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