Fight Aging!

Full reprogramming of cells occurs in the early embryo, driven by Yamanaka factor expression, the factors used often abbreviated to OSKM. It turns adult germ cells into embryonic stem cells, resetting epigenetic patterns and restoring mitochondrial function. Researchers have replicated this process to produce induced pluripotent stem cells from any adult cell sample. Partial reprogramming is intended to expose cells to Yamanaka factor expression for long enough to produce the reset of epigenetic patterns and improvement in mitochondrial function, but not for so long as to change cell state in other ways. This is thought to be a promising path to the production of rejuvenation therapies, but there are many challenges to overcome on the way to the clinic. Not least of these is that different cell types in any given tissue may have quite different requirements in terms of length of exposure or level of exposure to produce beneficial reprogramming with mimimal risk of generating potentially cancerous pluripotent cells.

Partial and full reprogramming can partially reverse age-related transcriptomic and epigenetic changes. Yet, it is unclear to what extent aging clocks are measuring biological age or cellular/organismal health. Regardless of what epigenetic aging clocks measure exactly, there are other biomarkers of rejuvenation that can be measured in partial reprogramming experiments. For example, if cycles of short-time reprogramming factor expression are followed by a recovery phase, phenotypic rejuvenation effects can be observed. By default, rejuvenation markers must be evaluated on a tissue-by-tissue basis.

An intriguing example is the brain, where cyclic OSKM without a recovery phase restores the proportion of neuroblasts and improves the production of neurons in vivo. Moreover, in vivo studies performed on mouse neurons and rat dentate gyrus cells suggest that OSKM can reverse age-associated neurological decline and enhance memory. Other mouse in vivo studies have shown that reprogramming enhances liver regeneration, promotes the repair of crushed optic nerves and ameliorates aging-associated loss of visual acuity, allows for muscle fiber regeneration, improves skin wound healing in aged mice, and promotes heart rejuvenation following myocardial infarction.

The mechanism of rejuvenation appears to partially depend on how cells are reprogrammed. Indeed, it was found that the mechanism of somatic cell reprogramming via small molecule regimens is distinct from transcription factor-mediated reprogramming. By constructing chromatin landscapes, researchers identified hierarchal histone modifications and sequential enhancer recommissioning which underlies regeneration programs following chemical reprogramming; this regeneration program appears to reverse the loss of regenerative potential in organismal aging but apparently it is not activated in OSKM reprogramming.

Reprogramming specific cells in vivo affects surrounding tissue. For example, it was found that in vivo activation of OSKM in myofibers led to proliferation of satellite cells in the stem cell niche of the myofibers, without inducing myofiber dedifferentiation; likely these changes are at least partially modulated via changes to the extracellular matrix (ECM). In fact, the ECM and its constituents are frequently affected by partial reprogramming. As mice age, collagen-associated transcript levels decrease in the pancreas but increase again, at least partially, following OSKM treatment with a two-week recovery period. Also, in fibroblast and adipocyte mesenchymal cell experiments with no recovery period, some ECM-associated processes are upregulated by partial reprogramming, including pathways linked to collagen.

Link: https://doi.org/10.1016/j.arr.2025.102737

RNA splicing is the process by which RNA is assembled from intron and exon sequences in genes. A given gene can be assembled into different RNAs depending on what is included or excluded. The balance of different RNAs produced from a gene tends to change with age, and this may be a cause of dysfunction. Starting from a position of screening for compounds that reduce age-related dysregulation in RNA splicing in nematode worms, researchers happen upon a compound that achieves this goal and extends life by manipulating the activities of gut microbes. Determining how and why life extension occurs in this case will take somewhat longer than the discovery of the approach - it need not have anything to do with RNA splicing. It seems unlikely that this specific compound will be relevant to mice or humans, given the large differences in the gut microbiome between lower animals and mammals, but someone will get around to checking in mice at some point.

Aging is associated with alternative splicing (AS) defects that have broad implications on aging-associated disorders. However, which drugs can rescue age-related AS defects and extend lifespan has not been systematically explored. We performed large-scale compound screening in C. elegans using a dual-fluorescent splicing reporter system. Among the top hits, doxifluridine, a fluoropyrimidine derivative used in chemotherapy, rescues age-associated AS defects and extends lifespan.

Combining bacterial DNA sequencing, proteomics, metabolomics, and the three-way screen system, we further revealed that bacterial ribonucleotide metabolism plays an essential role in doxifluridine conversion and efficacy. Furthermore, doxifluridine increases production of bacterial metabolites, such as linoleic acid and agmatine, to prolong host lifespan. Together, our results identify doxifluridine as a potent lead compound for rescuing aging-associated AS defects and extending lifespan, and elucidate the drug's functions through complex interplay among drug, bacteria, and host.

Link: https://doi.org/10.1371/journal.pgen.1011648

The most robust measurement of pathology in neurodegenerative conditions is conducted via imaging technologies, but these don't do well when it comes to the assessment of the more subtle earlier stages of these conditions. Further, imaging is relatively expensive. So for some years researchers have worked to develop a range of less costly, more convenient biomarkers to assess disease risk and disease progress. Progress has been made. Useful blood tests are emerging for Alzheimer's disease, for example.

Today's open access paper reviews recent advances and the present state of fluid biomarker assays for neurodegenerative conditions. Being able to use bodily fluids other than cerebrospinal fluid is arguably even more important than moving away from imaging when it comes to cost and convenience; no-one particularly wants to undergo the lumbar puncture procedure needed to access cerebrospinal fluid. Using blood, saliva, and so forth, becomes possible with the development of more sensitive assay technologies, able to detect the much lower levels of molecules related to neurodegeneration found outside the central nervous system.

Fluid-based biomarkers for neurodegenerative diseases

Neurodegenerative diseases are characterized by various pathological mechanisms, such as the accumulation of misfolded proteins, oxidative stress, neuroinflammation, and impaired neuronal signaling. For example, Alzheimer's disease (AD) is primarily associated with amyloid-beta (Aβ) plaque deposition and intracellular tau protein hyperphosphorylation leading to neurofibrillary tangles, while Parkinson's disease (PD) involves the accumulation of aggregated alpha-synuclein (α-syn) forming Lewy bodies. In contrast, amyotrophic lateral sclerosis (ALS) is marked by motor neuron loss, and multiple sclerosis (MS) is distinguished by demyelination and axonal damage. Despite varying pathologies, these diseases share common features, such as progressive neuronal loss, a lack of disease-modifying treatments, and the need for early diagnosis to mitigate disease progression. Currently, diagnostic tools such as cognitive assessments and neuroimaging (e.g., magnetic resonance imaging [MRI] and positron emission tomography [PET]) are widely used, but they are often only valid when the disease has reached advanced stages. This creates a need for novel diagnostic and prognostic tools that can detect and stage these diseases in their preclinical stages.

Fluid biomarkers, which can be obtained from bodily fluids like cerebrospinal fluid (CSF), blood, saliva, and urine, offer a non-invasive and potentially more sensitive means of detecting neurodegenerative diseases. Biomarkers are molecules that could reflect underlying pathological changes in the body, such as protein misfolding, neuronal damage, and neuroinflammation, at times even before clinical symptoms emerge. Detecting these changes early through fluid biomarkers may enable the timely trial of interventions which have the potential to slow or prevent disease progression. CSF has been a traditional source for detecting biomarkers of neurodegenerative diseases, as it is in direct contact with the central nervous system. In AD, for example, the CSF biomarkers Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) are well-established indicators of disease pathology. However, the invasive nature of lumbar punctures limits the routine use of CSF biomarkers in clinical practice.

Recent advances in fluid biomarker research have expanded beyond CSF to include blood and saliva, which are more accessible and less invasive. Blood-based biomarkers have gained particular attention, as they allow for repeated measurements over time and are suitable for large-scale population screening. Plasma Aβ42/40 ratios, various p-tau species, and neurofilament light chain (NfL) have shown promise in detecting Alzheimer pathology with accuracies comparable to CSF biomarkers. In PD, the detection of α-synuclein in blood has also demonstrated early diagnostic potential. Additionally, elevated levels of NfL in both blood and CSF have been observed in ALS and MS, making it a valuable marker for neuroaxonal injury across multiple neurodegenerative diseases.

Salivary levels of α-synuclein have been investigated as a potential marker for PD, while Aβ42 and tau proteins in saliva show potential for diagnosing Alzheimer's. Although concentrations of these biomarkers are lower in saliva compared to blood or CSF, advances in detection technology are improving the sensitivity of salivary biomarkers, making them a potential tool for large-scale screening. Urine biomarkers are also under investigation, with early studies identifying changes in the levels of proteins like Aβ, tau, and oxidative stress markers in the urine of patients with neurodegenerative diseases. Although urinary biomarkers are still in the early stages of research, they offer another non-invasive method for detecting disease-related changes, particularly in resource-limited clinical settings.

Alzheimer's disease progresses from an early aggregation of amyloid-β in brain tissue and mild cognitive symptoms to a later and much more harmful combination of inflammation and tau aggregation in brain tissue. A few years ago, researchers reported that measuring a tau species known as MTBR-tau243 in blood could be used to assess the state of this progression of Alzheimer's disease, and did so as accurately as more expensive brain imaging approaches. Here find an update on this approach to testing and its continued validation in patients at various stages of the progression of Alzheimer's disease.

Several blood tests for Alzheimer's disease are already clinically available. Such tests help doctors diagnose the disease in people with cognitive symptoms, but do not indicate the clinical stage of the disease symptoms - that is, the degree of impairment in thinking or memory due to Alzheimer's dementia. Current Alzheimer's therapies are most effective in early stages of the disease, so having a relatively easy and reliable way to gauge how far the disease has progressed could help doctors determine which patients are likely to benefit from drug treatment and to what extent.

In a new study, the researchers found that levels of a protein called MTBR-tau243 in the blood accurately reflect the amount of toxic accumulation of tau aggregates in the brain and correlate with the severity of Alzheimer's disease. Analyzing blood levels of MTBR-tau243 from a group of people with cognitive decline, the researchers were able to distinguish between people with early- or later-stage Alzheimer's disease and separate both groups of Alzheimer's patients from people whose symptoms were caused by something other than Alzheimer's disease.

Link: https://medicine.washu.edu/news/highly-accurate-blood-test-diagnoses-alzheimers-disease-measures-extent-of-dementia/

Researchers here explore the age-related nature of the correlation between atrial fibrillation and dementia risk. The earlier that atrial fibrillation is diagnosed in life, the higher the increased risk of later dementia. The interesting question is which of the possible mechanisms are most important in driving this relationship. The nature of atrial fibrillation suggests that both it and dementia arise from the same underlying causes, and that the atrial fibrillation is an earlier sign of those causes. It is associated with excess weight and hypertension, for example, both of which are harmful to the brain over the long term.

In a new study, the researchers assessed the independent association between atrial fibrillation (AF) and incident dementia in Catalonia, Spain. The population-based observational study included individuals who, in 2007, were at least 45 years old and had no prior diagnosis of dementia. The study included 2,520,839 individuals with an average follow-up of 13 years. At baseline, 79,820 patients (3.25%) had a recorded diagnosis of AF. In multivariable analyses adjusting for potential confounders, AF was, overall, a statistically significant but weak predictor of dementia, linked with a 4% increased risk of dementia.

However, age was found to significantly affect the association between AF and dementia. In prespecified analyses stratified by age, the strength of the association progressively weakened with increasing age: in patients aged 45-50, those with AF were 3.3 times more likely to develop dementia than those without AF. But in patients aged over 70 years, no association was found. Further analysis shows the association lost statistical significance from 70 years. By contrast, in patients diagnosed with AF before the age of 70, the condition independently increased the risk of dementia by 21%, and an even stronger effect was observed for early-onset dementia diagnosed prior to age 65, with AF increasing the risk by 36%.

Sensitivity analyses that removed cases of previous stroke during follow-up yielded similar results: AF was associated with a modest increase (6%) in the risk of dementia in the overall population, a stronger association (23% increased risk) in those diagnosed with AF in midlife (younger than 70 years old) and had the greatest effect towards early-onset dementia (52% increased risk). Therefore, patients with AF without a prior stroke still have a higher risk of dementia, with the greatest risk observed in early-onset dementia.

"The observation that the association between AF and dementia remains unchanged after excluding patients with prior stroke indicates that other mechanisms must be involved in the increased risk of dementia among AF patients. These mechanisms may include silent strokes - meaning those that showed no clinical symptoms and can only diagnosed with CT scan or MRI - and also microinfarcts, and microbleeds. Haemodynamic changes, which involve alterations in the flow and pressure of blood in the body caused by AF, and autonomic dysregulation, which refers to an imbalance in how the body controls automatic functions like heart rate, breathing, or blood pressure, could also play a role in the disease of small blood vessels in the brain associated with dementia. Additionally, systemic inflammation associated with atrial fibrillation may amplify these effects, creating a synergistic pathway that further increases dementia risk."

Link: https://www.eurekalert.org/news-releases/1078453

The ovary, along with the thymus, is one of the earliest organs to age into dysfunction. Studying the basis of ovarian aging may tell us something about aging more generally, an attractive prospect for researchers. For those who develop therapies, ovarian dysfunction may provide a somewhat easier point of intervention when assessing potential rejuvenation therapies that target underlying causes of aging, as the patients will be in better overall health, with fewer complicating comorbidities.

While those causes of aging are well catalogued at the present time, it remains challenging to understand their relative importance to any given age-related outcome. The web of cause, consequence, and interaction that lies between fundamental causes of aging and age-related conditions is very complex and little understood. The best way to find out whether a given cause of aging is important to give condition is to develop and test potential rejuvenation therapies that selectively target only that cause of aging. Here, for example, that would mean therapies targeting senescent cells, and assessing their effects on ovarian function.

Exploration of the mechanism and therapy of ovarian aging by targeting cellular senescence

Ovarian aging refers to the progressive decline in ovarian function with age, characterized by reduced follicle numbers, decreased quality of oocytes, changes of menstrual cycle, decreased fertility, and ultimately menopause. The decrease in estrogen levels due to ovarian aging can cause a series of clinical symptoms, such as vasomotor symptoms, osteoporosis, urogenital symptoms, neuropsychiatric dysfunction, cardiovascular diseases, endocrine diseases, and others. This aligns with the previous perspective that ovarian aging acts as a sensor for the overall aging of the female body. In humans, ovarian function typically begins to decline around 35 years of age, progressively deteriorates after 37, and ultimately ceases reproductive function around age 50. Notably, a growing number of women have been opting to delay childbearing to later stages of life, often influenced by social factors. Consequently, the diminishing fertility attributed to ovarian aging poses a significant challenge in the field of reproductive medicine, as no treatment modality has been proven to delay ovarian aging.

Cellular senescence refers to an irreversible cell cycle arrest caused by multiple stress responses, including accumulation of advanced glycation end products, oxidative stress, mitochondrial dysfunction, DNA damage, telomere shortening, and chronic inflammation. Cellular senescence exists throughout the life of multicellular organisms from development to death, and it also ubiquitously exists in both normal and senescent organs. Under physiological conditions, cellular senescence promotes organ differentiation and development by removing unwanted cells. With the accumulation of time or the degree of aging, cellular senescence further promotes organ aging through a variety of pathways, such as reducing the number of cells, decreasing cell quality, reducing metabolic level, accumulating metabolic waste, producing reactive oxygen species (ROS), thus damaging the organ and weakening the physiological function of the organ. Recently, cellular senescence was hypothesized to contribute to the age-related decline in ovarian function. Nevertheless, there remains a lack of a comprehensive theoretical framework concerning the role of cellular senescence in ovarian aging. Therefore, elucidating the role that cellular senescence may play in ovarian aging could lead to the development of novel therapies for reversing ovarian aging.

This review explores how cellular senescence may contribute to ovarian aging and reproductive failure. Additionally, we discuss the factors that cause ovarian cellular senescence, including the accumulation of advanced glycation end products, oxidative stress, mitochondrial dysfunction, DNA damage, telomere shortening, and exposure to chemotherapy. Furthermore, we discuss senescence in six distinct cell types, including oocytes, granulosa cells, ovarian theca cells, immune cells, ovarian surface epithelium, and ovarian endothelial cells, inside the ovary and explore their contribution to the accelerated ovarian aging. Lastly, we describe potential senotherapeutics for the treatment of ovarian aging and offer novel strategies for ovarian longevity.

A number of studies in recent years have shown that patients with Alzheimer's disease have a distinct gut microbiome composition in comparison to age-match peers. The gut microbiome changes with age, losing beneficial microbes and their production of metabolites necessary for tissue function, while gaining inflammatory microbes that contribute to the characteristic increase in chronic inflammatory signaling observed in older people. When it comes to the pro-inflammatory gut microbiome of Alzheimer's patients, it is still an open question as to whether this relationship exists because of the inflammation, in that inflammation drives the onset and progression of Alzheimer's disease, or whether other factors are at play. For example, a more pronounced age-related immune dysfunction could be a major contributing cause of both neurodegenerative conditions and shifts in the composition of the gut microbiome.

Alzheimer's disease (AD) is the most common form of dementia, characterized by an irreversible decline in cognitive function. The pathogenesis of several neurodegenerative disorders has been linked to changes in the gut microbiota, transmitted through the gut-brain axis. We set out to establish by case-control study methodology whether there were any differences in the composition and/or function of the gut microbiota between older resident adults in care homes with or without an AD diagnosis via analysis of the microbial composition from fecal samples. We performed primary analysis comparing controls (n = 19) against AD patients (n = 24).

These results indicate clear differences in the relative abundance of certain bacterial species and bacterial metabolites between care home residents with and without Alzheimer's disease that could be indicative of variable gut-brain axis activity. The AD cohort had significantly higher proportions of pro-inflammatory bacterial species and fewer 'beneficial bacteria'. We also found clear correlations between concentrations of beneficial bacterial metabolites and abundance of 'healthy bacteria'.

AD patients had increased levels of Escherichia/Shigella and Clostridium_sensu_stricto_1, which are linked to higher levels of gut inflammation. Escherichia/Shigella species can lead to higher levels of circulating lipopolysaccharide (LPS) and have been found in greater concentrations in the gut microbiota of individuals with mild cognitive impairment and in several prior AD studies. Certain strains of Escherichia/Shigella are known to form amyloid protein structures, known as curli, similar to those seen aggregating in the brains of AD patients. Although this is not definitively linked, it does raise one possibility as to how high levels of Escherichia/Shigella could potentially contribute to increased Alzheimer's pathology.

Similar to other studies, the AD cohort had decreased relative abundance of Bacteroides, Faecalibacterium, Blautia, and Roseburia species which are typically linked with good health. Both Roseburia and Faecalibacterium sp. are key butyrate producers and a significant decrease in the number of butyrate-producing bacteria, and subsequently butyrate, has previously been associated with AD. What cannot be determined from our data is whether the difference in microbiota is contributing to AD pathology or whether AD itself causes the microbial dysbiosis.

Link: https://doi.org/10.3390/geriatrics10020037

SIRT6 overexpression slows aging in mice for reasons that are yet to be fully understood. It influences a range of different mechanisms associated with aging, including efficiency of DNA repair. Efforts to determine which of these effects are the important ones, and the relationships of cause and effect between the outcomes it produces, will likely continue for years following the first clinical use of therapies based on SIRT6 upregulation. Research is slow and biology is complicated. Here is an update on one approach to therapeutic SIRT6 upregulation, using gene therapy to introduce a variant SIRT6 gene found in long-lived individuals. Using the standard sequence would probably also work, as that is what was done in the animal studies conducted to date - but would be harder to patent and otherwise defend in the ways needed to obtain funding from biotech investors.

Longevity biotech Genflow Biosciences has commenced a gene therapy trial aimed at addressing age-related decline in dogs. The trial is designed to evaluate the safety and efficacy of the company's SIRT6 gene therapy in extending healthspan in older canines. By targeting the SIRT6 gene, which has been linked to extended lifespan in centenarians, Genflow hopes to generate insights that could inform future treatments for both veterinary and human applications.

The study involves 28 dogs aged ten years and older. Over the course of a year, dogs receiving the therapy via intravenous injections will be compared to an untreated control group. Researchers will assess biological age using the GrimAge methylation clock, monitor changes in muscle mass and strength, evaluate mitochondrial function, track coat condition, and measure overall well-being. The six-month treatment period will be followed by a six-month observation phase to assess lasting effects. The results of the trial are expected by the end of 2025.

Genflow's broader focus is on developing gene therapies targeting aging-related diseases in humans, with its lead compound, GF-1002, in the pre-IND phase for metabolic dysfunction-associated steatohepatitis (MASH), a prevalent chronic liver condition. GF-1002, which delivers a variant of the SIRT6 gene found to be enriched in centenarians, has demonstrated adipogenic, anti-fibrotic, and anti-tumoral properties in preclinical studies.

Link: https://longevity.technology/news/genflow-begins-sirt6-gene-therapy-trial-in-dogs/

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.

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/

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

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 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.

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

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.