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white matter link https doi org 10 1038 s43587 026 01154 7 august 28th 2026 merkt is involved in enabling microglia to kill motor neurons in als permalink with comments permalink no comments posted by reason no comments yet add a comment 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 august 27th 2026 restoration of autophagy in retinal cells protects against glaucoma permalink with comments permalink no comments posted by reason no comments yet add a comment 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 august 27th 2026 stiffness of the extracellular matrix may drive some age related changes in gene expression permalink with comments permalink no comments posted by reason no comments yet add a comment 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 august 27th 2026 a systems view of the gut microbiome in aging permalink with comments permalink no comments posted by reason no comments yet add a comment 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 august 26th 2026 cytotoxic cd4 t cells in aging both protective and harmful permalink with comments permalink no comments posted by reason no comments yet add a comment 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 thes...