A Review of Targeting Senescent Cells to Treat Age-Related Conditions

Senescent cells cease to replicate and start to secrete a potent mix of growth factors and inflammatory signals. In youth, senescent cells are removed fairly rapidly by the immune system or mechanisms of programmed cell death. They are created constantly as cells reach the Hayflick limit on replication, but also as a result of potentially cancerous DNA damage or in response to injury. The normal, useful purpose of a senescent cell present for only a limited period of time is to help attract the attention of the immune system, coordinating regeneration and clearance of damaged cells.

Unfortunately the immune system falters in its task of clearing senescent cells as people become older, and a population of lingering senescent cells accumulates. The inflammatory signaling that is helpful in the short term becomes disruptive and harmful when sustained. Senescent cells provide a meaningful contribution to degenerative aging, and their signaling actively maintains tissue dysfunction. Studies in mice in recent years have demonstrated meaningful degrees of rejuvenation to result from the targeted removal of senescent cells in old animals.

A senotherapeutic drug is one that in some way targets senescent cells. Most of the focus is on senolytics, treatments that exploit one or more of the distinctive biochemical features of senescent cells in order to destroy them while minimizing harms to other cells. But there are other strategies, such as inhibiting entry to the senescent state, suppressing senescent cell signaling, improving the ability of the immune system to clear senescent cells, reversing the senescent state, and so forth.

In today's open access paper, the authors sketch a big tent when it comes to deciding whether or not a given therapy is senotherapeutic. Just about anything that upregulates autophagy could be called senotherapeutic for its ability to reduce the pace at which cells becoming senescent. We when look to the future we would like to see a more profound, rapid rejuvenation result from targeting senescent cells. We would like to see the research community improve greatly on early senolytics and their impressive results in aged mice, rather than focus on the modest effects produced by exercise or mTOR inhibitors like rapamycin, both of which upregulate autophagy and reduce the creation of new senescent cells.

Senescent cells as a target for anti-aging interventions: From senolytics to immune therapies

The selective elimination of senescent cells with molecule chemicals represents an innovative approach to target the hallmarks of aging. Since the discovery of the dasatinib and quercetin combination as the first senolytic agent, numerous clinical drugs, synthetic products and natural compounds have been identified as candidate senolytics and senomorphics. The therapeutic benefit of senolytics is supported by evidence from preclinical studies in diseased and physiological aging models, which has fueled their progression into multiple clinical trials. Mechanistically, most senolytics inhibit survival pathways to induce apoptosis in senescent cells with relatively little harm to normal, proliferating cells. On the other hand, senomorphics inhibit the senescence-associated secretory phenotype (SASP) expression and reduce inflammation in the surrounding tissue without inducing cell death, offering an often equally effective but safer alternative to senolytic drugs.

Despite the efforts of ongoing clinical trials, the safety profile of chronically administering these small molecule senotherapeutics remains to be validated. A primary consideration is the tradeoff broad-spectrum senolytic effect and the negative effects on normal proliferating cells, due to the lack of clearly defined boundaries between senescent and cells undergoing milder, but non-senescence-inducing stresses, or even non-senescent cells that express markers of senescence. For example, some well-known side effects of continuous navitoclax treatment include thrombocytopenia, internal bleeding, and neutropenia, which might arise from the inhibition of anti-apoptotic Bcl-2 family proteins in platelets and neutrophils. The same is true for other chemotherapeutic-derived senolytics, whose inherent genotoxicity may pose unwanted risks for normal cells. In contrast to small molecules, senescent cell associated antigen directed immune therapies offer a more targeted approach to senescent cells with uniquely upregulated surface markers. Preliminary studies have demonstrated efficacy in reducing senescent cell burden and improving physical parameters. However, there remains the question whether established such antigens are sufficiently representative of the heterogeneous senescent cell population, and to what extent they are able to ameliorate senescent cell burden in vivo. To date the number of candidate antigens remains relatively few, yet emerging technologies such as single cell proteomic and multi-omic analyses may dramatically enhancing the efficiency of antigen discovery.

During the development of senescent cell targeted therapies, it is important to note that the elimination of senescent cells may not always be beneficial. Cellular senescence is known to play beneficial roles during embryogenesis, wound healing, tumor suppression and maintenance of tissue integrity. Transient initiation of senescence as a response to liver damage or cutaneous injury is known to promote tissue regeneration and prevent excessive fibrosis. Studies have shown that genetic depletion of p16 high cells may lead to disrupted physical barrier and fibrogenesis in the liver, as p16-enriched sinusoids are eliminated without eliciting replacement by new cells. Where the elimination of senescent cells is unfeasible or may lead to adverse effects, reversing the senescent cell age through epigenetic reprogramming could be an alternative solution. Proof-of-concept studies with partial reprogramming have been successfully carried out through transient activation of Yamanaka factors or administration of chemicals. Although the full mechanism behind this epigenetic-mediated rejuvenation effect remains to be elucidated, it is nevertheless an intriguing research avenue awaiting future exploration.

To date, a number of senotherapeutics have progressed into clinical phase and tested in those with age-related disorders. Studies with longer durations in larger patient cohorts utilizing composite markers for a comprehensive evaluation of senescence are needed to thoroughly assess the long-term systemic effect of senotherapeutics in combating diseases and aging, hence their overall translational potential.

Since the characterization of the first senolytics, the field of senotherapeutics has expanded rapidly to encompass nearly all aspects of translational medicine. By integrating principles of pharmacological treatment and immunotherapy to eliminate or rejuvenate senescent cells, it is possible to achieve therapeutic effects superior to symptomatically intervening on aging-related diseases. Although unresolved challenges exist, we maintain a positive outlook that the safety and applicability of senotherapeutics will be improved. Continued efforts in this area of study, particularly in rigorous studies in discovery science and collaboration to validate the effectiveness and safety of senotherapeutics in clinical trials, hold great importance in combating aging and improving human longevity.

Hypertension Damages the Kidney Long Before Symptoms Arise

Studies show that the established pharmaceutical strategies for controlling high blood pressure produce a meaningful reduction in mortality risk, even though they do nothing to repair or reverse the underlying cell and tissue damage that causes hypertension. This outcome is possible because the raised blood pressure of hypertension is very damaging in and of itself, harming vital tissues throughout the body. The kidney is particular vulnerable to pressure damage, as researchers note here.

Researchers analysed kidney tissue from a total of 99 patients who either suffered from high blood pressure (arterial hypertension) and type 2 diabetes or did not have either of the two conditions. The investigation was conducted on unaffected renal tissue samples from tumour nephrectomies, a surgical procedure in which a kidney is removed in whole or in part to treat a kidney tumour.

Using modern imaging and computer-assisted methods, the size and density of the podocytes and the volume of the renal corpuscles (glomeruli) were determined in the tissue samples. Podocytes are specialised cells of the renal corpuscles (glomeruli) that play a crucial role in the filtering function of the kidney. Their size and density are important indicators of the health of the kidney tissue. Artificial intelligence in the form of deep-learning-based image analysis was used for the analysis. With the help of a specially trained algorithm, digital tissue sections were automatically analysed to precisely capture the structure of podocytes and glomeruli.

The results show that patients with hypertension have a reduced density of podocytes compared to healthy controls and that their cell nuclei are enlarged compared to those of healthy controls. These changes occurred independently of the additional diagnosis of type 2 diabetes and likely represent the first microscopically visible step towards impaired renal function. The study authors see this as an indication that high blood pressure can cause structural damage to the kidneys at an early stage and before clinical symptoms appear.

Link: https://www.meduniwien.ac.at/web/en/ueber-uns/news/2025/news-in-march-2025/hypertension-causes-kidney-changes-at-an-early-stage/

The Aging of the Adrenal Gland is Understudied

Researchers here review what is known of the structural and functional aging of the adrenal gland, and conclude that this is an understudied area. While it is fairly clear that changes in signaling generated by the adrenal gland can be hypothesized to be harmful over the long term, based on what is known of the roles of DHEA, cortisol, and so forth, it remains to be demonstrated conclusively that adrenal gland aging directly contributes to the onset and progression of the age-related conditions it correlates with.

Our hypothesis is that structural and functional changes of the adrenal cortex develop and progress with increasing age, resulting in reduced secretion of DHEA/DHEAS and increased secretion of cortisol. It is important to obtain further evidence to better characterise the degenerative changes of the adrenal cortex, and to elucidate the clinical consequences of this. Adrenal cortex senescence is an emerging entity which appears to fulfil the criteria for an ageing-related pathology.

Functional changes are observed with increasing chronological age, in particular there is reduced secretion of DHEA and DHEAS, and there is increased output of cortisol. Such changes are associated with a range of adverse clinical outcomes, including an increased risk of premature mortality, systemic lupus erythematosus (SLE), dementia, breast cancer, rheumatoid arthritis, schizophrenia, bipolar affective disorder, depression, Alzheimer's disease, diabetes, and low bone mineral density. These findings have been reported in studies carried out in humans.

However, further evidence is required before adrenal cortex senescence can be definitively regarded as an age-related pathology. Whilst numerous diseases are associated with low serum DHEA/DHEAS, this may just be an association, or a consequence of the disease process. It remains to be determined whether reduced secretion of DHEA/DHEAS has any pathological outcomes. Similarly, it is important to advance the understanding of whether the increased cortisol output observed with increasing age mediates any adverse clinical effects, its underlying pathophysiology, and to better characterise the ageing-related changes in aldosterone secretion. Furthermore, much of the research considering the structural and morphological changes of the ageing adrenal gland has been carried out in animal models, and evidence from human studies is relatively scarce.

Link: https://doi.org/10.1007/s40618-025-02566-9

The B Cell Population is More Inflammatory in Alzheimer's Patients

Chronic inflammation contributes to the onset and progression of all of the common age-related conditions. Researchers can examine a population of patients with a specific age-related disease and note specific differences in the immune system that contribute to inflammation. Because one is selecting for patients with greater inflammation by selecting those with the condition means that this sort of study may or may not represent a useful advance in knowledge. The need for better, more sophisticated approaches to reduce the chronic inflammation of old age is well understood. Some of these studies could reveal targets for the development of novel anti-inflammatory treatments, many will not.

The real challenge inherent to efforts to reduce late-life chronic inflammation is that, so far, it appears that the systems of regulation involved in maladaptive chronic inflammation are exactly the same as those needed for normal, transient inflammation. Changing the operation of the immune system to suppress unwanted inflammation also suppresses necessary inflammation, weakening the immune response to pathogens and potentially cancerous cells. The best path forward is to remove the age-related damage and dysfunction that provokes the immune system into inflammatory behavior, but comprehensively identifying and addressing all of those mechanisms that is a somewhat more distant prospect than the development of further ways to alter immune function.

Phenotypic alterations in peripheral blood B Lymphocytes of patients with Alzheimer's Disease

The immune system plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Microglia, the primary phagocytic cells in the brain, are responsible for the clearance of the amyloid-β (Aβ) and tau proteins. A significant number of AD-associated risk genes identified through genome-wide association studies (GWAS) are linked to the immune system. However, the phenotype and functional aspects of humoral immunity in AD remain incompletely understood. Our previous studies reported a panel of autoantibodies that are involved in the pathogenesis of AD. Other studies have also identified various autoantibodies in the circulation and cerebrospinal fluid of AD patients. In the AD brain, many brain-reactive autoantibodies are associated with Aβ deposition, supporting an autoimmune hypothesis in AD. Nevertheless, the mechanisms underlying the dysregulated autoantibody profile in AD have yet to be fully addressed.

B lymphocytes, a key component of the adaptive immune system, not only function as antigen-presenting cells to activate T cells and regulate inflammatory responses but also play a pivotal role in humoral immunity by secreting autoantibodies. We evaluated the immunophenotype of peripheral B lymphocytes in 27 AD patients confirmed by PET-Amyloid scan and 32 cognitively normal controls. We show that the phenotype of B lymphocytes is altered in AD patients. AD patients exhibit a decrease in both the numbers and proportions of switched memory (SwM) B cells and double-negative (DN) B cells. Additionally, B cells that produce proinflammatory cytokines including GM-CSF, IFN-γ, and TNF-α are increased, while those that produce the anti-inflammatory cytokine IL-10 are decreased in AD patients after in vitro stimulation. These alterations in B cell populations were linked to cognitive functions and biomarkers, including Aβ42/40 and pTau181, in AD patients.

UNITY Biotechnology Trial Results for Local Senolytics to Treat Macular Edema

UNITY Biotechnology was one of the first senolytics companies, and now conducts clinical trials of small molecule senolytic therapies based on well-established mechanisms by which senescent cells can be selectively forced into programmed cell death. The company has consistently pursued a strategy of delivering senolytic drugs locally to affect only specific diseased tissue, and has been criticized for doing so. Firstly such drugs will have limited off-label uses, and secondly for at least some conditions it seems plausible that local senescent cells are only part of the problem. There are many more senescent cells elsewhere in the body, and their signaling still contributes to inflammation in the affected organ. Still, it seems that UNITY's macular edema program has achieved better results in clinical trials than the program for knee osteoarthritis.

UNITY Biotechnology Announces Topline Results from the ASPIRE Phase 2b Study in Diabetic Macular Edema

UNITY Biotechnology, Inc., a biotechnology company developing therapeutics to slow, halt or reverse diseases of aging, today announced topline results from the Phase 2b ASPIRE clinical trial of intravitreal UBX1325 in patients with diabetic macular edema (DME) who had poor vision despite prior anti-VEGF treatment. UBX1325 is a novel BCL-xL inhibitor that is designed to eliminate senescent cells in diabetic retinal blood vessels, while leaving healthy ones intact. UBX1325 is administered via intravitreal injections that are standard procedure in clinical practice, minimizing treatment complexity and reducing the challenges of adapting to other technologies or surgical procedures.

Of the 1.7 million people in the U.S. with DME, approximately 750,000 patients have been diagnosed and are being treated. For the last 20 years, the standard of care for DME treatment has been anti-VEGF-related agents such as aflibercept. Despite vision improvements and stabilization with anti-VEGF therapy, one half of patients have a sub-optimal response and discontinue treatment after 6 months. For those that do respond, their vision gains generally plateau after 24 months of treatment and eventually start to decline despite cycling through different anti-VEGF treatment options.

The study results include data from all patients through 24 weeks, and the majority of patients through 36 weeks. UBX1325 treatment led to visual acuity gains of over 5 letters from baseline at weeks 24 and 36, and achieved non-inferiority to aflibercept at 9 out of 10 time points through 36 weeks, except for the average of weeks 20 and 24, where it achieved non-inferiority at an 88% confidence interval (compared to a 90% threshold pre-specified as primary analysis endpoint). UBX1325 continues to demonstrate a favorable safety and tolerability profile across multiple clinical studies to date. There have been no cases of intraocular inflammation, retinal artery occlusion, endophthalmitis or vasculitis across multiple studies.

Further Signs that Cholesterol Metabolism is Involved in the Development of Alzheimer's Disease

Excessive lipid droplets in brain cells, particularly microglia, are characteristic of a number of neurodegenerative conditions. Even though cholesterol is vital to cell function, excess cholesterol in cells is toxic, changing behavior for the worse or even killing cells given a large enough excess. A range of other evidence is also supportive of a role for changes in lipid metabolism, including cholesterol metabolism, in the development of conditions such as Alzheimer's disease. Here, researchers report a new finding that implicates the cholesterol intake of neurons in an area of the brain known to be vulnerable to Alzheimer's pathology.

Researchers gathered a large collection of brain tissue samples from deceased patients and compared two different brain regions within the same individual. From each brain, they collected a sample of the dopamine-producing Substantia Nigra (SN), a region resistant to degeneration in AD, and the noradrenaline-producing Locus Coeruleus (LC), a region that is highly vulnerable to Alzheimer's disease. The researchers then analyzed RNA from the different brain regions to measure the expression levels of different genes. They used this gene expression data to provide a full picture of which cellular processes vary between these two neuronal populations.

Their results showed a striking segregation between the LC and SN in how they regulate cholesterol levels. "One key difference between the brain regions had to do with cholesterol metabolism and homeostasis. The LC neurons exhibit signatures suggesting that they are super cholesterol-hungry - these neurons are doing both their best to produce their own cholesterol and take in as much as possible. The SN, on the other hand, doesn't have the same level of demands."

Using immunohistochemistry tissue staining - the gold standard to demonstrate proteins at single cell level in tissue from different cases - the researchers validated these findings. They found that the LC neurons express higher levels of LDLR, a part of a receptor called sigma-2 that helps cells take in cholesterol molecules. A consequence of this, is that toxic amyloid-beta oligomers (small clumps of amyloid-beta protein) may "sneak in" to the neurons via this same receptor. Conversely, the SN expresses a selective degrader of LDLR, making it less susceptible to these oligomers.

Link: https://www.eurekalert.org/news-releases/1078311

Reviewing the Role of Klotho in Aging and Kidney Disease

When people talk about the klotho gene, they usually mean α-klotho, one of the better documented longevity-associated genes. It encodes a transmembrane protein, is expressed in a number of organs that sheds a portion of its structure to circulate in blood and tissues, interacting with other cells. In animal models artificially increased klotho expression improves late life health and life span while artificially diminished klotho expression worsens late life health and reduces life span. Interestingly, increased levels of klotho can improve cognitive function even in young animals. In humans, data shows the same correlation between circulating levels of klotho and age-related health and longevity.

The mechanisms by which klotho affects health on an organ by organ basis are far from fully understood, particularly when it comes to effects on the brain. It is best understood in the kidney, where it is protective against damage and diminished function with age. One hypothesis is that its body-wide effects are secondary to to kidney function, that loss of kidney function is an important contribution to age-related issues throughout the body. It does seem likely that it has direct effects on other organs as well, however.

The usual challenge in mechanisms relating to aging is that many processes are underway at the same time, interacting with one another. It is somewhere between hard and impossible to determine the relative size of each contribution to the end result of pathology and disease. The fastest path to that goal is to produce a therapy that only affects one contribution and observe the outcomes, but that is not always possible or practical.

Klotho antiaging protein: molecular mechanisms and therapeutic potential in diseases

Aging is not only a compilation of ailments that occur in the later stages of life; it is a dynamic process that unfolds throughout the lifespan. The escalating issue of an aging population is a significant economic, social, and medical concern of modern society. Over time, aging causes a segmental and gradual loss of strength and biological function, which leads to a decline in resistance and increasing physiological weakness. Multiple biochemical pathways actively control aging. It is distinguished by a number of molecular and cellular features, including abnormal nutrient sensing, mitochondrial dysfunction, cellular senescence, epigenetic imbalance, and loss of connectivity between cells. Globally, chronic illnesses tend to be more common in the aging population. Chronic illnesses need lengthy therapy, which alters the character of healthcare facilities and raises demand for them.

On the other hand, Klotho is an anti-aging protein with diverse therapeutic roles in the pathophysiology of different organs, such as the kidneys and skeletal muscle. Numerous pathways implicated in aging processes are regulated by Klotho, including Wnt signaling, insulin signaling, and phosphate homeostasis. It also impacts intracellular signaling pathways, including TGF-β, p53/p21, cAMP, and protein kinase C (PKC). Klotho expression and circulation levels decrease with increasing age. Klotho-deficient mice have excessive phosphate levels because of phosphate excretion imbalance in the urine. However, they also exhibit a complicated phenotype that includes stunted development, atrophy of several organs, hypercalcemia, kidney fibrosis, cardiac hypertrophy, and reduced lifespans. Given that supplementation or Klotho gene expression has been shown to suppress and repair Klotho-deficient phenotypes, it is likely that Klotho might have a protective impact against aging illness.

Recent cross-sectional cohort research with 346 healthy individuals aged 18 to 85 years showed that serum Klotho levels are negatively correlated with age and that older individuals (ages 55 to 85) exhibited the lowest serum α-Klotho levels. Another observational cohort research, which had around 804 adults over 65 years old, was conducted in Italy and found a negative correlation between serum Klotho levels and all-cause mortality. Furthermore, those with decreased serum Klotho levels had a comparable increased risk for all-cause death, according to a meta-analysis of six cohort studies that included adult chronic kidney disease (CKD) patients. Additionally, preclinical research has demonstrated that overexpressing the Klotho gene in transgenic mice can postpone or reverse aging. Therefore, increasing Klotho levels emerges as a promising strategy in diabetic kidney disease, CKD, and aging disorders.

Fecal Microbiota Transplantation from Young Mice to Old Rats Reduces the Impact of Aging on the Heart

The aging of the gut microbiome involves a shift in the relative numbers of different microbial species. As a result the production of some beneficial metabolites declines while inflammatory microbial activities increase. At present there are few practical ways to permanently adjust the gut microbiome, one of which is the transplantation of fecal matter from a donor. Animal studies have demonstrated that fecal microbiota transplantation from a young animal to an old animal rejuvenates the gut microbiome, improves health, and extends life. Human studies are relatively limited, but this approach to treatment is established for patients with C. difficile infection. It remains to be seen as to whether it will find broader use, versus the more challenging approach of developing the means to culture a full or close to full gut microbiome artificially.

The gut microbiota has become a potential therapeutic target in several diseases, including cardiovascular diseases. Animal models of fecal microbiota transplantation (FMT) were established in elderly and young rats. 16S rRNA sequencing revealed that the gut microbiota of the recipients shifted toward the profile of the donors, with concomitant cardiac structure and diastolic function changes detected via ultrasound and positron emission tomography-computed tomography (PET-CT). The elderly recipient rats that received young fecal bacteria presented an overall reduction in aging characteristics, whereas young rats that received reverse transplantation presented an overall increase in aging characteristics.

After FMT, the structure and function of the hearts of the recipient rats changed correspondingly. The age-related thickening of the left ventricular wall and interventricular septum at the organ level, along with the disordered arrangement of cardiomyocytes and increased interstitial volume at the tissue level, decreased following FMT in young rats. These structural modifications are accompanied by alterations in cardiac function; however, systolic function did not significantly change, whereas diastolic function notably improved. The young rats that received reverse transplantation presented the opposite results as the aged rats did; that is, the structure and function of the heart were lower in the reverse-transplanted rats than in the same-aged control rats.

A group of significantly enriched myocardial metabolites detected by liquid chromatography-mass spectrometry (LC/MS) were involved in the fatty acid β-oxidation process. Together with altered glucose uptake, as revealed by PET-CT, changes in ATP content and mitochondrial structure further verified a metabolic difference related to energy among rats transplanted with the gut microbiota from donors of different ages. This study demonstrated that gut microbes may participate in the physiological aging process of the rat heart by regulating oxidative stress and autophagy. The gut microbiota has been shown to be involved in the natural aging of the heart at multiple levels, from the organ level to the metabolically plastic myocardiocytes and associated molecules.

Link: https://doi.org/10.1016/j.exger.2025.112734

ADAM19 Knockdown Reduces Harmful Senescent Cell Signaling in Flies

While much of the focus on cellular senescence in aging remains to find ways to selectively destroy these problem cells, there are also efforts to instead change their behavior. The reason why a growing burden of senescent cells in aged tissues is harmful, even when these cells make up only a tiny fraction of the overall cell population, is that they energetically secrete pro-inflammatory factors. This activity is disruptive to tissue structure and function when sustained over time. If senescent cells could be blocked from producing inflammatory secretions, their harms would be much reduced.

Accumulation of DNA damage can accelerate aging through cellular senescence. Previously, we established a Drosophila model to investigate the effects of radiation-induced DNA damage on the intestine. In this model, we examined irradiation-responsive senescence in the fly intestine. Through an unbiased genome-wide association study (GWAS) utilizing 156 strains from the Drosophila Genetic Reference Panel (DGRP), we identified meltrin (the drosophila orthologue of mammalian ADAM19) as a potential modulator of the senescence-associated secretory phenotype (SASP).

Knockdown of meltrin resulted in reduced gut permeability, DNA damage, and expression of the senescence marker β-galactosidase (SA-β-gal) in the fly gut following irradiation. Additionally, inhibition of ADAM19 in mice using batimastat-94 reduced gut permeability and inflammation in the gut. Our findings extend to human primary fibroblasts, where ADAM19 knockdown or pharmacological inhibition decreased expression of specific SASP factors and SA-β-gal. Furthermore, proteomics analysis of the secretory factor of senescent cells revealed a significant decrease in SASP factors associated with the ADAM19 cleavage site. These data suggest that ADAM19 inhibition could represent a novel senomorphic strategy.

Link: https://doi.org/10.18632/aging.206224

Human Glymphatic Function Declines with Age, Correlates with Cognitive Decline

Drainage of cerebrospinal fluid from the brain into the body is reduced with age. The known pathways become impaired. Firstly, drainage holes in the cribriform plate behind the nose ossify and close up. Secondly the glymphatic system that carries away fluid from the brain loses lymphatic vessel density and vessel function. The outcome of reduced fluid flow leaving the brain is that metabolic wastes build up, causing inappropriate changes in cell behavior, including an increase in inflammatory signaling produced by the innate immune cells called microglia. Neurodegenerative conditions are characterized by chronic inflammation in the brain, disruptive to tissue structure and function.

As a companion to yesterday's paper on VEGF-C gene therapy to restore glymphatic drainage of cerebrospinal fluid in aged mice, today I'll point out a study that assesses glymphatic fluid flow in aged humans. The researchers correlate reduced flow with both loss of cognitive function and structural changes in the brain characteristic of aging. A relatively recently developed imaging technique known as Diffusion Tensor Image Analysis Along the Perivascular Space (DTI-ALPS) was employed. This uses MRI to obtain an assessment of how much water is flowing out of the brain via lymphatic vessels and perivascular spaces in a region where a number of vessels are conveniently lined up in parallel. The technique doesn't actually measure flow, but rather measures the direction and extent of local diffusion of water molecules in many small volumes. If there is flow, one would expect a very unbalanced "diffusion", with a lot of movement in the direction of the flow. So far the technique appears to be producing good results.

Glymphatic function decline as a mediator of core memory-related brain structures atrophy in aging

This study aimed to elucidate the role of the glymphatic system - a crucial pathway for clearing waste in the brain - in the aging process and its contribution to cognitive decline. We specifically focused on the diffusion tensor imaging analysis along the perivascular space (ALPS) index as a noninvasive biomarker of glymphatic function. Data were drawn from the Alzheimers Disease Neuroimaging Initiative (ADNI) database and a separate validation cohort to analyze the ALPS index in cognitively normal older adults. The relationships among the ALPS index, brain morphometry, and memory performance were examined.

As a biomarker of glymphatic function, the ALPS index appeared to decline with age in both cohorts. According to the brain morphology analysis, the ALPS index was positively correlated with the thickness of the left entorhinal cortex (r = 0.258), and it played a mediating role between aging and left entorhinal cortex thinning. The independent cohort further validated the correlation between the ALPS index and the left entorhinal cortex thickness (r = 0.414). Additionally, in both the primary and validation cohorts, the ALPS index played a significant mediating role in the relationship between age and durable or delayed memory decline.

In conclusion, this study highlights the ALPS index as a promising biomarker for glymphatic function and links it to atrophy of the core memory brain regions during aging. Furthermore, these results suggest that targeting glymphatic dysfunction could represent a novel therapeutic approach to mitigate age-related memory decline.

There is No One Optimal Diet for Long Term Health

To my eyes, what one should take away from the study noted here is that adopting any form of healthier diet is beneficial over the long term. Another important item to consider is just how few people make it to age 70 without developing a major chronic medical condition. Thirdly, that the reasonable best case outcome for adjusting diet is to move the odds of avoiding chronic disease at age 70 from less than 10% to something more like 20%. Stepping back to consider the bigger picture, these are not good odds whether or not one's diet is healthy. These numbers are exactly why we need to spend less time focused on ever more detailed diet optimization and more time focused on assisting the development of potential rejuvenation therapies that address the underlying causes of aging.

As the global population ages, it is critical to identify diets that, beyond preventing noncommunicable diseases, optimally promote healthy aging. Here, using longitudinal questionnaire data from the Nurses' Health Study (1986-2016) and the Health Professionals Follow-Up Study (1986-2016), we examined the association of long-term adherence to eight dietary patterns and ultraprocessed food consumption with healthy aging, as assessed according to measures of cognitive, physical and mental health, as well as living to 70 years of age free of chronic diseases.

After up to 30 years of follow-up, 9,771 (9.3%) of 105,015 participants (66% women, mean age = 53 ± 8 years) achieved healthy aging. For each dietary pattern, higher adherence was associated with greater odds of healthy aging and its domains. The odds ratios for the highest quintile versus the lowest ranged from 1.45 (healthful plant-based diet) to 1.86 (Alternative Healthy Eating Index). When the age threshold for healthy aging was shifted to 75 years, the Alternative Healthy Eating Index diet showed the strongest association with healthy aging, with an odds ratio of 2.24.

Higher intakes of fruits, vegetables, whole grains, unsaturated fats, nuts, legumes, and low-fat dairy products were linked to greater odds of healthy aging, whereas higher intakes of trans fats, sodium, sugary beverages, and red or processed meats (or both) were inversely associated. Our findings suggest that dietary patterns rich in plant-based foods, with moderate inclusion of healthy animal-based foods, may enhance overall healthy aging, guiding future dietary guidelines.

Link: https://doi.org/10.1038/s41591-025-03570-5

Are Microplastics Contributing to Age-Related Conditions?

The epidemiological evidence for exposure to microplastic and nanoplastic particles to be harmful and contribute to age-related disease is sparse at this time, with nowhere near as sizable a weight of compelling evidence as exists for the analogous topic of particulate air pollution. This may be a matter of time, however; give it another two decades and the fields might look quite similar. Or they might not! It is too early to say. There is a lot of hype and excitement around the topic, so it seems likely that the necessary large human studies to establish and quantify any meaningful contribution to age-related disease will be conducted in the years to come. Meanwhile, the first few smaller studies suggesting that such a contribution exists are attracting a fair amount of attention.

Microplastics - defined as fragments of plastic between 1 nanometer and 5 millimeters across - are released as larger pieces of plastic break down. They come from many different sources, such as food and beverage packaging, consumer products and building materials. People can be exposed to microplastics in the water they drink, the food they eat and the air they breathe.

The study examines associations between the concentration of microplastics in bodies of water and the prevalence of various health conditions in communities along the East, West and Gulf Coasts, as well as some lakeshores, in the United States between 2015-2019. While inland areas also contain microplastics pollution, researchers focused on lakes and coastlines because microplastics concentrations are better documented in these areas. They used a dataset covering 555 census tracts from the National Centers for Environmental Information that classified microplastics concentration in seafloor sediments as low (zero to 200 particles per square meter) to very high (over 40,000 particles per square meter).

The researchers assessed rates of high blood pressure, diabetes, stroke, and cancer in the same census tracts in 2019 using data from the U.S. Centers for Disease Control and Prevention. They also used a machine learning model to predict the prevalence of these conditions based on patterns in the data and to compare the associations observed with microplastics concentration to linkages with 154 other social and environmental factors such as median household income, employment rate, and particulate matter air pollution in the same areas.

The results revealed that microplastics concentration was positively correlated with high blood pressure, diabetes, and stroke, while cancer was not consistently linked with microplastics pollution. The results also suggested a dose relationship, in which higher concentrations of microplastic pollution are associated with a higher prevalence of disease. However, researchers said that evidence of an association does not necessarily mean that microplastics are causing these health problems. More studies are required to determine whether there is a causal relationship or if this pollution is occurring alongside another factor that leads to health issues, they said.

Link: https://www.acc.org/About-ACC/Press-Releases/2025/03/25/10/19/New-Evidence-Links-Microplastics-with-Chronic-Disease

Gene Therapy with VEGF-C Restores Lost Lymphatic Drainage of Cerebrospinal Fluid in Aged Mice

Cerebrospinal fluid is produced constantly, circulates through the brain, and drains into the body. This flow carries metabolic waste from the brain, and researchers are coming to view the age-related impairment of cerebrospinal fluid drainage as an important contribution to loss of cognitive function and the development of neurodegenerative conditions in later life. Several pathways for drainage have been identified, each of which is known to lose function with advancing age.

Firstly, cerebrospinal fluid drains through holes in the cribriform plate behind the nose. This pathway ossifies and closes up with age or injury. Studies conducted by Leucadia Therapeutics have added a weight of evidence to the importance of impairment of this fluid drainage path to the development of Alzheimer's disease, which begins in a part of the brain specifically served by cribriform plate drainage. Secondly, the glymphatic system drains cerebrospinal fluid into lymphatic vessels. The meninges, the layered membrane surrounding the brain and spinal cord, is lined with lymphatic vessels and fluid passes into them from the brain. This system of vessels suffers atrophy and dysfunction with age, just like the rest of the lymphatic system. Analogies can be made to the decline of the vasculature for blood flow throughout the body; the density of small capillary vessels declines with age as the processes of maintenance and creation of new vessels become dysfunctional.

In today's open access paper, researchers show that this analogy holds for the approach of provoking increased vessel creation as a way to address the age-related loss of small vessels. It has been demonstrated that upregulation of VEGF via gene therapy improves angiogenesis in older mice. It also improves late-life health, likely in part by removing some of the loss of capillary density. For lymphatic vessels, the analogous signaling protein to promote generation of new vessels is VEGF-C. Here, researchers demonstrate that delivering VEGF-C as a gene therapy to the the meninges can restore cerebrospinal fluid drainage in old mice, and also improve measures of brain function. They show that inflammatory signaling in the brain is reduced once drainage is improved, lending support to the view that the whole problem of reduced drainage is that an increase in metabolic waste in the brain provokes a maladaptive inflammatory response from microglia, innate immune cells of the central nervous system.

Meningeal lymphatics-microglia axis regulates synaptic physiology

Meningeal lymphatic vessels, located in the dura mater of the meninges, drain cerebrospinal fluid (CSF) together with its content of central nervous system (CNS)-derived waste primarily into deep cervical lymph nodes. Since the discovery of meningeal lymphatic vessels, accumulating evidence from mouse models and humans has linked their dysfunction to various neurodegenerative conditions. Ablation of meningeal lymphatics by chemical, genetic, or surgical means exacerbates behavioral outcomes in mouse models of Alzheimer's disease, traumatic brain injury, and chronic stress. Conversely, enhancing the function of meningeal lymphatics ameliorates cognitive deficits in mouse models of Alzheimer's disease, aging, and craniosynostosis.

Here, we show that prolonged impairment of meningeal lymphatics alters the balance of cortical excitatory and inhibitory synaptic inputs, accompanied by deficits in memory tasks. These synaptic and behavioral alterations induced by lymphatic dysfunction are mediated by microglia, leading to increased expression of the interleukin 6 gene (Il6). IL-6 drives inhibitory synapse phenotypes. Restoring meningeal lymphatic function in aged mice via intracisternal injection of adeno-associated virus encoding VEGF-C reverses age-associated synaptic and behavioral alterations. Our findings suggest that dysfunctional meningeal lymphatics adversely impact cortical circuitry through an IL-6-dependent mechanism and identify a potential target for treating aging-associated cognitive decline.

Another Novel Metabolic Clock

There are now scores of published aging clocks built on various omics databases containing data for people at different ages. Many measurable aspects of metabolism and cell biochemistry change with age in sufficiently similar ways across the population to build clocks that reflect biological age, the burden of damage and dysfunction that causes mortality. Prior to the development of modern machine learning techniques, assembling such a clock would have been prohibitively difficult and expensive, but machine learning makes it straightforward enough for any small research group to create a new clock in a relatively short period of time. Thus there are now a great many aging clocks.

At this point the focus should shift to validation of clocks, as the whole point of having a measure of biological age is to be able to use it to rapidly assess the quality of potential rejuvenation therapies. At present no clock can be treated as entirely trustworthy; they do have quirks, and it remains unclear as to how underlying processes of damage, such as accumulation of senescent cells, produce changes in specific clock parameters. Without knowing these relationships, a clock might overestimate or underestimate the effects of a specific therapy on aging.

Metabolites that mark aging are not fully known. We analyze 408 plasma metabolites in Long Life Family Study participants to characterize markers of age, aging, extreme longevity, and mortality. We identify 308 metabolites associated with age, 258 metabolites that change over time, 230 metabolites associated with extreme longevity, and 152 metabolites associated with mortality risk. We replicate many associations in independent studies.

By summarizing the results into 19 signatures, we differentiate between metabolites that may mark aging-associated compensatory mechanisms from metabolites that mark cumulative damage of aging and from metabolites that characterize extreme longevity. We generate and validate a metabolomic clock that predicts biological age. Network analysis of the age-associated metabolites reveals a critical role of essential fatty acids to connect lipids with other metabolic processes. These results characterize many metabolites involved in aging and point to nutrition as a source of intervention for healthy aging therapeutics.

Link: https://doi.org/10.1016/j.celrep.2024.114913

Severity of Sarcopenia Correlates with Arterial Stiffness and Hypertension

Many dysfunctions and conditions of aging correlate with one another. For closer correlations, the question is whether this relationship exists because (a) one condition contributes meaningfully to the progression of the other, or (b) both conditions are similar in terms of which forms of underlying age-related cell and tissue damage contribute to their onset and progression. Or both! Here, researchers link the severity of sarcopenia, the age-related loss of muscle mass and strength, with arterial stiffness and hypertension. They review the existing hypotheses for causation in this relationship, noting that mechanisms exist to explain either direction of causation.

This cross-sectional study aimed to determine whether sarcopenia is related to arterial stiffness or hypertension in older adults without underweight and obesity. A total of 2,237 male and female adults in the Korea National Health and Nutritional Examination Survey who were ≥60 years and did not have underweight and obesity (body mass index of 18.5 to 25.0 kg/m2) were involved. Arterial stiffness and systolic and diastolic blood pressure showed an increasing trend from normal to moderate-to-severe sarcopenia. Subjects with moderate or severe sarcopenia were 3.545 or 8.903 times more likely to be in the highest tertile of arterial stiffness, and those with moderate or severe sarcopenia were 2.106 or 11.725 times more likely to be hypertensive.

While the exact mechanisms are not fully understood, several potential explanations for the relationship between sarcopenia, arterial stiffness or hypertension have been proposed. Reduced muscle mass and intramuscular fat infiltration cause a decrease in insulin-responsive target tissue, resulting in insulin resistance; consequently, arterial stiffness increases, which indicates the onset of hypertension. The results of the present study supported this potential mechanism in that insulin resistance, evaluated using the triglyceride-glucose index, showed a significant increasing trend from normal to moderate-to-severe sarcopenia. Additionally, chronic inflammation may be a potential explanation for the relationships of sarcopenia with arterial stiffness and hypertension. This potential mechanism was also supported by the finding in the present study that white blood cell counts showed a significant increasing trend from normal to moderate-to-severe sarcopenia.

Furthermore, individuals with sarcopenia commonly exhibit functional impairment or physical disability, which induces a reduction in muscle contraction-derived anti-inflammatory markers called myokines. Since decreased myokine levels are an independent predictor of increased risk of sarcopenia and arterial issues, myokine deficiency in sarcopenia is more likely to increase the risk of arterial stiffness or hypertension. Unfortunately, the present study does not provide objective data on myokine deficiency in sarcopenia patients. However, given that sarcopenia is a common cause of functional impairment or physical disability, decreased myokine secretion in sarcopenia patients is reasonable.

Finally, increased arterial stiffness may induce pulse pressure amplification in arteries. It may stimulate hypertrophy, remodeling or rarefaction in the microcirculation, which makes blood vessels unresponsive to the demand for changing blood flow, thereby leading to increased oxidative stress in muscles. Oxidative stress damages muscle components, such as reducing the number and function of satellite cells, and may induce muscle mass reduction. Depending on all of these factors, sarcopenia may be a trigger of arterial stiffness or hypertension, and arterial stiffness or hypertension may worsen sarcopenia.

Link: https://doi.org/10.3389/fpubh.2024.1469196