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- Investigating the Slowing of Brain Aging via Calorie Restriction
- Reviewing the Landscape of Therapies for Transthyretin Amyloidosis
- Later Investors Eliminating the Ownership of Early Investors is an Ugly Reality in Longevity Biotech
- Interactions Between Oral and Gut Microbiomes in the Context of Age-Related Disease
- Evidence for Accelerated Epigenetic Aging to Correlate with Loss of Cognitive Function
- Physical Activity as the Lifestyle Choice with the Largest Effect on Late Life Mortality
- Accelerated Aging via Clock Measures Correlates with Increased Risk of Osteoporosis
- The Importance of Inflammation in Alzheimer's Disease
- Midkine is Protective in Alzheimer's Disease
- Towards a Better Understanding of Lysosomal Stress
- Changes Over Time in the Correlation Between Education and Biological Age
- Old Age and Low Fitness Independently Correlate with Risk of Arrhythmia
- Dysfunction in Cerebrovascular Blood Flow in Alzheimer's Disease
- Herpes Zoster Vaccination Correlates with Lower Risk of Stroke and Heart Attack
- Variant Sequences that Reduce IL-6 Signaling Correlate with a Lower Risk of Cardiovascular Disease
Investigating the Slowing of Brain Aging via Calorie Restriction
https://www.fightaging.org/archives/2025/09/investigating-the-slowing-of-brain-aging-via-calorie-restriction/
Calorie restriction is the practice of eating fewer calories, as much as a 40% reduction from the usual ad libitum calorie intake, while still obtaining an adequate level of micronutrients. Various forms of intermittent fasting also act as calorie restriction; the important factor is likely the length of time spent in a state of hunger. In a variety of animal species, calorie restriction has been shown to slow aging and extend life span, as well as produce sweeping positive changes to the operation of cellular metabolism in tissues throughout the body.
Human studies of mild long-term calorie restriction have reproduced the short-term changes, but there is no data on effects on life expectancy. Researchers expect calorie restriction to produce smaller changes in long-lived species such as our own than it does in short-lived species such as mice. The reasoning here is that the calorie restriction response evolved because of seasonal famine, a way for the individuals of short-lived species to increase the odds of later reproduction in a period of relative plenty. A season is a large fraction of a mouse life span, but not of a human life span - so only short-lived species exhibit large gains in life span via calorie restriction. Further, we might expect that long-lived species become long-lived in part because some of the beneficial changes produced by calorie restriction in short-lived species become enabled by default, throughout life.
Today's open access paper is illustrative of many similar efforts to investigate the fine details of the calorie restriction response in one specific organ. Here, the cell populations of the brain were the focus, and researchers profiled gene expression for hundreds of thousands of distinct cells in different brain regions. The results are quite interesting.
Spatiotemporal profiling reveals the impact of caloric restriction in the aging mammalian brain
Aging induces functional decline in the mammalian brain, increasing its vulnerability to cognitive impairments and neurodegenerative disorders. Among the various interventions to slow aging and delay age-related diseases, caloric restriction (CR) is particularly notable for its consistency in extending lifespan across species, including worms, flies, rats, and mice. Importantly, CR has demonstrated beneficial effects on brain function, enhancing learning and memory and increasing resilience against neurodegenerative diseases. However, established methods such as bulk transcriptomics yield little insight into how CR acts on highly heterogeneous brain cell populations and regions to mitigate the molecular and cellular changes of aging.
Recent advances in single-cell transcriptomics and spatial transcriptomics have enabled the precise measurement of gene expression changes across distinct cell populations and brain regions. However, the low throughput of standard approaches remains a challenge, impeding the study of how hundreds of different brain cell states respond to anti-aging treatments, particularly for rare yet critical aging-associated cell populations (e.g., neurogenic cells and activated microglia). To improve throughput, we recently developed two scalable approaches, EasySci and IRISeq, which enable comprehensive single-cell and spatial transcriptomic analysis of the mammalian brain across ages and conditions.
In this study, we profiled more than 500,000 cells from 36 control and CR mouse brains across three age groups with EasySci single-nucleus transcriptomics and performed imaging-free IRISeq spatial transcriptomics on twelve brain sections from CR and control aged mice. We thereby explored the impact of CR in more than 300 cellular states and 11 brain regions. CR delayed expansion of inflammatory cell populations, preserved neural precursor cells, and broadly reduced the expression of aging-associated genes involved in cellular stress, senescence, inflammation, and DNA damage. CR restored the expression of region-specific genes linked to cognitive function, myelin maintenance, and circadian rhythm. In summary, we provide a high-resolution spatiotemporal map of the aging mouse brain's response to CR, detailing precise cellular and molecular mechanisms behind its neuroprotective effects.
Reviewing the Landscape of Therapies for Transthyretin Amyloidosis
https://www.fightaging.org/archives/2025/09/reviewing-the-landscape-of-therapies-for-transthyretin-amyloidosis/
The transport protein transthyretin is one of the few proteins in the body capable of misfolding or otherwise becoming altered in ways that allow formation of solid deposits of aggregated proteins. These aggregates and their surrounding biochemistry are toxic, a contributing cause of age-related dysfunction and disease. Transthyretin amyloidosis may be near universal in older people, but only a tiny fraction develop this form of amyloidosis to the exaggerated level required for it to be identified and diagnosed. The more likely outcome for any given individual is that amyloidosis goes undiagnosed while nonetheless contributing to, for example, cardiovascular mortality.
Thus while therapies to treat transthyretin amyloidosis now exist, regulators and industry treat it as a rare disease, focused only on very severe instances of the condition, whether or not caused by mutation. This ensures that therapies are sold at the very high prices that characterize the rare disease industry, and in turn makes it hard to take the important next step, which is to greatly expand the detection of lesser degrees of amyloidosis and more widely deploy the best of the existing treatments for the condition, those lacking severe side-effects, into the broader aged population.
Advances in the treatment of transthyretin amyloidosis
Transthyretin (TTR) is a tetrameric plasma protein primarily synthesised by hepatocytes in the liver. It plays a key role in the transport of thyroxine (T4) and retinol-binding protein bound to vitamin A. More than 220 mutations in the TTR gene have been identified, many of which are associated with hereditary forms of amyloidosis. TTR amyloidosis occurs when the TTR tetramer dissociates into monomers, which then misfold and aggregate into insoluble amyloid fibrils. These oligomers eventually aggregate into amyloid fibrils that deposit extracellularly in tissues such as the peripheral nerves, myocardium, gastrointestinal tract, kidneys and eyes. These deposits disrupt tissue architecture and function, leading to organ dysfunction and clinical symptoms. Mutations in the TTR gene destabilise the tetramer structure, accelerating the aggregation process. However, even wild type TTR can form amyloid fibrils with ageing, leading to the non-hereditary form of the disease.
Once considered rare, transthyretin amyloidosis (ATTR) is now recognised as more prevalent, largely due to improved diagnostic methods. Wild type transthyretin amyloidosis (ATTRwt) occurs sporadically and primarily affects older men. Autopsy studies reveal that over 25% of men above age 80 years have cardiac ATTR deposits, most of which go unrecognised during life. Prospective imaging studies suggest that up to 13% of patients with heart failure with preserved ejection fraction (HFpEF) and 12% of those undergoing transcatheter aortic valve replacement have cardiac ATTR. These findings highlight the extent of underdiagnosis in elderly populations with cardiac symptoms.
In recent years, substantial progress has been achieved in the treatment of ATTR, fundamentally transforming the clinical outlook for affected individuals. The introduction of TTR stabilisers, gene-silencing therapies, and emerging disease-modifying approaches - including monoclonal antibodies and CRISPR-based genome editing - has enabled a more comprehensive and multifaceted approach to disease management. These therapeutic advancements, in combination with innovations in non-invasive diagnostic techniques such as scintigraphy and advanced cardiac imaging, have significantly improved the potential for early detection, which is crucial for optimising treatment outcomes.
Despite these remarkable developments, several important challenges and unanswered questions persist. One major gap is the absence of head-to-head clinical trials comparing the efficacy and safety of different therapeutic classes. Additionally, while multiple treatment modalities are now available or in late-stage development, the optimal sequencing of therapies - or whether combination treatments may confer additive or synergistic benefits - remains unclear. Another concern is the high cost and variable accessibility of novel therapies, particularly gene-based treatments and biologics. There is a pressing need for real-world data on cost-effectiveness and long-term clinical benefit, as well as strategies to ensure equitable access across diverse healthcare settings.
Later Investors Eliminating the Ownership of Early Investors is an Ugly Reality in Longevity Biotech
https://www.fightaging.org/archives/2025/09/later-investors-eliminating-the-ownership-of-early-investors-is-an-ugly-reality-in-longevity-biotech/
The market for investment in biotechnology and pharmaceutical startup companies is tough at the best of times. Executive teams have to content with the broad valley of death that lies between enthusiasm for a company with early preclinical results in mice and enthusiasm for a company with initial human clinical data. Satisfying regulators, setting up Good Manufacturing Practice (GMP) manufacture of a drug, and producing that clinical data is exceptionally expensive, and the reality is that relatively few investors fund companies in late preclinical stages, even when the market is good. As soon as the market sours, investors pull away from preclinical companies near entirely.
The longevity industry emerged outside the established biotechnology venture capital community, and most companies were largely funded by family offices, angel investors, and other entities that do not tend to act like venture capital. They tend to make a single investment and are done, and have somewhere between no representation or very limited representation on the company board of directors, whereas venture capital funds tend to make ongoing investments as a company moves forward, make larger investments, and do tend to have board seats. They also have much more experience in manipulating terms and contracts to their favor.
The market for biotechnology and pharmaceutical investment has not been good for several years now, for the longevity industry and everyone else. Preclinical companies with acceptably good technologies have been dying through the simple mechanism of failing to find investors willing to fund their work and consequently running out of runway. So it goes for every industry when times are bad. But even the relatively successful longevity industry companies are now being forced into very unfavorable terms by later stage professional investors in order to fund their initial clinical trials and further progress towards regulatory approval.
I am aware of a number of investment deals conducted this year by ostensibly successful longevity biotechnology and pharmaceutical companies (with clinical trials in process, with Big Pharma deals, with good results for their technologies) in which the early investors were essentially wiped out, had their stake in the company dramatically reduced. There are a number of established ways in which this can happen legally, and the structure most often seen is some variant of Pay to Play with compulsory conversion of shares and a pull-through provision. Existing stock is converted into new stock under very different terms. Early investors are asked to contribute a new investment under pro rata terms, and their stock largely eliminated (cut down by 5 to 1, 100 to 1, some other large number) if they do not do this. One viewpoint is that this is simply the realization of a loss of value that has already happened due to a poor market. Another view is that it is fair to call this theft and extortion, a very uneven distribution of that loss of value. Either way, early investors typically have no leverage in this situation, and any attempt to fight the imposed terms legally would cost more than is lost.
This squeezing out of early investors as a matter of course, whenever later stage investors can get away with it, is short-sighted, I feel. The investors who typically force such provisions on a company, and the executive teams who accept in exchange for some preservation of their stake in the company, are burning long-term relationships for short-term gain. No executive who goes along with this will ever receive early stage investment again from anyone involved in one of their Pay to Play exercises. Further, people talk. At the community level, once it becomes known that early stage biotech investors in the longevity industry are often eliminated in later rounds by predatory institutional investors, there will be little early stage investment. Who funds the preclinical work? Not those later stage investors. Where will their future deal flow come from? Who knows. This is not good for the industry, and not good for anyone involved.
Interactions Between Oral and Gut Microbiomes in the Context of Age-Related Disease
https://www.fightaging.org/archives/2025/09/interactions-between-oral-and-gut-microbiomes-in-the-context-of-age-related-disease/
The gut microbiome has received a great deal of attention in recent years, spurred by the ability to accurately and cheaply assess the composition of the gut microbiome, specific species and their proportions, via 16S rRNA sequencing. Researchers have demonstrated that the composition of the gut microbiome shifts with age to favor species that generate chronic inflammation at the expense of species producing beneficial metabolites needed for tissue function. Researchers are also turning these tools to the oral microbiome, a distinct set of populations that might also contribute to aspects of aging in various ways.
In today's open access review paper, the authors make the point that the oral microbiome and gut microbiome are not entirely independent of one another. Microbes and metabolites can move between the two via a number of pathways. The paper restricts its context of age-related disease to frailty and sarcopenia, but many of the points made can equally be applied to other common age-related conditions. The chronic inflammation of aging in particular is disruptive to tissue structure and function throughout the body, an important mechanism driving the pathology of many age-related conditions.
The Oral-Gut Microbiota Axis as a Mediator of Frailty and Sarcopenia
Traditionally studied in isolation, the oral and gut microbiota are now being recognized as interconnected through anatomical and physiological pathways forming a dynamic "oral-gut microbiota axis". Both oral and gut microbiota undergo changes with aging, characterized by a decline in microbial diversity and a shift toward potentially harmful species. Interactions between oral and gut microbiota occur mainly through three pathways namely the enteral, the bloodstream and the fecal-oral routes. Alterations in the oral-gut microbiota axis contribute to chronic low-grade inflammation (i.e., "inflammaging") and mitochondrial dysfunction, key mechanisms underlying frailty and sarcopenia.
Microbial metabolites, such as short-chain fatty acids and modified bile acids, appear to play an emerging role in influencing microbial homeostasis and muscle metabolism. Furthermore, poor oral health associated with microbial dysbiosis may contribute to altered eating patterns that negatively impact gut microbiota eubiosis, further exacerbating muscle decline and the degree of frailty. Strategies aimed at modulating the microbiota, such as healthy dietary patterns with reduced consumption of ultra-processed foods, refined carbohydrates and alcohol, ensuring an adequate protein intake combined with physical exercise, as well as supplementation with prebiotics, probiotics, and omega-3 polyunsaturated fatty acids, are increasingly recognized as promising interventions to improve both oral and gut microbiota health, with beneficial effects on frailty and sarcopenia.
A better understanding of the oral-gut microbiota axis offers promising insights into nutritional interventions and therapeutic strategies for the age-related muscle decline, frailty, and systemic health maintenance.
Evidence for Accelerated Epigenetic Aging to Correlate with Loss of Cognitive Function
https://www.fightaging.org/archives/2025/09/evidence-for-accelerated-epigenetic-aging-to-correlate-with-loss-of-cognitive-function/
Researchers have developed many aging clocks in recent years. Machine learning techniques are applied to large sets of biological data assessed at various ages in order to identify algorithms that predict chronological age, mortality risk, disease risk, or other measures of interest. If an individual has a predicted age higher than chronological age, this is known as accelerated biological age. A major challenge facing the use of clocks at present is that most clocks are inscrutable, in the sense that little to nothing is known of how the individual values making up the clock algorithm are linked to specific underlying mechanisms of aging or specific outcomes of age-related dysfunction and disease.
One path to making this situation better is to run as many clocks as possible in as many human studies as possible: accumulate as much data as possible and see what emerges from that data. Thus we should expect to see many publications that are similar to today's open access paper in the years ahead, in which researchers apply one or more clocks to a specific study and health context. Here, the context is age-related cognitive decline, assessed in a test conducted seven years after the collection of initial clock data. As we might expect for a good clock, accelerated biological age correlated with a greater loss of cognitive function.
Association of DNA methylation age acceleration with digital clock drawing test performance: the Framingham Heart Study
Neuropsychological (NP) tests are typically used to measure cognitive functions for individuals, focusing on one or several specific cognitive domains. For example, the long-used Clock Drawing Test (CDT) evaluates executive functioning and spatial skills. The digital Clock Drawing Test (dCDT), a digital version of the standardized CDT done with pen and paper, provides a much more robust assessment of cognitive functioning. We used linear mixed regression to evaluate the associations between epigenetic aging metrics (Horvath, Hannum, GrimAge, PhenoAge, DunedinPACE) and digital Clock Drawing Test (dCDT) scores in the Framingham Heart Study (FHS), adjusting for covariates.
Among the 1,789 FHS participants (mean age 65 ± 13, 53% women), higher epigenetic age acceleration metrics at baseline predicted lower dCDT scores approximately seven years later. The magnitude of these associations was greater in older participants (≥65 years, n = 985). The strongest association was observed between the dCDT total score and DunedinPACE in the full sample (beta = -2.1), the younger (<65 years; beta = -1.9), and older (beta = -2.2) age groups. Additionally, the dCDT total score was associated with age acceleration estimated by Horvath (beta = -1.9) and PhenoAge (beta = -2.5) in older participants, while not in the full sample or younger participants. Furthermore, higher levels of DNAm-based PAI1 (beta = -0.9) and ADM (beta = -2.9), components of GrimAge, were significantly associated with lower dCDT total scores. In analyses of cognitive subdomains, simple motor function was significantly associated with DunedinPACEin both age groups, and with GrimAge in the older age group, suggesting that deterioration in various organ systems may particularly impact this domain.
Our findings suggest that advanced biological aging, particularly as captured by DunedinPACE and GrimAge components, is significantly associated with poorer cognitive performance measured by dCDT, especially in older adults, highlighting a potential link between systemic aging processes and cognitive decline.
Physical Activity as the Lifestyle Choice with the Largest Effect on Late Life Mortality
https://www.fightaging.org/archives/2025/09/physical-activity-as-the-lifestyle-choice-with-the-largest-effect-on-late-life-mortality/
Physical activity is influential on long-term health. The correlation with health and longevity is well documented in many large human data sets, while animal studies of exercise and fitness demonstrates causation. One might also look at the epidemiology of hunter-gatherer populations that engage in considerably more physical activity than is the case for most humans, and observe the much reduced incidence of common age-related conditions in those individuals, relative to the sedate inhabitants of wealthier regions of the world. Here find yet another paper in which the authors report that a sizable human study population exhibits the expected relationship between physical activity and mortality. This is one of many.
We used data from the 2005-2018 waves of the Chinese Longitudinal Healthy Longevity Survey (CLHLS), including participants aged 60 years and older. Healthy Lifestyle Index (HLI) was constructed based on five modifiable factors: body mass index (BMI), smoking status, alcohol consumption, physical activity, and dietary intake. Multimorbidity was defined as the presence of two or more chronic conditions. Cox proportional hazards regression was employed to assess the associations between healthy lifestyle, multimorbidity, and all-cause mortality, with stratified analyses by age, sex, and urban-rural residence.
A total of 21,418 participants were included, with 15,113 deaths recorded over a median follow-up of 3.44 years. The age- and sex-adjusted mortality rate was 149.19 per 1,000 person-years. Among the lifestyle factors, physical activity showed the strongest association with reduced mortality (hazard ratio, HR=0.68). Participants with a healthy lifestyle had significantly lower all-cause mortality risk compared to those with an unhealthy lifestyle (HR=0.65). Notably, the protective effect was more pronounced among those with multimorbidity (HR=0.58) than those without (HR=0.65).
Accelerated Aging via Clock Measures Correlates with Increased Risk of Osteoporosis
https://www.fightaging.org/archives/2025/09/accelerated-aging-via-clock-measures-correlates-with-increased-risk-of-osteoporosis/
The near term path to verifying the utility of aging clocks is for the research community to accumulate as much data as possible for as many different clocks as possible, and then sift through it in search of correlations, problems, and reliability. Hence one should expect to see a great many studies in the years ahead that are similar to the one noted here. Some early clocks are known to have unexpected quirks in their sensitivity to interventions known to affect aging and incidence of age-related disease, which might make us suspicious of trusting their output when assessing a novel form of therapy aimed at slowing or reversing aspects of aging. Even clocks that are as well exercised as those used here will require some form of validation for the use of a given form of anti-aging therapy before the results can be taken at face value, and that validation will be a slow and costly process.
Osteoporosis is a major age-related musculoskeletal condition, yet chronological age does not fully capture individual risk. Biological age acceleration (BAA), as a biomarker of systemic aging, may offer greater predictive value for osteoporosis and lifespan loss. We analyzed data from 293,224 participants in the UK Biobank cohort who were free of osteoporosis at baseline. BAA was estimated using two validated models - Klemera-Doubal Method Biological Age (KDM-BA) and PhenoAge. Polygenic risk scores (PRS) were used to account for genetic susceptibility. Multivariable Cox models examined associations of BAA and PRS with incident osteoporosis and all-cause mortality.
Over a median follow-up of 8.5 years, 9,780 participants developed osteoporosis. Each one standard deviation (SD) increase in KDM-BA and PhenoAge acceleration was associated with a 22.6% and 19.3% higher risk of osteoporosis, respectively. Participants in the highest tertile of BAA had a 38-43% increased risk compared to those in the lowest tertile. Individuals with both high BAA and high PRS had nearly threefold higher osteoporosis risk, indicating a strong additive effect. Accelerated aging was also linked to a 1.3-1.8-year reduction in life expectancy at age 45, independent of osteoporosis status.
The Importance of Inflammation in Alzheimer's Disease
https://www.fightaging.org/archives/2025/09/the-importance-of-inflammation-in-alzheimers-disease/
Continual, unresolved inflammation is a feature of all of the common age-related conditions, and particularly so in the brain. When sustained for the long-term, inflammatory signaling is disruptive to tissue structure and function, and thus contributes to dysfunction and eventual mortality. Here, researchers focus on the role of the chronic inflammation of aging in Alzheimer's disease specifically, though most of what is said can be applied to the etiology of other neurodegenerative conditions as well.
Alzheimer's disease (AD) is an age-related neurodegenerative disorder and the most common cause of dementia. While the amyloid cascade hypothesis has long dominated AD research, emerging evidence suggests that neuroinflammation may play a more central role in disease onset and progression. Increasingly, AD is recognized as a multifactorial disorder influenced by systemic inflammation and immune dysregulation, shifting focus toward peripheral immune mechanisms as potential contributors to neurodegeneration.
This review explores the hypothesis that inflammaging, the age-related increase in pro-inflammatory mediators, combined with lifelong exposure to infections, injuries, metabolic changes, and chronic diseases, among others, may prime the immune system, amplifying neuroinflammation and influencing the progression and exacerbation of AD pathology. To this end, we examined how systemic immune disturbances, including chronic pain, post-operative cognitive dysfunction, viral and bacterial infections, gut microbiome dysregulation, and cardiovascular disease, may act as risk factors for AD. Overall, evidence suggests that modulating peripheral inflammation, accompanied by early diagnosis, could significantly reduce the risk of developing AD.
Furthermore, we highlight key immune signaling pathways involved in both central and peripheral immune responses, such as the NLRP3 inflammasome and TREM2, which represent promising therapeutic targets for modulating inflammation while preserving protective immune functions. Strategies aimed at reducing systemic inflammation, identifying early biomarkers, and intervening before significant neurodegeneration occurs may provide novel approaches to delay or prevent AD onset.
Midkine is Protective in Alzheimer's Disease
https://www.fightaging.org/archives/2025/09/midkine-is-protective-in-alzheimers-disease/
You might recall past research efforts to understand whether proteins found alongside amyloid-β aggregates in the aging brain were causing pathology, and possibly causing more pathology than the amyloid-β itself. One of those proteins is midkine, and here researchers present evidence for the presence of midkine close to amyloid-β to be a protective response that in fact hinders amyloid-β aggregation.
Proteomic profiling of Alzheimer's disease (AD) brains has identified numerous understudied proteins, including midkine (MDK), that are highly upregulated and correlated with amyloid-β (Aβ) from the early disease stage but their roles in disease progression are not fully understood. Here, we present that MDK attenuates Aβ assembly and influences amyloid formation in the 5xFAD amyloidosis mouse model.
MDK protein mitigates fibril formation of both Aβ40 and Aβ42 peptides according to thioflavin T fluorescence, circular dichroism, negative-stain electron microscopy, and nuclear magnetic resonance analyses. Knockout of the Mdk gene in 5xFAD increased amyloid formation and microglial activation in the brain. Further comprehensive mass-spectrometry-based profiling of the whole proteome in these mouse models indicated significant accumulation of Aβ and Aβ-correlated proteins, along with microglial components. Thus, our structural and mouse model studies reveal a protective role of MDK in counteracting amyloid pathology in AD.
Towards a Better Understanding of Lysosomal Stress
https://www.fightaging.org/archives/2025/09/towards-a-better-understanding-of-lysosomal-stress/
Lysosomes are recycling systems inside a cell, organelles that contain enzymes capable of breaking down proteins and cell structures into raw materials for reuse. The cell maintenance processes of autophagy are responsible for identifying proteins and structures that should be recycled and deliver them to a lysosome. Lysosomal dysfunction is a feature of aging in long-lived cells, as the lysosomes become filled with persistent metabolic waste that they struggle to break down. Enlargement of lysosomes is observed in this situation, and researchers here explore this phenomenon with an eye to find ways to manipulate lysosomal state to improve cell function.
A vacuole is a membrane-bound compartment inside cells, like a water balloon, that stores water, molecules, or waste. In plant cells, the central vacuole is large and helps store nutrients, regulate pressure and maintain structural rigidity. Animal cells don't usually have vacuoles, but they contain related compartments called lysosomes. Lysosomal vacuolation refers to a condition in which lysosomes become abnormally enlarged like overinflated balloons, resembling plant vacuoles.
Lysosomes are essential for cell health. Like a waste disposal system, they digest damaged proteins, worn-out parts, and invading microbes. By degrading a broad range of macromolecules, lysosomes preserve cellular function and longevity. Lysosomal vacuolation is thought to be an indication of stress or dysfunction of lysosomes, and these vacuoles are found in a large spectrum of medical conditions, including lysosomal storage disorders, aging, infection, chemotherapy, cataracts, cadmium toxicity, prion diseases, and other neurodegenerative conditions, such as Parkinson's and Alzheimer's disease.
"Lysosomal vacuolation has been observed in many diseases and has puzzled scientists for decades. However, we still don't know whether it is harmful or beneficial, largely because the mechanisms behind vacuole formation remain poorly understood. We found that cells have a well-developed system to drive lysosomal vacuolation. In response to many different types of stress, lysosomes become filled up with solutes, which draws in water and stretches the lysosomal membrane - like inflating a balloon. The potential risk of lysosomal rupture is detected by a protein we named LYVAC, or lysosomal vacuolator. LYVAC attaches to these stressed lysosomes, where it delivers lipids, which serve as membrane building blocks to allow lysosomal expansion in a controlled way."
"This process of lysosomal vacuolation is a natural, highly regulated response. LYVAC plays a central role in this process, helping cells adapt to stress and maintain lysosomal stability. By targeting LYVAC, we can begin to understand the exact roles that lysosomal vacuoles play in different diseases. If vacuole formation turns out to be a key driver of disease, then blocking LYVAC could offer a promising new treatment strategy."
Changes Over Time in the Correlation Between Education and Biological Age
https://www.fightaging.org/archives/2025/09/changes-over-time-in-the-correlation-between-education-and-biological-age/
Greater educational achievement is well established to correlate with greater life expectancy. It is one of a web of correlations linking longevity, intelligence, education, wealth, and socioeconomic status. Untangling the causes of these correlations remains a work in progress, and this will likely continue to be the case for the foreseeable future. Here, researchers use an aging clock based on clinical parameters to produce biological age estimates from past epidemiological study data to show how the correlation between education and biological age has changed over time. They find that educational achievement correlated with a greater slowing of biological age ten years ago than was the case thirty years ago.
It is interesting to speculate as to why this might be the case. We might start with the hypothesis that more approaches to intervention in aging, and more knowledge of those approaches, have become available over time. Equally, this could simply be a consequence of a general improvement in medicine and approaches to health, that have the side-effect of modest gains in life expectancy. Then consider that people with a greater degree of educational achievement tend to be better placed to make use of those improvements.
Educational inequality in health has been increasing in the United States. The growth in health inequality has not been limited to specific conditions but has been observed across a wide range of outcomes, including disability, multimorbidity, self-rated health, and mortality. This study used data for adults aged 50-79 from the National Health and Nutrition Examination Survey to assess changes in biological aging across education groups over a 25-year period.
We found that while biological aging slowed for each education group, educational inequality increased owing to greater improvements among those with the highest education levels. Specifically, biological age differences between adults with 0-11 years of schooling and adults with 16+ years of schooling grew from one year in 1988-1994 to almost two years in 2015-2018. Growing inequality in biological aging was not attenuated by changes in smoking, obesity, or medication use. Overall, these results point to an increasing difference in physiological dysregulation by education among U.S. older adults, which might remain a source of greater and growing inequality in morbidity, disability, and mortality in the near future.
Old Age and Low Fitness Independently Correlate with Risk of Arrhythmia
https://www.fightaging.org/archives/2025/09/old-age-and-low-fitness-independently-correlate-with-risk-of-arrhythmia/
Arrythmia can be a precursor of later, more severe heart issues, indicative of a level of dysfunction in heart tissue arising due to aging or other causes. It can also result from electrolyte imbalances that in turn arise from lifestyle choices. Arrythmia is generally taken as a point of concern by physicians where it occurs in older patients. Here, researchers show that a low level of fitness is independently a risk factor in the development of arrythmia, distinctly from old age. There are many other well-known reasons to maintain fitness into later life, but perhaps this finding will motivate an additional segment of the population.
New research has revealed that older age and low aerobic fitness levels are strong and independent risk factors for a high burden of heartbeat irregularities, known as arrhythmias, that indicate future cardiovascular risk. 1,151 healthy individuals aged between the ages of 40 and 65, without any heart symptoms or structural heart disease, took part in the study. The mean age of participants was 52 ± 7 years and 88% were men and 12% were female. Participants' fitness and heart health were monitored during exercise stress testing using portable and continuous electrocardiography (ECG) that records the heart's electrical activity, also known as Holter monitoring.
Researchers grouped participants by their 'median ectopy daily burden' which is the average percentage of premature or early heartbeats per day. They categorised the participants into having a low or high ectopy (irregular heartbeat) burden. They found that 32% of participants had supraventricular tachycardia, 4% had atrial fibrillation and 6% had nonsustained ventriculatachycardia - all of which are complex arrhythmias.
Analysis revealed that 'high atrial ectopic burden' was associated with older age, male sex, lower fitness levels, high blood pressure, and a measure of reduced kidney health. High ventricular ectopic burden was associated with older age and a measure of reduced kidney health - but was not related to fitness levels. Multivariable analysis confirmed that older age and lower fitness levels were strong, independent risk factors for atrial ectopy burden. The researchers found that the chance of arrhythmia increased by 9% per year for atrial and 4% per year for ventricular arrhythmia. Age-stratified analysis demonstrated a marked rise in arrhythmia prevalence starting from the 50-54 age group.
Dysfunction in Cerebrovascular Blood Flow in Alzheimer's Disease
https://www.fightaging.org/archives/2025/09/dysfunction-in-cerebrovascular-blood-flow-in-alzheimers-disease/
To what degree is the neurodegeneration of Alzheimer's disease driven by reduced blood flow to brain tissue? This is as compared to the contributions of the well-studied aggregation of amyloid-β and tau proteins, or the neuroinflammation driven by senescent cells, persistent viral infection, and various forms of molecular damage in and around cells. One of the challenges inherent in investigations of aging and age-related disease is that it is very hard to determine the relative importance of the range of mechanisms likely involved in producing pathology, loss of function, and eventual mortality. Here, however, the data suggests that vascular dysfunction may indeed be more important than protein aggregation, at least in the earlier stages of Alzheimer's disease.
Instead of looking at the brain's amyloid plaques, researchers focused on the way blood flow through the brain is autoregulated in order to oxygenate the brain tissue, and whether possible dysregulation may cause cognitive impairment. The study harnessed data from 200 participants over five years, investigating the intricate dynamic relationship between natural changes in arterial blood pressure, carbon dioxide (CO2) levels in the blood, and the resulting fluctuations of cerebral blood flow and cortical tissue oxygenation. "When we exert cognitive effort, we generate CO2 from the metabolism in our cerebral cells, which obviously has to be taken away by our blood to avoid acidosis. Our body is endowed with this regulatory mechanism called vasomotor reactivity, which dilates (widens) our cerebral vessels when CO2 goes up in the blood, so that more blood can go through and the excess CO2 be washed out."
Fifteen years ago, researchers made a serendipitous observation: Alzheimer's patients show impaired vasomotor reactivity. "They cannot dilate the cerebral vessels to bring more blood in and provide adequate blood perfusion to the brain. This means they don't get the oxygen, nutrients, and glucose that we need for cognition in a timely manner." In the new study, researchers tested this observation, developing a novel marker called the Cerebrovascular Dynamics Index (CDI). This non-invasive test uses non-invasive Doppler ultrasound to measure blood flow velocity in some main arteries of the brain, and near-infrared spectroscopy to measure oxygenation in the front part of the brain's cortex. This quantifies how quickly and effectively the brain's blood supply responds to subtle changes in pressure and CO2.
The research team obtained some encouraging results - The CDI showed excellent diagnostic performance, differentiating individuals with mild cognitive impairment (MCI) or Alzheimer's from cognitively normal control subjects with an Area Under the Curve (AUC) of 0.96. AUC is a common statistical measure of diagnostic performance; a value of 1.0 is perfect, and 0.5 is random chance. For context, the amyloid PET test achieved an AUC of only 0.78, while the Montreal Cognitive Assessment (MoCA) and mini-mental state examination (MMSE) cognitive tests were 0.92 and 0.91, respectively. The difference between 0.78 and 0.96 translated to a "very substantial improvement" in the test's ability to correctly identify those with and without the condition.
Herpes Zoster Vaccination Correlates with Lower Risk of Stroke and Heart Attack
https://www.fightaging.org/archives/2025/09/herpes-zoster-vaccination-correlates-with-lower-risk-of-stroke-and-heart-attack/
Vaccinations have been shown to produce a phenomenon called trained immunity. Effects include (a) increased responsiveness to pathogens other than the one vaccinated against, and (b) reduced chronic inflammation in later life. Trained immunity is well studied for the former phenomenon, but less well studied for the latter; questions remain as to whether different forms of vaccination for the same pathogen have different effects, for example. Correlations between later life vaccination and reduced risk of age-related disease and dysfunction have been observed, but it remains an open question as to whether this reflects trained immunity effects versus late life vaccination, a voluntary process, selecting for people who tend to take better care of their health in other ways as well.
A new global systematic literature review and meta-analysis has shown that herpes zoster vaccination, used to prevent shingles, is associated with a statistically significant lower risk of heart attack and stroke. The study found that herpes zoster vaccination, with either the recombinant herpes zoster vaccine (RZV) or the live attenuated zoster vaccine (ZVL) was associated with an 18% and 16% reduction in risk of cardiovascular events in adults 18 and 50 years or older, respectively. In studies that reported on cardiovascular event absolute risk, the absolute rate difference ranged from 1.2 to 2.2 fewer events per 1,000 person-years.
The global systematic literature review was conducted using three scientific literature databases, and a meta-analysis was conducted of phase 3 randomized controlled trials and observational studies assessing the effect of herpes zoster vaccination on cardiovascular events. 19 studies were included in the review; eight observational studies and one randomized controlled trial (a pooled safety analysis of two Phase 3 randomized trials; not designed or powered to evaluate the effects of herpes zoster vaccination against cardiovascular events), met the meta-analysis inclusion criteria for herpes zoster vaccination effectiveness on cardiovascular events. Across all nine studies, 53.3% of participants were male. Seven studies reported mean ages from 53.6 years to 74.0 years.
Variant Sequences that Reduce IL-6 Signaling Correlate with a Lower Risk of Cardiovascular Disease
https://www.fightaging.org/archives/2025/09/variant-sequences-that-reduce-il-6-signaling-correlate-with-a-lower-risk-of-cardiovascular-disease/
Researchers here analyze human genetic variants in the IL-6 gene to show that reduced IL-6 activity correlates with a lower risk of cardiovascular disease. Circulating IL-6 is generally thought of as a pro-inflammatory signal, and it is a target for the development of therapies. Chronic inflammation in later life is an important contribution to dysfunction and disease, and better control over this maladaptive inflammatory reaction to the cell and tissue damage that characterizes aging is a desirable goal.
Human genetics supports a causal involvement of IL-6 signaling in atherosclerotic cardiovascular disease, prompting the clinical development of anti-IL-6 therapies. Genetic evidence has historically focused on the IL-6 receptor (IL6R) missense variants, but emerging cardiovascular treatments target IL-6, not its receptor, questioning the translatability of genetic findings. Here we develop a genetic instrument for IL-6 signaling downregulation comprising IL-6 locus variants that mimic the effects of the anti-IL-6 antibody ziltivekimab and use it to predict the effects of IL-6 inhibition on cardiometabolic and safety endpoints.
Similar to IL6R, we found that genetically downregulated IL-6 signaling via IL-6 perturbation is associated with lower lifetime risks of coronary artery disease, peripheral artery disease, and ischemic atherosclerotic stroke in individuals of European and East Asian ancestry. Unlike IL6R missense variants linked to bacterial infections, the IL6 instrument was associated with lower risk of pneumonia hospitalization. Our data suggest that IL-6 inhibition can reduce cardiovascular risk without major unexpected safety concerns related to the response to infection.
View the full article at FightAging
