Fight Aging!

Astrocytes make up a sizable fraction of the cells in brain tissue, responsible for supporting the functions of neurons and the microenvironment of the brain. Cellular senescence in these supporting populations grows with age and is thought to provide an important contribution to the aging of the brain and onset of neurodegenerative conditions. Lingering senescent cells secrete inflammatory signals, disrupting the function and structure of tissue in proportion to their numbers. The research community continues to investigate the biochemistry of the senescent state and how cells become senescent, details that may differ meaningfully from cell population to cell population, in search of novel approaches that might lead to drugs that can prevent senescence, destroy senescent cells, or even reverse the normally irreversible senescent state.

Astrocytes are the primary source of circulating high mobility group box-1 (HMGB1) which is intimately associated with aging and related disease in central nervous system (CNS). However, the multi-localization and multifunctional characteristics of HMGB1 indicate that it may regulate brain aging through various pathways and mechanisms which are not yet clearly defined. In this study, we find that the expression of HMGB1 decreases with aging in both human and mouse astrocytes. Conditional knockout of Hmgb1 in astrocytes induces the exacerbation of mice aging.

Physiologically, HMGB1 locates in the nucleus and acts as a DNA binding protein to modulate gene expression and DNA repair. During cell activation, injury or death, HMGB1 can also translocate to the extracellular microenvironment and serve as a damage-associated molecular pattern (DAMP) to activate immune responses. The roles of HMGB1 in cellular senescence are complicated. Some studies have observed that HMGB1 functions as a core senescence-associated secretory phenotype (SASP) component, being extracellularly released to drive inflammaging. Conversely, emerging evidence suggests that nuclear HMGB1 exhibits a protective role in cellular senescence by maintaining telomerase activity and telomere function.

By establishing a nuclear HMGB1 depletion model and interfering in the interactions of extracellular HMGB1, we find that nuclear HMGB1 is anti-senescent whereas extracellular HMGB1 is pro-senescent. Inhibiting HMGB1 nuclear export to enhance its nuclear retention effectively alleviates astrocyte senescence. Thus promoting the nuclear retention of HMGB1 is a new strategy for attenuating brain aging and related disorders.

Link: https://doi.org/10.1186/s12974-025-03684-0

Hemoglobin is the primary carrier for oxygen found in red blood cells. It preferentially binds oxygen in relatively high oxygen environments, such as lung tissue, and releases it in relatively low oxygen environments as it moves about the body. As is true of near all proteins, hemoglobin has many roles. Independently of its role in oxygen transport, it also interacts with a range of proteins involved in the regulation of inflammation, for example. Here find a discussion of the ways in which hemoglobin might be involved in the relationship between oxidative stress, inflammation, and the progression of degenerative aging. Oxidative stress is excessive alterations to cellular proteins caused by oxidative reactions; these take place constantly, and cells employ antioxidants and repair mechanisms to reduce their impact. Increased oxidative damage is a feature of aged tissues, however, and well known to associate with increased inflammation, disruptive to tissue structure and function.

Hemoglobin's significance extends beyond basic physiology; its levels and functional integrity are closely linked to health outcomes across the human lifespan. In elderly populations, deviations in hemoglobin levels - particularly anemia - are strongly associated with frailty, cognitive impairment, increased hospitalization, and mortality. On the other hand, abnormally high levels may predispose individuals to thrombosis and vascular complications. These observations suggest that hemoglobin serves as more than just a biomarker of oxygenation; it may be a critical regulator of longevity itself.

Moreover, the regulatory networks that govern hemoglobin synthesis are closely tied to adaptive mechanisms implicated in longevity. Hypoxia-inducible factors (HIFs), which regulate erythropoietin expression and hemoglobin production under low-oxygen conditions, are also known to modulate genes involved in angiogenesis, glucose metabolism, and cellular survival. Interventions that mildly activate HIF signaling - such as intermittent hypoxia, exercise, and pharmacological stabilizers - have demonstrated protective effects against aging-related degeneration, positioning HIF-hemoglobin pathways as promising targets in longevity research

Oxidative stress presents another dimension through which hemoglobin may influence lifespan. As hemoglobin undergoes auto-oxidation, it produces reactive oxygen species (ROS), which, in excess, can damage DNA, proteins, and lipids, triggering pro-aging processes. Aging tissues typically show reduced antioxidant capacity, making them more vulnerable to ROS-mediated injury. Maintaining redox balance through antioxidant defense systems and preserving the functional integrity of hemoglobin is therefore crucial to cellular longevity.

In addition to its role in oxygen transport, hemoglobin may also interact with various signaling pathways that influence inflammation, immune function, and vascular health. Chronic inflammation and immunosenescence are hallmarks of aging, and studies have shown that dysfunctional hemoglobin and heme overload can trigger pro-inflammatory cascades. Conversely, stabilizing hemoglobin structure and minimizing heme release may help modulate these pathways and contribute to healthier aging.

Link: https://doi.org/10.1097/MS9.0000000000004508

Chronic inflammation is a major component of degenerative aging. Short-term inflammatory signaling is necessary for the immune system to function, including its role in tissue regeneration following injury, as well as defense against malfunctioning, potentially cancerous cells. But when sustained over the long term without resolution, that same signaling becomes disruptive to tissue structure and function. It hinders regeneration, it encourages fibrosis and cancerous growth, and leads to an immune system less able to defend against pathogens.

The primary approach towards the development of novel means of suppressing unwanted inflammation is to interfere in specific inflammatory signals or the regulatory mechanisms that generate those signals. The challenge lies in the fact that the same signals and mechanisms are involved in both necessary short-term inflammation and undesirable long-term inflammation. Thus existing approaches produce an unwanted suppression of desirable features of the immune system, side-effects that harm long-term health.

Thus some researchers are attempting to identify aspects of the inflamed immune system that are (a) more relevant to chronic inflammation and less relevant to short-term inflammation, and (b) can be targeted in isolation of the rest of the immune system. In principle there should be ways to reduce undesirable effects while still obtaining benefit in adjusting the way in which the inflamed immune system operates. Today's open access paper reports on one such approach, a step in the right direction in that the researchers identify a way to suppress the contribution of monocyte cells to chronic inflammation without impairing the immediate inflammatory response.

Epoxy-oxylipins direct monocyte fate in inflammatory resolution in humans

The role of cytochrome P450-derived epoxy-oxylipins and their metabolites in human inflammation and resolution is unknown. We report that epoxy-oxylipins are present in blood of healthy, male volunteers at baseline and following intradermal injection of UV-killed Escherichia coli, an experimental model of acute resolving inflammation. At the site of inflammation, cytochrome P450s and epoxide hydrolase (EH) isoforms, which catabolise oxylipins to corresponding diols, are differentially upregulated throughout the inflammatory response, as is the biosynthesis of epoxy-oxylipins.

In this study we characterised the epoxy-oxylipin biosynthetic machinery in humans under baseline and inflammatory conditions demonstrating that blocking soluble epoxide hydrolase (sEH) significantly elevated the epoxy-oxylipins 12,13-EpOME and 14,15-EET. With little effect on the salient features of inflammation, except for accelerated pain resolution, sEH inhibition most notably reduced numbers of intermediate monocytes in blood and in inflamed tissue via the inhibition of p38 MAPK by 12,13-EpOME.

Reduced intermediate monocytes during tissue resolution uncovered potential a role for these cells in maintaining CD4 T cell viability and phenotype on the one hand, but also revealed their ability to drive cells death via cytotoxic CD8 T cells on the other. With clinical studies demonstrating that sEH inhibition is safe and well tolerated, therefore, sEH inhibition presents a hitherto unappreciated way of reducing inflammatory intermediate monocytes, which are implicated in the pathogenesis of chronic inflammatory disease.

Cells react to physical forces placed upon them, and changes in the character of those forces will tend to result in altered cell behavior. Cells in a three dimensional extracellular matrix do not behave in the same way as cells in a petri dish. Further, the extracellular matrix in aged tissues differs from that in young tissues in ways that can meaningfully affect its material properties, and thus the forces placed on cells within that matrix. Researchers here demonstrate that some fraction of the undesirable changes occurring in cells within bone tissue are the result of reduced mechanical stimulation. Vibration to induce that mechanical stimulation can restore some of the lost function in aged mice.

Emerging evidence highlights a critical role for mechanical signaling in modulating transcriptional and epigenetic processes. Bone marrow mesenchymal stem/stromal cells (BMSCs) are embedded in a dynamic microenvironment where they continuously perceive and respond to mechanical cues, affecting cellular traction force and directing cell behavior. Aging significantly alters the physical properties of the bone microenvironment, disrupting the mechanical signals transmitted to cells.

In this work, we show that aging reduces intracellular traction forces in BMSCs and aged bone tissue, a deficiency that can be reversed in vitro and in vivo through appropriate mechanical stimulation to restore the cell mechanics. Mechanistically, the restoration of cellular traction force enhances chromatin accessibility, leading to the activation of FOXO1 expression. Importantly, FOXO1 knockdown abolished the mechanically rejuvenating effects, underscoring its critical role in mediating cellular responses to mechanical forces.

Beyond bone recovery, mechanical interventions (vibrational loading) in aged mice improved locomotor activity, alleviated physical frailty, and reduced systemic inflammation. These findings highlight both local and systemic benefits of mechanical stimulation, offering a straightforward approach with significant translational potential for combating age-related tissue decline.

Link: https://doi.org/10.1038/s41467-026-68387-3

A sizable fraction of degenerative aging involves chronic inflammation. Various forms of cell and tissue damage trigger maladaptive inflammatory signaling, such as the presence of lingering senescent cells and DNA released into the cytoplasm by dysfunctional mitochondria. Sustained inflammatory signaling changes cell behavior for the worse and is disruptive to tissue structure and function. Many of the important mediators of inflammatory signaling are well known, such as TNFα, but inhibiting these signals is a blunt tool that causes unwanted side effects, such as loss of necessary immune function and impaired long-term health.

Tumor necrosis factor α (TNFα) regulates inflammation in metabolic diseases and probably aging-associated inflammation. Here, TNFα´s role in aging-related liver inflammation and fibrosis and underlying mechanisms was assessed in mice. In male C57BL/6J mice, aging increased hepatic inflammation, senescence markers p16 and p21 and Tnfa mRNA expression in liver tissue. In a second study, 4 and 24-month-old TNFα knockout and wild-type (WT) mice were compared for senescence, liver damage, intestinal barrier function, and microbiota composition. 24-month-old TNFα knockout mice were significantly protected from the aging-associated increase in hepatic senescence, inflammation and fibrosis found in WT mice.

This protection was related with preserved stem cell marker expression, maintained small intestinal barrier function and lower bacterial endotoxin in portal blood. While differing from young mice, intestinal microbiota composition of old TNFα knockout mice differed markedly from age-matched WT mice. Also, TNFα was found to alter permeability and tight junction protein levels being reversed by the presence of an JNK inhibitor in an ex vivo intestinal tissue model. Taken together, our results suggest that TNFα plays a key role in the development of aging-related liver decline in male mice.

Link: https://doi.org/10.1038/s41514-025-00326-w

Exposing cells to the Yamanaka transcription factors for a short period of time can produce rejuvenation of nuclear DNA structure, epigenetic regulation of that structure, and cell function. Cells in aged tissues become functionally younger following this partial reprogramming, expressing genes in the same way that younger cells do. Initial efforts to build treatments based on this finding have focused on gene therapy approaches, but gene therapy technologies come attached to thorny delivery issues. It remains somewhere between very difficult and impossible to deliver gene therapies to many of the tissues in the body, or to deliver systemically and evenly throughout the body.

Small molecule drugs, on the other hand, can be much better at achieving body-wide distribution of effects. If looking to the near future of the reprogramming field and its efforts to produce rejuvenation therapies, it seems likely that small molecule approaches to reprogramming will give rise to rejuvenation therapies that can affect the whole body well in advance of the development of any effective solutions for the long-standing delivery challenges associated with gene therapies. That said, the present small molecule combinations tested in animal studies still need a fair amount of work in order to produce an outcome acceptable to regulators. The discovery and optimization of entirely new classes of small molecule may be needed.

Molecular time machines unleashed: small-molecule-driven reprogramming to reverse the senescence

The core mechanism by which small-molecule compounds induce cellular reprogramming lies in their ability to mimic transcription factor functions, regulate intracellular signaling networks, and reverse aging-associated epigenetic alterations. Research indicates that specific combinations of small molecules can effectively activate pluripotency gene networks while simultaneously suppressing aging-related pathways, thereby achieving a reversal of cellular states.

First, small-molecule-compound-induced cellular reprogramming typically rewards the involvement of epigenetic modulators. Although the addition is not mandatory in all protocols - its necessity depends on factors such as reprogramming strategy, target cell type, and desired efficiency - epigenetic regulation plays a crucial role in cellular reprogramming. Research indicates that the reprogramming of fibroblasts often requires reversing differentiation-associated epigenetic barriers. Small-molecule epigenetic modulators actively clear these barriers: DNA methylation inhibitors (e.g., 5-aza-cytidine) reduce methylation levels at pluripotency gene promoters to enhance Oct4/Sox2 expression, while histone deacetylase (HDAC) inhibitors (e.g., Valproic acid, VPA) increase histone acetylation, open chromatin structures, and accelerate reprogramming.

Notably, epigenetic alterations have been identified as one of the core hallmarks of aging. During the aging process, the epigenome of cells and tissues undergoes significant and systematic changes. These alterations are not merely consequences of aging but also driving forces behind it. However, epigenetic modulators can reshape the epigenetic landscape of aging cells and reverse aging. Research has found that tranylcypromine (blocking H3K4me2 demethylation) and RepSox significantly reduces SA-β-gal activity in aged fibroblasts, upregulates pluripotency genes such as OCT4 and Nanog, and simultaneously downregulates age-associated stress response genes p21, p53, and IL6. This epigenetic reprogramming not only restores cellular proliferative capacity but also improves oxidative stress and heterochromatin loss, reversing aging characteristics across multiple dimensions.

Second, cellular signaling pathways serve as pivotal regulatory hubs in chemical reprogramming, precisely intervening in cellular fate by integrating epigenetic remodeling, metabolic reprogramming, and microenvironmental signals. Unlike the "hard switching" of genetic reprogramming (such as transcription factors), small molecules regulate signaling pathways more like a finely adjustable "dial," enabling more precise and controllable spatiotemporal dynamic regulation. None of these signaling pathways operate independently. The success of chemical reprogramming in combating aging relies on constructing an ecosystem of interacting signaling pathways that simulates embryonic development.

The aging of muscle tissue leading to loss of muscle mass (sarcopenia) and muscle strength (dynapenia) is a microcosm of aging in general, in that many different groups promote many different views of the relative importance of many different mechanisms. All of these mechanisms do in fact exist - muscle aging is a complex interplay of many interacting issues - but it is likely that any given view on the importance of any given specific mechanism will turn out to be wrong. The only practical way to establish the importance of a mechanism of muscle aging is to develop a means of blocking or repairing just that mechanism in isolation of all of the others, and observe the result. This applies as much to the examination of ferroptosis noted here as it does to any of the other mechanisms involved in muscle aging.

Age-related decline in physical function is a hallmark of aging and a major driver of morbidity, disability, and loss of independence in older adults, yet the molecular processes linking muscle aging to functional deterioration remain incompletely defined. Emerging evidence implicates ferroptosis, defined as iron-dependent, lipid peroxidation-driven cell death, as a compelling but underexplored contributor to age-related muscle wasting and weakness. Although ferroptosis signatures appear in aged muscle across cellular, animal, and human studies, their causal role in functional decline has not been clearly established.

Here, we synthesize current evidence to propose a framework in which iron dyshomeostasis, impaired antioxidant defenses, and dysregulated ferritinophagy converge to create a pro-ferroptotic milieu that compromises muscle energetics, structural integrity, and regenerative capacity. We delineate key knowledge gaps, including the absence of ferroptosis-specific biomarkers in human muscle and limited longitudinal data linking ferroptotic stress to mobility outcomes. Finally, we highlight potential therapeutic opportunities targeting iron handling and lipid peroxidation pathways. A better understanding of the contribution of ferroptosis to muscle aging may enable development of mechanistically informed biomarkers and interventions to preserve strength and mobility in older adults.

Link: https://doi.org/10.1111/acel.70367

Researchers here report on an approach to quantifying somatic mosaicism in a tissue sample. Mutational damage to nuclear DNA occurs constantly, but specific mutations only spread through a tissue over time to a sizable degree when they occur in one of the stem cells or progenitor cells that support that tissue by generating a supply of new daughter somatic cells. Somatic mosaicism has been shown to correlate with an increased risk of a few age-related conditions, particularly cancers, but it remains unclear as to how greatly it contributes to the overall progression of aging. Better ways to measure and catalog the extent of somatic mosaicism seem likely to help increase our understanding of its role.

The extensive presence of mutation-containing cells alongside normal cells, typically with no obvious difference between them, is known as somatic mosaicism. Now recognized as a common feature of human aging, it arises when a DNA "driver" mutation occurs in a cell, giving the cell and its progeny a slight but not yet cancerous growth or survival advantage. Researchers developed a technology called single-cell Genotype-to-Phenotype sequencing (scG2P), which allowed them to study somatic mosaicism in solid tissues - prior studies focused mostly on mosaicism in blood cells. Solid tissue samples are stored in ways that make mutational and gene activity information more challenging to access. Moreover, obtaining an accurate picture of solid tissue mosaicism typically requires profiling larger numbers of cells.

The team used scG2P to study esophageal tissue samples from six older adults. They found that more than half of the 10,000+ sampled cells contained clonal driver mutations and most had a single driver mutation in a gene called NOTCH1, which normally controls cell maturation, identity, division, and survival in the lining of the esophagus and other epithelial tissues in the body. The gene-activity readouts suggested that these NOTCH1 driver mutations induce clonal overgrowth by impairing normal cell development. The next most common driver-mutation gene in the samples was TP53, which makes the p53 protein, a crucial tumor suppressor that is inactivated in many cancers. TP53-mutant clones in the samples showed impaired maturation and also more frequent cell division compared to normal cells.

The findings are consistent with one of the central ideas of cancer biology: a single mutation is usually insufficient for malignancy and cancers arise from a series of mutations, which is increasingly common as we age.

Link: https://news.weill.cornell.edu/news/2026/01/scientists-identify-pre-cancerous-states-in-seemingly-normal-aging-tissues

Metabolism is complex, the interactions of countless molecules inside and outside cells. Evolution clearly does not optimize for the metabolism that provides individuals of a species with longer, more comfortable lives. We know this because any number of small tweaks to levels and interactions of specific proteins or metabolites have been shown to improve health and slow aging in multiple species. Success for a species is not necessarily aligned with success for any of the individuals making up that species.

Today's open access review is a guided tour of a handful of metabolites that are present in the body and for which studies have shown that upregulation (or in a few cases downregulation) can modestly slow aging in animal studies. This actually encapsulates quite a large fraction of recent research into aging, given that the list includes methionine restriction, a number of approaches assessed by the NIA Interventions Testing Program, hydrogen sulfide, and NAD+ upregulation. Should we be disappointed that such a large proportion of translational aging research is focused on approaches that cannot even in principle produce effects that improve all that much on the benefits of exercise? Perhaps so.

Lifespan-Extending Endogenous Metabolites

Taurine is a sulfur-containing β-amino acid synthesized endogenously from cysteine or methionine and present at high concentrations in many mammalian tissues. Taurine has been implicated in antioxidant and anti-inflammatory defenses, partly by supporting mitochondrial protein synthesis and function. Taurine supplementation shows protective effects in aging models. Animal studies suggest that supplementation can mitigate age-related deficits in cognition, cellular senescence, and tissue function. Evidence on natural taurine changes during healthy aging is mixed, highlighting species and individual variability.

Betaine, also called trimethylglycine, is a naturally occurring trimethylated amino acid present in plants, animals, and humans. Betaine donates a methyl group to homocysteine via betaine-homocysteine methyltransferase (BHMT) to regenerate methionine and S-adenosylmethionine (SAM), increasing the cellular SAM: SAH (S-adenosylhomocysteine) ratio. Emerging evidence across model organisms indicates that betaine can delay the aspects of aging. In aged mice, dietary betaine improved skeletal muscle mass, strength, and endurance, with preserved mitochondrial structure and respiration.

α-Ketoglutarate (α-KG) is a central tricarboxylic acid (TCA) cycle intermediate. Mechanistically, α-KG reduces cellular ATP levels and oxygen consumption while activating autophagy. Physiologically, endogenous α-KG levels increase during starvation in C. elegans, and its exogenous supplementation cannot augment longevity under dietary restriction, positioning α-KG as a key metabolite mediating the pro-longevity effects of nutrient limitation through ATP synthase inhibition and subsequent TOR pathway modulation.

Oxaloacetate (OAA) is an endogenous four-carbon metabolite of the citric acid cycle. In C. elegans, dietary OAA supplementation extends lifespan, requiring AMPK and the FOXO transcription factor DAF-16. This effect was hypothesized to result from OAA conversion to malate, consuming NADH and raising the NAD+/NADH ratio to mimic dietary restriction. However, translation of findings from invertebrates to mammals has been inconsistent.

Hydrogen sulfide (H2S) is an endogenous gasotransmitter. H2S has been shown to modulate aging in organisms ranging from worms to mammals. In C. elegans, exposure to H2S induces thermotolerance and extends lifespan. H2S levels generally decline with age, correlating with increased oxidative stress and inflammation. While H2S robustly extends lifespan in C. elegans and rodent studies report organ-level protection and improved some age-related dysfunctions with various H2S donors, evidence for H2S directly extending lifespan in mammals is lacking.

Nicotinamide adenine dinucleotide (NAD+) is a ubiquitous redox coenzyme which is central to cellular energy metabolism. It also serves as a substrate or cofactor for sirtuins, PARPs, and other enzymes that regulate DNA repair, chromatin remodeling, and stress responses. NAD+ levels decline with advancing age and lower NAD+ is correlated with a range of chronic age-related disorders.

Methionine is an essential amino acid critical for protein synthesis and serves as a precursor for SAM, a major methyl donor involved in numerous methylation reactions including DNA and protein methylation. Methionine restriction (MetR) extends lifespan across diverse models. In mice, it reduces adiposity and body size, reverses age-induced alterations in physical activity and glucose tolerance, and restores a younger metabolic phenotype. Reducing dietary methionine concentration from 0.86% to 0.17% increased rat lifespan by 30%.

Regular exercise is well established to correlate with improved health and reduced mortality in human epidemiological data, while animal studies demonstrate that exercise in fact causes improved health and reduced mortality. One of the noted benefits of exercise is an improvement in many aspects of immune function. In older people, that includes a reduction in the chronic inflammatory signaling that is characteristic of the aged immune system, as well as increased immune competency in defense against pathogens.

Immunosenescence, characterized by a progressive decline in immune function with age, leads to significant impairments in T-cell and B-cell responses, the reduced efficacy of dendritic cells, and diminished natural killer cell activity, ultimately decreasing the capacity to fight infections and clear tumors. This decline increases susceptibility to autoimmune diseases, chronic inflammation, and cancer, underscoring the urgent need for effective interventions.

Exercise emerges as a transformative strategy to combat immunosenescence by inducing metabolic remodeling that enhances insulin sensitivity, regulates immune cell phenotypes, and reduces chronic inflammation through the mTOR and AMPK signaling pathways. Furthermore, exercise promotes an optimal balance in immune responses by modulating lactate levels and supporting the transition from pro-inflammatory to anti-inflammatory states, effectively sustaining immune function in aging individuals. Exercise-induced lipid and amino acid metabolic changes play crucial roles in improving immune function by reducing visceral fat accumulation and optimizing amino acid metabolism, leading to restored immune cell functionality and healthier immune profiles in older adults.

The comprehensive organ-immune crosstalk facilitated by exercise, particularly through the release of myokines and modulation of the gut microbiota, enhances immune cell activity and contributes to systemic immune regulation, countering age-related immune decline. Notably, exercise effectively remodels both innate and adaptive immune cells by promoting the functionality of neutrophils, macrophages, and T cells while augmenting naive T-cell output from the thymus. These adaptations improve immune surveillance and response, reinforcing the assertion that exercise is vital for delaying the aging-related decline in immune health.

Link: https://doi.org/10.3390/biology15010058

If delving very deep into the structures that support flexibility and elasticity in tissues, one eventually arrives at specific proteins incorporated into cells and the extracellular matrix that act as springs or similar mechanical systems. Researchers here note that one such spring protein in heart muscle, known as titin, exhibits an increased proportion of less elastic isoforms in the context of heart failure. This makes heart muscle stiffer, and the heart less able to pump blood. Adjusting the regulation of isoform proportions to favor the more elastic isoforms can be achieved by inhibiting another specific protein, RBM20. The result is more elastic heart tissue and reduced pathology of heart failure.

Heart failure with preserved ejection fraction (HFpEF) is prevalent, deadly, and difficult to treat. Risk factors such as obesity and hypertension contribute to cardiac inflammation, metabolic defects, and pathological remodelling that impair ventricular filling in diastole. Addressing the mechanical aspects of cardiac dysfunction at the level of myofilaments provides a direct approach to improve diastolic performance across diverse HFpEF phenotypes.

Titin is a giant myofilament protein and functions as a molecular spring, which generates passive force when sarcomeres are stretched, thereby aiding in returning the sarcomere to its resting length. Titin contributes up to ∼70% of left ventricular (LV) physiological passive stiffness. In HFpEF, increased titin stiffness has been identified as a key pathological factor contributing to LV diastolic dysfunction in human and animal models.

In the adult heart, there are two main isoforms of titin: N2B and N2BA, with the N2B isoform being the stiffest. RNA binding motif-20 (RBM20) is a major splicing regulator that determines isoform expression of titin. Complete inhibition of Rbm20 activity leads to the expression of N2BA-G titin, which is very long and highly compliant. Mice expressing N2BA-G titin exhibit reduced LV chamber stiffness and attenuated systolic contractility. Meanwhile, partial inhibition of RBM20 activity results in the expression of N2BA-N titins, which are larger than the N2BA but not as large as the N2BA-G isoform. Mice expressing N2BA-N titins show reduced LV chamber stiffness while maintaining normal baseline systolic function and enhanced exercise tolerance.

Inhibition of RBM20 using antisense oligonucleotides (ASOs) induces expression of compliant titin isoforms. Here, we optimized RBM20-ASO dosing in a HFpEF mouse model that closely mimics human disease, characterized by metabolic syndrome and comorbidities, but without primary defects in titin or RBM20. Partial inhibition of RBM20 (∼50%) selectively increased compliant titin isoforms, improving diastolic function while preserving systolic performance. This intervention reduced left ventricular stiffness, enhanced relaxation, and mitigated cardiac hypertrophy, despite ongoing systemic comorbidities.

Link: https://doi.org/10.1093/cvr/cvaf171

A broad range of mechanisms contribute to a growing stiffening of blood vessels, a loss of ability to contract and dilate in response to environmental cues. Blood flow is vital, and this impairs its regulation. Vascular stiffening contributes to hypertension, atherosclerosis, and downstream issues in the cardiovascular system the tissues it supports. One of the causes of vascular stiffening is progressive inability of the smooth muscle surrounding vessels to sufficiently constrict the vessel. This dysfunction arises from its own grab bag of various mechanisms with various much debated degrees of importance relative to one another.

Today's open access paper is a dive into one specific aspect of the biochemistry of smooth muscle activity. The researchers characterize a particular age-related issue related to regulation of the cytoskeletal structure of vascular smooth muscle cells and its relationship to oxidizing molecules in the context of vessel constriction. The point to all of this is that the researchers demonstrate that age-related loss of the ability of smooth muscle tissue to constrict vessels can be reversed to some degree by overexpression of a specific protein involved in their mechanisms of interest. The best way to justify further investigation of a novel mechanism is by demonstrating its relevance in living tissues.

A mechanism for the disrupted redox regulation of vascular contractility during aging

Aging of vascular cells significantly contributes to the overall organismal aging phenotype and is a major independent risk factor for cardiovascular diseases. While many studies focused on endothelial cells, aging-related processes also affect the vascular smooth muscle cell (VMSC). An aged VSMC associated with disturbed arterial stiffness and, in particular, impaired contractility.

Cytoskeletal deregulation, mainly of the actin network, lies at the core of such changes. Importantly, cytoskeleton-linked mechanobiological processes strongly crosstalk with redox-dependent signaling at several levels, from sensing to tissue remodeling. In particular, an oxidant environment promotes actin polymerization and enhances contractility. It is conceivable, thus, that post-translational redox modifications, including e.g., protein sulfenylation, affect actin organization, but the precise role of such an oxidant environment on vascular contractility during aging is unknown.

We hypothesized that the aging-related impairment of redox and sulfenylation-regulated cytoskeleton dynamics associates with the disruption of chaperone signaling. A particular subgroup of redox chaperones is the protein disulfide isomerases, with prominence of its founding member PDIA1 (or simply PDI). This thioredoxin superfamily protein is mainly located in the endoplasmic reticulum (ER), where it supports oxidative protein folding. Meanwhile, it also exhibits functions out of the ER associated with mechano-regulation, including fine-tuning of cellular force distribution, integrin regulation, and β-actin organization, accounting for vascular remodeling modulation

We first show that protein sulfenylation supports vascular contractility and F-actin assembly during mechanoadaptation or agonist-induced contraction. Meanwhile, PDI supports sulfenylation-dependent actin remodeling. Moreover, aged murine arteries lose the sulfenic acid-related component of contractility, while PDI overexpression overrides this dysfunction and restores aging-related vascular contractility. We further confirm a direct PDI-actin interaction modulated by sulfenic acid. Overall, signaling connections between PDI and sulfenylated proteins behave as an upstream integrative system regulating F-actin assembly, a mechanism that is impaired during aging-induced vascular dysfunction.

Any individual transcription factor influences the expression of many different genes. Researchers have established that some transcription factors can induce radical changes in cell state and behavior, such as the Yamanaka factors used in reprogramming studies. For any specific desirable change in the behavior of aged cells, it is possible that one or more specific transcription factors exist to create that change - the challenge lies in identifying those transcription factors. Researchers are thus working to assess and catalog the many transcription factors present in the human genome. It is a large task. The work noted here covers just one cell type and by no means all of the space of possibilities even there. Nonetheless, that the researchers found potentially useful transcription factors suggests that this can be a fruitful line of research.

Cellular rejuvenation through transcriptional reprogramming has emerged as exciting approach to counter aging. However, to date, only a few of rejuvenating transcription factor (TF) perturbations have been identified. In this work, we developed a discovery platform to systematically identify single TF perturbations that drive cellular and tissue rejuvenation. Using a classical model of human fibroblast aging, we identified more than a dozen candidate TF perturbations and validated four of them (E2F3, EZH2, STAT3, ZFX) through cellular/molecular phenotyping.

Overexpressing E2F3 or EZH2, and repressing STAT3 or ZFX, reversed cellular hallmarks of aging - increasing proliferation, proteostasis, and mitochondrial activity, while decreasing senescence. EZH2 overexpression in vivo rejuvenated livers in aged mice, reversing aging-associated gene expression profiles, decreasing steatosis and fibrosis, and improving glucose tolerance. Mechanistically, single TF perturbations led to convergent downstream transcriptional programs conserved in different aging and rejuvenation models. These results suggest a shared set of molecular requirements for cellular and tissue rejuvenation across species.

Link: https://doi.org/10.1073/pnas.2515183123

Researchers here identify a correlation between grip strength and the functional connectome and blood supply of the caudate nucleus region of the brain in older adults. Many aspects of aging correlate with one another even if they do not interact directly, as any given specific form of age-related damage and dysfunction tends to affect many organs and systems in the body. Think of the effects of chronic inflammatory signaling, for example. It is interesting to consider whether there could be a role for the aging of the caudate nucleus in determining loss of muscle mass and strength, but that would be the subject of further research; it isn't obvious at all from what is presently known of the caudate nucleus as to how this connection could work.

Researchers used functional MRI scans to measure brain activity in older adults as they performed a maximum grip strength test. What the researchers found surprised them. Among the dozens of brain areas monitored, one emerged as the strongest predictor of grip strength: the caudate nucleus. Tucked deep in the brain, the caudate is known for helping manage movement and decision-making. But its role in muscular strength, and its potential to signal frailty, has until now gone largely unnoticed.

The researchers analyzed scans from 60 older adults. The study group comprised half men and half women, and all completed three sessions of functional MRI while undergoing strength testing. To ensure they were isolating brain effects from other factors like body size, the data was normalized to account for differences in sex and muscle mass. The result was a statistically significant correlation between brain network patterns and grip performance. Stronger blood flow and greater connectivity of the functional connectome in the caudate nucleus matched higher grip strength, independent of gender.

Link: https://www.eurekalert.org/news-releases/1112375

The balance of microbial populations making up the gut microbiome changes for the worse with aging. Populations that provoke inflammation increase in size at the expense of populations that manufacture beneficial metabolites. We have some idea of the size of the resulting contribution to degenerative aging as a result of fecal microbiota transplantation studies, from young donor to old recipient, carried out in killifish and mice. Old recipients provided with a young gut microbiome composition exhibit improved health and extended life.

Sustained programs of exercise are known to improve the composition of the gut microbiome, reducing the magnitude of some of the changes known to occur with age. This may be the result of improved immune function, and thus a greater ability of the immune system to remove unwanted, inflammatory microbes. It is thought that some fraction of the well-known reduced risk of age-related disease and mortality resulting from exercise may be due to an improved gut microbiome. The question, as usual, is how large a fraction.

In today's open access paper, researchers report on a study of exercise conducted in aged mice with the aim of obtaining potentially illuminating data on the relationship between exercise, health, and gut microbiome composition. The most interesting result is not the health benefits, which are expected, but rather that exercise becomes progressively less effective in altering the gut microbiome as the animals become older.

Age-dependent effects of exercise on gut microbiota-mitochondria axis and cognitive function in aging mice

Aging is accompanied by progressive impairments in mitochondrial bioenergetics, apoptosis regulation, and gut microbiota homeostasis, all of which contribute to cognitive decline. In this study, we investigated whether the effects of treadmill exercise on the gut microbiota-mitochondrion-neuronal plasticity axis differed between young (15 months) and old (28 months) mice. Male C57BL/6 mice were randomly assigned to the following groups: early sedentary, early exercise, late sedentary, or late exercise groups and completed an 8-week treadmill training protocol.

Cognitive function was assessed using the passive avoidance test and the Morris water maze test. Hippocampal mitochondrial respiration, Ca2+ retention capacity, and Bax/Bcl-2 expression were quantified, and the gut microbiota composition was analyzed using 16S ribosomal RNA sequencing.

Mice that did not exercise in old age exhibited memory impairment, decreased mitochondrial oxidative respiration, reduced Ca2+ retention, increased Bax expression, decreased Bcl-2 levels, and decreased abundance of Lactobacillus, Bifidobacterium, and Akkermansia. Exercise significantly improved behavioral performance, mitochondrial function, and apoptosis balance, while also increasing beneficial gut microbiota.

Notably, these effects were significantly greater in late-aged compared to early-aged mice. These results demonstrate that the efficacy of exercise in modulating the microbiota-mitochondrion-brain axis varies with age. Early-aged appears to represent a more responsive biological period during which exercise is more effective in improving mitochondrial integrity, microbiota composition, and cognitive resilience. These results suggest that initiating exercise early in the aging process may maximize neuroprotective effects and delay age-related functional decline.

The protein α-synuclein can misfold into a pathological form and then spread from cell to cell in the central nervous system. This occurs in everyone to some degree with age, but only some people experience a burden of α-synclein pathology large enough to lead to Parkinson's disease or other synucleinopathies. It is likely that everyone exhibits some loss of function due to α-synuclein, but as ever, it is hard to pin down exactly how much of each aspect of aging is due to any one specific mechanism. The only efficient way to obtain useful data is to fix that one specific problem and observe the outcome, which is what researchers did here in aged rats. A gene therapy produced intracellular antibodies that reduce α-synuclein levels, albeit perhaps not in the expected way, and the result is improved function in treated animals.

Abnormal accumulation of alpha-synuclein (αSyn) in axons and presynaptic terminals plays a critical role in αSyn-mediated dopaminergic neurodegeneration. A strong correlation between aging and elevated αSyn levels in the substantia nigra has been identified in both humans and non-human primates. This study aimed to investigate whether AAV-mediated NAC32 intrabody expression in the substantia nigra could ameliorate αSyn-associated dopaminergic dysfunction and improve age-related motor deficits in aged rats.

We first investigated the mechanism by which NAC32 reduces αSyn levels. Comparisons of αSyn burden, tyrosine hydroxylase (TH) expression, and locomotor activity were made between young and aged rats. In aged rats, we evaluated behavioral performance, dopaminergic markers, and synaptic markers following AAV1-NAC32 gene delivery into the substantia nigra. Our results showed that the NAC32-mediated αSyn reduction was not prevented by inhibition of proteasomal, lysosomal, or autophagic pathways and was associated with reduced αSyn mRNA levels.

Aged rats exhibited decreased locomotor activity, elevated αSyn levels, and reduced TH expression in the substantia nigra. NAC32 intrabody expression in the substantia nigra significantly reduced αSyn accumulation, restored TH expression, increased synaptic markers and striatal dopamine levels, and improved locomotor performance in aged rats. These effects occurred without detectable elevation of pro-inflammatory cytokine levels in bulk striatal tissue. Our findings suggest that AAV-mediated NAC32 intrabody expression in the substantia nigra may serve as a therapeutic strategy to mitigate αSyn-induced dopaminergic dysfunction and motor impairments associated with aging.

Link: https://doi.org/10.1038/s41598-025-34908-1

Researchers here review the evidence for chronic inflammation to contribute to the vascular dysfunction of hypertension, in which blood pressure increases to harmful levels. The particular focus is on the feedback loop in which inflammatory immune dysfunction contributes to dysfunction in the regulation of hematopoiesis, the manufacture of new immune cells by hematopoietic cells resident in bone marrow, which in turn causes greater inflammatory immune dysfunction. Sustained inflammatory signaling is harmful to tissue structure and function throughout the body, including the vasculature and systems that regulate blood pressure.

Hypertension is a highly prevalent chronic disease all around the world, and the pathogenic mechanism is complicated. The early and rapid decline of the function of human vascular system due to the aging of human body are characteristics of hypertension, which is accompanied by progressive pathological remodeling and arterial stiffening.

The pathogenetic action of oxidation and inflammation is the vital function in the process of endothelial dysfunction and arterial injury. Bone marrow is considered as the birthplace of the immune cell, and the role of bone marrow in hematopoiesis and immune response for the onset of hypertension has been confirmed. In turn, inflammatory and oxidative stress also affect the bone marrow and damage bone marrow function, causing a series of complications in hypertension, resulting in a vicious cycle. Recently, increasing evidence has suggested that bone marrow aging plays an important role in the onset and development of hypertension, and that the function of bone marrow in the pathogenesis of hypertension has been seriously overlooked. Bone marrow microvascular ageing is also involved in the progression of bone marrow ageing.

Thus, this review mainly focuses on bone marrow function in aging and hypertension progression, addresses the current studies on the roles of vascular aging, the bone marrow and the immune system in hypertension, and discusses their interaction and function in the pathogenesis of hypertension. Furthermore, some novel molecular pathological mechanisms are surveyed. This can add a new impetus to the mechanism research of hypertension onset.

Link: https://doi.org/10.1038/s41420-025-02851-9

The proteasome is a specialized protein complex that breaks down unwanted proteins into short peptide molecules for reuse in further protein synthesis. Any protein designated as unwanted by the addition of a ubiquitin tag can be broken down in this way. This activity is important, a form of cellular maintenance. When impaired, loss of proteasomal function allows damaged and damaging proteins to build up in the cell, degrading the function of other cellular components and activities. Unfortunately, aging causes loss of proteasomal function just as it degrades the function of all complex systems in the cell.

In today's open access paper, researchers discuss the link between the age-related impairment of proteasomal function and the chronic inflammation that is characteristic of aging. This is a part of the increased attention given to the cGAS-STING pathway and its relevance in aged tissues. The sensor cGAS evolved to detect nucleic acids characteristic of invading pathogens, but is unfortunately also triggered by mislocalized DNA from the cell nucleus or mitochondria that escapes into the cytoplasm of the cell. cGAS in turn activates STING, a central inflammatory regulatory. Diminished proteasomal activity allows the build up of misfolded and other harmful proteins that can disrupt mitochondrial function and structure sufficiently to allow mitochondrial DNA into the cell cytosol.

This sort of connection is why interventions that improve forms of cell maintenance such as proteasomal activity and autophagy tend to reduce age-related inflammation. These forms of intervention range from exercise to sophisticated genetic upregulation or downregulation of specific protein machinery used in cell maintenance processes. Some are more practical than others, and effect sizes vary. What they all have in common is that they help to reduce the level of damage in the form of broken proteins inside cells, thereby improving mitochondrial function, and reducing cGAS-STING activity and consequent inflammatory signaling.

Impaired Proteasome as a Catalyst for cGAS-STING Activation in Alzheimer's Disease

Misfolded proteins and protein degradation systems have contributed significantly to the understanding of Alzheimer's disease (AD). The ubiquitin-proteasome system (UPS), is vital for clearing abnormal proteins that could trigger inflammation if accumulated. Neurons are particularly vulnerable to UPS impairment due to their high reliance on precise protein homeostasis for function and survival. Findings from the studies of the 5×FAD and tau-P301S mice revealed that the synaptic proteasome function is impaired even in the early stages, a phase before overt plaque formation, correlating with early memory deficits. Blocking proteasome function in healthy neurons causes AD-like effects, such as oxidative stress, synaptic loss, and cognitive decline.

Conversely, boosting UPS activity can reverse these effects. Deletion of a 26S proteasome subunit causes neurodegeneration and Lewy-like inclusions, accompanied by abnormal mitochondria, linking proteasome failure to mitochondrial dysfunction and neuronal damage that extends beyond protein aggregation. Increased production of reactive oxygen species (ROS) can damage mitochondrial lipids and proteins, compromise membrane integrity, and ultimately cause membrane rupture. This occurs due to abnormal protein aggregation caused by proteasomal failure, which disrupts redox balance. Although UPS is involved in mitochondrial quality control, its impairment weakens the removal of damaged mitochondrial proteins, leading to oxidative stress that eventually causes mitochondrial membrane collapse. This collapse can then leak mitochondrial DNA into the cytosol. This leaked mtDNA acts as a damage-associated molecular pattern, thereby activating the cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) DNA-sensing pathway, to cause neuroinflammation.

It has been shown in a neuron-specific proteasome knockout mouse that the cGAS-STING pathway was activated, as evidenced by increased protein levels of cGAS and STING, and pro-inflammatory factors, such as STAT1, NF-κB, IL-1β, TNF-α, and IL-6, as well as signs of neurodegeneration, including decreased brain weight and necroptosis markers. These results link proteasomal dysfunction to immune responses and cell death in the brain

Researchers here conduct a meta-analysis of clinical trial results for the effects of resistance exercise on cognitive function. As might be expected given what is known of the effects of exercise on health, the amassed data strongly indicates that programs of resistance exercise improve cognitive function in older people. Mechanistically, it is known that exercise reduces inflammation, increases blood flow to the brain, improves immune function, improves mitochondrial function, increases autophagy, and touches on a range of downstream effects of those changes that may positively impact the state of the aging brain.

Resistance exercise has recently gained attention as a promising strategy to promote neuroplasticity and mitigate cognitive deterioration; however, evidence from randomized controlled trials (RCTs) remains inconsistent. This systematic review and meta-analysis aimed to evaluate the effects of resistance exercise on cognitive function in older adults.

17 RCTs (n=739) met the inclusion criteria. Pooled analyses showed that resistance training significantly improved overall cognitive function (standardized mean difference, SMD = 0.40), working memory (SMD = 0.44), verbal learning and memory (mean difference, MD = 3.01), and spatial memory span (SMD = 0.63), whereas effects on processing speed, executive function, and attention were not significant. Heterogeneity and publication bias analyses indicated stable and unbiased results. The magnitude of improvement appears to depend on age and exercise parameters, suggesting a potential dose-response relationship.

Link: https://doi.org/10.3389/fpsyt.2025.1708244

Researchers here provide data to support the claim that if everyone had the most favorable ε2 variant of the APOE gene, Alzheimer's disease incidence would be a tenth of what it is now. APOE is involved in cholesterol trafficking and metabolism, and in recent years it has been suggested that the APOE variants connected with higher risk of Alzheimer's cause dysfunction in microglia in the brain. Independently, that microglia become more inflammatory and dysfunctional with age has become an important line of research in the study of neurodegenerative conditions. Evidence strongly supports an important role for dysfunctional microglia in provoking the pathology associated with these conditions. Therapies focused on microglia have yet to emerge, but a number of approaches demonstrated in the laboratory and animal studies could lead to clinical trials given sufficient motivation and funding.

Variation in the APOE gene strongly affects Alzheimer's disease (AD) risk. However, the proportion of AD burden attributable to this variation requires clarification, which would help to elucidate the scope of strategies targeting apolipoprotein E (APOE) for AD prevention and treatment. We estimated the extents to which clinically diagnosed AD, AD neuropathology and all-cause dementia are attributable to the common APOE alleles in four large studies.

First, we used data on 171,105 and 289,150 participants aged ≥60 years from UK Biobank (UKB) and FinnGen, respectively. AD and all-cause dementia were ascertained from linked electronic health records in these cohorts. Second, we examined amyloid-β positivity from amyloid positron emission tomography scans of 4,415 participants of the A4 Study. Third, we analysed data from the Alzheimer's Disease Genetics Consortium (ADGC), where neuropathologically confirmed AD cases were compared to pathology-negative, cognitively intact controls (N = 5,007).

In each analysis, we estimated outcome risk among carriers of APOE risk alleles ε3 and ε4, relative to individuals with an ε2/ε2 genotype, and calculated attributable fractions to show the proportions of the outcomes due to ε3 and ε4. For AD, fractions ranged from 71.5% in FinnGen to 92.7% in the ADGC. In A4, 85.4% of cerebral amyloidosis was attributable to ε3 and ε4. The proportions of all-cause dementia attributable to ε3 and ε4 in UKB and FinnGen were 44.4% and 45.6%, respectively. Without strong underlying risks from APOE ε3 and ε4, almost all AD and half of all dementia would not occur. Intervening on APOE should be prioritised to facilitate dementia prevention.

Link: https://doi.org/10.1038/s44400-025-00045-9

The thymus is a small inner organ near the heart that is responsible for the maturation of T cells of the adaptive immune system. The supply of new T cells is critical to the maintenance of effective immune function over time. Unfortunately the thymus atrophies over the course of adult life, and in most people is largely made up of inactive fat tissue by as early as 50 years of age. The resulting diminished supply of replacement cells ensures that the T cell population thereafter becomes ever more made up of malfunctioning, exhausted, and senescent cells incapable of mounting an effective response.

Given the pressing need for ways to restore lost immune function in older individuals, it is good to see that a fair number of biotech startup companies are now competing to develop means of regenerating the aged thymus. After something of an abandonment of efforts following 2010s work on FOXN1 as a regulator of thymic growth, the past few years have seen a number of programs make the leap from academia to industry. Hopefully one or more will result in a form of therapy that is both effective and cost-effective.

The primary challenge presented by the thymus is targeted delivery of therapeutics. Quite a few approaches are known to kickstart the thymus into regrowth of the active regions of tissue capable of nurturing new T cells. Unfortunately they all produce serious side-effects in other tissues when delivered at sufficient high systemic doses to ensure that enough of the therapeutic make it to the thymus. For example, delivery of recombinant keratinocyte growth factor (KGF) reliably regrows the thymus in aged mice and non-human primates. There is a human drug based on KGF, used sparingly for some complications of cancer therapy. Dosing with this drug at levels sufficient to regrow the human thymus would result in very unpleasant complications, sufficiently serious to disqualify its use in this context.

There are as yet no robustly demonstrated ways to target therapies to the thymus other than direct injection, a procedure that carries sufficient cost and risk to make it infeasible for widespread use in older individuals. Thus while the new biotech startup noted in today's article is working on a growth factor approach for thymic regeneration, in reality that means that they are working on some combination of delivery system and therapy that can limit the effects of growth factors to the target thymic tissue. That is the core challenge, delivery.

Thymus regeneration startup emerges to 'restore immune function'

Swiss biotech TECregen emerged today with seed financing to develop a pipeline of therapies designed to regenerate the thymus and boost the aging immune system. The company is built around the idea that restoring the thymus can restore immune function at its source. The gradual loss of thymic function is increasingly viewed as a biological bottleneck for healthy aging. A shrinking thymus contributes to weaker responses to vaccines, slower recovery from infections and diminished immune surveillance against emerging cancers.

TECregen is developing a class of biologic drugs it calls thymopoietics, engineered to regenerate thymic epithelial cells and rebuild the microenvironment required for effective T-cell production. Thymic epithelial cells are the structural and functional backbone of the thymus; without them, T cells cannot mature properly. By rejuvenating this cellular niche, TECregen aims to restart the production of healthy, diverse T cells and restore immune resilience across a range of conditions, from immune aging to cancer-related immune suppression.

The basis of TECregen's approach involves applying advanced ligand engineering to growth factor biology. Growth factors are potent signaling molecules that influence inflammation, tissue repair, and regeneration, including processes within the thymus. According to the company, historic attempts to use growth factors therapeutically have been hampered by systemic toxicity and poor tissue selectivity, as these molecules can trigger unwanted effects in multiple organs. TECregen aims to engineer these signals to be functionally selective and tissue-targeted, with the goal of concentrating their activity in the thymus while minimizing off-target effects.

Cells become senescent constantly throughout the body and throughout life, near all as the result of reaching the Hayflick limit on replication, but also due to excessive cell stress, damage, or a toxic environment. A senescent cell ceases replication, enlarges, and secretes a pro-inflammatory, pro-growth mix of signals that attracts the attention of the immune system. In youth senescent cells are efficiently destroyed by the immune system, but this clearance slows down with age. Senescent cells thus accumulate in later life to cause chronic inflammation and disruption to tissue structure and function. The immune system also accumulates senescent cells, and researchers here investigate the epigenetic regulation of gene expression in these cells, with an eye to finding ways to reduce the burden of senescence in these populations.

The age-associated accumulation of senescent cells in tissues is one of the driving causes of aging and age-related disease. Although senescent cells secrete chemokines that facilitate the recruitment of cytotoxic immune cells for their elimination, senescent cells accumulate systemically with advancing age, suggesting that immune cell-mediated elimination of senescent cells becomes impaired with age. Recent evidence highlights a dysfunctional adaptive immune system as a potential cause for the age-associated accumulation in senescent cells. In older humans, both CD4+ and CD8+ T cells acquire features of senescence, which is linked to defective immune responses. However, the gene regulatory mechanisms that promote senescence of CD8+ T cells in aging humans, as well as the contribution of senescent CD8+ T cells to disease, remain poorly understood.

We defined and validated the transcription factor (TF) networks that control the senescence program in CD8+ T cells of a cohort of younger and older donors. One key finding of our study is that the acquisition of senescence is the main driver of epigenomic and gene expression dynamics of CD8+ T cells, with a minor contribution of chronological age. The transition to the senescence state is a major event in the epigenetic life of CD8+ T cells, as it involves the differential expression of 40% of all detectable TFs. Inhibition or downregulation of AP1, KLF5, or RUNX2 modulates the transcriptional output and partially restores the blunted response to stimulation of senescent CD8+ T cells.

Link: https://doi.org/10.1016/j.celrep.2025.116795

Much of the research into TGF-β signaling show that raised circulating levels of TGF-β drive chronic inflammation and related dysfunctions. Researchers have shown that reducing TGF-β levels can be used to improve health and extend life in mice, for example. Yet nothing is simple and straightforward when it comes to cellular biochemistry. Here, researchers provide evidence for a beneficial function of TGF-β, in that its presence restrains the inflammatory activity of the innate immune cells known as microglia to better preserve myelin structure in the aged spinal cord.

Microglia survey and regulate central nervous system myelination during embryonic development and adult homeostasis. However, whether microglia-myelin interactions are spatiotemporally regulated remains unexplored. Here, by examining spinal cord white matter tracts in mice, we determined that myelin degeneration was particularly prominent in the dorsal column (DC) during normal aging. This was accompanied by molecular and functional changes in DC microglia as well as an upregulation of transforming growth factor beta (TGF)β signaling.

Disrupting TGFβ signaling in microglia led to unrestrained microglial responses and myelin loss in the DC, accompanied by neurological deficits exacerbated with aging. Single-nucleus RNA-sequencing analyses revealed the emergence of a TGFβ signaling-sensitive microglial subset and a disease-associated oligodendrocyte subset, both of which were spatially restricted to the DC. We further discovered that microglia rely on a TGFβ autocrine mechanism to prevent damage of myelin in the DC. These findings demonstrate that TGFβ signaling is crucial for maintaining microglial resilience to myelin degeneration in the DC during aging. This highlights a previously unresolved checkpoint mechanism of TGFβ signaling with regional specificity and spatially restricted microglia-oligodendrocyte interactions.

Link: https://doi.org/10.1038/s41593-025-02161-4

The article I'll point out today manages to capture much of the gist of the present state of interactions between two opposing viewpoints on aging: firstly that aging is the consequence of an accumulation of cell and tissue damage, a byproduct of evolutionary focus on early life success, and secondly that aging is an evolved program in its entirety. In essence, the trend is now towards some form of synthesis of these two viewpoints, that the panoply of mechanisms making up degenerative aging contain something of both stochastic damage and programmed functions. One might look at the present state of the hyperfunction theory of aging as an at times confusing and contradictory effort to produce such a synthesis.

At the time that these views emerged in opposition, it mattered as to which viewpoint governed the direction of research and development aimed at intervening in the aging process. If aging is damage, then identifying and repairing damage is the only viable approach likely to produce sizable gains in health. If aging is a program (that produces damage), then adjusting gene expression and the operation of metabolism is the only viable approach likely to produce sizable gains in health.

One could point to the Strategies for Engineered Negligible Senescence for a clear paradigm of damage repair (and still can, as its component parts have been demonstrated to be useful by the results of animal studies). One could point to efforts to alter epigenetic control over gene expression, and thus the operation of metabolism, as clearly falling into a paradigm of attempts to control an aging program. That division has been muddied by the discovery that DNA double strand break repair produces epigenetic aging, coupled with the development of epigenetic reprogramming as an approach to restoring youthful epigenetic patterns to aged cells. Epigenetic reprogramming would have been called an effort to alter metabolism to adjust the aging program, but thanks to new discoveries can now be thought of as a form of damage repair. The world turns, and matters change.

Why Aging Is Not Fundamentally Programmed - and Why Programming Still Matters

Theories of aging can be broadly categorized into two groups. On one hand are those that think aging is caused by accumulation of damage due to entropy and that solving aging requires repairing these damages. On the other hand are those that think aging is driven by an evolved genetic program whose function is to cause aging. They think the solution to aging is to instruct the body to fix itself by reprogramming its cells.

The latter view has become more popular lately since it was discovered that cells can be reprogrammed to become younger in most aspects, by changing their gene expression. That shift was also amplified because several early "damage theories" were framed as overly narrow single-cause explanations that failed to explain aging (the free radical theory of aging is a classic example). Reprogramming therefore started feeling like a more complete theory. Some scientists think that if we could simply rejuvenate all the cells in the body through reprogramming their gene expression, we could then rejuvenate the whole body and effectively solve aging.

A critical error in modern aging debates is thinking that aging must be caused by either damage accumulation or programming, while in fact, both factors play a strong role in aging. More accurately, aging is fundamentally caused by accumulation of damages, but it is also influenced very strongly by programming. Reprogramming is a highly promising strategy to slow down and reverse aging. The point is, we will never get close to fully reversing aging in humans without addressing damage accumulation also. Reprogramming may partially restore many cells to more youthful states, but it cannot automatically remove a great portion of structural damages such as many of those found in the extracellular matrix.

Why does exercise slow the age-related loss of bone mineral density leading to osteoporosis? Researchers here find a critical role for mechanotransduction, the sensing of physical forces placed upon a cell, such as pressure or mechanical stress. Specifically the mechanosensor Piezo1 is triggered in mesenchymal stem cells in the bone marrow, and the subsequent response of this cell population acts to reduce inflammation, reduce fat cell generation in bone marrow, and thus allow the specialized cell populations working on bone extracellular matrix structures to better maintain a healthy bone mineral density. This opens the door to the development of therapies that can mimic this effect of exercise by triggering Piezo1 or downstream pathways.

With aging or osteoporosis, bone marrow adipogenesis is increased and inversely correlates with the loss of bone mass. Bone marrow adipocytes are derived from multipotent bone marrow mesenchymal stem cells (BMMSCs), which can differentiate into either fat or bone. BMMSCs are mechanosensitive cells, but how mechanical loading is implicated in the in vivo regulation of bone marrow adipogenesis and its impact on bone remodeling remain poorly understood. Here, we identify the mechanosensitive cationic channel Piezo1 in BMMSCs as a key suppressor of bone marrow adipogenesis by preventing local inflammation, thereby enhancing osteoblast differentiation and bone formation.

Importantly, our findings also indicate that Piezo1 invalidation abolishes exercise-induced benefits on bone volume and marrow adiposity, suggesting that Piezo1 senses physiological mechanical stress (presumably shear stress and compressive forces) in the bone marrow to regulate BMMSC fate decision. These findings demonstrate that Piezo1 activation in BMMSCs suppresses bone marrow adipogenesis to maintain bone strength by preventing the Ccl2-Lcn2 inflammatory autocrine loop, thus uncovering a previously unrecognized link between mechanotransduction, inflammation, and cell fate determination.

Link: https://doi.org/10.1038/s41392-025-02455-w

RNA splicing is the assembly of exons (and discarding of introns) to form a protein. Many genes contain the instructions for multiple proteins, and which protein is produced is governed by the operation of the splicing machinery. That operation is known to change with age, but the question remains open as to just how important RNA splicing is to age-related degeneration. Researchers here use a novel approach to identify genes with age-related alterations in expression that are similar in all tissues, and find that the results are biased towards RNA splicing machinery. The interesting part of the paper is the speculation in the discussion section regarding the reasons why alterations in RNA splicing activities could be important in aging, suggesting a connection to DNA damage. This line of thinking is particularly interesting given recent evidence for repeated activation of DNA repair processes to trigger the epigenetic changes characteristic of aging. Looking at DNA damage, epigenetic change, and altered alternative splicing may be three viewpoints into the same process of aging centered on the structure and function of nuclear DNA and its surrounding machineries of gene expression.

Although transcriptomic changes are known to occur with age, the extent to which these are conserved across tissues is unclear. Previous studies have identified little conservation in age-modulated genes in different tissues. Here, we sought to identify common transcriptional changes with age in humans (aged 20 to 70) across tissues using differential network analysis, assuming that differential expression analysis alone cannot detect all changes in the transcriptional landscape that occur in tissues with age. Our results demonstrate that differential connectivity analysis reveals significant transcriptional alterations that are not detected by differential expression analysis. Combining the two analyses, we identified gene sets modulated by age across all tissues that are highly enriched in terms related to "RNA splicing" and "RNA processing".

Alternative splicing is a fundamental process in eukaryotes that allows the same gene to encode multiple different transcripts, with approximately 95% of multi-exon genes producing transcripts that undergo alternative splicing. Therefore, it is intuitive that alterations in the splicing machinery would have systemic effects on the biological network. Indeed, aging appears to be accompanied by a high incidence of aberrant splicing and intron retentions. Changes in alternative splicing are also observed in several age-related diseases. Modulation of specific splicing factors has been shown to increase lifespan in model organisms, and splicing appears to be modulated in model organisms during dietary restriction and mTOR inhibition, two known lifespan-promoting interventions.

Determining the cause of this increased incidence of aberrant splicing is currently impossible. One hint is the presence of genes associated with DNA repair and DNA damage response. The idea that DNA alterations cause aging is one of the most classic theories of aging, and DNA damage is a hallmark of aging. It is possible, therefore, that damage to DNA is leading to aberrant splicing. Indeed, there seems to be a connection between RNA splicing and DNA damage response, even at the transcriptional level.

From the results described here, it is reasonable to imagine a scenario in which the age-associated increase in aberrant mRNAs, proteins, and eventually organelles, which were negatively affected by malfunctioning proteins, may impose significantly on catabolic processes such as RNA catabolism, protein catabolism, and autophagy. Lifespan extension by mTOR inhibition may thus be working by inducing the clearance of these defective components. Since these clearance mechanisms seem upregulated with age, mTOR inhibition is enhancing a naturally occurring attempt at adaptation by the cells.

Link: https://doi.org/10.18632/aging.206347

The composition of the gut microbiome changes with age in ways that harm long-term health, via growth in inflammatory species versus loss of species producing beneficial metabolites. This is well demonstrated in a range of species, including extensive human data. Presently widely available probiotic and prebiotic approaches only produce short-term adjustment in the balance of microbial popultions, but there are a few alternative approaches to adjust the gut microbiome that do produce permanent change with a single course of treatment. One of these is fecal microbiota transplantation. In animal studies, fecal microbiota transplantation from young donors to aged animals rejuvenates the composition of the gut microbiome, improves health, and extends life span.

Data suggests that some age-related conditions are associated with an altered gut microbiome, including Alzheimer's disease and Parkinson's disease. Interestingly, Parkinson's disease includes intestinal symptoms such as constipation that have motivated researchers to conduct some small trials of fecal microbiota transplantation; neurological symptoms of the condition were also improved as a result. Beyond this there is as yet little clinical evidence for effects of fecal microbiota transplantation in the context of aging. More data would be very useful, as this form of therapy is readily conducted, costs little, and certainly could be more widely used than is presently the case given a larger body of supporting evidence.

The application of fecal microbiota transplantation in Parkinson's disease

Parkinson's disease (PD) is a multisystem neurodegenerative disorder characterized by the aggregation of α-synuclein (α-syn) in dopaminergic neurons of the substantia nigra. The pathogenesis of PD remains incompletely understood, and disease-modifying therapies are lacking. Emerging evidence suggests that gut microbiota and their metabolites influence both intestinal and central nervous system (CNS) functions via the microbiota-gut-brain axis (MGBA). Recent studies have identified dysbiosis in the gut microbiota of PD patients, which may contribute to disease progression through two primary mechanisms: First, increased intestinal permeability, allowing pro-inflammatory factors and microbial metabolites to affect the enteric nervous system (ENS) and subsequently spread to the CNS via the vagal neurons; Secondly, disruption of the Blood-Brain barrier (BBB), leading to neuroinflammation and aberrant α-syn aggregation, ultimately resulting in dopaminergic neuron degeneration.

Fecal microbiota transplantation (FMT) has demonstrated significant efficacy in alleviating PD-associated constipation, characterized by an increased abundance of Firmicutes and decreased proportions of Proteobacteria and Bacteroidetes in treated patients. These microbial compositional changes correlate with effective amelioration of both constipation and tremor symptoms. In 2021, a study demonstrated that FMT significantly reduces Bacteroides abundance while increasing Prevotella and Blautia populations in PD patients with constipation. These microbial alterations were associated with marked improvements in PD symptoms. Another group conducted colonoscopic infusion of donor FMT in six PD patients, demonstrating significant improvements in motor symptoms, non-motor symptoms, and constipation over a six-month observation period. In 2024 researchers conducted a nasoduodenal FMT trial involving 43 early-stage PD patients. Post-transplantation assessments revealed significant improvements in both motor symptoms and constipation compared to baseline. Notably, the study also demonstrated FMT-mediated enhancement of cognitive functions, including amelioration of anxiety, depressive symptoms, and sleep disturbances.

Sensors such as cGAS in the cell evolved to detect invading pathogens and then interact with inflammatory regulators such as STING to produce an appropriate response. With age, however, many of the dysfunctions that arise in a cell can produce a maladaptive response on the part of cGAS and STING. The example noted here is the activation of dormant transposons in the genome, a feature of aging that emerges as epigenetic control over the structure of nuclear DNA and expression of nuclear genes changes for the worse. Retrotransposons like LINE-1 make up a sizable fraction of the genome as a result of their ability to copy themselves. They are most likely the remnants of ancient viral infections, important in aging as they become active, and likely important as a source of evolutionary change to genetic sequences as well. Retrotransposons can cause harm not just by damaging the genome as they copy themselves, but also via inflammatory reactions on the part of cGAS, STING, and other mechanisms evolved to react to anything that looks like viral machinery.

Aging is characterized by systemic inflammation and progressive cognitive decline, yet the molecular pathways linking peripheral aging signals to central nervous system dysfunction remain elusive. Here, we identify plasma extracellular vesicle (EV)-derived long interspersed nuclear element-1 (LINE-1) RNA as a potent systemic aging factor mediating neuroinflammation and cognitive impairment in humans and mice.

Plasma EV LINE-1 RNA levels markedly increase with age and strongly correlate with established brain aging biomarkers, including neurofilament light chain (NFL). Utilizing mouse models, we demonstrate that EVs from aged individuals penetrate the blood-brain barrier, deliver LINE-1 RNA to microglia, and initiate cGAS-STING signaling, leading to pronounced neuroinflammation, neuronal damage, and impaired cognition.

Pharmacological blockade of LINE-1 reverse transcription by 3TC or inhibition of STING signaling with H151 significantly ameliorates these age-associated deficits. Notably, aged peripheral tissues, especially brain and lung, emerge as primary sources of pro-aging EVs enriched with LINE-1 RNA, revealing a novel mechanism of inter-organ communication in aging. Our findings position EV-derived LINE-1 RNA and its downstream cGAS-STING pathway as critical systemic drivers of brain aging, presenting promising therapeutic targets for mitigating cognitive decline and age-related neurodegenerative diseases.

Link: https://doi.org/10.1111/acel.70350

Researchers here discuss what is known of the bidirectional relationship between the aging of skeletal muscle and the aging of the gut microbiome. Muscle tissue is metabolically active, generating myokine signals influential on other tissues. This signaling is far from fully mapped, but is known to be important to health, such as via mediating some of the benefits of exercise. Myokine signaling can also affect the composition of the gut microbiome. In turn, changes in the gut microbiome can contribute to the characteristic loss of muscle mass and strength that takes place with advancing age via increased inflammatory signaling or reduced generation of beneficial metabolites known influence muscle metabolism, such as butyrate.

The interplay between gut microbiota and sarcopenia has emerged as a cutting-edge research topic in the medical field, garnering significant attention. Sarcopenia is an age-related syndrome characterized by a progressive decline in skeletal muscle mass, strength, and function, which profoundly impacts the quality of life in older adults and imposes substantial socioeconomic burdens on many counties. Accumulating evidence indicates that alterations in the gut microbiota are not only linked to various intestinal disorders but also to aging-associated conditions, such as sarcopenia.

The gut microbiota plays a pivotal role in regulating skeletal muscle homeostasis via its metabolic products and is increasingly recognized as a potential pathophysiological factor contributing to sarcopenia development. Skeletal muscle, functioning as both a motor and endocrine organ, secretes myokines that exert critical regulatory effects on the gut microbiota. In sarcopenic individuals, reduced secretion of myokines correlates with decreased microbial diversity and compositional shifts, marked by diminished beneficial microbes and increased potentially harmful species. This establishes a vicious cycle of gut dysbiosis-sarcopenia-gut dysbiosis.

Modulation of the gut microbiota has been demonstrated to enhance muscle mass and function in elderly patients with sarcopenia. Metabolites derived from the gut microbiota, such as amino acids, lipopolysaccharides, and short-chain fatty acids, are known to modulate skeletal muscle protein metabolism by influencing anabolic and catabolic pathways. Nevertheless, the bidirectional mechanisms underlying the relationship between gut microbiota and age-related sarcopenia remain incompletely understood.

Link: https://doi.org/10.3389/fmicb.2025.1638880

Calcification of tissues involves the inappropriate deposition of calcium structures. It is a feature of aging in the cardiovascular system particularly, where calcification contributes to stiffening and dysfunction of tissues. Calcification proceeds alongside the development of atherosclerotic plaque, and thus has long been used as a marker to assess the extent of atherosclerotic cardiovascular disease, but it is a distinct mechanism and pathology. Two people with the same degree of vascular thickening and plaque development can have quite different degrees of calcification.

At the present time there is little that can be done about calcification of blood vessel walls and structures of the heart. As for many aspects of aging, there is evidence for some approaches to be able to modestly slow the progression of calcification, but means of robust and sizable reversal of calcification have yet to be developed. The best widely available approach achieved to date is EDTA chelation therapy, and this is nowhere near as effective or reliable as one might hope it to be.

In today's open access paper, researchers discuss the role of sirtuins in the mechanisms thought to be involved in modest slowing of vascular calcification. The primary point of focus is the long-standing antidiabetic drug metformin, and thus much of the data is derived from diabetic patients and mice. The likely effect sizes are small, and may be more relevant to a diabetic aging metabolism than to a normal aging metabolism. All in all, this is of more academic interest to those following the ongoing story of research into sirtuins than it is of relevance to efforts to treat aging as a medical condition.

Mechanism and treatment of Sirtuin family in vascular calcification

The SIRT family has shown potential in alleviating vascular aging by inhibiting inflammation, reducing endoplasmic reticulum stress, lowering mitochondrial oxidative stress, and promoting DNA damage repair, all of which contribute to the suppression of vascular calcification. Notably, SIRT1, SIRT2, SIRT3, SIRT6, and SIRT7 have demonstrated therapeutic potential in the treatment of vascular calcification (VC). The occurrence of VC involves the participation of multiple factors, primarily attributed to the abnormal deposition of calcium and phosphorus in the vascular wall. This article primarily discusses how the SIRT family can ameliorate VC through various.

Recently, some studies have confirmed that ferroptosis can promote VC, indicating that metformin may alleviate the development of hyperlipidemia-associated VC by inhibiting ferroptosis. Ferroptosis is a form of cell death characterized by iron-dependent lipid peroxidation, regulated by multiple pathways, including redox balance, lipid metabolism, and energy metabolism. Metformin enhances autophagy and inhibits abnormal cell proliferation through the AMPK/SIRT1-FoxO1 pathway, thereby mitigating oxidative stress in diabetic nephropathy. Previous studies have demonstrated that metformin can increase the expression of SIRT3 and GPX4, significantly elevate the levels of phosphorylated mTOR and phosphorylated AMPK, and improve polycystic ovary syndrome in mice by inhibiting ovarian ferroptosis.

SIRT proteins may serve as crucial intermediates for metformin's inhibition of ferroptosis-related vascular calcification. They play a synergistic role by regulating the antioxidant system, iron metabolism, and cellular phenotype transformation. Future research should concentrate on specific activation strategies for SIRT proteins, such as selective agonists, to enhance the targeted therapeutic effects of metformin.

Hesperidin has been shown to prevent the development of calcific aortic valve disease via the SIRT7-Nrf2-ARE axis. Future studies could further investigate the SIRT family's pathways that inhibit VC through ferroptosis. Moreover, the SIRT family influences VC through various signaling pathways, including the Wnt/β-catenin, Runx2, NF-κB, and JAK/STAT pathways, as well as the AMPK signaling pathway. Additionally, the role of the SIRT family in VC is noteworthy, with current research primarily focusing on SIRT1, SIRT2, SIRT3, SIRT6, and SIRT7, while the functions of other SIRT proteins in VC remain to be explored. Clinically, it has been observed that a significant number of patients requiring coronary intervention exhibit multiple calcifications in the vessel walls; thus, investigating methods to prevent and delay the progression of VC is a promising area for future research.

Longevity has always been a matter of interest, but absent an earnest scientific endeavor focused on intervention in aging it remained in the realm of fantasy, fraud, and futile wishes. That scientific endeavor was late in arriving, this delay largely the result of a cultural battle spanning the late 20th century that took place between the founders of modern anti-aging clinical practices and supplement industry companies on the one side versus the aging research community on the other. Only over the last thirty years has a scientific community finally emerged to earnestly and openly focus on treating aging as a medical condition.

The pursuit of youth and longevity has accompanied human societies for millennia, evolving from mythological and esoteric traditions toward a scientific understanding of aging. Early concepts such as Greek ambrosia, Taoist elixirs, and medieval "aqua vitae" reflected symbolic or spiritual interpretations. A major conceptual transition occurred between the late nineteenth and early twentieth centuries, when aging began to be framed as a biological process. Pioneering ideas by Metchnikoff, together with early and sometimes controversial attempts such as Voronoff's grafting experiments, marked the first efforts to rationalize aging scientifically. In the mid-twentieth century, discoveries including the Hayflick limit, telomere biology, oxidative stress, and mitochondrial dysfunction established gerontology as an experimental discipline.

Contemporary geroscience integrates these insights into a coherent framework linking cellular pathways to chronic disease risk. Central roles are played by nutrient-sensing networks such as mTOR, AMPK, and sirtuins, together with mitochondrial regulation, proteostasis, and cellular senescence. Interventions, including caloric restriction, fasting-mimicking diets, rapalogues, sirtuin activators, metformin, NAD+ boosters, senolytics, and antioxidant combinations such as GlyNAC, show consistent benefits across multiple model organisms, with early human trials reporting improvements in immune function, mitochondrial activity, and biomarkers of aging. Recent advances extend to epigenetic clocks, multi-omic profiling, gender-specific responses, and emerging regenerative and gene-based approaches. Overall, the evolution from historical elixirs to molecular geroscience highlights a shift toward targeting aging itself as a modifiable biological process and outlines a growing translational landscape aimed at extending healthspan and reducing age-related morbidity.

Link: https://doi.org/10.3390/molecules30244728

Aging clocks are a way to obtain a measure of the state of biological age, the burden of damage and dysfunction that causes age-related disease and mortality. A wide variety of clocks have been developed, but this technology has yet to realize its full promise, which is to be used as a standardized measure of the efficacy of potential age-slowing and age-reversing therapies. If researchers had a robust, reliable way to immediately assess the quality of a therapy, it would dramatically speed research, and focus progress on the best classes of therapies. We might ask why aging clocks have yet to provide this capacity; the article here looks at this question and what needs to be done in order to realize this goal.

What you want to do is what drives decision-making and sets the goalposts. So let's look at the intended uses for aging clocks: (1) R&D: You want to do experiments to understand biology and/or find new candidate therapies, and avoid waiting for aging and death as your readouts. (2) Consumer health optimization: You want to monitor and probability optimize your health. You'll do measurements at regular intervals, and change your behavior by whether the clock goes up or down. (3) Design and interpret clinical trials: You want to select who goes into your trial, or identify people who respond better or worse to some treatment, purely for your own learning. (4) FDA approval: You want to run a clinical trials and get Accelerated Approval from the FDA based on lowering clock scores, ahead of showing improvements in mortality or disease. (5) Medical care: You want to run tests know whether prescribed medicines and behaviors are working. Wrong results are a big deal, as they could lead to wrong treatments (and, in the US, lawsuits galore).

It's telling that today, aging clocks are frequently used for the first two purposes but approximately never for the last three (where the cost of being wrong is high). Evidently, people in charge of these costly decisions do not think that aging clocks are ready to use. Why is that? The original clocks were strictly correlated to chronological age, which is not a very useful thing to estimate. But later clocks have been trained to predict mortality, frailty, and other important outcomes. So the answer must be that we can't yet trust their predictions.

Bold research has given us a proof of concept that the aging process can be tracked with molecular measurements. We should appreciate that. And we should acknowledge that we won't benefit much from talking about clocks' potential for practical uses until we're able to properly benchmark the required performance metrics. So let's decide on the uses we think are most valuable, and make sure we build the infrastructure to track where we are now and whether we're improving. Funding such a clock assessment program is the highest leverage in longevity. Between accelerating R&D and eventually enabling human trials, good clocks are very much worth pursuing.

Link: https://norngroup.substack.com/p/do-we-have-a-useful-aging-clock

Disruption of the regulation of circadian rhythms is a known feature of aging. As for everything to do with our biochemistry, this disruption of the circadian clock is complicated. As a starting point, there isn't just one clock. The brain runs clocks, the periphery runs more clocks, and they coordinate with one another via signaling. That coordination breaks down with age, because everything breaks down with age in one way or another, as damage and dysfunction accumulates. We can also discuss whether the various clock mechanisms that sense aspects of the environment function correctly in later life, whether the appropriate signaling is still generated in the right way, whether the receptors for those signals still operate correctly to generate the appropriate cell and tissue responses, and so forth. There are many points at which normal function can be eroded as damage mounts - and it clearly is eroded in the old.

Today's open access paper presents a novel way of looking at how the disruption of the circadian clock may contribute to age-related disease, specifically the risk of neurodegenerative disease in this case. The researchers used study data on movement and heart activity to characterize individual variations in the resilience of the circadian clock to alterations in the environment. An older person who is more affected by the environment is said to have a weak clock, whereas one who is less affected by changes in the environment has a strong clock. A strong clock correlates with a lower risk of dementia. This says little about causation, of course. The same accumulating cell and tissue damage of aging may provoke weakness in the circadian clock at the same time as it contributes to neurodegeneration. That weak clocks correlate with risk of dementia may just be pointing out that people with a greater burden of damage are more impacted than those with less of a burden of damage.

Do our body clocks influence our risk of dementia?

Circadian rhythm is the body's internal clock. It regulates the 24-hour sleep-wake cycle and other body processes like hormones, digestion, and body temperature. It is guided by the brain and influenced by light exposure. With a strong circadian rhythm, the body clock aligns well with the 24-hour day, sending clear signals for body functions. People with a strong circadian rhythm tend to follow their regular times for sleeping and activity, even with schedule or season changes. With a weak circadian rhythm, light and schedule changes are more likely to disrupt the body clock. People with weaker rhythms are more likely to shift their sleep and activity times with the seasons or schedule changes.

A new study involved 2,183 people with an average age of 79 who did not have dementia at the start of the study. Researchers reviewed heart monitor data for various measures to determine circadian rhythm strength. These measures included relative amplitude, which is a measure of the difference between a person's most active and least active periods. High relative amplitude signified stronger circadian rhythms.

Researchers divided participants into three groups, comparing the high group to the low group. A total of 31 of 728 people in the high group developed dementia, compared to 106 of the 727 people in the low group. After adjusting for factors such as age, blood pressure, and heart disease, researchers found when compared to people in the high group, those in the low, weaker rhythm group had nearly 2.5 times the risk of dementia, with a 54% increased risk of dementia for every standard deviation decrease in relative amplitude.

Association Between Circadian Rest-Activity Rhythms and Incident Dementia in Older Adults

Aging is associated with changes in circadian rhythms. Rest-activity rhythms (RARs) measured using accelerometers are markers of circadian rhythms. Altered circadian rhythms may be risk factors of neurocognitive outcomes; however, results are mixed. This was a retrospective examination of data from the Atherosclerosis Risk in Communities (ARIC) study. ARIC participants who wore the a long-term continuous monitoring patch in 2016-17 for ≥3 days and were free of prevalent dementia were included. RARs were derived from investigational accelerometer data from the patch.

Of the 2,183 participants (age 79 ± 4.5 years), 176 (8%) developed dementia. The median follow-up time was 3 years, and the mean patch wear time was 12 days. After multivariable adjustment, each 1 standard deviation decrement in relative amplitude and 1-SD increment in intradaily variability were associated with 54% and 19% greater risk of dementia, respectively. Further research to determine whether circadian rhythm interventions can reduce dementia risk is warranted.

Exercise and physical fitness has been shown to reduce the predicted biological age generated by various epigenetic clocks. Researchers here provide evidence for some of this effect to be mediated by a reduction in inflammatory signaling, also well known as an outcome of exercise and physical fitness. Chronic inflammation is harmful to tissue structure and function, and is also a feature of aging and age-related disease. To the degree that long-term inflammatory signaling unrelated to injury and infection can be minimized, the results should be improved health and modestly slowed aging.

Physical activity (PA) is recognized as a cornerstone of healthy aging, yet the molecular mechanisms linking PA to biological aging remain poorly understood. DNA methylation (DNAm)-based biological aging indicators, such as PhenoAge, provide a means to assess the relationship between PA and aging at the molecular level.

β2-microglobulin (β2M) is elevated in states of chronic inflammation and is implicated in immune senescence. Elevated levels are detected in the plasma and cerebrospinal fluid of aged mice and older adults. This study analyzed data from 936 participants in the U.S. population, assessing associations between PA, β2M levels, and PhenoAge.

Our study showed that increased PA was significantly associated with lower β2M levels, and mediation analysis revealed that reductions in β2M explained 37.67% of the association between PA and PhenoAge. These results align with findings that PA mitigates inflammation by reducing pro-inflammatory cytokines and improving immune function. Importantly, the direct effect of PA on PhenoAge remained significant even after accounting for β2M, suggesting additional pathways through which PA exerts anti-aging effects, such as epigenetic regulation or mitochondrial function.

Link: https://doi.org/10.1016/j.jare.2025.11.047

Retro Biosciences was one of the more comprehensively funded companies in the longevity industry at launch, and has pursued a number of different programs. The first program to reach an initial clinical trial is a small molecule drug to upregulate autophagy, a goal pursued by a wide range of programs, most notably those focused on mTOR inhibitors and related calorie restriction mimetics. Increased autophagy should modestly slow aging, though as always the size of the effect is a guess until human data emerges - and that might take a while. Rapamycin upregulates autophagy, has long been known to do that, costs little, and we still have no idea what it does to the pace of aging in humans.

Longevity biotech Retro Biosciences has achieved its goal of becoming a clinical-stage company in 2025, after dosing the first participant in a clinical trial of its autophagy-focused drug candidate. Retro's clinical drug candidate, RTR242, is a small-molecule therapy designed to restore lysosomal function, a core component of autophagy - our cells' waste-handling and recycling system. In healthy, younger cells, lysosomes maintain an acidic environment that allows the autophagy process to break down damaged proteins and cellular debris. As people age, and particularly in neurodegenerative diseases such as Alzheimer's, lysosomes lose acidity and efficiency. The result is a buildup of toxic protein aggregates that place chronic stress on neurons and contribute to their dysfunction and eventual loss. Retro's approach aims to repair this decline at its source, reactivating the cell's own cleanup machinery rather than targeting the problem downstream.

The Phase 1 study is a randomized, double-blind, placebo-controlled trial in healthy volunteers, conducted at a specialized early-phase clinical unit in Australia. In addition to standard safety and tolerability measures, the study includes exploratory biomarkers tied to autophagy and lysosomal biology, giving Retro its first opportunity to observe whether its mechanistic hypotheses translate into measurable biological signals in humans. Failures in cellular clearance are a common feature across many degenerative conditions, so if the biology proves tractable in humans, the hope is that the approach could have applications beyond neurodegeneration, informing approaches to other disorders where accumulated cellular damage plays a central role.

Link: https://longevity.technology/news/retro-bio-commences-first-in-human-trial/

As you may know, there are significant differences in incidence and outcomes of Alzheimer's disease between the sexes. In research, differences of this nature can help in developing a better understanding of which mechanisms are more versus less important in the disease process, and so guide efforts to produce therapies. The biochemistry of the brain is enormously complex, and thus so is the pathology of Alzheimer's disease. It remains the case that decades of research cannot do any better than practical experimentation when it comes to determining which mechanisms cause the most harm. See the present focus on clearance of amyloid-β aggregates from the brain, for example. Only once the necessary immunotherapies existed could the research community determine that amyloid-β aggregates are not as important as hoped in the pathology of the condition.

The focus of today's open access paper is largely the role of inflammatory, dysfunctional microglia in Alzheimer's disease, and whether this provides a sizable contribution to sex differences in disease outcomes. The role of microglia in Alzheimer's disease is a growing area of research interest that seems likely to lead to novel therapies and initial clinical trials in the years ahead. Microglia are innate immune cells of the central nervous system, somewhat analogous to the macrophages found elsewhere in the body. In addition to attacking pathogens and destroying unwanted cells, they are also involved in regeneration and maintenance of nervous system tissue, including some of the changes to neural circuits needed for learning and memory. When microglia become overly inflammatory, it is harmful to the structure and function of the brain.

Microglial interferon signaling and Aβ plaque pathology are enhanced in female 5xFAD Alzheimer's disease mice, independent of estrous cycle stage

Alzheimer's disease (AD) presents with a sex bias in which women are at higher risk and exhibit more rapid cognitive decline and brain atrophy compared to men. Microglia play a significant role in the pathogenesis and progression of AD and have been shown to be sexually differentiated in health and disease. Whether and how microglia contribute to the sex differences in AD remains to be elucidated. Herein, we characterized the sex differences in amyloid-beta (Aβ) plaque pathology and microglia-plaque interaction using the 5xFAD mouse model and revealed microglial transcriptomic changes that occur in females and males.

Despite women with symptomatic late-onset AD being in the post-menopausal stage, metabolic and pathological changes are seen prior to menopause. For this reason, and because Aβ pathology develops decades prior to clinical presentation, we focused on two hormonally distinct stages of the female rodent estrous cycle (proestrus and diestrus). Our results showed that Aβ plaque morphology is sexually distinct, with females having greater plaque volume and lower plaque compaction compared to males of the same age. Neuritic dystrophy was also increased in female 5xFAD mice, independent of estrous cycle stage. While microglia transcriptomes were not overtly different at the proestrus or diestrus stages, female 5xFAD microglia upregulated genes involved in glycolytic metabolism, antigen presentation, disease-associated microglia, and microglia neurodegenerative phenotype compared to males, some of which have been previously reported.

In addition, we found a novel female-specific enhancement of IFN signaling in microglia, as evidenced by a striking proportion of differentially expressed type 1 interferon genes characteristic of interferon-responsive microglia (IRM). Finally, we validated our transcriptomic results at the protein level and observed that female 5xFAD mice had an enrichment in Aβ+ IRMs compared to males. Collectively, we show that there are sex-specific alterations in Aβ plaque morphology and that endogenous hormonal fluctuations across the estrous cycle do not overtly affect Aβ pathology or microglial transcriptomic profiles. Furthermore, our study identifies a novel sex-specific enhancement of interferon signaling in female microglia responding to Aβ, which may constitute a new therapeutic target for personalized medicine in AD.

Cystathionine γ-lyase (CSE) levels are reduced with age, and researchers here show that removing CSE entirely in mice reproduces aspects of brain aging. That isn't enough to prove that the smaller reductions that take place with age do in fact make a meaningful contribution to neurodegeneration, but it is sufficient to justify greater attention and further research into to the mechanisms involved. The researchers chose to focus on CSE because it is involved in the production of hydrogen sulfide (H2S) in the brain. You may recall that the ability of increased H2S to be somewhat protective in the context of aging, such as via effects on inflammation and autophagy, has grown as a topic of interest in recent years. It is hard to effectively deliver H2S to the brain, however, as both normal and beneficial levels are very low; it is arguably better to try to adjust the operation of the biochemistry responsible for producing H2S instead.

Once considered to function predominantly in the peripheral systems, cystathionine γ-lyase (CSE) is emerging as a key player in neuroprotection. Prior studies had considered cystathionine β-synthase (CBS) to be the principal enzyme governing H2S signaling in the brain. In this study, through an integrated approach combining genetic, proteomic, biochemical, and behavioral studies, we demonstrate that CSE is crucial for maintaining brain homeostasis and that loss of CSE is sufficient to trigger cognitive deficits.

CSE, the enzyme responsible for neuronal cysteine and hydrogen sulfide production, is dysregulated in aging and neurodegenerative diseases including Alzheimer's disease and Huntington's disease, both marked by cognitive decline in addition to motor deficits. To determine whether CSE loss directly causes cognitive decline, we genetically ablated CSE in mice. This loss was sufficient to induce oxidative damage, compromise blood-brain barrier integrity, impair neurogenesis and neurotrophin signaling, and elicit cognitive deficits. Global proteomic analysis further revealed molecular alterations that contribute to impaired neurogenesis.

Our findings establish CSE as an essential guardian of homeostatic brain health and identify it as a potential therapeutic target for neurodegenerative disorders.

Link: https://doi.org/10.1073/pnas.2528478122

Treatment immediately following stroke is not the most obvious path to take for the clinical development of therapies intended to improve drainage of cerebrospinal fluid via the glymphatic system, but nonetheless that is the approach taken by the research program noted here. A range of compelling evidence points to age-related impairment of the drainage of cerebrospinal fluid from the brain as an important issue, but is largely focused on the slow development of neurodegenerative conditions as a result of the buildup of metabolic waste in the brain. The immediate aftermath of a stroke is a very different scenario, amenable to different approaches to improvement of drainage channels, such as the non-invasive devices proposed here that would probably be infeasible for long-term use.

The "brain-draining lymphatics" are a set of drainage pathways that clear waste from the brain, with dysfunction of this "clean-up and drainage network" linked to Alzheimer's disease and other neurological and neurodegenerative diseases (NNDs). Researchers found that improving brain-draining lymphatic function can boost recovery following ischemic stroke and are now developing non-invasive devices that help the neck's lymphatic vessels pump more effectively, improving the clearance of excess fluid and harmful waste from the brain right after stroke has occurred - at a time when every second counts.

The researchers are also using advanced imaging techniques to study the brains of 140 participants. Initial studies have found that women have less lymphatic vessel coverage in the brain's outer layer compared to men, potentially leading to less efficient waste drainage and explaining why women are at higher risk or have worse outcomes for many NNDs, including stroke and Alzheimer's disease. "The brain was considered to be devoid of a lymphatic system. It wasn't until 2015 that two separate teams discovered that lymphatics in the brain's outer layer transport fluid and waste products from the brain to lymphatic vessels in the neck. We now know that this system plays a crucial role in keeping the brain healthy. By boosting this natural clean-up system, we hope to change how ischemic stroke and other NNDs are treated."

Link: https://www.monash.edu/news/articles/scientists-unlock-brains-natural-clean-up-system-to-develop-new-treatments-for-stroke-and-other-neurological-diseases

The overt manifestations of the aging of hair follicles, going gray and losing hair, often appear to bother people to a greater degree than the impending failure of their internal organs. In principle a sufficient understanding of the mechanisms of aging should lead to ways to avoid both outcomes. Rejuvenation therapies that repair the cell and tissue damage of aging should do as much for hair as for any other part of the body. Under the hood, however, there is still the matter of the ferocious complexity of cellular biochemistry and its changes with age. A hair follicle is not like a muscle fiber or a glomular unit of the kidney or a portion of a neural network in the brain. These are all made of cells, but completely different in the details of their responses to the damage that is characteristic of aging.

As illustrated by the fact that effective therapies to address hair aging do not yet exist, the research community does not fully understand the ways in which the processes of hair growth and coloration run awry with age. Hair growth is quite complex. It is not a continuous process, but one that proceeds in phases of communication between cells of various types that make up a hair follicle. Different cells do different things at different times and in different locations in the follicle - and this can all be impaired in any number of ways. In response to this sort of challenge, the research community settles into a mode of gathering ever more detailed data, in search of patterns that might lead towards greater understanding and points of intervention.

Single-cell RNA sequencing profiles age-related transcriptional landscapes in human hair follicle cells

Hair loss and graying, the earliest visible signs of skin aging, are driven by the functional decline of hair follicle stem cells and their niches. To elucidate the transcriptional mechanisms involved in scalp aging, we conducted a comprehensive analysis of human scalp samples using single-cell RNA sequencing and spatial transcriptomic technologies. Our study profiled the transcriptomes of 57,181 cells from scalp samples obtained from four young, six middle-aged, and one elderly individual. The integrated bioinformatic pipeline included cell clustering, spatial deconvolution, pseudotime trajectory, as well as cell-type specific gene expression, and intercellular communication analysis. An additional 92 volunteers were included, comprising 90 (37 young, 27 middle-aged, and 26 elderly) for trichoscopic examination, one young individual for senescence-associated β-galactosidase (SA-β-gal) staining, and one elderly individual for both MKI67 immunofluorescence and SA-β-gal staining.

This approach led to several key findings: we identified three subtypes of mitotic keratinocytes that localized in the interfollicular epidermis (IFE), outer root sheath (ORS), and hair matrix, with pseudotime trajectory further confirming their transitional stage. Furthermore, in middle-aged scalps, we observed activated activator protein 1 (AP-1) transcription factor complex in keratinocytes, upregulated DCT gene in melanocytes, and decreased bone morphogenetic protein (BMP) and noncanonical wingless/integrated (ncWNT) signaling in dermal papilla (DP)-keratinocytes cross-talk.

In the age-associated analysis of single-cell transcriptomics, AP-1 activation emerged as a hallmark of middle-aged hair follicle and epidermal cells, consistent with its known role in chromatin remodeling and senescence-associated transcriptional reprogramming. The downstream targets of AP-1 - such as MYC, SOCS3, DUSP1, NR4A1, and NFKBIA - form an intricate regulatory network that influences cell cycle progression, inflammatory responses, and stem cell depletion. This coordinated regulation reflects a dynamic cellular strategy in aging skin - balancing stem cell activation and stress adaptation while restraining excessive proliferative and inflammatory signaling to maintain tissue homeostasis. In addition, DCT was upregulated in melanocytes in the middle-age group, suggesting overactive melanin synthesis caused by inflammaging. Future studies leveraging in vivo and in vitro human hair follicle models are essential to elucidate the causal role of this AP-1-centered network and to evaluate whether targeting AP-1 or its downstream pathways could delay stem cell depletion and offer novel therapeutic avenues for age-related hair loss and graying.

Any broad consideration of exosomes is entirely too broad to fit in one paper. Exosomes are one category of extracellular vesicles, membrane-wrapped packages of molecules released by cells as a part of cell to cell communication. At this point the diversity of extracellular vesicles and circumstances leading to their generation and selection of specific contents are not well mapped, but nonetheless one major component of ongoing research is to establish sources of exosomes or other vesicles that can be used as a basis for therapy. It is well understood at this point that the benefits of stem cell transplantation emerge from the signals produced by the transplanted cells in the short time they survive. Harvesting extracellular vesicles from stem cells in culture and then infusing these vesicles instead of the cells produces similar outcomes in preclinical studies, but is logistically easier to manage. Developers are moving towards formal clinical trials, while extracellular vesicle treatments are already widely available via medical tourism and other avenues.

Aging is accompanied by a gradual decline in physiological resilience and an increased risk of chronic diseases collectively known as age-related disorders, including neurodegeneration, cardiovascular disease, and osteoarthritis. Exosomes, nano-sized extracellular vesicles, have emerged as critical mediators in the aging process and related pathologies. By moving bioactive cargo such as proteins, lipids, and mRNAs exosomes facilitate intercellular communication and modulate processes central to aging, including inflammation, immune response, senescence, and tissue repair.

Exosomes contribute to "inflamm-aging," influence stem cell function, and reflect age-associated molecular alterations, positioning them as potential biomarkers for early diagnosis and disease monitoring. Understanding dual role of exosomes as both contributors to aging and platforms for intervention offers new avenues for promoting healthy longevity and mitigating the burden of age-associated diseases. Also, their inherent stability, low immunogenicity, and capacity for targeted delivery make exosomes promising candidates for therapeutic applications in regenerative medicine and anti-aging interventions.

This review synthesizes current knowledge on exosome biogenesis, composition, and functional roles in aging and age-related diseases. We discuss emerging evidence supporting their use as diagnostic and prognostic tools and their potential in cell-free therapies aimed at modulating age-related decline. Despite their promise, several challenges impede clinical applications. Addressing these limitations will be essential to fully harnessing the therapeutic potential of exosomes in aging. Notwithstanding these obstacles, exosomes exhibit significant potential for personalized and combinatorial therapies. Understanding the dual role of exosomes as both contributors to aging and tools for its modulation may open new avenues for interventions to promote healthy longevity.

Link: https://doi.org/10.1186/s12967-025-07379-1

Researchers here present indirect evidence for the toxic aggregation of amyloid-β and tau protein in the aging brain to drive the accumulation of white matter hyperintensities seen in brain imaging. These hyperintensities are areas of damage, resulting from a range of causes that include rupture of blood vessels, localized inflammatory response, and more. The more white matter damage in the brain, the worse the outcome in terms of cognitive loss and progression of neurodegenerative conditions.

White matter hyperintensities (WMHs) are increasingly recognized as markers of cerebrovascular pathology in Alzheimer's disease (AD), yet their temporal relationship with amyloid and tau accumulation remains unclear. While previous studies suggest bidirectional associations between WMHs and AD pathology, regional associations between WMHs and AD pathology have yet to be examined. This study investigated the temporal and regional associations between PET measures of amyloid (Aβ) and tau pathology and WMH burden in older adults.

Baseline analyses revealed significant bidirectional associations between WMH burden and both Aβ and tau pathology, with stronger effects in posterior brain regions. Longitudinal analyses showed that baseline Aβ levels were associated with future WMH progression in frontal and occipital regions, while baseline tau was linked to WMH increases in frontal and parietal regions. However, baseline WMH burden was not associated with future accumulation of either Aβ or tau pathology in any region. These findings suggest that Aβ and tau pathology drive future WMH progression rather than the reverse, with distinct regional patterns for each pathology type.

Link: https://doi.org/10.64898/2025.12.18.25342588

Models are not reflections of real systems, but are better thought of as tools to help us understand how real systems might work under the hood. The production, assessment, and consideration of models over time helps researchers to constrain and guide research into real systems. Any individual model may not be all that helpful on its own. Certainly, its conclusions have to be considered in the context of the assumptions it makes and the behavior of different models in the same field.

Today's open access model discusses the Saturating-Removal model of aging, derived from observations of the growth in senescent cell burden with age and its contribution to degenerative aging. It is a form of damage accumulation model, perhaps more akin to reliability theory as applied to aging than other modeling in the field, though still quite different from that approach. The paper is an interesting read. As one might expect, the model of damage accumulation predicts that methods of damage repair - i.e. rejuvenation therapies that address issues such as senescent cell accumulation - will be needed to move the needle on human life span.

Maximal human lifespan in light of a mechanistic model of aging

There is a gap in understanding the rigidity of maximal human lifespan in terms of molecular and cellular mechanisms of aging. Despite advances in characterizing the molecular and cellular changes with age in humans and model organisms, it is unclear which mechanisms affect median and maximal lifespan differentially. For example, although it is often thought that aging is due to accumulating damage, it is not known how median and maximal lifespan are differentially affected by damage production rate, removal rate, stochastic noise, and threshold for death. Understanding which factors affect maximal lifespan may offer clues for future longevity interventions.

To address this, we applied an advance that links mechanistic aging processes to demographic variables such as median and maximal lifespan. This advance is a mathematical model of stochastic damage accumulation called the Saturating-Removal (SR) model (see chapter seven in Systems Medicine as a point of reference). The SR model was developed based on dynamics of senescent cells in mice and has since been shown to capture a wide range of aging patterns including the exponential rise in hazard with slowdown at old age, exponential disease incidence, effect of parabiosis, longevity interventions and their combinations, and aging differences between species. Recently, the model has been used to reexamine the heritability of human lifespan and provide insights into the compression of morbidity.

Here we show that variation in human lifespan is consistent with person-to-person differences in SR model parameters, subject to a strong constraint. Differences in damage production or removal rates greater than a few percent produce unrealistically long lifespans, whereas variation in threshold or noise preserves the observed upper limit near 120 years. This pattern is supported by analyses of NHANES exposure cohorts, centenarian sibling data, ages of the longest-lived individuals, and historical cohorts adjusted for extrinsic mortality. As a contrasting case, survival curves from Hutchinson-Gilford progeria - a disorder of accelerated aging due to nuclear lamina defects - indicate altered production dynamics.

Finally, we extended our analysis to additional mathematical models of aging and mortality and show that similar constraints apply. Together, these findings suggest that damage production and removal parameters in humans are tightly constrained with little person-to-person differences. Extending maximal human lifespan will require modifying the production or removal of aging-related damage, processes that appear largely unaffected by lifestyle, historical improvements, or common genetic variation.

Here find a tour of an aspect of mitochondrial structure that might be unfamiliar, the boundary between the inner and outer mitochondrial membranes and their features called the mitochondrial contact site and cristae organizing system (MICOS). It is of interest to the researchers here because their data shows that MICOS becomes particularly disarrayed in neurons exposed to Alzheimer's disease pathology, and mitochondrial dysfunction is a feature of Alzheimer's disease and aging more generally. Further research with a broader focus remains needed determine how this fits in to the present consensus on the age-related mitochondrial dysfunction that occurs throughout the body.

Mitochondrial contact site and cristae organizing system (MICOS) complexes are critical for maintaining the mitochondrial architecture, cristae integrity, and organelle communication in neurons. MICOS disruption has been implicated in neurodegenerative disorders, including Alzheimer's disease (AD), yet the spatiotemporal dynamics of MICOS-associated neuronal alterations during aging remain unclear. Using three-dimensional reconstructions of hypothalamic and cortical neurons, we observed age-dependent fragmentation of mitochondrial cristae, reduced intermitochondrial connectivity, and compartment-specific changes in mitochondrial size and morphology. Notably, these structural deficits were most pronounced in neurons vulnerable to AD-related pathology, suggesting a mechanistic link between MICOS disruption and the early mitochondrial dysfunction observed in patients with AD.

Our findings indicate that the loss of MICOS integrity is a progressive feature of neuronal aging, contributing to impaired bioenergetics and reduced resilience to metabolic stress and potentially facilitating neurodegenerative processes. MICOS disruption reduced neuronal firing and synaptic responsiveness, with miclxin treatment decreasing mitochondrial connectivity and inducing cristae disorganization. These changes link MICOS structural deficits directly to impaired neuronal excitability, highlighting vulnerability to AD-related neurodegeneration. These results underscore the importance of MICOS as a critical determinant of neuronal mitochondrial health and as a potential target for interventions aimed at mitigating AD-related mitochondrial dysfunction.

Link: https://doi.org/10.64898/2025.12.13.693635

It is well established that greater physical fitness correlates with improved late life health and greater life expectancy. Here researchers report a modest decrease in the predicted age produced by a proteomic aging clock following a 12 week program of exercise. This is much as one would expect given what we know about the effects of regular exercise on long-term health, coupled to the point that most people in the wealthier regions of the world exercise too little and suffer the consequences in the form of faster age-related degeneration and a greater risk of age-related disease. Matters tend to improve when you take those people and have them undertake a greater amount of exercise.

Biological aging varies between individuals and may be influenced by health behaviors. Using data from 45,438 UK Biobank participants, we found that a higher proteomic aging score (ProtAgeGap) was linked to lower physical activity and increased risk of type 2 diabetes. The UK Biobank cohort included both men and women. In a 12-week supervised exercise study (MyoGlu, NCT01803568) in 26 men, ProtAgeGap decreased by the equivalent of 10 months.

While most of the 204 proteins in the score remained stable, some, like CLEC14A, changed with exercise and were linked to improved insulin sensitivity. Transcriptomic data from muscle and fat tissue supported these protein-level changes, highlighting pathways, such as PI3K-Akt and MAPk signaling, involved in tissue remodeling and metabolism. Our findings suggest that while proteomic aging is mostly stable, it can be modestly reversed by exercise. Specific proteins within the signature may act as sensitive indicators of metabolic adaptation, supporting the idea that proteomic aging is a modifiable marker linked to lifestyle and disease risk.

Link: https://doi.org/10.1038/s41514-025-00318-w

At the high level, the lymphatic system has a lot in common with the vascular system. The cargo is lymph and immune cells rather than blood and immune cells, but the structure and function of vessels is quite similar. Both types of vessel are lined with endothelial cells, while a layer of smooth muscle manages contraction, dilation, and pulsation of vessels to manage volume, pressure, and fluid flow. Like blood vessels, lymphatic vessels exhibit dysfunction with age, such as in their ability to appropriately contract and dilate. This impairs fluid flow, producing a range of consequences. One of the more recently discovered issues is the impaired drainage of cerebrospinal fluid from the brain via the glymphatic system, a potentially important contribution to neurodegenerative conditions. There are others.

A great deal of effort has gone into developing drugs that influence the biochemistry regulating the action of smooth muscle in blood vessels, as this is one of the ways to force a reduction in high blood pressure. Now that researchers have compelling reasons to turn their focus towards analogous issues in the lymphatic system, there is a vast body of work to pull from, and many existing drugs and drug candidates to assess in animal studies. Interestingly, in today's open access paper, researchers report considerable success in restoring the contractility of lymphatic vessels in aged mice by exploiting a mechanism that doesn't occur in blood vessels. The results suggest that the specific approach taken should be developed and tested as a way to slow the onset of neurodegenerative conditions by restoring drainage of cerebrospinal fluid.

Selective Activation of NaV1.3 Restores Lymphatic Contractility in Age and Injury

Intrinsic lymphatic contractility is essential for tissue fluid balance, immunity, and organ function, yet no FDA-approved pharmacologic treatments specifically restore lymphatic contractility. Lymph is returned to the circulation by ion channel-driven cyclic contractions of collecting lymphatic vessels. Although voltage-gated sodium (NaV) channels drive cardiomyocyte excitability, their role in lymphatic muscle cell (LMC) physiology is not well defined. We identified NaV1.3 (also known as SCN3A), a NaV channel historically viewed as developmentally restricted and limited in adult tissues, as unexpectedly and selectively expressed in adult lymphatic muscle but absent from heart, vascular smooth muscle, and mature brain.

In mouse and human lymphatic vessels, NaV1.3 is expressed in adult LMCs. Although dispensable for basal lymphatic contractions, NaV1.3 acted as a pharmacologically recruitable reserve that amplified contractile output. Acute NaV1.3 activation with the NaV1.3-specific activator Tf2 (derived from scorpion venom) increased lymphangion ejection fraction and accelerated interstitial fluid clearance. Tf2 fully restored lymphatic pumping in aged mice and partially rescued radiation-induced contractile deficits. All Tf2 responses were abolished in NaV1.3 knockout mice, confirming NaV1.3 dependence.

In conclusion, NaV1.3 is a selectively druggable ion channel in adult lymphatic muscle that can be recruited to restore lymphatic pump function across aging and injury. Targeted NaV1.3 activation provides a molecular entry point for treating diseases characterized by lymphatic pump failure, a domain with no existing pharmacologic therapies.

Senescent cells accumulate with age as the immune system slows down and clears them less effectively. The immune system itself also accumulates senescent cells of various types. Once senescent, a cell ceases to replicate, grows in size, and generates pro-growth, pro-inflammatory signaling that becomes harmful when sustained over time. The more senescent cells in the body, the worse the outcome of this signaling; senescent cells are an important component of degenerative aging. Here, researchers focus on effector T cells, important to the immune response, and which become senescent in increasing numbers with age.

Senescent cells play important roles in various biological processes that promote fitness and health, however, their timely elimination by immune cells is critical to maintain tissue homeostasis and prevent disease. Despite this, senescent cells progressively accumulate systemically with age, suggesting that certain immune cells also become senescent and dysfunctional during aging. Supporting this, we previously demonstrated that CD8 T cells, immune cells capable of targeting senescent cells, increasingly develop characteristics of senescence with advancing age in humans.

Here, we further characterized the senescence state of human SA-βGal-expressing CD8 T effector cells, their functional capabilities, and their involvement in aging and disease. Single-cell RNA sequencing revealed that SA-βGal-expressing CD8 T cells with unique transcriptional signatures develop in all stages of T cell differentiation, including in effector memory (em) T cells.

SA-βGal-expressing CD8 Tem cells expressed various classical markers of senescence and were significantly impaired in their ability to proliferate, produce cytokines, and eliminate senescent human stromal cells, compared to CD8 Tem cells with low SA-βGal activity. Gene signatures of senescent SA-βGal-expressing CD8 Tem cells were enriched in CD8 T cells from older human donors, patients with age-related disorders, cancer, and smokers. Furthermore, our results demonstrate that T cell senescence is distinct from and dominant over T cell exhaustion, limiting the response of CD8 Tem cells to immunotherapy.

Link: https://doi.org/10.64898/2025.12.16.694716

Autophagy is the name given to an important collection of processes that identify broken and unwanted cellular structures and convey them to a lysosome, where they are broken down and recycled. The identification and conveyance differ greatly from target to target, but all of the specific forms of autophagy converge on delivery to a lysosome. Up to a point, more autophagy and more efficient autophagy improves cell function by clearing out damaged and dysfunctional structures and protein machinery. This in turn translates to a modest slowing of aging if sustained over time throughout the body, which is why the research community spends so much time focused on autophagy. Here, researchers discuss mitophagy, meaning autophagy of mitochondria, and its importance in maintaining cell function.

Mitochondrial dysfunction is one of the core drivers of aging. It is manifested by reactive oxygen species (ROS) accumulation, mitochondrial DNA (mtDNA) mutations, imbalanced energy metabolism, and abnormal biosynthesis. Mitochondrial autophagy maintains cellular homeostasis by selectively removing damaged mitochondria through mechanisms including the ubiquitin-dependent pathway (PINK1/Parkin pathway) and the ubiquitin-independent pathway (mediated by receptors such as BNIP3/FUNDC1).

During aging, the decrease in mitochondrial autophagy efficiency leads to the accumulation of damaged mitochondria, forming a cycle of mitochondrial damage-ROS-aging damage and aggravating aging-related diseases such as neurodegenerative diseases and cardiovascular pathologies. The targeted regulation of mitochondrial autophagy (drug modulation and exercise intervention) can restore mitochondrial function and slow aging. However, autophagy has a double-edged sword effect; moderate activation is anti-aging, but excessive activation or dysfunction accelerates the pathological process. Therefore, targeting mitochondrial autophagy may be an effective anti-aging technique; however, future focus should be on the tissue-specific regulatory threshold and the dynamic balance mechanism to achieve precise intervention.

Link: https://doi.org/10.1038/s41420-025-02913-y

That genetic variation appears to determine little of the variation in life expectancy for the vast majority of people is perhaps the most useful information yet to emerge from the creation of very large databases of genetic and health information, such as the UK Biobank. That this is the case doesn't rule out the existence of rare beneficial mutations with relatively large effects on life expectancy, however. See, for example, the PAI1 loss of function mutants who appear to live seven years longer than near relatives - though one should be wary of small sample sizes when it comes to determining the size of the effect in these circumstances.

In today's open access paper, researchers report on their identification of a rare mutation in cGAS, an important determinant of age-related chronic inflammation. When nuclear DNA or mitochondrial DNA is mislocalized in the cell as a result of age-related damage and dysfunction, cGAS is a part of the maladaptive process by which the STING pathway is triggered to produce an inflammatory response. This pathway evolved to defend against infectious pathogens, so one can't just turn off cGAS-STING signaling because it is essential to normal immune function and health. Too much of it is a bad thing, however, and important in degenerative aging. This newly discovered mutation appears to split the difference, resulting in greater longevity without evidently impaired function.

One might compare this discovery with recent work in the comparative biology of aging, where cGAS and STING are shown to be less inflammatory in response to the molecular damage of aging in long-lived species. For example, researchers have engineered mice to express the less inflammatory naked mole-rat cGAS, and this has the outcome of reducing age-related inflammation to slow degenerative aging. Similarly, another research group engineered mice to expresss the STING gene from bats, which also produced a beneficial reduction in age-related inflammation.

Rare longevity-associated variants, including a reduced-function mutation in cGAS, identified in multigenerational long-lived families

Life expectancy has steadily increased in the last two centuries, while healthspan has been lagging behind. Survival into extreme ages strongly clusters within families which often exhibit a delayed onset of (multi)morbidity, yet the underlying protective genetic mechanisms are still largely undefined. We performed affected sib-pair linkage analysis in 212 sibships enriched for ancestral longevity and identified four genomic regions at 1q21.1, 6p24.3, 6q14.3, and 19p13.3. Within these regions, we prioritized 12 rare protein-altering variants in seven candidate genes (NUP210L, SLC27A3, CD1A, CGAS, IBTK, RARS2, and SH2D3A) located in longevity-associated loci.

Notably, a missense variant in CGAS (rs200818241), was present in two sibships. Using human- and mouse-based cell models, we showed that rs200818241 reduced protein stability and attenuated activation of the canonical cGAS-STING pathway in a cell-type specific manner. This dampened signalling mitigated inflammation and delayed cellular senescence, mechanisms that may contribute to the survival advantage of CGAS variant carriers. Our findings indicate novel rare variants and candidate genes linked to familial longevity and highlight the cGAS-STING pathway as a potential contributor to the protective mechanisms underlying human longevity.

Histones are structures in the cell nucleus that act as spools. Regions of nuclear DNA are compacted into a protected, inactive form when spooled around histones. The modification of histones by the addition and removal of chemical decorations are an important part of determining the winding and unwinding of DNA, and thus which gene sequences are exposed to translational machinery and can be expressed at any given time. One sizable component of aging is that this highly complex regulation of DNA structure changes, altering gene expression in undesirable ways.

Researchers here take initial steps towards mapping the effects on aging of succinylation of histones, the addition of a succinyl group. Their initial data suggests that more succinylation is a good thing, in that it correlates with greater longevity and a slower pace of aging. Providing mice with a diet supplemented with succinic acid to provoke greater histone succinylation produces modest benefits. That more succinylation is beneficial in this way is an unexpectedly direct outcome for something as complex as regulation of histone function, but the data is the data.

Histone post-translational modifications (PTMs) are critical regulators of chromatin structure and gene expression, with broad implications for development, metabolism, and aging. While canonical modifications such as methylation and acetylation are well characterized, the role of histone succinylation remains poorly understood.

Here, we investigated histone succinylation in the context of aging and exceptional longevity. Using mass spectrometry-based proteomics, we quantified histone succinylation in B-cells from four groups: young individuals, older individuals without parental longevity (OPUS), long-lived individuals, and offspring of long-lived individuals (OPEL). We found that histone succinylation was significantly elevated in the OPEL group compared to both young and OPUS cohorts. Nuclear proteomics further revealed enrichment of succinylated proteins in OPEL samples, supporting a role for succinylation in chromatin organization.

To test whether succinate availability impacts healthspan, we supplemented middle-aged mice with succinic acid. While body weight, frailty index, and cognition were unaffected, succinic acid improved motor coordination and muscle strength. Together, our findings provide preliminary evidence that enhanced histone succinylation may serve as a protective epigenetic mechanism in individuals predisposed to exceptional longevity, and that succinate supplementation can selectively improve aspects of physical performance during aging.

Link: https://doi.org/10.1111/acel.70346

Researchers here discuss the application of lipid nanoparticle delivery of messenger RNA as a basis for the development of cancer vaccines. As is the case for vaccines against infectious disease, there are many different ways to provoke an immune response to cancer-specific antigens. Use of messenger RNA to express the desired antigen is the most recent of these technologies. A great of effort has gone into the development of cancer vaccines over the years, and thus it seems likely that a wide range of messenger RNA cancer vaccines will be developed. As yet, however, little of this past effort has resulted in regulatory approval of cancer vaccines and use in the clinic. That low success rate may or may not change with the introduction of messenger RNA as an approach, time will tell.

The landscape of cancer immunotherapy has been redefined by mRNA vaccines as rapid clinically viable strategies that help induce potent, tumor-specific immune responses. This review highlights the current advances in mRNA engineering and antigen design to establish an integrated immunological framework for cancer vaccine development.

Achieving durable clinical benefit requires more than antigen expression. Effective vaccines need precise epitope selection, optimized delivery systems, and rigorous immune monitoring. The field is shifting from merely inducing immune responses to focusing more on the biochemistry and molecular design principles that combine magnitude, polyfunctionality, and longevity to overcome tumor-induced immune suppression.

We examine an integrated immunological framework for mRNA cancer vaccine development, examining how rational molecular engineering of vaccine components, from nucleoside modifications and codon optimization to untranslated regions and linker sequences, shapes immunogenicity and therapeutic efficacy. Future directions will depend on balancing combinatorial strategies combining vaccination with immune checkpoint inhibitors and adoptive cell therapies.

Link: https://doi.org/10.3390/vaccines13121222

The proof of concept demonstration outlined in today's research materials is chiefly interesting as a demonstration that energy metabolism may be more important than suspected in the onset and progression of Alzheimer's disease. The brain has high energy requirements, and it was certainly thought that age-related neurodegeneration is caused in part by the negative impact on energy metabolism of a reduced supply of oxygen and nutrients to the brain alongside impaired mitochondrial function. But how big is that part, relative to other contributions? This is always the question, and the fastest way to obtain answers remains to try various forms of therapy and observe the results.

The cautions here are twofold. Firstly that Alzheimer's mouse models are artificial and each model encapsulates assumptions about the driving pathology of the condition that may or may not be relevant in humans. Mouse model Alzheimer's pathology is not the human disease. Secondly, the researchers here focus on NAD+, a necessary component of mitochondrial energy metabolism that declines in availability with age. While they claim important differences in the specifics of the approach taken, increasing NAD+ levels via vitamin B3 derivatives and a few other methodologies has in the past performed poorly in clinical trials for a range of conditions. So on the one hand the data in mice presented here is quite good, and may indeed say something important about energy metabolism in the aging brain, but on the other both the approach taken and the models used come with caveats.

New Study Shows Alzheimer's Disease Can Be Reversed in Animal Models to Achieve Full Neurological Recovery, Not Just Prevented or Slowed

Researchers have shown that the brain's failure to maintain normal levels of a central cellular energy molecule, NAD+, is a major driver of Alzheimer's disease (AD), and that maintaining proper NAD+ balance can prevent and even reverse the disease. NAD+ levels decline naturally across the body, including the brain, as people age. Without proper NAD+ balance, cells eventually become unable to execute critical processes required for proper functioning and survival. In this study, the team showed that the decline in NAD+ is even more severe in the brains of people with AD, and that this also occurs in mouse models of the disease.

After finding that NAD+ levels in the brain declined precipitously in both human and mouse AD, the research team tested whether preventing the loss of brain NAD+ balance before disease onset, or restoring brain NAD+ balance after significant disease progression, could prevent or reverse AD, respectively, using a well-characterized pharmacologic agent known as P7C3-A20.

Not only did preserving NAD+ balance protect mice from developing AD, but delayed treatment in mice with advanced disease also enabled the brain to fix the major pathological events of AD. Moreover, both lines of mice fully recovered cognitive function. This was accompanied by normalized blood levels of phosphorylated tau 217, a recently approved clinical biomarker of AD in people, providing confirmation of disease reversal and highlighting a potential biomarker for future clinical trials.

Pharmacologic reversal of advanced Alzheimer's disease in mice and identification of potential therapeutic nodes in human brain

Alzheimer's disease (AD) is traditionally considered irreversible. Here, however, we provide proof of principle for therapeutic reversibility of advanced AD. In advanced disease amyloid-driven 5xFAD mice, treatment with P7C3-A20, which restores nicotinamide adenine dinucleotide (NAD+) homeostasis, reverses tau phosphorylation, blood-brain barrier deterioration, oxidative stress, DNA damage, and neuroinflammation and enhances hippocampal neurogenesis and synaptic plasticity, resulting in full cognitive recovery and reduction of plasma levels of the clinical AD biomarker p-tau217.

P7C3-A20 also reverses advanced disease in tau-driven PS19 mice and protects human brain microvascular endothelial cells from oxidative stress. In humans and mice, pathology severity correlates with disruption of brain NAD+ homeostasis, and the brains of nondemented people with Alzheimer's neuropathology exhibit gene expression patterns suggestive of preserved NAD+ homeostasis. Forty-six proteins aberrantly expressed in advanced 5xFAD mouse brain and normalized by P7C3-A20 show similar alterations in human AD brain, revealing targets with potential for optimizing translation to patient care.

Companies working on novel therapeutics targeting senescent cells, to selectively destroy these errant cells or alter their metabolism to reduce harmful inflammatory signaling, are largely steering clear of neurodegenerative conditions, at least for now. Any successful systemic treatment that destroys senescent cells or suppresses the inflammatory signaling of senescent cells throughout the body will likely see off-label use for many age-related conditions, of course, but not all such treatments will affect the burden of senescent cells in the brain. The present consensus in the research community is that cellular senescence in the various populations of supporting cells in the brain appears to be important in the onset and development of neurodegenerative conditions, and therefore more attention should be given to the application of senotherapeutics to the aging of the brain.

Cellular senescence is a state of stable cell cycle arrest, initially identified in proliferative cells, accompanied by persistent metabolic activity and the secretion of a pro-inflammatory cocktail of molecules known as the senescence-associated secretory phenotype (SASP). Initially, it acts as a beneficial mechanism by halting the proliferation of damaged cells, thus suppressing tumor development, and facilitating wound repair through the coordinated release of specific factors. The pathology arises from the chronic accumulation of these senescent cells. Their persistent SASP creates a toxic tissue environment. In the brain, the accumulation of senescent microglia and astrocytes is a major driver of neuroinflammation. Recent studies directly link this process to cognitive decline and neurodegenerative pathologies, making the clearance of senescent cells (senolysis) a promising strategy to combat brain aging.

The identification of senescence as a modifiable factor in brain aging has led to the emergence of senotherapeutics, a new class of pharmacological interventions aimed at either eliminating senescent cells (senolytics) or modulating their harmful secretory profile (senomorphics). Senolytics, such as dasatinib and quercetin, selectively induce apoptosis in senescent cells by targeting pro-survival pathways unique to the senescent state.

Senotherapeutics offer a promising and innovative approach to managing brain aging and its associated cognitive decline. By targeting the fundamental process of cellular senescence, either through selective elimination of senescent cells or modulation of their harmful secretions, these interventions have demonstrated the ability to reduce neuroinflammation, improve synaptic function, and enhance cognitive performance in preclinical models. Although clinical translation is still in early stages, ongoing trials and emerging delivery technologies provide a pathway toward safe and effective use in humans. Challenges such as blood-brain barrier permeability, senescence biomarker development, and long-term safety must be addressed through continued research and technological advancement.

Link: https://doi.org/10.3390/neurolint17120204

The lack of consistency between clinical trials conducted for any given medical condition is a continual point of complaint in the research community. It is a hard problem to solve, as illustrated by the long history of such complaints and little consequent difference in the state of trial design. Still, one can make efforts. The best way forward is perhaps to propose a detailed standard and then advocate for it. For the longevity field, the authors of this paper take a first step in that direction with a set of recommendations for data collection in studies of therapies to treat aging.

Biomarkers of aging have the potential to transform geroscience clinical trials because of their broad applications in stratifying participants, prioritizing interventions, and monitoring responses to geroprotectors. As longevity biotechnology companies (LBCs) continue to plan and launch innovative clinical trials, standard practices in collecting data and applying biomarkers of aging will allow the field to support parallel and ongoing validation and benchmarking efforts for aging biomarkers. Moreover, defining standard best practices will ensure future reuse of valuable clinical data. Here, we propose recommendations for such collections. We believe that wide adoption of these recommendations will allow LBCs to produce and leverage the highest quality data from their clinical trials, while also benefiting the geroscience field more broadly with minimal additional effort.

In an ideal world, studies would collect as many samples as possible in order to establish a repository of biospecimens and data for research. Although a comprehensive repository is useful, it may not be feasible for collection in all trial protocols. As such, we propose a prioritization framework for assessment of what is most important to collect, based on three main pillars: 1) feasibility, 2) representation, and 3) range of use. Feasibility refers to the effort required for collection in trials; representation refers to how representative the sample is of the overall aging process; and range of use relates to the number of different analyses that can be conducted with the sample. Based on these criteria, we recommend that, at minimum, blood, which provides a snapshot of biological features, and wearable data, providing continuous information on functional features, should be collected and stored.

In addition to the importance of collecting biological and wearable data, it is essential to collect corresponding participant information. Associated data should include detailed demographic information, medical history, family medical history, and health outcome data, where possible. Irrespective of the indication under assessment in the trial, a broad range of health outcomes corresponding to age-related disease (e.g. cardiovascular diseases, dementia, and cancers) should be monitored, with monitored outcomes determined by balancing additional trial complexity and data richness, and also considering the length of the study.

Informed patient consent is an essential part of all clinical trial protocols, ensuring the subjects understand the purpose of a trial, what data will be collected and processed, and their responsibilities and rights as a study participant, including the ability to cease participation at any time. Beyond the minimum consent requirements for clinical trials, it is becoming increasingly important to obtain explicit consent for future activities associated with biomarker research and analysis of biobanked samples to reduce the need to re-engage trial participants for consent once the trial has been completed.

Link: https://doi.org/10.1038/s41514-025-00313-1