher reported burden of age-related comorbidities in MG populations, MG patients demonstrated higher mean age at death than both MS patients and the general population.

Differences in disease biology are also likely relevant. MS is characterized by chronic neuroinflammation, demyelination, and progressive neurodegeneration, leading to loss of neurological reserve and increasing vulnerability to systemic complications. These downstream effects extend beyond the central nervous system and contribute to long-term morbidity. MG, by contrast, affects neuromuscular transmission without causing structural neurodegeneration. Although MG can produce severe weakness and life-threatening crises, many patients experience meaningful functional recovery with treatment. The absence of a progressive neurodegenerative component may help explain the more favorable long-term outcomes observed in this analysis.

An additional complexity is the apparent mismatch between comorbidity burden and survival. Prior studies suggest that MG populations, particularly those with late-onset disease, often carry a higher burden of age-related comorbidities, including hypertension, diabetes, and pulmonary disease. In contrast, MS populations may have fewer traditional comorbidities but higher rates of psychiatric and cardiovascular conditions. Despite this, MG patients in the present analysis demonstrated higher age at death than both MS patients and the general population. This finding is difficult to reconcile and suggests that factors beyond comorbidity burden alone are influencing outcomes. At present, this observation should be interpreted as hypothesis-generating.

Tauopathies emerge in the aging brain, a pathological level of phosphorylation of the tau protein that is disruptive to cell function. Evidence suggests a feedback loop between tau phosphorylation and consequent aggregation into neurofibrillary tangles on the one hand and chronic inflammation in brain tissue on the other, ultimately leading to the widespread death of neurons. Here, researchers show that another feedback loop exists between pathologically altered tau and mitochondrial dysfunction in brain cells. Since it is well established that mitochondrial dysfunction promotes inflammatory signaling via a range of mechanisms, such as maladaptive reactions to mitochondrial DNA fragments released into the cell cytoplasm, this new discovery fleshes out the bigger picture considerably.

Tau molecules spend some of their time sitting on microtubules. But tau molecules spend even more of their time detached from their seats on microtubules. During this downtime, a free-floating tau molecule becomes especially prone to confrontations such as the stapling of a chemical cap onto its exposed parts by neighborhood enzymes. These modifications predispose tau molecules to clumping with one another, potentially aggregating into neurofibrillary tangles. A single tau molecule can acquire numerous chemical caps along its length, all the more pumping up its potential for mischief. More often than not, the chemical cap that gets attached is what chemists call a phosphate group. A single tau molecule can accommodate as many as 80 separate phosphate-group additions, or phosphorylations. Tau "hyperphosphorylation" is a uniting feature linking all tauopathies.

The newly discovered pathological pathway is entirely independent of both neurofibrillary-tangle formation and microtubule instability. Instead, it involves a switch in the directionality of mitochondria's energy-production line, with a resulting disruption of mitochondria's primary function: the conversion of calories from glucose or fat to energy by what's known as the electron-transport chain. This multiple-component complex passes electrons, conveyor-belt-style, from one to the next of its components, the last of which converts a precursor molecule into ATP, our cells' universal energy currency. The new study shows that when the hyperphosphorylated tau molecule interacts with a key mitochondrial component, it jams up the conveyor belt, causing electrons to flow backward. Aptly named "reverse electron transport," this snarl produces large amounts of highly reactive, noxious chemicals, with accompanying inflammation and damage to proteins.

The researchers proved that reverse electron transport was occurring in animal models of tauopathy as well as in tauopathy-afflicted human brain tissues. Healthy nerve cells, largely spared of hyperphosphorylated tau's malevolent presence, showed no sign of reverse electron transport or its downside effects. Next, they showed how reverse electron transport is activated: Tau molecules enter mitochondria - although only when they're phosphorylated. There, they can bind to a component of the electron-transport chain called NDUSF3, warping that protein's shape. When this happens, electrons drop off the conveyor belt and start flowing backward. Genetically or pharmacologically depleting tau halted this defection. Reverse electron transport is a textbook example of a vicious circle. The massive release of highly reactive chemicals dramatically boosts the odds that individual tau molecules will get hyperphosphorylated, leading to additional activation of reverse electron transport. Once started, this can self-perpetuate.

An experimental drug called CPT prevented hyperphosphorylated tau from binding to NDUSF3, blocking reverse electron transport without impairing normal electron flow. In fly and mouse models of tauopathy, CPT treatment rescues behavioral deficits, reduces neuroinflammation and mitigates neurodegeneration. Cerapeut, Inc. is developing CPT as a therapeutic drug for the treatment of neurodegenerative diseases.

Link: https://med.stanford.edu/news/all-news/2026/08/tau-alzheimers.html

Muscle tissue is metabolically active. In response to use during physical activity, muscle cells secrete a range of signals, as a class now called myokines or exerkines. These signals produce overall beneficial effects on cell behavior and tissue function throughout the body. The precise details of this process are still under investigation, and only the major signals are fairly well mapped - a great deal remains to be discovered in terms of exactly how exercise improves function. Here, researchers review what is presently known of this connection between exercise and a slowing of the progression of age-related neurodegeneration. The research community is quite interested in producing exercise mimetic therapies of various sorts, and one approach to that goal is the identification of specific signals or responses to those signals that can be manipulated.

Parkinson's disease (PD) is a progressive neurodegenerative disorder with motor and non-motor symptoms, driven by dopaminergic loss and α-synuclein accumulation. Beyond neurodegeneration, growing evidence highlights skeletal muscle health as a key determinant of prognosis, with sarcopenia and frailty contributing to greater disability, fall risk, and reduced quality of life. This narrative review synthesizes current evidence on the interplay among exercise, muscle status, and exerkine signaling in PD, emphasizing their potential roles in neuroprotection and functional outcomes.

Sarcopenia and reduced muscle strength are highly prevalent in PD and independently associated with disease severity, frailty, and falls, while grip strength has emerged as a simple biomarker of progression. Clinical trials consistently show that aerobic, resistance, and multimodal exercise programs improve gait, balance, mood, cognition, and quality of life, with progressive resistance and balance training yielding the greatest motor benefits.

At a mechanistic level, skeletal muscle functions as an active endocrine organ, releasing a variety of exercise-induced signaling molecules known as exerkines. These include brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), irisin, cathepsin B, myostatin, and growth/differentiation factor 15 (GDF15). Together, these exerkines facilitate muscle-brain crosstalk and are thought to contribute to the neuroprotective effects of exercise in PD. Through anti-inflammatory, antioxidant, and mitochondrial regulatory pathways, they support dopaminergic neuron survival and promote synaptic plasticity and neuronal resilience.

Link: https://doi.org/10.1002/nep3.70032

In order to produce an airtight answer to the question of whether obesity accelerates aging, versus merely being very bad for one's health, one has to have an airtight definition of aging. It is always possible to fall back to the oldest and least useful definition of aging, which is a rise in risk of mortality over time driven by intrinsic causes. Arguably the effects of obesity fit that definition, but then replace the introduction of excess calories with the introduction of infectious viral particles, and suddenly someone will say that if obesity accelerates aging as judged by mortality risk, then a few weeks of influenza infection also accelerates aging by the same measure. Or ingesting outright toxins (dramatically) accelerates aging. This is unsatisfying.

Thus any reasonable discussion of whether obesity accelerates aging has involve a tour of what obesity does to cellular biochemistry, and also has to involve judgement calls on which of those changes are versus are not aging. Everything changes with age. Some of that is cause, some of it consequence. Natural aging is a certain balance of certain harmful mechanisms; if we observe what looks like accelerated aging, and under the hood we see that it is just one or just two of those mechanisms running amok, then is it really accelerated aging? Or is it just poor health resulting from the accumulation of cell and tissue damage? Obesity certainly accelerates the age-related accumulation of senescent cells. But harmful levels of irradiation achieve that outcome as well! A great many things can superficially look like accelerated aging: inefficient DNA repair; slow poisoning; malnutrition; and of course obesity. There is a great deal of room to argue over whether they are in fact accelerated aging or not, but all that debate hinges on how exactly one defines aging.

There is one way in these considerations can be useful, and that is managing expectations as to whether therapies that treat aging are going to be more versus less useful as treatments for various forms of what appear to be accelerated aging. For a therapy to be useful, mechanisms have to align. We know that the apparently dramatically accelerated aging of Hutchinson-Gilford progeroid syndrome (HGPS) is driven by mutation that harmfully alters a critical protein involved in the structure of the cell nucleus. Those protein alterations occur in normal aging to only a small degree. Treatments for aging are thus unlikely to be useful in HGPS and vice versa. Obesity, however, is clearly correlated with an increased burden of senescent cells. Senotherapeutics developed for use in the treatment of aging may well be beneficial for obese individuals even at younger ages.

Obesity accelerates aging: Mechanisms and therapeutic implications

To explore how to delay aging effectively, scientists have summarized twelve aging characteristics that may be slowed, stopped, or reversed through intervention: genomic instability, telomere depletion, epigenetic changes, loss of protein balance, loss of autophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular aging, stem cell depletion, changes in intercellular communication, chronic inflammation, and dysbiosis. The accumulation of these characteristics is associated with an increased prevalence of various age-related diseases. Research indicates that interventions aimed at slowing the aging process can postpone the onset and progression of various diseases in numerous rodent models.

There are intricate and multifaceted connections between obesity and aging. Obesity is associated with a variety of chronic and degenerative diseases, such as type 2 diabetes, osteoarthritis, cancer, and cardiovascular and renal dysfunction, and may lead to premature aging. A large amount of research evidence suggests that obesity can affect the accumulation of various aging biomarkers, including telomere shortening, epigenetic changes, disruptions in protein homeostasis, mitochondrial dysfunction, cellular senescence, stem cell depletion, and alterations in intercellular communication. Meanwhile, interventions aimed at extending health and lifespan, such as calorie restriction and exercise, are associated with reducing obesity.

Undoubtedly, obesity is an accelerator of aging and aging-related diseases, and its intervention directly impacts the development of aging. However, the overlapping characteristics mentioned above merely indicate potential mechanisms by which obesity promotes aging, with the specific molecular mechanisms involved remaining unclear. These findings suggest that future efforts should focus on further exploring these mechanisms and validating them through targeted biological markers to advance precision medicine development.

A sizable body of evidence points to a meaningful role for the accumulation of senescent cells in the onset and development of age-related pulmonary conditions such as idiopathic pulmonary fibrosis. These are conditions characterized by chronic inflammation and harmful structural remodeling in lung tissue. Animal studies suggest that senolytic therapies to clear senescent cells can turn back the course of disease. An initial small academic human trial of senolytic treatment in patients with idiopathic pulmonary fibrosis produced promising results, but little to no follow up has occurred. This is the standard problem for generic drugs and otherwise low-cost therapies: since little profit can be made, no-one can raise sufficient capital to pay for the high costs of clinical trials.

Aging is the primary risk factor for most chronic diseases and is accompanied by the progressive accumulation of senescent cells within tissues. While cellular senescence initially serves as a protective mechanism that limits the proliferation of damaged cells, its persistent presence contributes to tissue dysfunction through the secretion of a broad spectrum of inflammatory and profibrotic mediators. The resulting chronic low-grade inflammation, oxidative stress, immune dysregulation, and impaired regenerative capacity are increasingly recognized as hallmarks of age-related pathology. Chronic pulmonary diseases, including chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, increase markedly with age and are increasingly regarded as manifestations of accelerated lung aging. Their development and progression are further exacerbated by obesity and type 2 diabetes mellitus, two highly prevalent metabolic disorders characterized by chronic metabolic stress, mitochondrial dysfunction, systemic inflammation, and enhanced accumulation of senescent cells.

Emerging evidence suggests that cellular senescence represents a common biological denominator linking metabolic and pulmonary disease. Through persistent inflammatory and profibrotic signaling, senescent cells establish a self-perpetuating cycle of chronic inflammation, extracellular matrix remodeling, fibrosis, endothelial dysfunction, and impaired tissue repair, thereby driving progressive deterioration of both metabolic and pulmonary function. The recognition of cellular senescence as one of the important drivers of both chronic pulmonary and metabolic diseases has stimulated growing interest in therapeutic strategies aimed at reducing senescent-cell burden or attenuating its detrimental effects. Current approaches include both novel senotherapies specifically targeting cellular senescence, as well as established therapies used in metabolic diseases that have recently been shown to exert senescence-modulating effects. Although clinical evidence remains limited, targeting cellular senescence offers a unique opportunity to address the underlying biology of aging rather than individual disease manifestations.

Link: https://doi.org/10.3389/fragi.2026.1812724

There are now scores of aging clocks in the literature, most of which have come and gone and see little adoption. Most research is focused on gathering more data for handful of mainstream clocks, but these clocks are intended to capture a measure of aging generally across the whole body, keyed to outcomes such as mortality risk. Evidence suggests that different organs and tissues can age at different rates, however. Thus there remains a need for the development and validation of tissue-specific aging clocks. Here, researchers review the present state of development for clocks intended to measure aging in the brain specifically.

Brain aging represents a critical risk factor for neurodegenerative diseases and cognitive decline, yet the measurement of biological brain age remains challenging. Brain aging clocks, which quantify the discrepancy between predicted brain age and chronological age, have emerged as powerful tools for assessing brain health and predicting disease outcomes. Recent advances have transformed these clocks from simple global metrics to sophisticated, multi-modal approaches that capture regional heterogeneity, measure the pace of aging, and achieve cellular resolution.

This review examines the methodological evolution of brain aging clocks, including the development of regional brain age gradients, pace-of-aging measurements, and multi-modal integration strategies. We then explore the cellular and molecular mechanisms underlying accelerated brain aging, with particular emphasis on cellular senescence, cell-type-specific aging patterns, vascular dysfunction and blood-brain barrier breakdown, mitochondrial decline, proteostasis failure, synaptic loss, and the accumulation of senescent cells in neurodegenerative conditions. Epigenetic clocks and emerging plasma biomarkers (neurofilament light, GFAP, phosphorylated tau), particularly DNA methylation-based approaches, are discussed in the context of their relationship with neuroimaging markers and cognitive outcomes.

Clinical applications are reviewed, including the prediction of neurodegenerative disease, the impact of socioeconomic and geographic disparities on brain aging, and emerging senotherapeutic interventions. Finally, we address current challenges in biomarker standardization, the need for longitudinal validation, and future directions toward precision aging medicine. Together, these advances position brain aging clocks as essential tools for understanding neural aging mechanisms and developing targeted interventions to promote healthy brain aging.

Link: https://doi.org/10.1016/j.exger.2026.113260

The major divide in theories of aging lies between the mainstream camp of damage accumulation and antagonistic pleiotropy on the one hand, and the minority camp of programmed aging theories on the other. The damage accumulation camp sees aging as a side-effect of the focus of evolutionary mechanisms on early life reproductive success, favoring the development of biological systems that are front-loaded for early life success, with little investment in maintenance over time. Programmed aging purists view aging as a process that is under active natural selection, however, not a side-effect at all. Why degenerative aging would be selected for is debated, but group selection to reduce the risk of runaway population growth has been argued, as well as the winnowing effect of environmental change on non-aging species, as aging allows for faster adaptation to that change, out-competing non-aging competitor species.

The relatively recently developed hyperfunction theories of aging have a foot in each camp, and might crudely be thought of as a compromise position, though that isn't why they emerged. It has been a difficult area of the field to follow, as it wasn't always clear that everyone involved had the same view of the definition of hyperfunction. Today's open access paper provides a good summary of the consensus hyperfunction view, insofar as such a thing now exists: biological programs that determine early life growth and development continue to operate in adult life in maladaptive ways, and become overtly harmful over time, giving rise to aging. This is roughly a direct conceptual fusion of the concepts of antagonistic pleiotropy and programmed aging. Does any of this theorizing matter? To the degree that it determines research priorities for the development of therapies to treat aging, it probably does.

A brief history of the hyperfunction theory of aging and future directions

Understanding the mechanisms underlying aging processes is crucial for biogerontology and for developing translational approaches. There is much debate, however, regarding the fundamental nature and drivers of aging. The idea that aging arises from genetically encoded processes has gained traction in recent years, the so-called "programmatic theories". It is important not to conflate programmatic and programmed theories, as the latter view aging itself as an evolved adaptation serving a function, while in programmatic theories late-life decline is driven by developmental programs that run-on without aging being adaptive.

In past decades, the idea that aging results from a program or from continued developmental processes became less popular. The evolutionary theory of aging argued against a programmed (i.e., adaptive) aging process, predicting that such a program would be selected against. The dominant view was that aging arises from the declining force of natural selection with age, the so-called "selection shadow". In this model, both genetic variants with detrimental late-life effects, or variants beneficial early in life but harmful later, can become fixed in populations, contributing to aging; here, aging is not an adaptation and, in that sense, not programmed.

The increasing emphasis on molecular damage in aging research was likely driven, at least in part, by advances in molecular biology and biochemistry. The explosion of molecular discoveries in the second half of the 20th century revealed a vast and intricate number of cellular components and biological processes, which in turn led to a proliferation of theories linking aging to defects in each of these many processes. Because virtually any important biochemical or molecular process can malfunction and become harmful to cells, it is easy to conceive new damage-based theories of aging. This abundance of molecular detail reinforced the perception that aging is driven by stochastic damage and led to many theories and frameworks positing damage accumulation as the root cause of aging. It was against this trend that a new wave of programmatic theories emerged at the start of the 21st century.

In 2006, a seminal conceptual paper proposed the quasi-programmed theory of aging, introducing the term hyperfunction. It proposed "a quasi-program for aging, a continuation of the developmental program that is not turned off, is constantly on, becoming hyper-functional and damaging, causing diseases of aging." While acknowledging that damage occurs with age, it was argued that such damage plays a negligible role in determining lifespan. Instead, quasi-programs are the principal drivers of aging and limiting human lifespan.

Although programmatic theories, such as hyperfunction, provide powerful conceptual frameworks for understanding the aging process, much work remains to be done. They are still outside the dominant geroscience paradigms, such as the "hallmarks" and "pillars" of aging. The unfortunate consequence - I would argue - is that most aging studies focus exclusively on adult life, hindering efforts to connect aging to developmental processes. If aging processes follow trajectories set early in life, then studying the whole life course is imperative to elucidate aging mechanisms. Besides, if repair and maintenance mechanisms are downregulated during development, then studying early development may prove valuable for identifying rejuvenation therapies, as already demonstrated in partial reprogramming.

Iron metabolism is strongly connected to oxidative stress, the excessive production of reactive oxygen species and other oxidative molecules that outpaces the ability of cells to avoid, resist, or repair the consequent damage. It can lead to a form of programmed cell death called ferroptosis. Here, researchers describe how iron metabolism and ferroptosis are seen to contribute to the development of atherosclerosis. This isn't a very well developed area of research into cardiovascular disease, in that while one can paint an interesting mechanistic picture at the high level, much of the detail remains to be filled in, and robust forms of therapy based on manipulation of iron metabolism or ferroptosis have yet to emerge.

Disturbances in iron homeostasis have a bidirectional impact on the development of atherosclerosis. The classic "iron hypothesis" states that systemic iron overload increases the risk of cardiovascular diseases (CVDs), while controlling iron deficiency can protect blood vessels. Histopathological studies have confirmed that atherosclerotic plaques have a higher iron deposition compared to healthy blood vessels, and this phenomenon can be observed from the early stages of atherosclerosis. Macrophages recycle iron from senescent red blood cells, and intra-plaque hemorrhage exacerbates the phagocytosis of red blood cells, which is considered a key mechanism for iron deposition.

An increase in intracellular iron concentration enhances the uptake of oxidized low-density lipoprotein (ox-LDL), hinders cholesterol efflux, and accelerates the formation of foam cells in the plaque environment. This process leads to a decrease in GPX4 expression, an excessive production of reactive oxygen species (ROS), and an exacerbation of lipid peroxidation - all three together exacerbate intracellular oxidative stress, directly aggravating endothelial dysfunction and ultimately increasing plaque instability.

Despite the promising therapeutic potential of targeting ferroptosis discussed throughout this manuscript, several important limitations must be acknowledged. First, the disease specificity of ferroptosis-driven pathology remains incompletely defined; not all conditions involving cell death or oxidative stress may benefit from ferroptosis inhibition, and the contribution of ferroptosis varies substantially across different diseases and even across stages of the same disease. Second, the optimal timing of intervention is challenging to determine, as ferroptosis may play divergent roles in early versus late disease phases, and premature or delayed intervention could be ineffective or even detrimental. Third, systemic modulation of iron metabolism carries risks of off-target effects on other organs, including potential hepatotoxicity, cardiotoxicity, and disruption of normal iron homeostasis in tissues with high iron turnover. Fourth, while natural compounds are often proposed as ferroptosis modulators, they have pharmacological limitations such as poor solubility, low bioavailability, off-target bioactivity, and unknown long-term safety profiles.

Link: https://doi.org/10.1016/j.redox.2026.104330

That we cannot accurately and robustly measure biological age is a major impediment to the development of rejuvenation therapies. Without the ability to quickly focus on approaches with the largest effects on biological age, the field spends far too much time on marginal classes of therapy, and optimization of any given approach is challenging, haphazard, and slow. The development of aging clocks in recent years is a step in the right direction, but clock data is not trustworthy in the matter of assessing the effects of any given intervention until they are fully calibrated to that intervention via life span studies - which defeats the point of having a fast clock measure. That this is a problem is widely appreciated in the field of aging research, so we might hope that we will see meaningful progress towards reliably and accurate measurement of biological age in the years ahead.

Aging is a major risk factor for numerous chronic diseases and a leading contributor to global mortality. Slowing the rate of aging would have revolutionary implications for health and longevity. A fundamental barrier to achieving this goal, however, is the difficulty of accurately measuring the effects of rejuvenating interventions. The development of precise gerontometric methods, therefore, is a priority for both science and preventive medicine.

In this opinion article, the authors suggest the principles and discuss the implementation of precision gerontometry using recent advances in metabolomics. Although metabolomic approaches have limited accuracy in determining biological age, the described approach, which averages multiple metabolites from a large metabolomic signature of aging, circumvents this limitation. It allows for measurement of biological age change with an accuracy of approximately one month. Such precision gerontometry enables accelerated testing of candidate anti-aging interventions, helping to eliminate ineffective ones, speed the development of effective ones, and ultimately extend the duration of healthy human life, with profound social and humanitarian benefits.

Link: https://doi.org/10.3390/metabo16070463

Alzheimer's disease, and the other common age-related neurodegenerative conditions, are characterized by chronic inflammation in brain tissue. Aging in general is characterized by an increased level of constant inflammatory signaling. Numerous different mechanisms contribute to this constant inflammation, such as maladaptive reactions to mitochondrial DNA fragments released into the cytoplasm as a result of age-related mitochondrial dysfunction, and a growing burden of senescent cells that actively secrete pro-inflammatory signals. The gut microbiome changes in ways that provoke inflammation as well, and the intestinal barrier becomes leaky with age, allowing more unwanted bacteria and bacterial metabolites into the body. In the brain, clearance of metabolic waste is achieved in large part by circulation of cerebrospinal fluid and its drainage into the body via channels that atrophy or become dysfunctional with age. Reduced flow allows metabolic waste to build up in brain tissue, including the protein aggregates associated with neurodegenerative conditions - and all of this increases maladaptive inflammatory responses on the part of immune cells in the brain.

Any reasonably complete list of contributions to age-related inflammation is much longer than the few high points noted above. Comprehensively dealing with the inflammation of old age is a task that will require more than one therapy, if the objective is to remove the causes. This is perhaps why much of medical research tends to favor sabotaging inflammatory signaling or aspects of immune cell function rather than addressing causes. It is a bad long term strategy from the point of view of achieving radically better human health, but it works in the short term to get drugs approved and investors their profits. The therapy that is the subject of today's open access report on its initial clinical trial results is an example of the dominant class of approach to chronic inflammation - find a central mechanism involved in coordinating the inflammatory response, and sabotage it. Unfortunately the initial data suggests that this particular anti-inflammatory therapy may not work as well in humans as it does in mouse models of inflammatory neurodegeneration.

Immunotherapy with a short-lived anti-PD-L1 antibody in Alzheimer's disease: a phase 1b, randomized, double-blind trial

While Alzheimer's disease (AD) is initiated by amyloid plaque accumulation, its progression involves local neuroinflammation that the brain cannot resolve when age-related dysfunction of the systemic immune system limits peripheral immune support. Preclinical studies using rodent models showed that transient systemic blockade of programmed death-ligand 1 is associated with reduced neuroinflammation, neuroprotection and attenuation of disease progression. Based on the underlying mechanism, a new short-lived anti-programmed death-ligand 1 antibody with fragment crystallizable (Fc) region-effector silencing and reduced neonatal fragment crystallizable receptor (FcRn) binding (IBC-Ab002) was engineered.

Here, we report a randomized, double-blind, phase 1b first-in-human trial in early AD, with safety and tolerability as the primary endpoint. Forty participants were enrolled across five ascending dose cohorts (1 mg/kg to 30 mg/kg), with dosing administered four times at 3-month intervals. Treatment was well tolerated, with no treatment-related serious adverse events or evidence of amyloid-related imaging abnormalities. Exploratory analyses at week 48 showed directional changes in cerebrospinal fluid biomarkers of neuronal and synaptic damage favoring the 30 mg/kg dose, although no doses reached statistical significance given the limited sample size. The safety and tolerability profile supports further clinical development of systemic, intermittently administered IBC-Ab002 in early AD.

Mitochondrial transplantation is a promising approach to treating age-related mitochondrial dysfunction. Cells readily take up mitochondria from their surroundings. The major challenge in the development of practical mitochondrial transplantation therapies is the robust production of the large numbers of mitochondria needed for a human therapy. Ways to improve the survival and uptake of mitochondria are thus helpful because they reduce the manufacturing burden, lowering the number of mitochondria needed for a successful treatment. Researchers here upon tools used in lipid nanoparticle therapies and gene therapies and demonstrate that they can be used to improve the delivery and uptake of mitochondria into cells in tissues.

Mitochondrial transplantation has emerged as a promising strategy for modulating cellular bioenergetics in mitochondrial dysfunction. However, isolated mitochondria suffer from poor stability and limited cellular uptake, restricting their therapeutic application. To address these limitations, we developed a surface engineering strategy that stabilizes isolated mitochondria while enabling interactions with target cells, providing a platform for selective organ- and cell-targeting. Polyethylene glycol (PEG) with lipid/carbon chains was introduced to mitochondria-associated membrane structures, forming a protective hydration layer on the mitochondrial surface. This PEG layer also serves as a modular platform for functionalization with biomolecules, such as peptides and antibodies, thereby broadening its biomedical applications.

In this study, we examined whether mitochondrial function in target cells can be modulated using PEG-shielded mitochondria functionalized with a cell-penetrating peptide (CPP) via a maleimide linkage. Our results suggest that CPP-PEG-modified mitochondria exhibit efficient cellular internalization and are associated with increased mitochondrial respiratory activity, consistent with intracellular bioenergetic modulation. These findings suggest that spatially controlled presentation of CPP at the terminus of a PEG layer may provide an effective approach for stabilizing isolated mitochondria while modulating intracellular dynamics and functional responses. This surface engineering strategy offers a proof-of-concept design framework for mitochondria-associated engineering and future bioenergetic strategies.

Link: https://doi.org/10.1002/admi.70583

The bacterial species P. gingivalis is a cause of periodontitis, a common form of inflammatory gum disease that in addition to damaging gums, teeth, and bone in the mouth, also contributes to the development of inflammatory age-related conditions elsewhere in the body. Here researchers report on a novel approach to selectively removing P. gingivalis from the mouse, using a combination of a photosensitive dye conjugated to an antibody that binds to surface features on this species of bacteria. When irradiated with near infrared light, this kills the targeted cells. Treating a mouse model of periodontitis in this way successfully reduced inflammation and resolved the condition.

Traditionally, periodontitis was viewed as a simple infection; however, it is now recognized as a complex polymicrobial disease driven by synergistic interactions within the oral microbiota and a subsequent aberrant host immune response. Periodontitis is typically initiated by a shift from symbiotic to dysbiotic microbial communities. In this process, 'keystone pathogens' such as Porphyromonas gingivalis, even at low abundance, can remodel the surrounding commensal bacteria into a highly inflammatory state.

Recently, a new cancer-targeted therapy called near-infrared photoimmunotherapy (NIR-PIT), which combines antibody-dye conjugates and near-infrared light, has emerged. The cell death mechanism of NIR-PIT is unique. Specifically, when the conjugate is irradiated with near-infrared light in the presence of sufficient electron donors, the hydrophilic side chain (silanol) of the IR700 molecule dissociates through a photochemical ligand reaction, and the remaining structure, including the antibody, rapidly becomes hydrophobic and aggregates. At the same time, the antibodies bound to the surface antigens also aggregate on the tumor cell membrane. The aggregation reaction of IR700 causes physical stress on the antigen-antibody complex and selectively destroys the target cells

We recently developed NIR photoantimicrobial-targeted therapy (NIR-PAT2) to treat infectious diseases. For NIR-PAT2, as targeting molecules, we exploit immunoglobulin Y (IgY). NIR-PAT2 with IgY could be used for body surface and lumens, such as skin, hair, eye, digestive tract. The aim of this study was to develop a bacteria-targeted therapeutic modality using NIR-PAT2. While we acknowledge the inherent limitations of single-pathogen targeting in a complex polymicrobial disease, we hypothesized that selectively eliminating a keystone species would disrupt the synergistic drivers of dysbiosis. We define this approach as a precision-modulating therapy, designed to selectively ablate P. gingivalis while preserving the ecological integrity of the oral community. Here, we demonstrate that NIR-PAT2 successfully modulates oral dysbiosis, leading to the resolution of periodontitis and the restoration of a healthy-associated microbial profile in a murine model.

Link: https://doi.org/10.1186/s12967-026-08336-2

Telomeres are repeated DNA sequences found at the ends of chromosomes. A little telomere length is lost with each cell division, and short telomeres trigger cell senescence or programmed cell death. It is a part of the system ensuring the Hayflick limit on the replication of somatic cells. The stem cells that create replacement somatic cells can lengthen their own telomeres, but there are very few stem cells in comparison to the number of somatic cells making up the majority of tissue. This is how evolution reduces cancer to an acceptable level, by dramatically restricting the number of cells capable of unfettered replication, and thus reducing the odds of a malfunction leading to runaway replication.

With age stem cell function declines, reducing the pace at which stem cells deliver replacement somatic cells with long telomeres. As a result, average telomere length falls and the proportion of cells with very short telomeres increases in tissues throughout the body. This has a meaningful negative effect on health, a driver of chronic inflammation, increased numbers of senescent cells, and impaired tissue function. In today's open access paper, researchers report on their efforts to specifically sabotage the cascade of mechanisms that emerge in response to short telomeres in a cell, showing that it improves health in aged mice, at least in the short term. The flip side of the coin, not investigated here, is that this could increase cancer risk by promoting damage to DNA via the continued operation of damaged cells, usually avoided because cells with very short telomeres are destroyed on some timescale.

Therapeutic inhibition of telomeric DNA damage response rescues hematopoietic dysfunction driven by telomere shortening and aging

Telomeres progressively shorten and accumulate damage with aging, and this contributes to cellular senescence and hematopoietic dysfunction. When critically short, telomere ends are detected as DNA damage and trigger a telomeric DNA damage response (tDDR), a signaling cascade involving posttranslational protein modifications, such as phosphorylation of histone H2AX at serine 139 (known as γH2AX), which promotes recruitment of DDR factors including phosphorylated KRAB-associated protein 1 (pKAP1) at damaged sites. Persistent tDDR drives cellular senescence and cell death. The inability of senescent cells to proliferate impairs tissue regeneration, and their secretion of proinflammatory factors, collectively known as the senescence-associated secretory phenotype, promotes chronic, low-grade inflammation, disrupting the local microenvironment and eventually causing systemic frailty.

Whether the tDDR causally impairs hematopoiesis remained unclear. Here we show in telomerase-deficient Telomerase RNA component (TERC) knockout mice, which recapitulate telomere-driven hematopoietic dysfunction and aging, that targeting telomeric noncoding RNAs with telomeric antisense oligonucleotides (tASO) suppresses tDDR in hematopoietic organs, reduces senescence and inflammation, alleviates hematopoietic dysfunction, and enhances hematopoietic stem cell fitness and repopulating potential in vivo. Similar observations were recapitulated in aged wild-type mice, and ex vivo treatment with tASO improved the function of human hematopoietic stem cells from aged donors.

Taken together, our results identify tDDR as a pathogenic driver of hematopoietic decline and support tASO-mediated tDDR inhibition as a potential therapeutic strategy for telomere biology disorders and age-associated hematopoietic aging.

Technically, even very small effects can be classed as rejuvenation if they move the right markers, if they in some way reduce the burden of damage and dysfunction of aging. Exercise probably rejuvenates to some degree, by any reasonable definition. Yet we know the bounds of the possible when it comes to exercise and other widely used interventions, and the outcomes are nowhere near as large as we would like. Fit people are still aging to death, and end up frail in the later stages of life.

In the matter of restoring lost function to the hematopoietic stem cell populations of the bone marrow that are responsible for generating the cells that make up the immune system, there are a number of interventions that have been shown to outperform the effects of exercise in mice. One of the more interesting examples is the results of a single treatment of CASIN, which improves stem cell function globally, improves immune function, and extends life. Restored immune function is an important goal in the treatment of aging, given the sizable influence the immune system has over the course of aging.

Aged hematopoietic stem cells (HSCs) are characterized by increased phenotypic number, decreased self-renewal and long-term reconstitution capacity, myeloid-biased differentiation, and clonal hematopoiesis. In this review, we summarize the life cycle of HSCs, integrate recent advances in understanding the cell-intrinsic and extrinsic mechanisms that drive HSC aging, and highlight innovative rejuvenation strategies that could be harnessed to delay HSC and systemic aging.

Exercise enhances systemic health through improved circulation and metabolism. However, it was found that exercise has little effect on rejuvenating HSCs. It is plausible that exercise preferentially accelerates lymphopoiesis via niche remodeling rather than directly rejuvenates aged HSCs. Dietary restriction (DR) modulates HSC function through multiple nutrient-sensing pathways. Pharmacological approaches targeting the same metabolic pathways also show rejuvenation effects on HSCs. Nicotinamide riboside (NR) enhances mitochondrial function and restores the metabolic competence and regenerative capacity of aged HSCs. Similarly, mTOR inhibition with rapamycin reverses age-related functional decline of HSCs, improving self-renewal, reconstitution potential, and antiviral immunity in aged mice.

Sirt3 is a mammalian deacetylase that exhibits age-dependent expression decline in HSCs. Sirt3 knockout in aged mice impairs HSC self-renewal capacity, while its overexpression enhances regenerative potential. Sirt7 deletion induces premature activation, lymphoid differentiation bias, and functional exhaustion of HSCs. In contrast, Sirt7 overexpression reverses these aging hallmarks, and restores balanced lineage output and reconstitution capacity in geriatric murine models. Transient expression of Yamanaka factors (e.g., Oct4, Sox2, Klf4, and c-Myc) showed systemic rejuvenation effects and extended life span in mice, whether it can reverse HSC aging remains to be tested.

A marked increase in non-polarized cells is observed among aged HSCs, attributed to elevated Rho-GTPase activity of Cdc42 during aging. Casin, a small-molecule Cdc42 inhibitor, restored the proportion of polarized HSCs in aged mice and moderately enhanced their long-term reconstitution potential. In vivo Casin treatment significantly extended the lifespan of aged mice and reduced systemic inflammatory cytokines. Aged HSCs exhibit MMP reduction and pronounced mitochondrial heterogeneity, with low-activity subpopulations displaying characteristic aging phenotypes. Mito-Q treatment in aged mice partially restored MMP and augmented transcriptional activity in HSCs.

Oral administration of the senolytic drug ABT263, an inhibitor of the anti-apoptotic proteins BCL-2 and BCL-xL, effectively cleared senescent HSCs, ameliorated irradiation-induced premature hematopoietic aging, and partially restored the regenerative ability of HSCs.

Link: https://doi.org/10.1186/s13059-026-04119-6

Researchers here discuss a bidirectional relationship between age-related alterations in bile acid metabolism, centered in the liver, and changes in the composition of the gut microbiome. These changes take place in the context of increasing dsyfunction of the intestinal barrier with age, allowing unwanted bacteria and bacterial metabolites into the body to provoke chronic inflammation and other dysfunction. Researchers have demonstrated in animal studies that restoration of a youthful gut microbiome composition can improve health and extend life; an interesting question is the degree to which restoration of a youthful bile acid metabolism can achieve similar outcomes.

Bile acids (BAs), byproducts of cholesterol metabolism in the liver, are not only vital for lipid digestion and absorption of lipid-soluble vitamins but also act as signaling molecules influencing aging, inflammation control, immune homeostasis, and tumor development. They regulate gut microbiota growth and composition, while gut microbiota significantly influence BA hydrolysis and the synthesis of secondary and tertiary BAs. This interplay affects immune function and metabolic phenotypes, and may contribute to obesity, diabetes, non-alcoholic fatty liver disease, inflammatory bowel disease, and certain cancers.

100 elderly and 100 young participants were enrolled in this study. Fecal and serum BAs were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), while gut microbiota composition was assessed through 16S rRNA gene sequencing. Elderly participants exhibited significantly lower levels of primary fecal BAs, particularly cholic acid (CA) and chenodeoxycholic acid (CDCA), alongside an increase in secondary BAs such as lithocholic acid (LCA), leading to a marked reduction in the primary/secondary BAs ratio.

Serum showed a decline in both conjugated and unconjugated BAs, primary/secondary BAs ratio, while a notable rise in 12α-OH/non-12α-OH BAs. Furthermore, increased levels of P21, LPS, IL-6, and TNF-α in the elderly were associated with specific BA changes, including reduced fecal unconjugated primary BAs and increased LCA. Significant differences in gut microbiota composition were observed, with the elderly displaying a higher abundance of microbiota capable of 7α-dehydroxylation. Correlations were observed among BAs, gut microbiota alterations, and markers of chronic inflammation and intestinal barrier dysfunction.

In conclusion, aging is associated with significant changes in the BA pool, which are associated with gut microbiota dysbiosis. These alterations may be related to intestinal barrier dysfunction and chronic low-grade inflammation. Modulating BA metabolism presents a potential strategy for mitigating the aging process.

Link: https://doi.org/10.3389/fragi.2026.1741360

Reduced protein intake is robustly demonstrated to improve long-term health and slow aging in animal studies, and the human evidence is supportive. Many of the sensors and triggers of the beneficial metabolic response to fasting and other forms of calorie restriction react to protein availability specifically, increasing cellular maintenance activities to improve cell and tissue function. "Protein" in dietary matters usually means essential amino acids, those not manufactured in the body. The actual definition that leads to a measurement reported on a food label is more complicated than this, but is still largely an attempt to reflect availability of essential amino acids per ingested unit of a given food type.

As researchers point out in today's open access paper, despite the strong evidence for lower protein intake to be favorable over the long term, government bodies continue to recommend higher protein intake, driven by ongoing concerns over the prevalence of obesity (high protein intake tends to reduce overall calorie intake) and frailty (high protein intake tends to increase muscle growth). There is also the point that not all protein sources are the same from a health perspective. For example, obtaining protein from plant sources is well established to produce better effects on health than protein from animal sources. Further, the intake level of different essential amino acids have different, overlapping effects on health. There is quite a deep rabbit hole underneath the simple point that lower protein intake should be considered beneficial, and researchers here attempt to explore some of it.

Reviewing What is Known of the Ability of Reduced Protein Intake to Slow Aging

In rodents, the ratio of dietary macronutrients profoundly impacts lifespan, with low-protein, high-carbohydrate diets extending lifespan and improving metabolic health. A low-protein diet, also referred to as protein restriction (PR), is a robust geroprotective regimen that lowers total dietary protein intake while still meeting nutritional needs. PR improves healthspan and increases the lifespan of yeast, flies, and rodents. Despite these findings, human dietary recommendations generally suggest increasing protein intake. While the official Recommended Dietary Allowance (RDA) for protein is 0.8 g/kg of bodyweight regardless of sex or age, intakes of 1.0-1.2 g protein/kg of bodyweight are routinely recommended for individuals over the age of 65 to prevent sarcopenia and frailty, and the most recent Dietary Guidelines for America suggest 1.2-1.6 g protein/kg of body weight. These recommendations are supported by studies finding that short-term high protein diets promote weight loss, largely by promoting satiety and reducing food intake in highly compliant subjects.

However, accumulating evidence challenges the idea that higher protein intake is beneficial. Human association studies have found that high-protein diets are associated with an increased risk of diabetes, cancer, and mortality, as well as an increased risk of death due to cardiovascular events. An analysis of the National Health and Nutrition Examination Survey (NHANES) data found that higher protein consumption correlates with increased mortality and age-associated disease incidence, including diabetes.

Randomized controlled trials (RCTs) support the metabolic benefits of PR in humans. We reported that individuals consuming a low-protein diet for 43 days exhibited decreased body weight and fat mass and reduced fasting blood glucose despite increased caloric intake, mirroring our findings in rodents. A recent study in lean men found that a 5-week PR intervention improves insulin sensitivity and increases energy expenditure.

In this review, we detail, for the first time, the hallmarks of PR: improved metabolic health, induction of nutrient-sensing pathways, decreased senescence, improved mitochondrial function, altered epigenome, and the promotion of healthy aging. Taken together, these hallmarks describe the robust impact of PR on aging-related phenotypes. While these hallmarks are seen in most organisms on dietary PR, some variations exist based on biological sex or animal strain. The hallmarks discussed in this review are highly interconnected, providing a firm foundation for future exploration on the causal nature of these hallmarks to understand which hallmarks are most important in orchestrating the response to PR.

Calorie restriction mimetic drugs reproduce some (usually small) fraction of the beneficial metabolic changes that take place with a reduced calorie intake. An increase in the efficiency of the cellular maintenance processes of autophagy appears to be the crucial point. Researchers here report on their assessment of the alterations produced by the small number of calorie restriction mimetics with robust evidence to slow aging and extend life in mice. This part of the research field seems quite capable of generating any number of treatments that will likely work in humans, but unfortunately from what we know of the effects of calorie restriction, this class of therapy is unlikely to produce a large increase in life span in our species. Short-lived species exhibit a much greater extension of life in response to these metabolic manipulation strategies than is the case in long-lived species. This makes sense from an evolutionary perspective: if the calorie restriction response exists because it helps individuals to survive a seasonal famine to reproduce in later times of plenty, then short-lived species will evolve a much greater plasticity of life span. A season is a much larger fraction of the life span of a mouse than it is of a human.

The pace of aging can be delayed by mutations, dietary manipulations, and drugs, yet the metabolic mechanisms underlying longevity interventions remain poorly understood. Here we present a multi-tissue metabolomic analysis of male UM-HET3 mice treated from 4 to 12 months of age with five validated longevity interventions: rapamycin, acarbose, 17α-estradiol, canagliflozin, or caloric restriction. Using a feature-stabilized XGBoost pipeline applied to seven tissues, we show that metabolomic profiles can identify treated mice as likely recipients of a lifespan-extending intervention well before survival differences emerge. A leave-one-intervention-out procedure confirmed that models trained on any four interventions successfully classified mice from a fifth, unseen intervention, implying shared metabolic alterations across mechanistically distinct treatments.

The most influential metabolites - defined as the minimum set explaining 50% of cumulative model gain - differed substantially across tissues. Only ergothioneine, a dietary antioxidant, ranked highly in more than two tissues: it was elevated by all five interventions in plasma and brain, and by four of five in muscle. Enrichment analyses further identified coordinated remodeling of lipid classes in plasma, perigonadal fat, and kidney. These findings reveal tissue-specific metabolic reprogramming shared across mechanistically distinct longevity interventions and, pending validation against interventions that do not extend lifespan, suggest a path toward metabolomic screening of candidate anti-aging drugs.

Link: https://doi.org/10.64898/2026.06.24.734388

The major hormones produced by the thyroid gland are broadly influential on metabolism and the function of many organs, and thyroid dysfunction is common enough in later life for this aspect of human biochemistry to be very well studied. A range of different unpleasant outcomes and named diseases arise from various imbalances in the production of thyroid hormones. Here, researchers take a particular type of thyroid behavior known to the medical community as non-thyroidal illness syndrome and reframe it as a part of the evolved response to calorie restriction that acts to slow aging - though as it is usually observed in practice by physicians, during times of acute illness, it may be maladaptive.

Non-thyroidal illness syndrome (NTIS), historically termed euthyroid sick syndrome, is characterized by reduced serum triiodothyronine (T3), variable thyroxine (T4), and typically normal or suppressed thyroid-stimulating hormone (TSH) in the absence of intrinsic thyroid disease. Traditionally viewed as an adaptive response to acute illness that does not require intervention, NTIS is increasingly being recognized within broader contexts of metabolic adaptation, including aging, caloric restriction, and pharmacologically induced weight loss. This narrative review reexamines NTIS as a context-dependent metabolic reprogramming response that may represent an evolutionarily conserved survival and longevity mechanism.

Evidence from critical care endocrinology, mitochondrial biology, aging research, caloric restriction studies, and emerging data on glucagon-like peptide-1 (GLP-1) receptor agonists is synthesized to explore the mechanistic and clinical implications of low T3 states. During acute physiologic stress, including infection, trauma, and starvation, reduced peripheral T4-to-T3 conversion and increased reverse T3 production appear to promote metabolic downshifting through decreased mitochondrial oxygen consumption, reduced anabolic signaling, and the redistribution of energy toward immune defense and cellular repair. These adaptations parallel pathways associated with enhanced metabolic efficiency and longevity. Similar thyroid hormone changes are increasingly observed in individuals undergoing significant weight loss, sustained caloric restriction, or GLP-1 receptor agonist therapy.

While transient reductions in T3 may reflect adaptive energy conservation, persistent low T3 states in the setting of chronic inflammation, cardiometabolic disease, sarcopenia, or advanced aging may contribute to impaired mitochondrial function, reduced metabolic flexibility, and loss of physiologic resilience. NTIS may therefore represent a spectrum of adaptive and maladaptive responses influenced by physiologic context, duration, and inflammatory burden. A systems-based, longevity-oriented framework may improve the interpretation of low T3 states and help guide future research aimed at distinguishing beneficial metabolic adaptation from pathologic endocrine suppression.

Link: https://doi.org/10.7759/cureus.110397

Anti-aging medicine has long been a small specialty field of practice culturally adjacent to sports medicine, but considerably less rigorous and more derided by the mainstream. The present development of a longevity industry, based on means to slow and reverse aspects of aging conclusively demonstrated in laboratory animals and now slowly making their way towards the clinic, is going to have interesting effects on the field of anti-aging medicine. Over some period of time, anti-aging medicine will become reputable, a field in which physicians manage the delivery of treatments for aging that actually work. The field will swell to become the majority of all medical practice, as the majority of all serious illness and death is age-related.

Initially, this growth and takeover of mainstream medicine will look fairly prosaic, as it will likely occur in advance of the availability of any very impressive therapies. It will be built on lifestyle choice, weight management, and calorie restriction mimetic drugs like rapamycin, and the involvement of governments will be driven primarily by the desire to reduce the burden of ever expanding entitlement spending in an aging population. The really interesting therapies and outcomes will arrive later, finding a system ready and waiting for them. As an example of what this early transition will look like, one might read today's open access position paper on the Italian health system, proposing the changes needed for an effective focus on aging.

Towards integration of healthspan strategies into the Italian National Health Service

Italy currently ranks among the world's oldest nations, with adults aged ≥65 years accounting for 24.1% of the population - the highest proportion in the EU - and a projected median age of 51 years by 2050. While life expectancy at birth reaches 85.4 years for women and 81.4 for men, Healthy Life Years amount to only 69.6 and 68.5, respectively, documenting a substantial lifespan-healthspan divide. The prevalence of multimorbidity and disability exceeds 60% in adults aged ≥75 years; women bear a disproportionate share of this burden, both as patients and as caregivers. Meanwhile, the Italian National Health Service (Servizio Sanitario Nazionale, SSN) remains hospital-centric, regionally fragmented, and predominantly reactive, with prevention accounting for a historically modest share of total expenditure.

Against this background, longevity medicine is an emerging, prevention-oriented discipline that aims to extend healthspan - defined here as the portion of life lived in good health, with preserved physical and cognitive function and without significant disability or multimorbidity. It integrates multi-omic biomarkers, digital monitoring, adaptive trial methodology, and life-course risk stratification within a translational framework. Although most constituent tools remain at an exploratory or surrogate stage, and clinical utility has yet to be established, the emphasis on early intervention and precision prevention offers potential to reduce the accumulation of age-related disease and ease long-term pressure on the SSN.

This position paper analyzes Italy's demographic and epidemiological trajectory, examines the structural constraints of the SSN, and outlines the scientific foundations of longevity medicine. It advocates for multidisciplinary translational research and identifies five strategic investment priorities: (i) clinically validated biomarkers of biological age; (ii) interoperable digital monitoring platforms; (iii) Bayesian adaptive multimodal trials; (iv) explainable-AI risk stratification tools; and (v) longevity-informed curricula in medical training. These proposals should be regarded as a staged agenda for evaluation; their relevance will depend on whether they deliver measurable gains in patient-relevant outcomes, feasibility, and cost-effectiveness within the SSN.

Questions regarding the relative importance of different mechanisms and dysfunctions to the progression of aging and eventual mortality are hard to answer definitively. Even given a straightforward class of therapies to target one specific mechanism of aging in isolation of all others, such as senolytics to clear lingering senescent cells, one still has to look at a lot of different studies, extrapolate from mice to humans, and the answer is fuzzy. The other sort of fuzzy answer comes from statistical techniques applied to large longitudinal human epidemiological data sets: compare humans who exhibited different levels of the mechanism in question, and see what happened to them over time. That is the approach taken here in the matter of the chronic inflammation as a driver of aging and age-related mortality. As you can see, the answer produced is a sizable range, arguably not all that informative.

Global population aging underscores the urgent need for biomarkers quantifying biological aging trajectories. While DNA methylation-derived pace of aging (DunedinPoAm) measures individual differences, its generalizability across diverse populations and mechanistic links to systemic inflammation remain underexplored. This study aimed to systematically examine the longitudinal associations between the DunedinPoAm and all-cause mortality in a multiethnic cohort, and to quantify the extent to which systemic inflammatory biomarkers mediate these associations using causal mediation analysis.

For this cohort study, information on a nationally representative cohort of 21,004 U.S. adults was extracted from the National Health and Nutrition Examination Survey (NHANES) conducted from 1999 to 2002. Data were analyzed from 2,532 participants, with a mean follow-up duration of 18.5 ± 1.29 years. Higher DunedinPoAm quartiles exhibited graded mortality risks (Q4 vs. Q1: hazard ratio, HR = 2.50), which persisted after multivariable adjustment. Restricted cubic splines revealed a non-linear association, indicating the presence of threshold effects. Systemic inflammation mediated 2.33% to 23.5% of the mortality risk associated with DunedinPoAm, driven by CD4+ T cells, B cells, CRP and comprehensive inflammatory indices. A significant interaction with diabetes underscored metabolic dysregulation as a vulnerability factor.

Link: https://doi.org/10.1186/s13148-026-02206-w

The heart regenerates poorly in comparison to other tissues, and the maladaptive inflammation that occurs following a heart attack does not help the situation. Fibrosis and scarring occurs in inflamed heart tissue, causing loss of function and heart failure. Stem cell therapies and the use of exosomes derived from stem cells are well demonstrated to reduce unwanted inflammation in animal studies, and are fairly widely used in the medical tourism industry. Here researchers report on the assessment of the ability of an exosome therapy to reduce heart failure following an induced heart attack in pigs, showing that it reduces the formation of scar tissue and helps to maintain heart function.

Myocardial ischemia-reperfusion (MIR) injury drives adverse remodeling and heart failure after ST-elevation myocardial infarction (STEMI), yet no therapy directly targets the fibrotic response. Here, we developed a good manufacturing practice-compatible extracellular vesicle (EV)-enriched secretome from bone marrow mesenchymal stromal cells and identified a laminin-521-based production strategy suitable for clinical translation.

The EV-enriched secretome exhibited in vitro immunomodulatory activity, and in murine MIR-injury models, treatment preserved left ventricular ejection fraction, reduced platelet-derived growth factor receptor beta (PDGFRβ)-associated myofibroblast activation quantified by positron emission tomography (PET) imaging, attenuated fibrosis, and promoted reparative macrophage polarization.

In a clinically relevant porcine ischemia-reperfusion model, intracoronary administration was cardioprotective. We further developed a clinically approved PDGFRβ-targeted PET-imaging platform for longitudinal assessment of fibrotic activity in STEMI patients, where preliminary observations suggest that myofibroblast activation persists for up to 2 months after STEMI in selected patients. Together, these findings establish a translational therapeutic-diagnostic framework for individualized management of MIR injury.

Link: https://doi.org/10.1016/j.stem.2026.07.003

Cells become senescent throughout life, because of stress or damage or reaching the Hayflick limit on replication, but senescent cells only begin to accumulate with age. When a cell becomes senescent, it grows in size, ceases to replicate, and turns its energies to creating signals promoting inflammation and growth. The immune system is responsible for destroying senescent cells after they have served their purpose, which is usually to attract the attention of immune cells to locations where they are needed to prevent or repair issues. While clearance of senescent cells is efficient in young people, it becomes much less efficient with age, allowing a population of lingering senescent cells to grow over time in tissues throughout the body. The pro-growth, pro-inflammatory signals that are helpful in the short term become harmful when sustained over the long term, disruptive to tissue structure and function and helping to promote the damaging state of chronic inflammation that is characteristic of later life.

Senolytic therapies to selectively destroy senescent cells exist, such as the dasatinib and quercetin combination, but are not widely used, conclusive clinical trial data has not yet been generated, because these are low cost drugs and supplements. No-one can make enough money from them to justify investment in large clinical trials. Meanwhile many companies are working to develop novel, patent-protected senolytic therapies that will be able attract sufficient funding for conclusive clinical trials, and those will be the (much more expensive) drugs that make their way into widespread use. This is the way that modern regulated medicine works.

Meanwhile, another faction of the research community is more interested in finding ways to suppress the inflammatory signaling of senescent cells rather than destroy them. This approach also has its low cost drugs, such as rapamycin, that are unlikely to be the subject of very large clinical trials for their ability to suppress the bad behavior of senescent cells any time soon. Nowhere near as many companies are actively working on novel drugs to alter senescent cell behavior, but the academic research community is identifying new possibilities at a fair pace. Today's open access paper, for example, describes a novel way in which mitochondria support the generation of inflammatory signaling by senescent cells, which opens up a few possible targets for careful sabotage.

Mitochondrial metabolism and epigenetic crosstalk drive SASP

Senescent cells promote tissue dysfunction in part through the senescence-associated secretory phenotype (SASP). Cytosolic mitochondrial nucleic acids activate innate immune signalling to initiate this inflammatory programme. Here we show that mitochondrial metabolism provides a second layer of control that enables execution of the inflammatory programme. In senescent cells, the mitochondrial pyruvate-citrate-acetyl-CoA axis is upregulated, increasing the availability of acetyl-CoA to support histone acetylation at SASP genes. Whereas mitochondrial DNA-driven signalling activates inflammatory transcription factors, acetyl-CoA availability is required for robust transcription of SASP genes.

Accordingly, enhancing acetyl-CoA levels promotes SASP gene expression, whereas inhibition of SLC25A1, the mitochondrial citrate exporter, reduces histone acetylation at SASP loci, limiting activity of this programme. In vivo, inhibition of SLC25A1 reduces chromatin accessibility at SASP loci, dampens inflammation, and improves healthspan in aged mice. Together, these findings identify a mitochondrial metabolic checkpoint that enables the epigenetic execution of innate immune signalling, revealing a mechanism that selectively controls the inflammatory output of senescent cells.

Researchers here restricted old mice to eating only during the 12 hours of the day in which they are usually inactive or asleep, for three days every week, and continued this restriction for a period of 8 weeks. The mice placed on time restricted feeding exhibited improved muscle function versus those who could eat at all times of the day. Studies of reduced or time restricted food intake tend to converge on the concept that benefits derive from spending some amount of time in a state of hunger, however that is achieved. Low nutrient availability triggers a range of adaptive processes in cell behavior, including increased cell maintenance activities. The result is improved cell function, improved tissue function, and a slowing of the pace of aging. While short-term effects are quite similar across species, the effect on pace of aging over the longer term is far larger in short-lived species than in long-lived species.

Sarcopenia, defined as the age-related decline in skeletal muscle mass and function, markedly reduces physical performance, threatens functional independence, and diminishes quality of life in older adults. Although the clinical manifestations of sarcopenia typically emerge later in life, underlying molecular alterations, particularly within the mitochondrial network, occur well before symptom onset. Growing evidence indicates that dietary interventions, including caloric restriction as well as changes in meal timing, composition, and overall intake, play a critical role in attenuating age-associated pathologies. Time-restricted feeding (TRF) is a dietary regimen in which all caloric intake is confined to a defined daily time window and has emerged as a feasible and widely adopted variant of caloric restriction.

This study investigates the effects of inactive phase TRF on skeletal muscle health in a middle-aged murine model, with a particular focus on its potential to delay or attenuate the decrease of physical performance only by modifying daily feeding schedules. Our findings demonstrate that inactive phase TRF allows to dissect the impact of mistimed nutrient intake and confers beneficial effects on skeletal muscle, including improved muscle strength and maintenance of basal glycemia during early aging. These effects were accompanied by a tendency to increase succinate dehydrogenase expression and significantly reduced lipid droplet accumulation. These effects correlate with muscle type-specific adaptations of the mitochondrial network and sarcoplasmic reticulum-mitochondria interaction in response to TRF.

Collectively, these findings support the potential of inactive phase TRF as an easy-to-follow therapeutic intervention during middle age to maintain physical performance in early aging.

Link: https://doi.org/10.1038/s41598-026-60902-2

Aging clocks of many varieties have been produced in recent years by applying machine learning techniques to a wide range of biological data that changes with age. This approach yields a tool that is disconnected from our understanding of the mechanisms of aging; links between the forms of cell and tissue damage and dysfunction that drive aging and the measures making up the clocks have yet to be determined. This makes it hard to interpret results, and hard to make practical use of a clock to assess the quality of any given approach to slowing or reversing aging. We have no idea in advance as to whether a given clock will perform well for a given intervention, and finding out is a slow process. The primary approach to this challenge taken by the research community is to produce new clocks at a fair pace, and gather as much data as possible on how the clocks behave, in search of patterns of clock behavior.

The outcome most often used to develop aging biomarkers is age itself, i.e. years lived since birth. However, in humans, relying on years lived as an outcome introduces a range of biases, most prominently confounding of aging with survival; humans in their 70s and beyond are, by definition, successful agers, having outlived most of their peers. The results of machine learning analysis differentiating older from younger people could therefore reflect not only aging-related biological damage, but also resilience.

An alternative approach that may overcome this limitation is to apply machine learning to an outcome that represents something closer to what many interventions aim to modify: the current rate of aging-related biological deterioration. We developed such a measure, Pace of Aging, by modeling changes over 20 years of follow-up in a panel of organ-function measurements among participants in the Dunedin Longitudinal Study. Critically, it also proved sensitive to the effects of calorie restriction, the intervention best established to slow aging in a range of laboratory models.

If using Pace of Aging in machine learning analysis to develop aging biomarkers can yield more sensitive endpoints for clinical trials, this would be consequential for the field. However, there are alternative explanations for the calorie restriction trial result. The participants in the trial (CALERIE) were healthy midlife adults, similar to the Dunedin Study members whose data were used to develop DunedinPACE. In contrast, the leading survival-time biomarker, the GrimAge epigenetic clock, was developed using data from older adults, many of whom had prevalent chronic disease. The critical factor could therefore be similarities between the participants whose data were used to develop the biomarker and the participants in the clinical trial.

To adjudicate between these competing hypotheses, biomarker design vs. demographic similarity, we developed a novel Pace of Aging biomarker in the same older-adult cohort used to develop GrimAge and tested its response to intervention in the CALERIE trial. We obtained data from the Framingham Heart Study Offspring Cohort. We adapted our Pace of Aging method for mixed-age cohorts with variable follow-up of organ-function measures and applied it to develop a novel DNA methylation biomarker of Pace of Aging in data from the Framingham Heart Study Offspring Cohort. When applied in independent cohorts, this novel biomarker (1) demonstrated exceptional technical reliability; (2) revealed a pattern of accelerating Pace of Aging with advancing age, replicating a finding first observed for our original Pace of Aging biomarkers developed in the Dunedin Study. In analysis of a randomized controlled trial of calorie restriction in healthy, non-obese humans (CALERIE), our novel Pace of Aging biomarker was slowed by calorie restriction, parallel to our original Pace of Aging biomarker.

Link: https://doi.org/10.64898/2026.07.07.26357388

A broad variety of aging clocks have been created in recent years. Such a clock is produced via machine learning techniques applied to any sufficiently complex set of biological data that tends to change with age. Everything from imaging to blood chemistry to omics data sets can and has been used for this purpose. A reference data set is processed to derive combinations of measurements that predict chronological age, or mortality risk, or some other output. A good clock then produces similar results in other data sets. A potentially useful clock also has the characteristic that a predicted clock age higher than chronological age correlates with a greater risk of mortality and age-related disease.

It is proposed that aging clocks are a measurement of biological age. If starting out with the very simple concept that biological aging is an increase in the risk of mortality due to intrinsic causes, then clocks that show correlation between clock age and mortality risk can reasonably be considered a first step in that direction. At any more detailed level of inquiry, however, it becomes a great deal less clear as to whether any given clock is actually decent measure of biological age. It is also difficult to gain consensus on how exactly to define biological age in any more detailed way. This is in part because aging is very complex. Any given clock is probably only sampling the consequences of some of the mechanisms involved. Can we trust that any given clock will correctly predict the outcome of a therapy that only affects one mechanism of aging, such as a senolytic drug that clears senescent cells from aged tissues? Not without actually running a lengthy study to find out.

Thus researchers are at present accumulating as much data as they can on the way in which various mainstream aging clocks behave in response to interventions and circumstances. In today's open access paper, for example, researchers look at how clock age correlates with mortality risk following surgery in older people. It is well known that surgery is an increasingly hazardous choice at older ages, but really the hazard scales with damage and dysfunction, not age. The level of accumulated damage and dysfunction varies from person to person of a given age, and thus perhaps clocks can help to better assess the risk attending some of the hard medical choices that have to be made in later life.

Biological aging increases risk of postoperative morbidity and mortality: an international, multi-cohort study

Surgery is very common and risky for older adults. Though surgical procedures on aging patients occur commonly, the outcomes are mixed. After major surgery, the risk of poor functional recovery, long-term disability, institutionalization, and 1-year mortality is significant. Surgery contributes to significant physiologic stress, and resilience to and recovery from physiological stress impacts postoperative outcomes. Chronological age (time since birth) is an insufficient proxy for surgical resilience, and restricting surgical care by chronological age is imprecise and potentially harmful. Instead, biological estimates of aging, termed biological age, provide a quantitative metric of aging for people across the entire age spectrum, and may better reflect vulnerability to surgical stress.

We evaluated PhenoAge, a validated biological age metric, in an international multi-cohort study comprising over 430,000 surgical patients across the UK, USA, and South Korea. In the UK Biobank (N = 291,845), PhenoAge was a robust, independent predictor of 1-year mortality (odds ratio, OR = 1.043), major adverse cardiovascular events (OR = 1.041), and 30-day readmission (OR = 1.02), even after adjusting for chronological age, Fried Frailty Index, Charlson comorbidity score, American Society of Anesthesiologists (ASA) physical status, surgical complexity, and other common surgical risk factors. "Fast Agers" faced a 49% higher risk of mortality than "Normal Agers". The main findings were replicated across three independent international cohorts (MOVER, OR = 1.03; Weill Cornell, OR = 1.036; INSPIRE, OR = 1.05), and validated prospectively at a large academic medical center, where PhenoAge predicted acute 3-day complications (OR 1.20).

Navitoclax (or ABT-263) was one of the earliest chemotherapeutics assessed for its ability to selectively clear senescent cells as a senolytic drug. The side effects on platelet function are pronounced, which is probably why it has received less attention than the dasatinib and quercetin combination discovered around the same time. Here, researchers report on a senolytic combination that allows for navitoclax to be used at much lower doses. It is possible that this might make it interesting again, though that ship may have sailed. There are so very many lines of research and development into novel and better senolytics these days, and any attempt to produce widespread use of low cost known senolytics is probably going to remain centered around dasatinib and quercetin, or possibly the use of fisetin if human clinical trial data ever emerges on its efficacy.

Eliminating both senescent and cancer cells through pharmacological intervention presents a powerful therapeutic strategy against aging and tumor progression. Navitoclax has emerged as a promising candidate with both senolytic and antitumor activity, but its clinical application remains limited due to dose-dependent thrombocytopenia and tumor-specific resistance. To overcome these limitations, we combined dichloroacetate and metformin with a 10-fold reduced dose of Navitoclax (ABT-263) and show that this pharmacology, termed, DMA, selectively targets the metabolic vulnerabilities underlying senescent and malignant cells.

We demonstrate that DMA effectively ablates different types of senescent and cancer cells in vitro by exacerbating their defects in ATP production. Notably, the treatment is well tolerated by healthy human cells and in mice in vivo, and in fact improves the functional performance of aged mice after acute administration and extends lifespan after prolonged dosing. While the in vivo effects of DMA are yet to be fully explored, our findings suggest that it might represent a new, clinically viable way to combat cancer and senescence without toxicity to healthy cells and tissues.

Link: https://doi.org/10.18632/aging.206399

The ability to accurately determine the composition of the gut microbiome via 16S rRNA sequencing is resulting a great deal of very interesting data on differences in the gut microbiome that are characteristic of aging, age-related diseases, and long-lived individuals. Here, researchers report that centenarians tend to have more Clostridium scindens in their gut microbiome, and demonstrate in aged mice that a metabolite produced by this bacterial species reduces intestinal barrier dysfunction. That the intestinal barrier becomes more leaky with age is an important contributing cause of chronic inflammation and other forms of dysfunction caused by the presence of unwanted bacteria, metabolites, and other molecules in the circulatory system and tissues throughout the body.

Microbial networks and keystone taxa play pivotal roles in maintaining gut microecological stability and host homeostasis, irrespective of their abundance. However, most previous studies of aging-associated gut microbiota have relied on abundance-based analyses, largely overlooking microbial networks and microbe-host interactions. Here, we employed a co-occurrence network approach to identify keystone taxa during aging in humans and mice. We found that centenarians harbor distinctive keystone taxa dominated by members of Clostridium, of which Clostridium scindens (C. scindens) can significantly enhance microbial network stability, probably contributing to longevity and reduced susceptibility to age-related diseases.

Mechanistically, C. scindens produces indole-3-acetic acid (IAA) from tryptophan via the enzymes amidase (AMIE) and aldehyde dehydrogenase (ALDH). Oral administration of either C. scindens or IAA effectively mitigates intestinal aging by restoring gut barrier dysfunction in aged mice. Further analysis revealed that C. scindens-derived IAA restores intestinal dysfunction through activation of aryl hydrocarbon receptor (AHR) signaling, leading to upregulation of intestinal CLDN10, a key tight junction protein. Structurally, IAA enhances Claudin-10 transcription by promoting AHR binding to its promoter region.

Our findings provide new insights into the characterization of microbial networks in centenarians and highlight that C. scindens and IAA may contribute to healthy longevity by promoting gut microecological stability and host homeostasis.

Link: https://doi.org/10.1002/imt2.70134

Senescent cells accumulate with age and contribute to degenerative aging via their pro-growth, pro-inflammatory signaling. Even when less than 1% of all cells are senescent in a tissue, the signaling generated by those senescent cells alters the behavior of other cells for the worse, and is disruptive to tissue structure and function. When it comes to what to do about the burden of senescent cells in aged tissues, much of the focus is on the development of senolytic drugs that can selectively destroy these errant cells to some degree. The most popular alternative path is the development of senomorphic drugs that can suppress senescent cell signaling to some degree, but unlike the senolytic development community this cannot yet boast the large number of companies dedicated to producing novel drugs.

Just as there are a great many senolytic compounds in the small molecule libraries and even among presently approved small molecule drugs, there are also a great many senomorphic compounds. Quality varies widely, and, sadly, all too few outperform the effects of lifestyle choices on the burden and behavior of senescent cells. Those that do are relatively neglected by the medical and development communities because they are cheap and out of patent protection; there is not enough profit to be made to support the high costs of clinical trials. So even relative well-known senomorphics like rapamycin are far less widely used than they might be, and it is left to the very slow pace of the academic community to scrape up sufficient funds to conduct large-enough clinical trials to convince more physicians to prescribe for their patients.

Senomorphics are drugs that have to be used continuously, and are unlikely to suppress all problem signaling. Senolytics are drugs that can be used intermittently, and are unlikely to kill all senescent cells. There are clearly trade-offs of cost and convenience in addition to the debates over the potential side-effects of continuously altered senescent cell behavior versus destruction of cells that may be generating harm, but may also be propping up a tissue's structure. For example, what happens when destroying senescent cells broadly in an individual with severe atherosclerotic plaques in which a sizable fraction of cells are senescent? These debates are so far largely conducted in the absence of firm data, and that will likely continue to be the case until both approaches are more widely used in humans.

Senomorphic agents: Multi-target strategies to tame the senescence-associated secretory phenotype for healthy ageing

Cellular senescence serves as a pivotal driver of organismal ageing and its associated pathologies. This detrimental effect is primarily mediated through the secretion of a complex mixture of inflammatory factors, proteases, and other bioactive molecules, collectively termed the senescence-associated secretory phenotype (SASP), which promotes the onset and progression of multiple age-related diseases. Targeting this pathological process, the field of senotherapeutics has recently evolved two principal strategies: senolytics and senomorphic agents.

Senomorphic agents have emerged as a complementary or alternative strategy with distinct advantages. The core principle of this approach is to modulate, rather than eliminate, the function of senescent cells. By inhibiting key signaling pathways such as NF-κB, mTOR, and JAK/STAT, senomorphic agents directly curb the production of the deleterious SASP. This strategy may attenuate inflammation and tissue damage while potentially preserving certain physiological functions of senescent cells. However, the optimal balance between senolytic "clearance" and senomorphic "modulation" remains undefined, and the translational path for both strategies is fraught with challenges that have not been systematically addressed in the literature.

The present review offers three distinctive perspectives. First, we conceptualize the SASP-regulatory network as a hierarchical architecture - from upstream stress sensors to downstream epigenetic effectors - providing a systematic framework for understanding where and how senomorphic agents intervene. This framework is novel in that no prior review has explicitly organized the SASP-regulatory pathways into functional layers. Second, we critically analyze the translational barriers that have received insufficient attention in the existing literature, including the limitations of animal models, the lack of gerodiagnostic biomarkers, and the challenges of tissue-specific delivery. Third, we propose a disease-stage-adapted strategy that integrates senomorphic modulation with senolytic clearance, moving beyond the "either-or" debate toward a synergistic, precision-based paradigm. By bridging mechanistic insights with translational realities, this review aims not only to summarize the current state of the field but also to chart a roadmap for future clinical development of senomorphic therapies.

A number of prevalent age-related conditions are notably different in timing and progression between the sexes. No doubt the list of differences by sex will grow as the research community explores the first therapies that target important mechanisms of aging. Here, researchers report on an attempt to treat intervertebral disc degeneration in mice using a senolytic drug that selectively destroys the BCL-2 and BCL-xL proteins that a senescent cell needs in order to resist programmed cell death. There is a reasonable weight of evidence to point to senescent cell accumulation as an important contribution to intervertebral disc degeneration, but the outcomes here are somewhat less than hoped. Male mice suffer a greater level of pathology from the condition in this model, but also benefit to a greater degree from the senolytic therapy. BCL-2 and BCL-xL may not be the best targets for removal of senescent cells in this condition, or alternatively, the burden of senescence in this condition may be different in character or degree by sex.

The senolytic PROTAC (753b) eliminates senescent cells (SnCs) by targeting ubiquitin-mediated destruction of the anti-apoptotic BCL-2/BCL-xL proteins. Here, systemic treatment with 753b was tested for reduction of age-related intervertebral disc degeneration (IDD) in mice. Five aging male and female mice were intraperitoneally injected with 753b or vehicle between 16 and 22 months of age. Among vehicle controls, intervertebral disc (IVD) histology using Safranin-O/Fast Green staining of paraffin embedded transverse sections revealed significantly greater IDD in 22 month old males than age-matched females.

In 22-month-old males, 753b treatment significantly reduced matrix metalloproteinase (MMP)-mediated aggrecan proteolysis as shown by Western blots, loss of disc matrix aggrecan by immunohistochemistry, age-related histomorphologic features of IDD, and serum protein levels of IL-6 and TNFα protein in treated male mice. While expression of IVD cellular senescence markers IL-6, IL-8, TNFα and p16INK4a assessed by RT-PCR of IVD tissue increased with age in both 22 month old female and male mice, expression of these markers was not reduced by 753b treatment.

These results demonstrate that 753b treatment of aging mice reduced IDD in males but not females, which suggests sex-based differences in the role of senescence in IDD and may have an impact on the potential for females to benefit from anti-senescent therapies for IDD. The observed therapeutic effects of 753b on IVDs of the male mice suggest a global reduction of cellular senescence burden through systemic, non-cell autonomous processes.

Link: https://doi.org/10.18632/aging.206394

Cerebrospinal fluid drainage from the brain into the body is necessary to remove metabolic waste from the brain. The flow declines with age, and evidence strongly suggests that this is an important contribution to the build up of protein aggregates and other waste that drive the onset and development of neurodegenerative conditions. Much of the focus is on the glymphatic system of vessels at the base of the brain, but because Alzheimer's disease starts in the olfactory bulb region of the brain, a few researchers have focused on drainage through openings in the cribriform plate stucture located behind the nose. Restoring passage of cerebrospinal fluid through the cribriform plate via surgical intervention is the task undertaken by Leucadia Therapeutics, for example. Here, researchers further explore that drainage path to find other potential blockages that occur between the olfactory bulb and cribriform plate, and that may also need to be dealt with.

Researchers discovered microscopic openings in the arachnoid membrane, which they named "arachnoid fenestrations", that allow cerebrospinal fluid to pass directly into meningeal lymphatic vessels. The findings reveal the most detailed pathway yet for brain waste clearance and identify a drainage route that progressively deteriorates during aging but can be functionally restored in aged mice. The researchers identified a specialized lymphatic network located between the olfactory bulbs and the cribriform plate, the perforated bone separating the brain from the nasal cavity. Unlike other regions of the arachnoid membrane, this area contained numerous microscopic openings measuring approximately 2 to 12 micrometers in diameter.

Fluorescent tracers injected into the cerebrospinal fluid accumulated around these openings, crossed the arachnoid barrier, entered meningeal lymphatic vessels, traversed the cribriform plate, and continued through lymphatic vessels in the nasal mucosa before draining into cervical lymph nodes. Similar arachnoid fenestrations were also identified in cynomolgus monkeys, suggesting that this specialized drainage structure is conserved beyond mice. To determine whether these openings were essential for CSF drainage, the researchers physically blocked them using microspheres too large to pass through the fenestrations. This dramatically reduced cerebrospinal fluid drainage to cervical lymph nodes, providing direct functional evidence that the fenestrations serve as critical exit portals for CSF.

Instead of delivering treatment by penetrating the meninges, the membrane that cover the brain, the team administered an adeno-associated viral vector expressing vascular endothelial growth factor-C (VEGF-C) through the nasal cavity. VEGF-C is a signaling molecule that promotes lymphatic vessel growth. This less invasive intranasal approach selectively expanded lymphatic vessels surrounding the olfactory bulbs and within the nasal mucosa. Although it did not restore the age-related loss of arachnoid fenestrations or enlargement of the cribriform plate openings, the expanded lymphatic network restored cerebrospinal fluid drainage in aged mice to levels comparable to those observed in young animals.

Link: https://www.eurekalert.org/news-releases/1137060