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- Treating Aging as the Cure for the Pharmaceutical Industry's Financial Woes
- Microglial Dysfunction and Cholesterol Metabolism Dysregulation in the Aging Brain
- Endothelin B Receptor Inhibition Improves Axon Regrowth Following Injury
- Fragmentation of Protein Aggregates is Needed for Clearance via Aggrephagy
- Bringing Affordable VEGF Gene Therapy to Medical Tourism Clinics
- Continued Efforts to Identify Blood Biomarkers for Early Alzheimer's Disease
- Greater Particulate Air Pollution Correlates with Greater Severity of Dementia
- Evidence for Particulate Air Pollution to Encourage α-Synuclein Aggregation
- Elevated Homocysteine as a Contributing Cause of Aortic Stiffness
- Cysteine in Longevity-Related Redox Signaling
- Long-Lived Turtles are Highly Resistant to Cancer
- Pro-Inflammatory Macrophages in Muscle Regeneration
- In Search of Specific Links Between the Gut Microbiome and Aging
- Immune System Aging as an Important Contribution to Osteoporosis
- Senescent Cells Accumulate Iron While Resisting the Consequent Ferroptosis
Treating Aging as the Cure for the Pharmaceutical Industry's Financial Woes
https://www.fightaging.org/archives/2025/09/treating-aging-as-the-cure-for-the-pharmaceutical-industrys-financial-woes/
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-sized 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-sized 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-sized 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.
Microglial Dysfunction and Cholesterol Metabolism Dysregulation in the Aging Brain
https://www.fightaging.org/archives/2025/09/microglial-dysfunction-and-cholesterol-metabolism-dysregulation-in-the-aging-brain/
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.
Endothelin B Receptor Inhibition Improves Axon Regrowth Following Injury
https://www.fightaging.org/archives/2025/09/endothelin-b-receptor-inhibition-improves-axon-regrowth-following-injury/
The peripheral nervous system is capable of regeneration, albeit not as much as desired. Lasting loss of function following injury is certainly possible, particularly following injury to larger nerves. The research community has long been interested in finding ways to improve this situation, some of which might be applicable to the much less regenerative central nervous system as well. Peripheral nerves are made up of bundled axons, long connections between neurons that pass signals back and forth. It is the regeneration of these axons that is the primary concern. Peripheral nervous system axons can be as much as several feet long, but even these are capable of regeneration and regrowth - at least until old age dismantles this ability along with many others.
In today's open access paper, researchers uncover an approach to improving peripheral axon regeneration that works in both young and old tissues. This appears to function at least in part by changing the behavior of the satellite glial cells that surround peripheral neurons making up nerve ganglia. The function of these glial cells is not completely understood, and therefore how this approach functions in detail is not completely understood. At the high level, it seems likely that (a) satellite glial cells regulate the environment of the ganglia in ways that are conducive to normal function, analogous to the supporting role of glial cells in the brain, (b) their ability to do this declines with age, and © there are ways to favorably change the behavior of satellite glial cells that have few negative consequences. The small molecule drug used in this study may or may not count as one of those ways, but more targeted approaches can be envisaged.
Endothelin B receptor inhibition rescues aging-dependent neuronal regenerative decline
Peripheral sensory neurons regenerate their axons after injury to regain function, but this ability declines with age. The mechanisms behind this decline are not fully understood. While excessive production of endothelin 1 (ET-1), a potent vasoconstrictor, is linked to many diseases that increase with age, the role of ET-1 and its receptors in axon regeneration is unknown.
Using single-cell RNA sequencing, we show that satellite glial cells (SGCs), which completely envelop the sensory neuron cell body residing in the dorsal root ganglia (DRG), express the endothelin B receptor (ETBR), while ET-1 is expressed by endothelial cells. Inhibition of ETBR ex vivo in DRG explant cultures improves axon growth in both adult and aged conditions.
In vivo, treatment with the FDA-approved compound, Bosentan, a ETBR/ETAR antagonist used to treat pulmonary hypertension, improves axon regeneration and reverses the age-dependent decrease in axonal regenerative capacity. Single-nuclei RNA sequencing and electron microscopy analyses reveal a decreased abundance of SGCs in aged mice compared to adult mice. Additionally, the decreased expression of connexin 43 (Cx43) in SGCs in aged mice after nerve injury is partially rescued by Bosentan treatment.
These results reveal that inhibiting ETBR function enhances axon regeneration and rescues the age-dependent decrease in axonal regenerative capacity, providing a potential avenue for future therapies.
Fragmentation of Protein Aggregates is Needed for Clearance via Aggrephagy
https://www.fightaging.org/archives/2025/09/fragmentation-of-protein-aggregates-is-needed-for-clearance-via-aggrephagy/
Many proteins can form transient aggregates, in which misfolding or chemical decoration allows solid clumps of protein to precipitate from solution and disrupt cellular biochemistry. A much smaller number of proteins can form persistent aggregates, however, and this unfortunate mechanism is an important contributing cause of a variety of age-related conditions. This is particularly the case in the brain. Consider amyloid-β, tau, and α-synuclein, for example, contributing to Alzheimer's, Parkinson's, and other neurodegenerative conditions. Meanwhile in the rest of the body, transthyretin amyloid is likely important in heart failure, while a number of other types of amyloid (such as medin) likely contribute to aging in more subtle ways.
Our biochemistry is capable of clearing protein aggregates via a form of autophagy called aggrephagy. Autophagy is the name given to a collection of processes that identify and flag unwanted molecules and structures, and in a variety of ways deliver those flagged molecules and structures into a lysosome. Once inside a lysosome, enzymes break down the material for recycling. Clearly the normal operation of aggrephagy is not sufficient to the task of keeping persistent aggregates from accumulating to cause disease, but it does have an impact. Thus the research community is interested in finding ways to meaningfully enhance the operation of aggrephagy. That in turn requires a better understanding of how exactly aggrephagy functions.
Your cells break down protein clumps to smaller pieces before taking it to the trash
A new study shows that our cells' ability to clean out old protein clumps, known as aggregates, also includes a previously unknown partnership with an engine that breaks down bigger pieces into smaller before "taking it to the trash." The process involves something called the proteasomal 19S subunit and DNAJB6-HSP70-HSP110 chaperone module, which together practically form a grinder. This is a very important key that may lead to better treatments of diseases like characterized Alzheimer's, Parkinson's, Huntington's, ALS, and other diseases that are characterized by the accumulation of clumps, in most cases formed by a specific protein
"We know that augmenting autophagy, which is one of the two major cleaning systems in our cells, can delay the onset of several of the devastating neurodegenerative diseases mentioned. Our findings suggest that a combined treatment where we enhance both the breaking down of the big protein clumps into smaller pieces to make them a better substrate for autophagy and autophagy, may be a much better therapeutic approach for these diseases. We are just starting to decipher the mechanism of this whole cell-cleaning process, and we need to deep dive into the details before we can start to work on actual treatments, but understanding how we can enhance it, will certainly help to eliminate, at least partially, those toxic protein aggregates leading to the above-mentioned lethal neurodegenerative diseases."
A chaperone-proteasome-based fragmentation machinery is essential for aggrephagy
Perturbations in protein quality control lead to the accumulation of misfolded proteins and protein aggregates, which can compromise health and lifespan. One key mechanism eliminating protein aggregates is aggrephagy, a selective type of autophagy. Here we reveal that fragmentation is required before autophagic clearance of various types of amorphous aggregates. This fragmentation requires both the 19S proteasomal regulatory particle and the DNAJB6-HSP70-HSP110 chaperone module. These two players are also essential for aggregate compaction that leads to the clustering of the selective autophagy receptors, which initiates the autophagic removal of the aggregates. We also found that the same players delay the formation of disease-associated huntingtin inclusions. This study assigns a novel function to the 19S regulatory particle and the DNAJB6-HSP70-HSP110 module, and uncovers that aggrephagy entails a piecemeal process, with relevance for proteinopathies.
Bringing Affordable VEGF Gene Therapy to Medical Tourism Clinics
https://www.fightaging.org/archives/2025/09/bringing-affordable-vegf-gene-therapy-to-medical-tourism-clinics/
Many classes of therapy can be robustly manufactured with little risk of issues and do not need the full cost in time, effort, and funds of Good Manufacturing Practice (GMP) specified by the FDA in order for any given batch of the drug to be demonstrated to be safe. The most frequently used AAV vector serotypes, for example, are relatively safe in this way. One can manufacture a batch of an AAV drug with any one of the very experienced manufacturers in the same way one would for research in animals, and then run all of the quality assays needed to demonstrate that the batch is safe. This costs a lot less than full GMP but should produce essentially equivalent outcomes in safety.
Medical tourism allows companies to bring drugs to the clinic in a responsible way without having to spend vast sums conforming to what the major regulators of the world, the FDA and EMA, believe is sufficient. Here I'll point out an example of a company doing this for VEGF gene therapy, a potential way to upregulate angiogenesis in order to reverse the age-related loss of capillary density that impairs function in tissues throughout the body. VEGF gene therapy in mice has been demonstrated to modestly extend life span. Forms of VEGF gene therapy have been trialed successfully in humans, and as noted here, have been approved in Russian for some years.
Keeping up with the longevity gene therapies
The recent revelation that Khloé Kardashian has received a gene therapy purported to promote tissue rejuvenation came as something of a surprise to many. The celebrity influencer received the capillary-boosting VEGF treatment from regenerative medicine specialist in Mexico. The therapy, which is claimed to help combat the age-related loss of vasculature in tissues and organs, was provided by Unlimited Bio, which operates out of Próspera, an autonomous special economic zone in Honduras designed to foster rapid biomedical innovation. The company says it is on a mission to conduct 100 clinical trials of genetic preventive therapies within 10 years, using the regulatory structures of Próspera to enable faster approvals and streamlined processes.
The founding mission of Unlimited Bio is ambitious: run 100 clinical trials within 10 years, building multiple gene therapies under one umbrella and combining them to combat the effects of aging. The first therapy to be offered by Unlimited Bio is a gene therapy delivered via plasmid, which delivers the genetic instructions for vascular endothelial growth factor (VEGF) into cells to stimulate the growth of new blood vessels (angiogenesis). "We wanted to start with a simple, well-established gene therapy. This therapy was first approved in Russia and Ukraine in 2011 for lower limb ischemia, and more than 10,000 patients have received it safely over 15 years. Of course, not everything that works for a disease will have benefits in healthy people, but VEGF is a unique case. Capillaries are essential for oxygen and nutrient delivery. With age, capillary density declines, which may contribute to sarcopenia and other age-related conditions. By enhancing capillarization, VEGF essentially upgrades our body's 'delivery system' - adding more roads for nutrients and oxygen to reach cells. That's why we believe it has strong longevity potential."
Unlimited Bio licensed the VEGF therapy for use in Prospera in preventive indications, and within six months of incorporation, had its first product on the market. While only a small number of people have received the treatment to date, the Kardashian effect is already being seen. "Since several well-known influencers received the therapy, interest has grown rapidly. I can say it is the most affordable preventive gene therapy worldwide - comparable to stem cell treatments."
Continued Efforts to Identify Blood Biomarkers for Early Alzheimer's Disease
https://www.fightaging.org/archives/2025/09/continued-efforts-to-identify-blood-biomarkers-for-early-alzheimers-disease/
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.
Greater Particulate Air Pollution Correlates with Greater Severity of Dementia
https://www.fightaging.org/archives/2025/09/greater-particulate-air-pollution-correlates-with-greater-severity-of-dementia/
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).
Evidence for Particulate Air Pollution to Encourage α-Synuclein Aggregation
https://www.fightaging.org/archives/2025/09/evidence-for-particulate-air-pollution-to-encourage-%ce%b1-synuclein-aggregation/
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."
Elevated Homocysteine as a Contributing Cause of Aortic Stiffness
https://www.fightaging.org/archives/2025/09/elevated-homocysteine-as-a-contributing-cause-of-aortic-stiffness/
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.
Cysteine in Longevity-Related Redox Signaling
https://www.fightaging.org/archives/2025/09/cysteine-in-longevity-related-redox-signaling/
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.
Long-Lived Turtles are Highly Resistant to Cancer
https://www.fightaging.org/archives/2025/09/long-lived-turtles-are-highly-resistant-to-cancer/
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.
Pro-Inflammatory Macrophages in Muscle Regeneration
https://www.fightaging.org/archives/2025/09/pro-inflammatory-macrophages-in-muscle-regeneration/
The innate immune cells known as macrophages adopt different packages of behaviors (known as polarizations) depending on circumstances. Most research is focused on the difference between the pro-inflammatory M1 polarization and the anti-inflammatory M2 polarization. M2 is considered to be more regenerative, and many issues in aging are thought to involve the presence of too many M1 macrophages. Yet M1 macrophages do play a role in regeneration, as noted here, and this contribution is also disrupted with age to inhibit the ability to regrow muscle in older individuals. This is one of the aspects of macrophage behavior that illustrates the limitations of the simple M1/M2 model; the underlying reality is more of a spectrum of behaviors, and one M1-like macrophage is not necessarily undertaking the same tasks as another.
Impaired muscle regrowth in aging is underpinned by reduced pro-inflammatory macrophage function and subsequently impaired muscle cellular remodeling. The essential role of pro-inflammatory macrophages during tissue remodeling are well appreciated given that they are early responders to facilitate the clearance of tissue debris and initiate intracellular communication such as stimulation of satellite cell proliferation and regulation of the deleterious accumulation of collagen and intramuscular adipose from fibroblasts and fibro-adipogenic progenitors.
Macrophage phenotype is metabolically controlled through citric acid cycle intermediate accumulation and activation of hypoxia-inducible factor 1-alpha (HIF1A). We hypothesized that transient hypoxia following disuse in old mice would enhance macrophage metabolic inflammatory function thereby improving muscle cellular remodeling and recovery. Old (20 months) and young adult mice (4 months) were exposed to acute (24h) normobaric hypoxia immediately following 14-days of hindlimb unloading and assessed during early re-ambulation (4- and 7-days) compared to age-matched controls.
Treated aged mice had improved pro-inflammatory macrophage profiles, muscle cellular remodeling, and functional muscle recovery to the levels of young control mice. Likewise, young adult mice had enhanced muscle remodeling and functional recovery when treated with acute hypoxia. Treatment in aged mice restored the muscle molecular fingerprint and biochemical spectral patterns (Raman Spectroscopy) observed in young mice and strongly correlated to improved collagen remodeling. Finally, intramuscular delivery of hypoxia-treated macrophages recapitulated the muscle remodeling and recovery effects of whole-body hypoxic exposure in old mice. These results emphasize the role of pro-inflammatory macrophages during muscle regrowth in aging and highlight immunometabolic approaches as a route to improve muscle cellular dynamics and regrowth.
In Search of Specific Links Between the Gut Microbiome and Aging
https://www.fightaging.org/archives/2025/09/in-search-of-specific-links-between-the-gut-microbiome-and-aging/
The composition of the gut microbiome changes with age, and researchers have demonstrated that many of these changes correlate with worse outcomes in aging. In animal studies, altering the composition of the gut microbiome to be more youthful produces health benefits, indicating that changes in the gut microbiome contribute to aging, but similar data in humans remains sparse. Mendelian randomization is a way to use genetic differences across a study population to infer whether or not a given correlation indicates causation. The results are not conclusive, but add support for causation to the be the case. Here, researchers mine a large database of gut microbiome composition, genetics, and health outcomes in an attempt to find specific cases in which an aspect of the gut microbiome, such as increased numbers of a given microbial species or altered production of a specific metabolite, is a contributing cause of an aspect of degenerative aging.
In the past 20 years, the involvement of gut microbiome in human health has received particular attention, but its contribution to age-related diseases remains unclear. To address this, we performed a comprehensive two-sample Mendelian Randomization investigation, testing 55,130 potential causal relationships between 37 traits representing gut microbiome composition and function and age-related phenotypes, including 1,472 inflammatory and cardiometabolic circulating plasma proteins from UK Biobank Pharma Proteomic Project and 18 complex traits.
A total of 91 causal relationships remained significant after multiple testing correction and sensitivity analyses, notably two with the risk of developing age-related macular degeneration and 89 with plasma proteins. The link between purine nucleotides degradation II aerobic pathway and apolipoprotein M was further replicated using independent genome-wide association study data. Finally, by taking advantage of previously reported biological function of Faecalibacterium prausnitzii we found evidence of regulation of six proteins by its function as mucosal-A antigen utilization.
These results support the role of gut microbiome as modulator of the inflammatory and cardiometabolic circuits, that may contribute to the onset of age-related diseases, albeit future studies are needed to investigate the underlying biological mechanisms.
Immune System Aging as an Important Contribution to Osteoporosis
https://www.fightaging.org/archives/2025/09/immune-system-aging-as-an-important-contribution-to-osteoporosis/
The aging of the immune system leads to chronic inflammatory signaling, a consequence of the accumulation of forms of molecular damage and the maladative changes in cell behavior that occur in response to that damage. It is easy enough to point to the inflammation of aging and link it to accelerated onset and progression of all of the common age-related conditions, as sustained inflammation is indeed disruptive to tissue structure and function throughout the body. It is likely that there are also other, more subtle mechanisms involved in the relationship between immune aging and any specific age-related condition, however.
Osteoporosis (OP) is a systemic skeletal disorder characterized by decreased bone mineral density (BMD) and deteriorated bone microarchitecture, which leads to an increased risk of fragility fractures. Noticeably, the immune system has been recognized as a crucial regulator in bone metabolism. In recent years, osteoimmunology studies have shown that the immune system plays a key role in bone remodeling. The term "immunoporosis" was first proposed in 2018 to establish a novel field emphasizing the role of immune cells in OP pathogenesis.
Specifically, immunoporosis refers to the immunology of OP: it denotes the immune-driven mechanisms that underlie bone fragility, focusing on age-related alterations in innate and adaptive immune cells. These alterations drive chronic low-grade inflammation and enhance responsiveness to damage-associated molecular patterns (DAMPs) and other stress signals, thereby disrupting bone remodeling and resulting in increased bone resorption and reduced bone formation. For instance, activated T cells (e.g., Th17 and Treg), proinflammatory cytokines [e.g., interleukin (IL)-17, tumor necrosis factor-alpha (TNF-α), and receptor activator of nuclear factor-κB ligand (RANKL)], and innate immune cells (e.g., dendritic cells (DCs) and macrophages) may promote osteoclast formation and bone loss.
Traditional therapies for OP (e.g., bisphosphonates, denosumab, and PTH analogs) have shown immunomodulatory properties, indicating the clinical significance of this immunological pathway. Critically, aging can lead to immunosenescence, a phenomenon marked by reduced immune cell diversity, functional decline, and increased inflammatory cytokine production. It may further drive inflammaging, a state of persistent, low-grade systemic inflammation that further exacerbates bone resorption and impairs bone formation. Inflammaging and immunosenescence are now accepted as central contributors to aging-related bone loss.
Senescent Cells Accumulate Iron While Resisting the Consequent Ferroptosis
https://www.fightaging.org/archives/2025/09/senescent-cells-accumulate-iron-while-resisting-the-consequent-ferroptosis/
Ferroptosis is a form of programmed cell death driven by iron accumulation and involving extensive lipid peroxidation as the kill mechanism. Senescent cells accumulate with age to cause tissue dysfunction and are resistant to programmed cell death. Most present approaches to the selective destruction of senescent cells as a form of therapy involve some form of sabotage of one or more programmed cell death resistance mechanisms. Here, researchers show that senescent cells both accumulate iron and resist ferroptosis, which suggests potential targets for novel forms of senolytic drug capable of selectively destroying senescent cells with minimal harm to normal cells.
Senescent cells, characterized by irreversible cell cycle arrest and inflammatory factor secretion, promote various age-related pathologies. Senescent cells exhibit resistance to ferroptosis, a form of iron-dependent cell death; however, the underlying mechanisms remain unclear. Here, we discovered that lysosomal acidity was crucial for lipid peroxidation and ferroptosis induction by cystine deprivation. In senescent cells, lysosomal alkalinization causes the aberrant retention of ferrous iron in lysosomes, resulting in resistance to ferroptosis.
Treatment with the V-ATPase activator EN6 restored lysosomal acidity and ferroptosis sensitivity in senescent cells. A similar ferroptosis resistance mechanism involving lysosomal alkalinization was observed in pancreatic cancer cell lines. EN6 treatment prevented pancreatic cancer development in xenograft and Kras mutant mouse models. Our findings reveal a link between lysosomal dysfunction and the regulation of ferroptosis, suggesting a therapeutic strategy for the treatment of age-related diseases.
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