Fight Aging!

Angiopoietin-2 (ANGPT2) is not to be mistaken for angiopoietin-like protein 2 (ANGPTL2), but both appear problematic in similar contexts. Angiopoietins are in the vascular growth factor family, and angiopoietin-like proteins are, as the name suggests, somewhat similar. They are involved in the inflammatory response to damage that resolves into regeneration in the vascular system. Unfortunately, as in the rest of the body, the mechanisms involved in this response to damage run awry with advancing age and contribute to dysfunction rather than helping to address it. So, to pick a few examples, the presence of ANGPTL2 is a marker of cellular senescence and contributes to inflammatory heart disease. Meanwhile, ANGPT2 is known to be involved in the maladaptive reaction to ischemic injuries such as a heart attack, inducing excessive inflammation and further loss of function.

The vasculature extends into the brain, of course, and the aging of the cardiovascular system is known to influence the aging of the brain, an energy-hungry organ that operates at the edge of maximum metabolic capacity at the best of times. The brain is also a distinct microenvironment from the rest of the body; where blood vessels pass through the brain, they are wrapped by the structures of the blood-brain barrier. The blood-brain barrier restricts the passage of cells and molecules to and from the brain. Unfortunately, vascular dysfunction also implies blood-brain barrier dysfunction, and thus leakage of unwanted molecules and cells into the brain where they can induce damage and inflammation. In today's open access paper, researchers extend what is known of the issues induced by ANGPT2 expression in the aging vasculature to include harmful effects on the blood-brain barrier, and thus a contribution to the onset and progression of neurodegenerative conditions.

Angiopoietin-2 aggravates Alzheimer's disease by promoting blood-brain barrier dysfunction and neuroinflammation

Alzheimer's disease (AD) is a fatal neurodegenerative disorder. Emerging evidence highlights neuroinflammation as a crucial factor in AD pathogenesis and progression, with the disruption of the blood-brain barrier (BBB) significantly contributing to this process. The BBB constitutes a pivotal aspect of the neurovascular unit (NVU), a distinct structural and functional complex formed by endothelial cells, pericytes, and astrocytes within the central nervous system (CNS), specialized for tightly regulated interactions among vascular cells, glial cells, and neurons. NVU cell interactions are crucial for maintaining brain homeostasis, modulating immune responses, and facilitating neural communication. BBB disruption is closely linked to NVU dysfunction, which contributes to neuroinflammation and cognitive impairment in many neurological disorders, including AD.

In this study, we identified ANGPT2 as a key vascular determinant upregulated in human AD brains, as demonstrated by transcriptomic analyses and validated in postmortem tissues. To investigate its role in AD pathogenesis, we utilized the 5xFAD transgenic mouse model, which harbors five familial AD mutations that accelerate β-amyloid deposition.

Endothelial-specific deletion of ANGPT2 reduced β-amyloid accumulation, whereas ANGPT2 overexpression via adeno-associated viral (AAV) delivery exacerbated β-amyloid deposition. Mechanistically, ANGPT2 inhibition of TIE2 signaling compromised BBB integrity and amplified microglial activation and neuroinflammation, ultimately exacerbating cognitive dysfunction. Furthermore, single-nucleus RNA sequencing (snRNA-seq) from AD mice revealed ANGPT2-driven transcriptional changes consistent with microglial dysfunction and neuronal impairment. Collectively, these findings demonstrate that ANGPT2 promotes BBB dysfunction and neuroinflammation, thereby serving as a critical driver of AD pathology and progression.

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