Fight Aging!

In studies in mice, it is much easier to show a slowing of atherosclerotic plaque growth over time than it is to show regression of existing plaque. Only a tiny number of approaches have shown any robust ability to regress obstructive plaque in the arteries once it has formed. Thus one should suspect that any new approach presented with data to show a slowing of plaque growth may not actually have the capacity to regress plaque - otherwise the researchers would have presented that much more desirable outcome instead.

Here, researchers turn the well established approach of engineering T cells to have chimeric antigen receptors to the problem of oxidized LDL particles. LDL particles carry cholesterol from the liver out into the body, and when they become oxidized they cause additional stress to cells and accelerate the development of plaque by worsening an already toxic plaque environment in blood vessel walls. Engineering T cells to target and clear oxidized LDL particles is clearly beneficial, producing a sizable slowing of plaque growth. This reinforces other lines of research indicating that oxidized LDL is an important mechanism in these mouse models.

CAR T cell therapy has revolutionized treatment for blood cancers. It works by engineering a patient's own T cells in the lab and training them to recognize a marker found on cancer cells, creating an immune response that destroys the cancer. Scientists have been exploring the potential of this powerful technology to treat other diseases. Researchers have now engineered a CAR regulatory T cell (Treg) that targets oxidized LDL (OxLDL), the main inflammation-stoking form of LDL cholesterol that drives plaque buildup in atherosclerosis.

Initial lab-dish tests with human cells confirmed that the anti-OxLDL CAR Tregs suppress inflammation in response to OxLDL, greatly reducing the buildup of the cells that are a central feature of atherosclerotic plaques. The team then engineered a mouse version of the anti-OxLDL CAR-Treg and tested it in mice that were genetically predisposed to high cholesterol and atherosclerosis. After about twelve weeks of treatment, the treated mice's hearts and aortas showed a roughly 70 percent lower atherosclerotic plaque burden compared to control mice - indicating a clear preventive effect of the CAR-Tregs. Despite this effect, there was no disruption of general immune function in the treated mice.

Link: https://www.eurekalert.org/news-releases/1106906

The amino acid arginine has been shown to act as a chaperone, or improve the ability of existing chaperone molecules to reduce aggregation of misfolded proteins such as the amyloid-β associated with the development of Alzheimer's disease. Researchers here supplement the diets of mice with sizable doses of arginine in order to produce effects on amyloid-β aggregation; the equivalent dose in humans would be something like 1 gram per kilogram of body weight, daily. One caveat is that the mouse model of Alzheimer's used here is relevant to familial early onset Alzheimer's rather than the much more common sporadic late onset form of the condition. Nonetheless, it is an interesting study.

Although amyloid β (Aβ)-targeting antibody therapies for Alzheimer's disease (AD) have recently been developed, their clinical efficacy remains limited, and issues such as high cost and adverse effects have been raised. Therefore, there is an urgent need for the establishment of safe and cost-effective therapeutic approaches that inhibit Aβ aggregation or prevent its accumulation in the brain.

In this study, we report that arginine, a clinically approved and safe chemical chaperone, suppresses Aβ aggregation both in vitro and in vivo. We demonstrated using an in vitro assay that arginine inhibits the aggregation formation of the Aβ42 peptide in a concentration-dependent manner. In a Drosophila model of AD expressing the Aβ42 peptide with an Arctic mutation E22G, the oral administration of arginine dose-dependently reduced Aβ42 accumulation and rescued Aβ42-mediated toxicity. In an AppNL-G-F knockin mouse model harboring human APP familial mutations, the oral administration of arginine suppressed Aβ plaque deposition and reduced the level of insoluble Aβ42 in the brain. The arginine-treated AppNL-G-F knockin mice also showed the improvement of behavioral abnormalities and the reduced expression of the neuroinflammation-associated cytokine genes.

These results indicate that the oral administration of arginine not only reduced Aβ deposition, but also ameliorated Aβ-mediated neurological phenotypes in animal models of AD. These findings identify arginine as a safe and cost-effective drug candidate that suppresses Aβ aggregation, and highlight its repositioning potential for rapid clinical translation for AD treatment. Arginine is also potentially applicable to a wide range of neurodegenerative diseases caused by protein misfolding and aggregation.

Link: https://doi.org/10.1016/j.neuint.2025.106082

A large body of evidence indicates that forms of air pollution harm long-term health. This is largely epidemiological data, observing correlations with incidence of mortality and age-related disease in populations exposed to different levels of pollutants. A number of regions of the world exhibit, through happenstance, very similar populations that are exposed to significantly different levels of particulate and chemical pollutants. Consider studies covering the Puget Sound in the US or parts of China. These natural experiments provide an increased confidence that the observed correlations are a matter of air pollution causing harm to health.

The primary mechanism by which air pollution is thought to accelerate the onset and progression of age-related disease is via induction of chronic inflammation. Airway exposure to pollutants stresses cells, changes their behavior, and contributes to the burden of continual, unresolved inflammation that is characteristic of aging. This exposure exists on a spectrum, with smoking and indoor wood smoke at one end and the less severe degrees of industrial pollution in wealthier parts of the world at the other. Since effects are driven by inflammation, we should expect near all age-related conditions to be aggravated over time by exposure to air pollution, scaling by the severity of the exposure.

Air Pollution Exposure and Muscle Mass and Strength Decline in Older Adults: Results From a Swedish Population-Based Study

Emerging evidence suggests that air quality may impact muscle health. However, most studies are limited by cross-sectional designs or short follow-ups. We assessed the association of long-term exposure to ambient air pollutants with changes in muscle mass and strength in older adults. We included 3,249 participants from the SNAC-K longitudinal study (mean age 74.3 years; 35.8% males). Muscle strength (measured through handgrip and chair stand tests), muscle mass (derived from calf circumference) and physical performance (assessed through walking speed at a usual pace) were assessed over a 12-year period. Probable sarcopenia was defined as reduced muscle strength as per the EWGSOP2 criteria. Residential exposure to PM2.5, PM10, and nitrogen oxide (NOx) was estimated for the 5 years preceding baseline. Cox regressions and linear mixed models examined the association of air pollutant exposure with, respectively, probable sarcopenia and longitudinal changes in muscle parameters.

Over 12 years, the cumulative incidence of probable sarcopenia increased with higher exposure (above vs. below the median values) to NOx (36% vs. 28%), PM2.5 (35% vs. 28%) and PM10 (35% vs. 28%). The association between air pollutant levels and the risk of probable sarcopenia was nonlinear, with an increased risk showing a plateau at very high levels. Higher exposures were associated with an increased risk of developing probable sarcopenia, by 25% for NOx and PM2.5 to 33% for PM10. Elevated pollutant exposure was associated with significantly greater annual declines in lower-limb strength (chair stand test: 0.40-0.48 s) and walking speed (0.004 m/s).

Thus long-term exposure to moderate levels of ambient air pollutants may increase the risk of probable sarcopenia and accelerate declines in lower-limb strength and physical performance in older adults.

Metabolism is exceedingly complex, and incompletely understood. This is true of individual cells, let alone organisms made up of very large numbers of those cells. Most of the work done on interventions intended to slow aging takes the form of attempts to alter metabolism into a more favorable state in which aging progresses at a modestly slower pace, usually via the use of small molecules. This approach is doomed to failure at this stage of technological progress. We do not know enough of metabolism, we cannot control enough of metabolism. Studies show that combining any two marginally aging-slowing small molecules is as likely as not to produce an interaction that results in a marginal acceleration of aging. Similarly, researchers here demonstrate that a sizable fraction of marginally aging-slowing interventions only work at certain ages, and become marginally aging-accelerating at other ages. And at the end of the day, why is so much of the focus placed on interventions that cannot achieve more than a small benefit?

A growing number of compounds are reported to extend lifespan, but it remains unclear whether they reduce mortality across the entire life course or only at specific ages. This uncertainty persists because the commonly used log-rank test cannot detect age-specific effects. Here, we introduce a new analytical method that addresses this limitation by revealing when, how long, and to what extent interventions alter mortality risk.

Applied to survival data from 42 compounds tested in mice by the National Institute on Aging Interventions Testing Program, our method identified 22 that reduced mortality at certain ages, more than detected by the log-rank test, while 15 increased mortality at certain ages. Most compounds were effective only within restricted age ranges; just 8 reduced mortality late in life, when burdens of aging are greatest. Compared to conventional methods, this approach uncovers more beneficial and harmful effects, offers deeper insight into timing and mechanism, and can guide development of future anti-aging therapies.

Link: https://doi.org/10.1038/s41467-025-65158-4

Muscle tissue is metabolically active, particularly following exercise, in ways that improve function in other tissues. As a class, molecules secreted by muscle cells that affect other tissues are called myokines, and are not presently fully mapped and understood. The research community is actively engaged in identifying myokines and myokine interactions that could be targets for novel therapies that mimic some of the benefits of exercise. Here, researchers show that increased levels of the myokine cathepsin B can reduce the loss of function in the brain that occurs in a mouse model of Alzheimer's disease. Interestingly, this same treatment impairs cognitive function in normal mice, indicating that (a) there can be too much of this myokine in circulation, and (b) the relationship between cathepsin B signaling and cognitive function is likely complex.

Increasing evidence indicates skeletal muscle function is associated with cognition. Muscle-secreted protease Cathepsin B (Ctsb) is linked to memory in animals and humans, but has an unclear role in neurodegenerative diseases. To address this question, we utilized an AAV-vector-mediated approach to express Ctsb in skeletal muscle of APP/PS1 Alzheimer's disease (AD) model mice. Mice were treated with Ctsb at 4 months of age, followed by behavioral analyses 6 months thereafter.

Here we show that muscle-targeted Ctsb treatment results in long-term improvements in motor coordination, memory function, and adult hippocampal neurogenesis, while plaque pathology and neuroinflammation remain unchanged. Additionally, in AD mice, Ctsb treatment normalizes hippocampal, muscle, and plasma proteomic profiles to resemble that of wild-type (WT) controls. In AD mice, Ctsb increases the abundance of hippocampal proteins involved in mRNA metabolism and protein synthesis, including those relevant to adult neurogenesis and memory function. Furthermore, Ctsb treatment enhances plasma metabolic and mitochondrial processes.

In muscle, Ctsb treatment elevates protein translation in AD mice, whereas in WT mice mitochondrial proteins decrease. In WT mice, Ctsb treatment causes memory deficits and results in protein profiles across tissues that are comparable to AD control mice. Overall, the biological changes in the treatment groups are consistent with effects on memory function. Thus, skeletal muscle Ctsb application has potential as an AD therapeutic intervention.

Link: https://doi.org/10.1111/acel.70242

Every cell contains hundreds of mitochondria, a population of complex organelles that evolved from an ancient lineage of symbiotic bacteria that merged with early forms of cell to form the first eukaryotic cells. Mitochondria still act like bacteria in many ways, retaining a fragment of their original circular DNA, replicating by division, fusing together and passing around component parts, but are nonetheless now tightly integrated into cellular metabolism. Most mitochondrial genes have migrated into the cell nucleus, and a complex process of quality control known as mitophagy operates to recycle worn and damaged mitochondria.

The primary function of mitochondria is the manufacture of adenosine triphosphate (ATP), a chemical energy store molecule used to power the cell. The core of the protein machinery inside a mitochondrion that carries out this manufacture is the electron transport chain, also known as the respiratory chain. Collectively the structures of the chain are capable of building up the necessary energy to form ATP by, as one might guess from the name, reductive and oxidative chemical reactions that transport electrons along the chain. The electron transport chain consists of many distinct proteins that join together to form four protein complexes. These complexes themselves can also assemble in a number of ways to form supercomplexes. Indeed, researchers have shown that supercomplex formation is necessary for normal levels of ATP production.

Sadly, mitochondrial function (as measured by ATP production) declines with age, a consequence of damage to mitochondrial DNA and changes in gene expression that negatively impact mitochondrial structure, dynamics, and quality control. There is interest in the research community in finding ways to improve mitochondrial function. Many of the approaches demonstrated to date are essentially compensatory, in that they tend to work at any age to increase ATP production. Unfortunately near all compare poorly to the increase in mitochondrial function produced by exercise, and while we all know that exercise is a good thing, it is impossible to exercise an escape from aging. Better approaches are needed.

Today's open access paper covers a novel approach to improve mitochondrial function. Supercomplex formation in the electron transport chain is not a matter of chance, it is guided into happening by the activities of other proteins. This is usually the case for any critical function in a cell. Researchers discovered that supercomplex formation is in part steered by COX7RP, via the usual approach of disabling the expression of the COX7RP gene and observing the results. Interestingly, increasing the expression of COX7RP in genetically engineered mice in order to increase supercomplex formation in mitochondria both improves normal mitochondrial function and slows the onset of aspects of aging.

Mitochondrial Respiratory Supercomplex Assembly Factor Contributes to Lifespan Extension in Mice

Accumulating evidence from experimental animal models and human clinical studies suggests that mitochondrial function is closely associated with both lifespan extension and age-related decline. It is well established that aging is generally accompanied by a decline in mitochondrial function, which is attributed to mitochondrial DNA damage, increased oxidative stress, and deterioration of mitochondrial quality control mechanisms. These changes are characterized by reduced respiratory activity, altered mitochondrial dynamics, and increased production of reactive oxygen species (ROS). The age-related decline in mitochondrial function has been implicated in the pathogenesis of various aging-associated diseases.

We previously demonstrated that cytochrome c oxidase subunit 7a related polypeptide (COX7RP), or COX7A2L, is a critical factor that assembles mitochondrial respiratory chain complexes into supercomplexes, which is considered to modulate energy production efficiency. Whether COX7RP contributes to metabolic homeostasis and lifespan remains elusive.

We here observed that COX7RP-transgenic (COX7RP-Tg) mice exhibit a phenotype characterized by a significant extension of lifespan. In addition, metabolic alterations were observed in COX7RP-Tg mice, including lower blood glucose levels as well as reduced serum triglyceride (TG) and total cholesterol (TC) levels. Moreover, COX7RP-Tg mice exhibited elevated ATP and nicotinamide adenine dinucleotide levels, reduced ROS production, and decreased senescence-associated β-galactosidase levels. Single-nucleus RNA-sequencing (snRNA-seq) revealed that senescence-associated secretory phenotype genes were downregulated in old COX7RP-Tg white adipose tissue (WAT) compared with old WT WAT, particularly in adipocytes.

This study provides a clue to the role of mitochondrial respiratory supercomplex assembly factor COX7RP in resistance to aging and longevity extension.

Researchers here report a novel mechanisms by which aging impairs the immune system. The spleen is an immune organ, an important location where immune cells congregate to communicate with one another and coordinate the immune response to pathogens. The spleen is also responsible for filtering damaged and worn red blood cells from the circulation. Unfortunately the aged spleen accumulates too much iron and metabolic waste as a result of reduced efficiency in clearing out those unwanted red blood cells. Exposure to this aged spleen environment is here shown to degrade the efficacy of T cells of the adaptive immune system.

Mechanisms of T cell aging involve cell-intrinsic alterations and interactions with immune and stromal cells. Here we found that splenic T cells exhibit greater functional decline than lymph node T cells within the same aged mouse, prompting investigation into how the aged spleen contributes to T cell aging.

Proteomic analysis revealed increased expression of heme detoxification in aged spleen-derived lymphocytes. Exposure to the heme- and iron-rich aged splenic microenvironment induced aging phenotypes in young T cells, including reduced proliferation and CD39 upregulation. T cells survived this hostile niche by maintaining a low labile iron pool, at least in part, via IRP2 downregulation to resist ferroptosis but failed to induce sufficient iron uptake for activation. Iron supplementation enhanced antigen-specific T cell responses in aged mice.

This study identifies the aged spleen as a source of hemolytic signals that systemically impair T cell function, underscoring a trade-off between T cell survival and function and implicating iron metabolism in immune aging.

Link: https://doi.org/10.1038/s43587-025-00981-4

Parkinson's disease is a considered to be caused by misfolding and aggregation of α-synuclein, a particularly pernicious malfunction of protein structure that can spread from cell to cell like a prion, encouraging other molecules of α-synuclein to also misfold in the same way. Mitochondria are prominently involved in Parkinson's disease because forms of impairment to mitochondrial function, whether by aging or inherited mutation, make the motor neurons in the brain that are already most vulnerable to death due to α-synuclein pathology even more vulnerable to that fate. Here, however, researchers turn this around, and provide evidence for a specific dysfunction in mitochondria to accelerate α-synuclein pathology. Biology is complex: both arrows of causation could be true, and both could be significant.

Mitochondrial dysfunction is a hallmark of Parkinson's disease (PD), but the mechanisms by which it drives autosomal dominant and idiopathic forms of PD remain unclear. To investigate this, we generated and performed a comprehensive phenotypic analysis of a knock-in mouse model carrying the T61I mutation in the mitochondrial protein CHCHD2 (coiled-coil-helix-coiled-coil-helix domain-containing 2), which causes late-onset symptoms indistinguishable from idiopathic PD.

We observed pronounced mitochondrial disruption in substantia nigra dopaminergic neurons, including distorted ultrastructure and CHCHD2 aggregation, as well as disrupted mitochondrial protein-protein interactions in brain lysates. These abnormalities were associated with a whole-body metabolic shift toward glycolysis, elevated mitochondrial reactive oxygen species (ROS), and progressive accumulation of aggregated α-synuclein.

In idiopathic PD, CHCHD2 gene expression also correlated with α-synuclein levels in vulnerable dopaminergic neurons, and CHCHD2 protein accumulated in early Lewy aggregates. These findings delineate a pathogenic cascade in which CHCHD2 accumulation impairs mitochondrial respiration and increases ROS production, driving α-synuclein aggregation and neurodegeneration.

Link: https://doi.org/10.1126/sciadv.adu0726

Therapeutic use of extracellular vesicles seems likely to replace much of the present use of stem cell therapy, as these first generation stem cell transplantation therapies achieve benefits near entirely via the signaling generated by the transplanted cells in the short period of time in which they survive. Much of that signaling takes the form of extracellular vesicles, membrane-wrapped packages of molecules. Vesicles can be harvested from cell cultures, and are much easier to store and transport than is the case for cells, allowing centralization of the harder part of the manufacturing process that is managing stem cell cultures.

In recent years researchers have moved on from simply harvesting vesicles to finding ways to induce cells to create a lot more vesicles than is normally the case. The mechanical process of membrane extrusion is one approach to the generation of vesicles that compare favorably with naturally generated vesicles, but which are more readily produced in large amounts. In today's open access paper, researchers combine membrane extrusion with engineered cells to produce a more favorable mix of molecules in the manufactured extracellular vesicles. The intent is to generate a therapy that can improve the environment following damage to the heart, and thereby reduce further harms and encourage greater regeneration.

Artificial cell derived vesicles from Ginsenoside Rg1-primed mesenchymal stromal cells mitigate oxidative stress and DNA damage in myocardial ischemic/reperfusion injury

Myocardial ischemia/reperfusion injury (MI/RI) remains a major challenge in the treatment of acute myocardial infarction due to the lack of effective therapeutic options. While mesenchymal stromal cells (MSCs) and their derivates show promising potential for MI/RI therapy, their clinical application is hindered by low transplantation efficiency and insufficient yield. In this study, we engineered nanoscale artificial cell-derived vesicles (ACDVs) by extruding Ginsenoside Rg1-primed MSCs (Rg1-MSCs), resulting in Rg1-ACDVs.

Rg1-ACDVs displayed superior therapeutic efficacy compared to non-primed ACDVs and extracellular vesicles derived from Rg1-MSCs (Rg1-EVs). Multi-omics analysis revealed that Rg1-ACDVs possess distinct molecular signatures associated with promoting cell cycle progression and reducing DNA damage. These findings were further validated experimentally, demonstrating that Rg1-ACDVs effectively reduce reactive oxygen species (ROS) accumulation and mitigate DNA damage both in vitro and in vivo.

This study highlights the synergistic benefits of combining Ginsenoside Rg1 priming with nanoscale engineering and introduces Rg1-ACDVs as a scalable and innovative strategy, offering a promising approach for improving clinical outcomes in MI/RI therapy.

Why does the inflammatory gum disease periodontitis tend to be worse in men versus women? As a possible answer to that question, researchers here demonstrate a sex difference in mammals in the inflammatory processes that drive the pathology of periodontitis. The condition progresses from chronic inflammation to bone loss and tooth loss, one example amongst many of the way in which unresolved inflammatory signaling changes the behavior of cells for the worse to cause disruption to tissue structure and function.

The inflammasome initiates inflammation via the maturation of interleukin-1 beta (IL-1β). Periodontitis is a prevalent, male-biased disease characterized by inflammation-driven bone loss, yet the mechanisms of this sex bias is unknown. This study explored whether enhanced inflammasome activity represents a causal mechanism for this bias. Analyses of three separate human studies (more than 6,200 samples) show that males have significantly higher IL-1β in the gingival crevicular fluid than females during health and periodontitis. This pattern is experimentally reproduced with different versions of the ligature-induced periodontitis mouse model where males show greater IL-1β secretion than females.

The inflammasome drives bone resorption in males but not females as revealed by analyses of inflammasome gene-deletion mice. Pharmacologic treatment with a caspase-1/4 inhibitor reduces inflammatory cell infiltration, dampens osteoclastogenesis signaling (via the receptor activator of nuclear factor-kappa B (RANKL) pathway), and prevents bone resorption in males but not females during experimental periodontitis. While ovariectomized females show no change in their nonresponsiveness to caspase-1/4 inhibition, orchiectomized males no longer respond to the inhibition, suggesting the importance of an intact male reproductive system in the mediation of this inhibition.

Thus, our study identifies inflammasome activation as causal for male-biased experimental periodontitis and supports sex-stratified studies to foster future advancement of inflammasome therapeutics in periodontics.

Link: https://doi.org/10.1073/pnas.2507092122

Much of the focus on the gut microbiome in aging revolves around its composition, the relative size of various populations of different microbial species, and how that composition changes over time. There is another dimension to consider, however, which is the activity and behavior of specific microbial species and how that is affected by the environment they find themselves in. This second dimension is relatively underexplored at the present time. As researchers here note, there may well be opportunities to improve health by adjusting the behavior of gut microbes in deterministic ways, rather than by changing the size of their populations.

Microbiota-derived metabolites have emerged as key regulators of longevity. The metabolic activity of the gut microbiota, influenced by dietary components and ingested chemical compounds, profoundly impacts host fitness. While the benefits of dietary prebiotics are well-known, chemically targeting the gut microbiota to enhance host fitness remains largely unexplored.

Here, we report a novel chemical approach to induce a pro-longevity bacterial metabolite in the host gut. We discovered that wild-type Escherichia coli strains overproduce colanic acids (CAs) when exposed to a low dose of cephaloridine, leading to an increased life span in the host organism Caenorhabditis elegans. In the mouse gut, oral administration of low-dose cephaloridine induced transcription of the capsular polysaccharide synthesis (cps) operon responsible for CA biosynthesis in commensal E. coli at 37 °C, and attenuated age-related metabolic changes. We also found that low-dose cephaloridine overcomes the temperature-dependent inhibition of CA biosynthesis and promotes its induction through a mechanism mediated by the membrane-bound histidine kinase ZraS, independently of cephaloridine's known antibiotic properties.

Our work lays a foundation for microbiota-based therapeutics through chemical modulation of bacterial metabolism and highlights the promising potential of leveraging bacteria-targeting drugs in promoting host longevity.

Link: https://doi.org/10.1371/journal.pbio.3002749

Hypertension is the name given to a state of high blood pressure. The onset of this condition typically progresses over time, as aging or lifestyle choices cause slowly increasing dysfunction in the systems of regulation and feedback that control blood pressure. A number of mechanisms are involved in determination of blood pressure, such as the kidney's regulation of the volume of fluid in blood, the ability of blood vessels to contract and dilate to change the overall volume of the vascular system, and the pace at which the heart beats. The important processes of regulation are known as the renin-angiotensin-aldosterone system, in which signals pass back and forth from kidney to vasculature and other involved organs, including liver and brain.

One of the ways in which animal models of hypertension are created is to break the normal regulation of blood pressure by introducing excess angiotensin II, as increased angiotension II is seen in many cases of human hypertension. In today's open access paper, researchers note that inducing hypertension in this way produces dysfunction in cells in the vasculature and brain before blood pressure increases. This suggests that even the early stages of hypertension cause harm that contributes to the well-established correlation between hypertension and cognitive decline, and in a different way than this relationship is commonly considered, not via increased structural damage to the brain resulting from a greater pace of rupture of microvessels.

Hypertension Affects the Brain Much Earlier than Expected

Hypertension impairs blood vessels, neurons, and white matter in the brain well before the condition causes a measurable rise in blood pressure, according to a new preclinical study. Patients with hypertension have a 1.2 to 1.5-fold higher risk of developing cognitive disorders than people without the condition, but exactly why is not understood. While many current hypertension medications successfully lower high blood pressure, they often show little or no effect on brain function. This suggests blood vessel changes could cause damage independently of the elevated pressure associated with hypertension.

To induce hypertension in mice, the researchers administered the hormone angiotensin, which raises blood pressure, mimicking what happens in humans. Then, they looked at how different types of brain cells were impacted three days later (before blood pressure increased) and after 42 days (when blood pressure was high, and cognition was affected). At day three, gene expression dramatically changed in three cell types: endothelial cells, interneurons, and oligodendrocytes. Endothelial cells, which line the internal surface of blood vessels, aged prematurely with lower energy metabolism and senescence, indicating they stopped dividing. The researchers also observed early signs of a weakened blood-brain barrier, which regulates the influx of nutrients into the brain and keeps out harmful molecules.

Hypertension-induced neurovascular and cognitive dysfunction at single-cell resolution

Hypertension is a leading cause of cognitive impairment, attributed to cerebrovascular insufficiency, blood-brain barrier disruption, and white matter damage. However, how hypertension affects brain cells remains unclear. Using single-cell RNA sequencing (scRNA-seq) in a mouse model of hypertension induced by angiotensin II, a peptide involved in human hypertension, we mapped neocortical transcriptomic changes before (3 days) and after (42 days) onset of neurovascular and cognitive deficits. Surprisingly, endothelial transport disruption and senescence, stalled oligodendrocyte differentiation, and interneuronal hypofunction and network imbalance emerged after 3 days, attributable to angiotensin II signaling. By 42 days, when cognitive impairment becomes apparent, deficits in myelination and axonal conduction, as well as neuronal mitochondrial dysfunction, developed.

These findings reveal a previously unrecognized early vulnerability of endothelial cells, interneurons, and oligodendrocytes, and they provide the molecular bases for subsequent neurovascular dysfunction and cognitive impairment in hypertension. These data constitute a valuable resource for future mechanistic studies and therapeutic target validation.

This is a very readable review, for all that the authors have stapled together two quite distinct topics into the one binder. Firstly, cellular senescence in various cell types in the cardiovascular system and its role in driving the onset and progression of cardiovascular disease. Secondly, efforts to develop cell therapies to treat cardiovascular disease, including the present generation of stem cell therapies that largely reduce inflammation without achieving any other goals, and further the attempts to induce regeneration and restoration of lost function by delivering replacement cells that are intended to survive, integrate, and support the age-damaged local cell populations.

The issue of population aging presents a significant challenge for many countries, and the related physical health implications have been receiving increasing attention. Senescence impacts several aspects of the cardiovascular system, contributing to diseases such as atherosclerosis, myocardial infarction (MI), pulmonary hypertension, and heart failure (HF). In recent decades, scientists have significantly advanced in understanding the molecular and cellular processes involved in cardiovascular aging, including telomere shortening and damage, oxidative stress, mitochondrial dysfunction, and DNA damage. Molecules such as p53, p21, and p16Ink4a, along with enhanced signals for SA-β-gal, are commonly used to detect senescent cells.

Researchers have identified pathways and factors that could be potential targets for treating or alleviating cardiovascular aging. Furthermore, the rapid advancement of regenerative medicine, including mesenchymal stem cell (MSC) and induced pluripotent stem cell (iPSC) transplantation, has positioned heart regeneration as a promising strategy for addressing age-related cardiovascular diseases. This review summarizes the current understanding of senescent cells, such as cardiomyocytes, endothelial cells, fibroblasts/myofibroblasts, and vascular smooth muscle cells, and their roles in associated cardiovascular diseases. We will also discuss recent factors contributing to cardiovascular aging, including but not limited to Akt and AMPK, and emphasize the potential of heart regeneration research and insights into future regenerative therapies for cardiovascular aging.

Link: https://doi.org/10.1186/s13287-025-04731-6

Sirtuins are a family of proteins that largely undertake specific modification of other proteins, removing certain decorations that have been attached to those proteins. A great deal of the exceedingly complex regulation of cellular metabolism involves changing the function of molecules by adding or removing decorations such as acetyl groups, methyl groups, and so forth. Several sirtuins have been investigated in the context of aging, showing some ability to alter the operation of cellular metabolism to modestly slow aspects of aging in animal models. Sirtuin 1 was excessively overhyped and is probably not in actual fact very relevant to aging, but sirtuin 6 has the appearance of being more reliable in its effects, albeit still not large effects in the grand scheme of things.

Aging is a major risk factor for multiple diseases, facing humanity with the challenge of how to prolong healthspan. Here, we explore a molecular mechanism underlying the prolongevity activity of the Sirt6 enzyme in supporting healthy aging. We show that Sirt6 maintains youthful hepatic levels of hydrogen sulfide (H2S), a gasotransmitter linked to the benefits of caloric restriction, by regulating cystine uptake and methionine metabolism. Sirt6 also prevents age-related increase in S-adenosylmethionine (SAM).

Mice overexpressing Sirt6 or fed a caloric restriction (CR) diet live longer with improved health. CR increases Sirt6 levels, and its beneficial effects are mediated by the gasotransmitter H2S, a one-carbon pathway product. Yet, the role of this pathway in Sirt6-regulated longevity remains elusive. Here, we show that Sirt6 controls hepatic one-carbon metabolism, preventing the aging-dependent H2S reduction, and the elevation of the methyl donor, S-adenosylmethionine (SAM).

Sirt6 downregulates Slc7a11 expression in an Sp1-dependent manner, decreasing cystine uptake and increasing cystathionine gamma lyase (Cgl) H2S production activity. Additionally, comparative acetylome in old livers revealed Sirt6-related differential acetylation of most of the one-carbon enzymes. Specifically, Sirt6-dependent Matα1 deacetylation reduces its SAM production activity and cystathionine beta synthase (Cbs) binding, thereby reducing its activation of Cbs-dependent H2S production. The net outcome is H2S and SAM levels as observed in young animals. Thus, we unveil a fundamental mechanism for the promotion of healthy longevity by Sirt6.

Link: https://doi.org/10.1073/pnas.2514084122

A protein is a sequence of amino acids joined together to form a single molecule, and consequently amino acids are everywhere in our biochemistry. Their presence influences many processes, and the complexity of cellular biochemistry continues to ensure that relatively little of this is anywhere near completely mapped. Circulating amino acid levels, as measured in blood samples, have received more attention in the context of aging and longevity in recent years. There are a few hundred different amino acids beyond the twenty used to manufacture proteins, some of which must be obtained via diet as they are not synthesized by our biochemistry. Researchers have found a number of associations between specific amino acid levels and aging, as well as demonstrating that supplementation or restriction of specific dietary amino acids can modestly influence the pace of aging in animal studies.

In today's open access paper, researchers demonstrate a small effect on male lifespan emerging from epidemiological data on tyrosine levels. The underlying mechanisms remain to be discovered, but this sort of study is intended as a prompt for others to dig into what might be happening under the hood. The authors of this paper speculate on mechanisms, but it is just speculation at this point. Tyrosine is not an essential amino acid, but is synthesized from the essential amino acid phenylalanine and so its availability in the body is still effectively constrained by diet. Phenylalanine restriction has not been shown to produce benefits in the way that restriction of some other essential amino acids does, and in fact severe restriction causes neurological issues if intake is sustained at very low levels.

The role of phenylalanine and tyrosine in longevity: a cohort and Mendelian randomization study

Protein restriction increases lifespan, however, the specific amino acids affecting lifespan are unclear. Tyrosine and its precursor, phenylalanine, may influence lifespan through their response to low-protein diet, with possible sex disparity. We applied cohort study design and Mendelian randomization (MR) analysis. Specifically, we examined the overall and sex-specific relationships between circulating phenylalanine and tyrosine and all-cause mortality in the UK Biobank using Cox regression. To test causality, in two-sample MR analysis, we used genetic variants associated with phenylalanine and tyrosine in UK Biobank with genome-wide significance and uncorrelated with each other, and applied them to large genome-wide association studies of lifespan, including parental, paternal, and maternal attained ages in the UK Biobank.

Tyrosine was associated with shorter lifespan in both observational and MR study, with potential sex disparity. After controlling for phenylalanine using multivariable MR, tyrosine remained related to a shorter lifespan in men (-0.91 years of life) but not in women. Phenylalanine showed no association with lifespan in either men or women after controlling for tyrosine.

Based on our results, targeting tyrosine may be a potential strategy for improving lifespan. Partly consistent with our findings, animal experiment suggests that restricting dietary protein in rats extends lifespan while lowering tyrosine concentrations in liver and muscle. The biological processes linking tyrosine to lifespan have not been thoroughly determined. Tyrosine was associated with insulin resistance. According to evolutionary biology, more investment in growth and reproduction often comes at the expense of lifespan, while insulin acts as one of the key regulators of growth and reproduction. Consistently, insulin resistance has been shown to be related to multiple diseases and decreased lifespan. Insulin resistance may also have sex-specific effects.