Fight Aging!

The most interesting comparative biology programs aim to use the cellular biochemistry of unusually regenerative, long-lived, and cancer resistant species as a tool to better understand our vulnerabilities to aging and injury. In principle, understanding why a species is unusually long-lived could point to a basis for therapies to slow aging in humans, while understanding why species such as naked mole-rats, elephants, whales, and turtles have such low incidence rates of cancer could point to ways to shut down human cancers. This remains a hypothesis, as comparative biology research has not yet advanced to the point at which technology demonstrations of transferring biochemistry between species are commonplace, or at which any of the discoveries seem easily used as a basis for the development of therapies. It may just be a matter of time, or it may be that this is a project for a more distant future in which engineering significant changes in human biochemistry is an easier undertaking.

Turtles occupy the extremes of biology, but perhaps are best known for their longevity: even the shortest-lived species (the chicken turtle, Deirochelys reticularia) exceed 20 years, whereas others, such as Galapagos and Aldabra giant tortoises, can live well over 150 years. Turtles also exhibit remarkable variation in adult body size. Theoretically, organisms with more cells and higher lifetime cellular turnover should face greater cancer risk. Therefore, large, long-lived species must have evolved mechanisms to mitigate this increased risk. On the basis of their considerable variation in both body mass and lifespan, turtles are a promising group for studying the evolution of natural cancer resistance. However, cancer reports in turtles remain exceedingly rare - far less common than in mammals, birds, or even other reptiles.

To build on previous studies, we analyzed 290 additional necropsies from 64 turtle species across eight zoos in Europe, the United Kingdom, and the United States, representing nine taxonomic families. Despite extensive taxonomic and geographic coverage - from the tiny black-breasted leaf turtle (Geoemyda spengleri; 150 grams) to the Galapagos giant tortoise (Chelonoidis spp.; less than 300 kilograms) - we found only one case of neoplasia, in the mata mata (Chelus fimbriata), with no malignancies detected. This corresponds to neoplasia and cancer prevalence estimates of 0.34% and 0%, respectively. These values are similar to those reported by other groups. Taken together, this data reinforces the conclusion that cancer is very uncommon in turtles. When cancer does occur, it rarely metastasizes, suggesting that turtles may possess biological or evolutionary traits contributing to their low cancer prevalence.

Genomic analyses of large, long-lived species such as Galapagos and Aldabra giant tortoises, have revealed positive selection and duplications in key tumor suppressor genes, metabolic regulators, immune response genes, and pathways involved in genome maintenance. Moreover, comparative studies indicate that Galapagos tortoises exhibit enriched expression of tumor suppressors, proteostasis regulators, and metabolic pathways associated with growth control, potentially contributing to their reduced cancer susceptibility. Functional assays in Galapagos giant tortoise cell lines further suggest an enhanced ability to trigger apoptosis to mitigate endoplasmic reticulum stress, which may help clear damaged cells before tumorigenesis can occur.

Link: https://doi.org/10.1093/biosci/biaf100

Some potentially damaging molecules are produced during the normal operation of metabolism. Cells have evolved numerous mechanisms to clean up that damage, but have also evolved to treat the presence of these damaging molecules as a part of the complex systems of signaling that regulate metabolism and cell maintenance. Thus when mitochondria are altered to produce a mild increase in reactive oxygen species (ROS), the usual byproduct of their production of the chemical energy store molecule adenosine triphosphate (ATP), cells react with increased maintenance and improved function. The end result in short-lived laboratory species such as nematodes and flies is a greater resilience to the damage of aging and a modestly extended life span. Researchers would like to tie this and similar exhibitions of mild stress producing a modest slowing of aging into a more unified big picture, and examining the oxidation of cysteine present in proteins in these processes is one step along that path.

Reactive oxygen species (ROS) and hydrogen sulfide (H2S) are naturally produced during metabolic processes. At physiological levels, they act as oxidation-reduction (redox) signaling molecules and regulate a myriad of cellular processes. Redox signaling occurs largely through rapid and reversible oxidation of reactive cysteine residues in target proteins, leading to changes in protein ligand binding affinity, subcellular localization, and function. Recent studies have demonstrated that ROS and H2S play an essential role in various longevity models, and that a mild increase in ROS or H2S levels is sufficient to extend lifespan in model organisms. Meanwhile, the number of aging-related proteins that are modulated by ROS- or H2S-mediated post-translational modification is constantly growing.

In this review, we aim to summarize key results that support cysteine-based redox regulation of organismal aging and lifespan. The human proteome contains ∼210,000 cysteine residues, and mass spectrometry-based chemoproteomics analyses reveal that thousands of cysteines are oxidant-sensitive. Under physiological conditions, ROS and H2S signaling are intrinsically connected via cysteine oxidation. For example, treating HeLa cells with EGF induces a transit increase in H2O2 production and promotes global sulfenylation, followed by a wave of proteome-wide cysteine persulfidation. H2O2-mediated sulfenylation of the active site cysteine Cys797 enhances EGF receptor (EGFR) tyrosine kinase activity, which is suppressed by pretreatment with H2S. These results suggest that ROS- and H2S-mediated cysteine modifications may play antagonistic roles in growth factor signaling, and raise an important question whether the crosstalk between ROS and H2S also exists in other processes including aging.

Link: https://doi.org/10.1016/j.redox.2025.103852

Researchers studying neurodegenerative conditions have increasingly focused on the role of microglia in recent years. Microglia are innate immune cells analogous to the macrophages found in the rest of the body. They undertake a broad range of tasks including defense against pathogens, destruction of malfunctioning cells, coordination of tissue maintenance and regeneration, and assisting in alterations to the networks of synaptic connections between neurons necessary for the function of the brain. With age, some microglia become overly active and inflammatory, while others become senescent, further exaggerating those behaviors. This is disruptive and harmful to the brain.

Separately, a body of evidence suggests that cholesterol metabolism in the brain becomes dysfunctional with age. The brain is separated from the rest of the body by the blood-brain barrier and the two sides separately conduct transport, recycling, and manufacture of cholesterol. Every cell needs cholesterol, an important component in cell membranes, but too much cholesterol in any given cell is toxic. A balance of manufacture, transport, and recycling is thus important. Outside the brain cholesterol is only manufactured in the liver and distributed via the circulatory system. In the brain, cholesterol is primarily manufactured by astrocytes, a large population of cells. The brain is much more cholesterol-rich than other tissues, and cholesterol metabolism is correspondingly more important.

Linking these two topics, dysregulation of cholesterol metabolism appears to be involved in inflammatory microglial dysfunction. Excess cholesterol in the form of lipid droplets is observed in microglia in the aged brain, for example. Further, the APOE protein is involved in cholesterol transport, and one of the variant sequences, APOEε4, is associated with a greater risk of Alzheimer's disease. Researchers have shown that this variant increases the vulnerability of microglia to cholesterol excess, making microglia more inflammatory and disruptive to brain tissue. Today's open access paper expands upon this link between cholesterol, microglia, and Alzheimer's disease.

Microglial States Are Susceptible to Senescence and Cholesterol Dysregulation in Alzheimer's Disease

Cellular senescence is a major contributor to aging-related degenerative diseases, including Alzheimer's disease (AD), but much less is known about the key cell types and pathways driving senescence mechanisms in the brain. We hypothesized that dysregulated cholesterol metabolism is central to cellular senescence in AD. We analyzed single-cell RNA-seq data from the The Religious Orders Study / Memory and Aging Project (ROSMAP) and Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD) cohorts to uncover cell type-specific senescence pathologies.

In ROSMAP single nuclei RNA-seq data (982,384 nuclei from postmortem prefrontal cortex), microglia emerged as central contributors to AD-associated senescence phenotypes among non-neuronal cells. Homeostatic, inflammatory, phagocytic, lipid-processing, and neuronal-surveillance microglial states were associated with AD-related senescence in both ROSMAP (152,459 microglia nuclei from six brain regions) and SEA-AD (82,486 microglia nuclei) via integrative analysis.

We assessed top senescence-associated bioprocesses and demonstrated that senescent microglia exhibit altered cholesterol-related processes and dysregulated cholesterol metabolism. We identified three gene co-expression modules representing cholesterol-related senescence signatures in postmortem brains. To validate these findings, we applied these signatures to snRNA-seq data from induced pluripotent stem cell derived microglia（iMGs) exposed to myelin, amyloid-β, apoptotic neurons, and synaptosomes. Treatment with AD-related substrates altered cholesterol-associated senescence signatures in iMGs.

This study provides the first human evidence that dysregulated cholesterol metabolism in microglia drives cellular senescence in AD. Targeting cholesterol pathways in senescent microglia is an attractive strategy to attenuate AD progression.

High levels of the circulating amino acid homocysteine are regarded as a risk factor for the development of atherosclerosis. It can occur due to dietary deficiency, particularly in B vitamins, but since elevated levels are fairly common in later life there are clearly other contributing factors. Well established approaches based on diet and supplements do exist to attempt to lower homocysteine levels. Researchers here provide evidence in an animal model for raised homocysteine to also contribute to the stiffness of arteries. Blood vessel stiffening can induce hypertension, which in turn can accelerate the growth of atherosclerotic plaques in blood vessel walls, and also increase the risk of plaque rupture to cause a heart attack or stroke.

Hyperhomocysteinemia, an elevated level of homocysteine in the blood, is an independent risk factor for atherosclerosis and, more generally, cardiovascular disease. However, its relationship with aortic biomechanics has not been investigated yet. To better understand the influence of elevated homocysteine levels on aortic biomechanics, we propose an animal model in which hyperhomocysteinemia, hypercholesterolemia, and their combination were induced in rabbits by balloon injury of the abdominal aorta, special diets, and intravenous homocysteine injections.

The effects of a diet deficient in B vitamins and choline, which are required for homocysteine degradation, a cholesterol-rich diet, their combination, and increased homocysteine concentration are investigated in relation to abdominal aortic biomechanics in rabbits. For this purpose, equibiaxial and non-equibiaxial extension tests were carried out, and the influence of risk factors on the stress-stretch relationship, mechanical anisotropy, and tissue inelasticity is discussed. The mechanical characterization of the tissue was supported by microstructural histological analyses.

Our study reveals that deficiency of B vitamins and choline cause aortic stiffening even in the absence of hypercholesterolemia, suggesting a possible independent role in the development of atherosclerosis. Further increasing homocysteine concentration through intravenous injections in rabbits fed B vitamins and choline-deficient diet also results in a stiffer stress response and more pronounced inelastic phenomena with respect to the control group.

Link: https://doi.org/10.1016/j.actbio.2025.06.003

Parkinson's disease and Lewy body dementia are synucleinopathies, forms of neurodegeneration characterized by the misfolding and aggregation of α-synuclein. Given an initial misfolding event, this pathology can spread from cell to cell through the nervous system and brain, one misfolded molecule encouraging others to also misfold in the same way. The resulting disruption of cell biochemistry kills neurons, particularly those involved in motor control. Here, researchers report evidence for particulate air pollution, known to correlate with increased risk of neurodegenerative conditions, to contribute to synucleinopathies by encouraging α-synuclein aggregation.

Researchers have uncovered a possible molecular connection between air pollution and an increased risk of developing Lewy body dementia (LBD). The team discovered that exposing mice to fine particulate air pollution (PM2.5) triggered formation of an abnormal alpha-synuclein (αSyn) strain, PM2.5-induced preformed fibril (PM-PFF). These toxic protein clusters shared key structural and disease-related features with those found in the brains of patients with Lewy body dementia.

The researchers also analyzed hospital data from 56.5 million U.S. patients admitted between 2000 and 2014 with neurodegenerative diseases. They focused on patients hospitalized for the first time with Lewy body-related conditions, and used data from the individuals' ZIP codes to estimate their long-term exposure to PM2.5. The scientists found that each interquartile range increase in PM2.5 concentration in these ZIP code areas resulted in a 17% higher risk of Parkinson's disease dementia and a 12% higher risk of dementia with Lewy bodies.

Exploring the biological reason for this association between exposure to PM2.5 and Lewy body dementia, the researchers then exposed both normal mice and mice genetically modified to lack the alpha-synuclein protein (αSyn-/- animals) to PM2.5 pollution every other day for a period of 10 months. "In normal mice, we saw brain atrophy, cell death and cognitive decline - symptoms similar to those in Lewy body dementia. But in mice lacking alpha-synuclein, the brain didn't exhibit any significant changes. We believe we've identified a core molecular link between PM2.5 exposure and the propagation of Lewy body dementia."

Link: https://www.genengnews.com/topics/translational-medicine/possible-molecular-link-between-air-pollution-and-lewy-body-dementia-identified/

The pharmaceutical industry suffers from all of the issues that plaque heavily regulated industries that have been heavily regulated for a long time. Costs increase, restrictions increase, the ability to create new medicines declines. Everyone sees at least part of the problem, but no one person and no one group is in a position to change enough of the perverse incentives that operate during regulatory capture in order to meaningfully steer away from a collapse into mediocrity and inability to make progress. People have certainly tried! The past few decades have seen intense lobbying and patient advocacy on the part of quite well funded groups and influential insiders in regulators and industry, aiming to reduce the cost and speed up regulatory approval of new therapies. Yet this is the same period of time in which the cost of drug development has more than doubled, largely due to increased regulatory requirements.

The article I'll point out today is written largely from the perspective of investors, entrepreneurs, and other businessfolk. The author advances the idea that (a) the way out of this present industry malaise is to make drugs to treat aging, because they will have a vastly greater value than present disease-specific drugs, and (b) that nearly everyone presently involved in the aging field is going about this in the wrong way. I largely agree at the high level, and perhaps would quibble on the details. Certainly, I think that the most practiced and well funded areas of biomedical research and development are a poor fit for the treatment of aging as a medical condition, particularly the present fixation on genetics and gene variants. Aging is universal. Certainly genetic variants have some small influence on the process, but the underlying mechanisms of aging are the same for everyone. This limits the scope of the benefits that can be achieved as a result of discovering a gene variant that reduces disease risk, understanding how it works, and then building drugs to manipulate the relevant mechanism.

We only have to look as far as atherosclerotic cardiovascular disease to see this in action. Every drug class that lowers LDL cholesterol (statins, PCSK9 inhibitors, etc) emerged from the discovery of human populations with a variant gene that exhibited lifelong low LDL cholesterol and consequent reduced risk of developing sufficient atherosclerosis to cause a heart attack or stroke (by as much as 50% for some variants). Yet reducing LDL cholesterol via small molecule drugs in later life has been shown to produce only a 10% to 20% reduction in mortality risk, many people cannot tolerate the side-effects of statins, and lowering LDL cholesterol does not regress existing atherosclerotic plaque reliably or to any great degree. This is not a curative approach.

Where are all the trillion dollar biotechs?

Of the many trends people chase in biotech, the only one that proves sure and consistent is declining returns. Even after adjusting for inflation, the number of new drugs approved per $1 billion of R&D spending has halved approximately every nine years since 1950. Deloitte's forecast R&D internal rate of return (IRR) for the top 20 pharmas fell below the industry's cost of capital (~7-8%) between 2019 and 2022. In other words, while the industry remained profitable overall, the incremental economics of R&D investment were value-eroding rather than value-creating. So, while other industries have a reason to treat the current market downturn as transient, the business of developing medicine has a more fundamental problem to deal with - it is quite literally shrinking out of existence.

When was the last time the industry managed to get the IRR number to go up? It wasn't better targets, it wasn't AI, and it wasn't cheap Chinese trials. Both in the case of the 2021 and 2024 industry comebacks, the average return on investment rose because of sales of drugs for extremely large patient populations - COVID-19 vaccines and GLP-1 receptor agonists. To me, big indications almost always mean age-related indications, since aging is the only disease that affects everyone ("aging is the biggest total addressable market (TAM) on Earth"). So if you asked me to write a recipe for an industry-wide fix, I would start with age-related diseases: Alzheimer's, sarcopenia, and heart disease. Solving those would almost certainly put pharma growth back on track. Yet in 2024, of the 50 new drugs approved, only 2 targeted age-related indications (Resmetirom and Donanemab). The same trend was true in all the previous years.

I generally don't subscribe to the idea that pharma isn't solving aging because their thinking is old-school or outdated. This ignores the fact that companies like Novartis, Regeneron, and Eli Lilly have long-standing "aging" research arms, and that many pharmas are experienced with multi-morbidity and all-cause mortality trials. If aging represents a trillion-dollar market, but the field still has little traction in addressing it, it's not because people with PhDs are blind to opportunities or complacent about the lack of progress. I've written about this before, but the reality is that, despite our best efforts and billions in investments, we just aren't very good at treating age-related diseases.

Our best heuristics for drug development are just failing to work here. First, genetic targets have poor propagation to late-stage damage. I think of genetic variants as models for early prevention. Unfortunately, factors that prevent late-stage disease are, in most cases, harmful to carry as a genetic variant in youth. For example, targets that ended up being successful for reducing fibrosis in age-related lung disease, idiopathic pulmonary fibrosis - like PDGFR, FGFR, and VEGFR - are essential for tissue repair, capillary growth, and connective tissue formation. This means our standard approach to discovering treatment targets is much harder to apply here.

In alternative approaches to target discovery, aging also breaks our intuition about cause and effect. We are used to the idea that, if something seemingly causes damage, then clearing it will fix the disease. In age-related macular degeneration, for instance, accumulation of complement proteins in extracellular retinal debris was one of the most consistent clinical features observed in patients. However, when complement cascade activation was pharmaceutically halted, there was no improvement in vision decline. Similarly, one of the most obvious features of Alzheimer's is amyloid plaques in post-mortem patient brains. Multiple drugs have now cleared plaques successfully, yet they show no evidence of improved cognition. In fact, most beta-amyloid drugs shrink patients' brains. Multidimensional problems, of course, require multidimensional solutions.

Most industries have eras when progress stalls before a new paradigm unlocks scale again. Electricity needed transmission grids, computers needed operating systems, and aviation needed jet engines. For biotech, whether the shift will come from new modalities, new regulatory frameworks, or entirely new ways to validate efficacy in humans is not yet clear, but we can, perhaps, outline the boundaries within that future will exist: manufacturing and trials should get cheaper with each run, regulations should become more adaptive, approval frameworks should increase and not decrease in variance, and new therapeutic modalities should focus on unlocking new biology, not just producing slightly better iterations on problems we already know how to solve. Until those new paradigms take hold, building a trillion-dollar biotech will remain caught in Lewis Carroll's logic: running as fast as we can just to stay in place, and twice as fast to make any real progress.

Exposure to particulate matter and other air pollution is generally agreed upon to be bad for long-term health. The worse the exposure, the worse the outcome. The epidemiological data is quite convincing, particularly studies in those parts of the world where, by happenstance, very similar populations are exposed to very different degrees of air pollution. The consensus on biological mechanisms is that pollutants interact with lung and airway tissues to provoke greater systemic inflammation. That inflammation in turn accelerates the onset and progression of all of the major fatal conditions of aging. Here the focus is on dementia, but other studies have shown similar influences on cardiovascular disease.

This cohort study used data associated with autopsy cases collected from 1999 to 2022 at the Center for Neurodegenerative Disease Research Brain Bank at the University of Pennsylvania. Data were analyzed from January to June 2025. Participants included 602 cases with common forms of dementia and/or movement disorders and older controls after excluding 429 cases with missing data on neuropathologic measures, demographic factors, APOE genotype, or residential address.

One-year mean PM2.5 concentration prior to death or prior to last Clinical Dementia Rating Sum of Boxes (CDR-SB) assessment was estimated using a spatiotemporal prediction model at residential addresses. Dementia severity was measured by CDR-SB scores. Ten dementia-associated neuropathologic measures representing Alzheimer's disease, Lewy body disease, limbic-predominant age-related TDP-43 encephalopathy, and cerebrovascular disease were graded or staged.

In a total of 602 autopsy cases (median age at death, 78 years), higher PM2.5 exposure prior to death was associated with increased odds of more severe Alzheimer disease neuropathologic change (ADNC) (odds ratio 1.19). In a subset of 287 cases with CDR-SB records (median age at death, 79 years), higher PM2.5 exposure prior to CDR-SB assessment was associated with greater cognitive and functional impairment (β = 0.48). Lastly, 63% of the association between higher PM2.5 exposure and greater cognitive and functional impairment was statistically mediated by ADNC (β = 0.30).

Link: https://doi.org/10.1001/jamaneurol.2025.3316

While the first blood-based assays are entering use for the early detection and diagnosis of Alzheimer's disease, they remain expensive and are so far employed for only a limited number of patients. More work is needed to identify associations between circulating factors and disease progression, in order to produce better combinations of biomarker assays that can be more widely deployed at a lower cost. Thus expect to see more research along the lines of the paper noted here, in which the association between loss of cognitive function and circulating levels of some of the better known biomarkers are more carefully studied in a given population.

Subjective cognitive decline (SCD) may be an early indicator of Alzheimer disease and related dementias (ADRD), yet its association with plasma biomarkers remains unclear among middle-aged and older adults. his cross-sectional study used survey-weighted data from the Study of Latinos-Investigation of Neurocognitive Aging, an ancillary study of the Hispanic Community Health Study/Study of Latinos. Participants were aged 50 to 86 years and resided in 4 major US cities. Data were collected from 2016 to 2018 and analyzed between December 2024 and June 2025.

Plasma biomarkers included amyloid-beta (Aβ42/Aβ40), phosphorylated tau-181 (ptau-181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). SCD was assessed using the short-form Everyday Cognition Scale (ECog-12), evaluating global-, executive-, and memory-related SCD, and a single-item cognitive concerns question.

Among 5,712 adults (mean age 63.47 years), higher ln(ptau-181) was associated with ECog-12 memory (unstandardized β = 0.088). Higher ln(NfL) levels were associated with greater ECog-12 global (unstandardized β = 0.169), executive (unstandardized β = 0.182), and memory (unstandardized β = 0.156) domains. Higher ln(GFAP) levels were associated with greater ECog-12 global (unstandardized β = 0.109) and executive (unstandardized β = 0.121) domains. Ln(Aβ42/40) was not associated with SCD domains. Cognitive concerns significantly modified the associations between ln(NfL) and ECog-12 domains, with more pronounced associations among those reporting cognitive concerns. These findings underscore the potential utility of p-tau181, NfL, and GFAP, but not Aβ42/40, in early ADRD detection strategies.

Link: https://doi.org/10.1001/jamanetworkopen.2025.31038

Senescent cells accumulate with age in tissues throughout the body, primarily when a cell reaches the Hayflick limit on replication, but also because of damage or stress. When a cell becomes senescent it ceases to replicate and undergoes profound metabolic changes that cause it to secrete a pro-inflammatory, pro-growth set of signals known as the senescence-associated secretory phenotype (SASP). This serves a useful purpose in the context of potentially cancerous cells, attracting the immune system to destroy them, and aids in regeneration from injury. In youth, senescent cells are efficiently destroyed by the immune system, but with advancing age this clearance slows down. A growing imbalance between creation and destruction allows senescent cells to accumulate, and the inflammatory signaling that is useful in the short term becomes increasingly harmful when sustained for the long term.

One of the possible approaches to the treatment of aging is to destroy senescent cells. While appearing to be beneficial in mice, extending life span and reversing age-related dysfunction in many studies, there are some concerns that removing senescent cells could cause harm in some contexts. For example if senescent cells are supporting the structure of a sizable atherosclerotic plaque then clearing them could increase the risk of plaque rupture and a consequent heart attack or stroke. While not yet supported by a sizable body of evidence, this viewpoint has led a number of research teams to search for ways to reduce the SASP rather than destroy senescent cells. If a senescent cell just sat there and did not signal, then its contribution to degenerative aging would be largely eliminated. One might look at the senescent cells in long-lived naked mole-rats, for example, as they exhibit an attenuated SASP and do not appear to contribute to aging in way that senescent cells do in mice.

Thus one sees papers like today's open access research materials, in which researchers dig into the fine details of the mechanisms by which the senescent state triggers inflammatory signaling. Researchers are looking for potential targets for therapies that could interfere in the generation of the SASP without causing meaningful side-effects in the biochemistry of non-senescent cells.

Targeting CyclinD1-CDK6 to Mitigate Senescence-Driven Inflammation and Age-Associated Functional Decline

Cellular senescence is a stable form of cell-cycle arrest triggered by stresses such as DNA damage, oncogene activation, and telomere shortening. Senescent cells accumulate with age in many tissues and contribute to chronic inflammation, tissue dysfunction, and age-related pathologies through secretion of pro-inflammatory cytokines, chemokines, and interferon-stimulated genes (ISGs), collectively termed the senescence-associated secretory phenotype (SASP). Persistent DNA damage signaling in senescent cells promotes the formation of cytoplasmic chromatin fragments (CCFs) and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which sustains SASP and systemic inflammation. Identifying the molecular drivers that maintain this chronic inflammatory state is essential for understanding and targeting age-related dysfunction.

Cyclin D1 (CCND1), classically defined as a regulator of G1 progression through activation of CDK4/CDK6 and phosphorylation of the retinoblastoma protein (pRB), is paradoxically elevated in senescence despite proliferative arrest. The functional significance of CCND1 upregulation in non-proliferating, senescent cells remain unclear. Moreover, whether CCND1's unconventional accumulation contributes causally to persistent DNA damage signaling, cytoplasmic chromatin stress, or inflammatory gene expression has not been explored.

Here, we investigate the role of CCND1 and its associated kinase CDK6 in sustaining DNA damage, cytosolic chromatin accumulation, and inflammatory signaling in senescence. Using complementary in vitro and in vivo models, we reveal an essential role for the CCND1-CDK6 complex in promoting persistent DNA damage, CCF formation, and cGAS-STING-driven inflammation. Mechanistically, we identify previously unrecognized interactions between CCND1 and chromatin-associated kinesin proteins, such as KIF4A, which has been implicated in chromatin architecture and DNA repair. Finally, we show that genetic ablation of CCND1 in aged hepatocytes or pharmacological inhibition of CDK4/6 significantly attenuates chronic inflammatory signaling and ameliorates age-associated functional decline, suggesting broad therapeutic implications.

The category of glial cells covers all of the supporting cells of the brain, everything not a neuron, a big tent that includes immune cells such as microglia, the oligodendrocytes that manufacture myelin sheathing for axons, and the sizable astrocyte population, among others. These are very different cell populations with very different functions and behaviors, but all become dysfunctional with age. The present consensus is that glial cell dysfunction is important in aging and neurodegenerative conditions, each population contributing to loss of cognitive function in various ways. Given the size of the topic and the complexity of the brain, a review such as this one can really only skate the surface, however, even when focusing on only one region of the brain.

Among brain regions, the cerebellum (CBL) has traditionally been associated with motor control. However, increasing evidence from connectomics and functional imaging has expanded this view, revealing its involvement in a wide range of cognitive and integrative processes. Despite this emerging relevance, the CBL has received comparatively less attention in aging research, which has focused mainly on other central nervous system (CNS) regions such as the neocortex and hippocampus.

This review synthesizes the current evidence on glial cell aging across the CNS, emphasizing how cerebellar circuits follow distinct trajectories in terms of cellular remodeling, transcriptional reprogramming, and structural vulnerability. Recent findings highlight that cerebellar astrocytes and microglia exhibit specific signatures related to aging compared to their cortical counterpart, including moderate reactivity, selective immune response, and spatial reorganization. Cerebellar white matter (WM) undergoes structural alteration, suggesting that oligodendroglial cells may undergo region-specific alterations, particularly within WM tracts, although these aspects remain underexplored.

Despite the presence of glial remodeling, the CBL maintains a notable degree of structural and functional integrity during aging. This resilience may be the result of the CBL's ability to maintain synaptic adaptability and homeostatic balance, supported by its highly organized and compartmentalized architecture. A better understanding of the dynamics of cerebellar glial cells in aging may provide new insight into the mechanisms of brain maintenance and identify potential biomarkers for healthy brain aging.

Link: https://doi.org/10.3390/ijms26157553

Mouse data has consistently shown fisetin to be senolytic, capable of selectively destroying the senescent cells that accumulate in tissues with age. Doses most often used are equivalent to around 20 mg/kg in humans, but dosing strategies range from a one-time course of treatment of a few days to intermittent doses provided over months. Unfortunately, despite planned and actually undertaken human trials of fisetin supplementation, there is still no published data of its senolytic capacity in humans. The dasatinib and quercertin combination and the locally delivered senolytic developed by UNITY Biotechnology before they ran out of funds remain the only senolytics with human data for clearance of senescent cells.

Advancing age is the strongest risk factor for cardiovascular diseases (CVDs), primarily due to progressive vascular endothelial dysfunction. Cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to age-related endothelial dysfunction by promoting mitochondrial oxidative stress and inflammation, which reduce nitric oxide (NO) bioavailability. However, the molecular changes in senescent endothelial cells and their role in endothelial dysfunction with aging remain incompletely unclear. As such, in this study we sought to identify the endothelial cell senescence-related signalling pathways, endothelial-derived SASP factors, and their impact on endothelial function with aging.

Single-cell transcriptomics was performed on aortas from young (6 months) and old (27 months) mice with and without in vivo senolytic treatment with fisetin (100 mg/kg/day administered in an intermittent dosing paradigm) to characterize endothelial cell senescence and transcript expression changes. Senescent endothelial cells exhibited elevated expression of SASP factors, particularly Cxcl12, which was reversed by fisetin supplementation, with responses also reflected in circulating CXCL12 concentrations. Plasma from old mice impaired endothelial function by inducing vascular cell senescence, reducing NO, increasing mitochondrial oxidative stress, and promoting endothelial-to-mesenchymal transition-effects partially driven by CXCL12 and prevented by fisetin.

Link: https://doi.org/10.1101/2025.08.13.670216

It is difficult to overstate the importance of immune system dysfunction as a component of degenerative aging. All of the common fatal age-related diseases are strongly connected to immune dysfunctions, particularly the chronic inflammation that occurs with age. At the high level, researchers tend to divide immune aging into two components: immunosenescence is a loss of the ability of the immune system to defend against pathogens and destroy unwanted cells; inflammaging is a state of continual, unresolved inflammatory signaling, a maladaptive reaction to the altered environment and molecular damage of aged tissues. Both immunosenescence and inflammaging are just different viewpoints into one very complex bundle of dysfunctional mechanisms, signals, behaviors, and cell populations, however. One does not occur without the other, because they both arise from the same underlying issues.

Identifying the underlying issues that give rise to immune aging is an important part of building therapies to reverse the dysfunction. Some areas of focus are more promising than others. For example, attempts to fairly bluntly manipulate the signaling environment to suppress inflammation by inhibiting specific circulating proteins or their interactions with receptors are favored by the research and development communities, even though these approaches also suppress necessary inflammatory signaling and thereby inhibit the effectiveness of the immune system. Better approaches include restoration of hematopoietic stem cell function in bone marrow, regrowth of the thymus, and adjustment of the gut microbiome, where in principle there will be much less in the way of unpleasant trade-offs between benefit and side-effect.

Targeting immunosenescence and inflammaging: advancing longevity research

Aging profoundly affects the immune system, leading to two interrelated phenomena: immunosenescence and inflammaging. Immunosenescence is characterized by the immune system's functional decline, reduced immune surveillance, diminished T cell diversity and a weakened response to new infections and vaccinations. Inflammaging, on the other hand, refers to chronic, low-grade inflammation driven by factors such as senescent cells, damage-associated molecular patterns, and alterations in the gut microbiome. Together, these processes accelerate tissue degeneration, systemic dysfunction, and the development of age-related diseases while further impairing immune function.

Emerging therapeutic strategies targeting immunosenescence and inflammaging offer hope for restoring immune balance, reducing inflammation, and extending healthspan. Interventions such as thymus rejuvenation, hematopoietic stem cell modulation and senolytic therapies can potentially combat immune decline. Additionally, technologies targeting IL-11 inhibition and toll-like receptors (TLR5 or TLR7) activation have effectively reduced chronic inflammation and enhanced immune resilience. Specifically, IL-11 inhibition mitigates systemic inflammation and supports tissue regeneration, while TLR5 or TLR7 activation strengthens immune function and promotes regenerative capacity, collectively contributing to lifespan extension.

However, understanding the complexity of immunosenescence and inflammaging is critical to developing effective therapeutic interventions. While chronic inflammation is often viewed as detrimental, inflammation plays a vital role in immune defense, tissue repair, and vaccine efficacy. The challenge lies in maintaining a balance - promoting inflammation's protective effects while mitigating its chronic, maladaptive impacts during aging. Ultimately, by addressing both immune decline and chronic inflammation, these strategies can potentially transform how aging and age-related diseases are managed. Success in these endeavors could extend lifespan and meaningfully improve healthspan, ensuring healthier aging for future generations.

Cardiovascular disease correlates very well with incidence of dementia, and this is well demonstrated via analysis of epidemiological data in papers such as the one noted here. Disruption of the flow of blood to the brain is a possible causal mechanism, but one can also consider that both classes of condition are driven by the same underlying processes, such as chronic inflammation. More generally, aspects of aging correlate because aging is an accumulation of damage throughout the body and damaged systems tend to become dysfunctional and fail. The correlation between cardiovascular disease and dementia is strong enough, however, to suggest an additional bidirectional relationship of direct causation.

Cardiovascular disease (CVD) and dementia represent two of the most pressing global health challenges, particularly in low- and middle-income countries. While vascular pathology is increasingly recognized as a contributor to cognitive decline, few studies have systematically explored the global association between CVD and dementia using standardized, population-level data. This study aimed to investigate the relationship between CVD and dementia incidence across 204 countries, stratified by economic status, development level, and geographic region.

Age-standardized incidence rates for cardiovascular disease (CVD) and dementia in 2021 were sourced from the Global Burden of Disease Study. Globally, CVD incidence was significantly associated with dementia incidence (Pearson r = 0.777; Spearman ρ = 0.868). CVD explained approximately 43.0% of the variance in dementia incidence at the population level (r^2 = 0.4303), even after adjusting for key confounders. The association was notably stronger in low- and middle-income countries and developing regions. Among CVD subtypes, peripheral arterial disease (β = 0.903), cardiomyopathy (β = 0.869), and atrial fibrillation (β = 0.708) demonstrated the strongest independent associations with dementia incidence.

Link: https://doi.org/10.1002/hsr2.71179

Losing weight improves health outcomes. To put it another way, carrying excess visceral fat tissue causes ongoing harm via a range of mechanisms connected to the disrupted, inflammatory metabolism it induces. Thus a growing number of studies demonstrate that weight loss achieved through GLP-1 receptor agonist use improves outcomes in the presently largely overweight populations of the wealthier regions of the world. It is always possible that GLP1-1 receptor agonist drugs have other effects that are meaningful along the way, but losing weight is so influential on health that very robust data would have to be presented to be convincing that non-weight-loss effects are important in the context of overweight individuals.

Heart failure with preserved ejection fraction (HFpEF) is a major cause of hospitalization, often occurring in patients with cardiometabolic comorbidities such as obesity and type 2 diabetes. Although early trials of semaglutide and tirzepatide have shown promising results in improving symptoms, those findings were based on few clinical events, leaving treatment recommendations uncertain.

To evaluate the effectiveness and safety of semaglutide and tirzepatide in patients with cardiometabolic HFpEF in clinical practice, five cohort studies were assessed using national US health care claims data from 2018 to 2024. Two cohort studies emulated the STEP-HFpEF DM (semaglutide) and SUMMIT (tirzepatide) trials to benchmark results. Eligibility criteria were then expanded to evaluate treatment effects in patients typically treated in clinical practice. Finally, a head-to-head comparison of tirzepatide and semaglutide was implemented. Follow-up was up to 52 weeks.

The primary end point was a composite of hospitalization for heart failure or all-cause mortality. In analyses using expanded eligibility criteria, 58,333 patients were included in the semaglutide vs sitagliptin cohort, 11,257 for tirzepatide vs sitagliptin, and 28,100 for tirzepatide vs semaglutide. Initiators of semaglutide (hazard ratio, HR, 0.58) and tirzepatide (HR, 0.42) had substantially lower risk of the primary end point compared with sitagliptin. Tirzepatide had no meaningfully lowered risk compared with semaglutide (HR, 0.86).

Link: https://doi.org/10.1001/jama.2025.14092

Cognitive function can be measured in many different ways. It is generally considered to consist of a number of different domains that are influenced by different aspects of brain physiology and biochemistry, and which can improve and decline to different degrees over the course of a lifetime. We should expect the various forms of memory, executive function, sensory processing, and cognitive control to be capable of differing in trajectories as degenerative aging progresses, for example. Indeed, studies show this to be the case. While the story of aging writ large is a story of decline, the details have considerable latitude to vary.

The brain develops, and then the brain declines. There is thus a peak of cognitive function, distributed across some range of chronological ages for a given population. The location of that peak will likely vary for the different domains of cognitive function in any specific study population for the reasons given above. Here, researchers show that cognitive control peaks relatively early in adult life, at least relative to the usual perceptions of the character of growing old. As matters actually progress, a person may be sharply intelligent in their late 20s, then not so sharp but a great deal more experienced in their late 40s. A part of that loss of sharpness is a decline in cognitive control.

When does our brain start getting 'old'? Charting the lifespan trajectories of cognitive control

Cognitive control refers to the cognitive process through which individuals regulate attention, thought, and action to achieve specific goals, allowing them to focus on objectives while excluding distractions. For example, maintaining concentration on reading in a library where people are conversing relies heavily on the cognitive control's regulation of attention. Although the patterns of cognitive and behavioral changes related to cognitive control have been well established and serve as diagnostic criteria for development-related and aging-related diseases, systematic research on the corresponding brain activities' changes with age remains limited.

This study collected 139 neuroimaging studies related to cognitive conflict tasks, encompassing 3,765 participants aged 5 to 85 years. Through systematic meta-analysis using seed-based effect size mapping (SDM), generalized additive models (GAM), and model comparison methods, researchers were able to construct the lifespan trajectory of brain activities associated with cognitive control for the first time. The core finding revealed a significant inverted U-shaped lifespan developmental trajectory, where brain activity gradually increases during childhood and adolescence, peaks during adulthood, and slowly declines in later life. The GAM-fitted peak age was found to be between 27 and 36 years.

This period coincides with the peak of individual intellectual maturity and overall cognitive ability, providing a scientific explanation for the high social productivity and creativity exhibited by humans during this phase from a neural mechanism perspective. Notably, the gradual decline in brain function following this peak period suggests the need to prioritize the maintenance and exercise of brain function during middle adulthood to mitigate potential cognitive decline associated with aging.

The lifespan trajectories of brain activities related to conflict-driven cognitive control

Cognitive control is fundamental to human goal-directed behavior. Understanding its trajectory across the lifespan is crucial for optimizing cognitive function throughout life, particularly during periods of rapid development and decline. While existing studies have revealed an inverted U-shaped trajectory of cognitive control in both behavioral and anatomical domains, the age-related changes in functional brain activities remain poorly understood.

To bridge this gap, we conducted a comprehensive meta-analysis of 139 neuroimaging studies using conflict tasks, encompassing 3765 participants aged 5 to 85 years. We adopted the seed-based d mapping (SDM), generalized additive model (GAM), and model comparison approaches to investigate age-related changes in brain activities to characterize the lifespan trajectories of cognitive control. Our analyses revealed two key findings: (1) The predominant lifespan trajectory is inverted U-shaped, rising from childhood to peak in young adulthood (between 27 and 36 years) before declining in later adulthood; (2) Both the youth and the elderly show weaker brain activities and greater left laterality than young adults. These results collectively reveal the lifespan trajectories of cognitive control, highlighting systematic fluctuations in brain activities with age.