LongeCityNews Last Updated: 31 December 2025 - 07:27 AM

Control of hypertension is arguably one of the best success stories for small molecule drug development relevant to aging, emerging from an era prior to any meaningful attempt to address the root causes of age-related conditions. The results are about the best one could expect from this compensatory manipulation of cell behavior, in that the problem of high blood pressure can be made to go away in a sizable portion of patients, with an acceptable profile of side-effects. This is in large part an outcome that results from the nature of the regulation of blood pressure, in which multiple very different systems exhibit multiple very different avenues for changing their behavior. One can pick and choose from ways to target the kidney's regulation of blood volume, the dilation of vascular smooth muscle, or even heart rate if the goal is to reduce blood pressure.

Despite the present range of antihypertensive drugs, or perhaps because of it given that investment tends to cluster in areas in which success is already proven, research and development continues apace. Considerable funding and effort is devoted to building the foundations of incrementally better antihypertensive drugs, based on an improved understanding of the regulation of blood pressure and the various proteins involved in that complex process. Today's research materials are one example of many.

Yet still, none of this panoply of programs and therapies target the underlying causes of hypertension, the damage and dysfunction of aged tissues that gives rise to manifestations such a raised blood pressure. Those underlying causes continue to cause other harms, and aging progresses. If control by compensation is all that can be achieved, then that is what should be done. But far better approaches to age-related disease can be produced in principle, actual rejuvenation therapies that will treat age-related conditions by removing their causes.

Key protein ACE2 could protect against high blood pressure and diabetes

Researchers analysed nine key proteins in over 45,000 blood samples from the UK Biobank. ACE2 levels were increased in individuals with a diagnosis of high blood pressure or diabetes, both of which are risk factors for heart disease. The effect was seen particularly in females and was influenced by changes in genes that are associated with diabetes. Using a genetic analysis method called two-sample Mendelian randomisation, the researchers found evidence that these higher ACE2 levels may, in fact, be trying to protect against high blood pressure and type-2 diabetes. ACE2 breaks down angiotensin II, a compound that tightens blood vessels, and produces substances that relax blood vessels. In this way, the elevated levels of ACE2 seen in individuals with high blood pressure may be compensatory, by helping to relax constricted blood vessels.

ACE inhibitors are common drugs for treating high blood pressure and work by blocking the ACE1 protein which, in contrast to ACE2, makes angiotensin II. These findings could influence how ACE inhibitor drugs are used and by which patients, as it's likely that ACE2:ACE1 balance has a role in how successful ACE inhibitors are in treating blood pressure. Individuals with naturally altered levels of ACE2 may be better suited to certain ACE inhibitors, and this may lead to more tailored treatments based on blood ACE2 levels. Future research will explore whether increasing ACE2 activity or mimicking its effects could improve treatment for high blood pressure and diabetes. Previous preclinical studies of a common anti-diabetic drug, metformin, showed that it increases ACE2 expression as part of its action.

Circulating Cardiovascular Proteomic Associations With Genetics and Disease

To understand the relationships between circulating biomarkers and genetic variants, medications, anthropometric traits, lifestyle factors, imaging-derived measures, and diagnoses of cardiovascular disease, we undertook in-depth analyses of measures of 9 plasma proteins with a priori roles in genetic and structural cardiovascular disease or treatment pathways (ACE2, ACTA2, ACTN4, BAG3, BNP, CDKN1A, NOTCH1, NT-proBNP, and TNNI3) from the Pharma Proteomics Project of the UK Biobank cohort (over 45,000 participants sampled at recruitment).

We identified significant variability in circulating proteins with age, sex, ancestry, alcohol intake, smoking, and medication intake. Phenome-wide association studies highlighted the range of cardiovascular clinical features with relationships to protein levels. Genome-wide genetic association studies identified variants near GCKR, APOE, and SERPINA1, that modified multiple circulating protein levels (BAG3, CDKN1A, and NOTCH1). NT-proBNP and BNP levels associated with variants in BAG3. ACE2 levels were increased with a diagnosis of hypertension or diabetes, particularly in females, and were influenced by variants in genes associated with diabetes (HNF1A and HNF4A). Two-sample Mendelian randomization identified ACE2 as protective for systolic blood pressure and type-2 diabetes.

Researchers here take an interesting approach to reviewing the evolution of the field of aging research over the past century, employing machine learning approaches to process abstract summaries from the entire literature in search of meaningful patterns. Some of the findings are much as might be expected given the way in which top-down funding choices shape trends in research, while others are more subtle commentaries on the difference between the map and the territory, such as in the matter of the hallmarks of aging and its relationship with aging research as it actually exists.

Aging research has advanced significantly over the past century, from early studies on animal models to a current emphasis on clinical and translational applications. As research literature expands exponentially, traditional narrative reviews can no longer capture the field's complexity, highlighting the need for new, unbiased synthesis tools. Here, we leverage advanced natural language processing (NLP) and machine learning (ML) techniques to analyze 461,789 abstracts related to aging published between 1925 and 2023.

A central finding of our study is the marked evolution in research priorities over the past 50 years. Early decades were dominated by a focus on animal models and cellular mechanisms, which laid the groundwork for our mechanistic understanding of aging. In contrast, recent decades show a pronounced shift toward clinical research and healthcare applications, reflecting both technological advances and changing societal priorities as populations age. This transition is further underscored by a consolidation of research themes around a few dominant topics; most notably, those related to healthcare and clinics, and an intensive emphasis on neurodegenerative diseases where Alzheimer's disease (AD) and dementia have emerged as the most studied conditions in the aging field. The overwhelming dominance of AD and dementia research may not solely reflect emerging scientific trends but could also be partially driven by funding policies. For instance, agencies like the National Institute on Aging have historically allocated a substantial proportion of their research funding to Alzheimer's and related dementias, shaping the field's research priorities.

Our clustering analysis revealed distinct thematic groups that not only segregate clinical and basic biological research but also highlight specific tissue- and system-focused studies (e.g., those related to the central nervous system or skeletal muscle). Links between biology of aging clusters (such as oxidative stress and cellular senescence) and clinically oriented clusters remain sparse. This suggests that despite the overall growth in aging research, a significant gap persists between fundamental aging mechanisms and their translation to clinical settings.

Beyond these broad trends, a focused analysis on the biology of aging research literature uncovered distinct clusters corresponding to fundamental aging processes. When we compared these clusters with the well-established hallmarks of aging, we found that while some clusters align closely with these predefined categories, others do not clearly fit into them. This discrepancy suggests that the biology of aging contains more diversity than the classical hallmarks scheme alone might capture.

Link: https://doi.org/10.18632/aging.206340

Damaged and dying neurons in the brain release distinctive proteins that make their way into the bloodstream and can thus be measured. Researchers here note that by this metric, the death of neurons occurs throughout life, but increases with age. The pace of neuron death further increases in patients with neurodegenerative conditions, as might be expected. Interestingly, the established treatment of recombinant GM-CSF protein is shown to greatly reduce this age-related increase in neuron death. Recombinant protein therapies are notably costly and the effects of a single dose typically do not last long, but perhaps more attention given to this mechanism will lead to a more cost effective approach to therapy that can preserve neurons in the aging brain.

A new cross-sectional study of people of all ages has revealed that a protein released into the blood from dying brain neurons, called UCH-L1, and another protein released from damaged neurons, called NfL, are at low concentrations in the blood in early life and their levels are exponentially higher every year through age 85. Early life changes in this biomarker likely reflect a normal process of aging, but in later stages of life, increases in UCHL-1 are linked with poorer outcomes. This discovery could lead to earlier testing and new therapies for Alzheimer's disease (AD) and possibly for cognitive decline due to normal aging.

The drug sargramostim (also called Leukine), a synthetic form of the natural human protein GM-CSF, has been used for 30 years to treat a variety of conditions including cancer. It has also shown promise in its first clinical trial by improving blood biomarkers of brain pathology. The biomarker improvement lasted only as long as the drug was taken, yet memory improvement on one measure lasted longer. When people with AD were given sargramostim in the clinical trial, their blood levels of the UCH-L1 measure of neuronal cell death dropped by 40%, similar to levels seen in early life.

Sargramostim treatment led to improved scores on one of the cognitive tests performed, the Mini-Mental State Exam (MMSE), compared to those taking a placebo. Other cognitive tests showed no change. Whether the drug will reduce Alzheimer-associated neuronal damage only with continuous use is unclear and needs more study. At 45 days after treatment ended, the blood UCH-L1 concentration had returned to pre-treatment levels but the improvement in the MMSE measure of cognition was retained. More research will also be needed to determine if the drug can reduce normal age-associated neuron death and cognitive decline.

Link: https://news.cuanschutz.edu/news-stories/brain-neuron-death-occurs-throughout-life-and-increases-with-age-a-natural-human-protein-drug-may-halt-neuron-death-in-alzheimers-disease

As research into senescent cells continues to gather momentum over the years, links to specific conditions are spilling over from aging into other fields of medical research. Temporal lobe epilepsy isn't an age-related condition, but a number of the most unpleasant outcomes inflicted on the brain by aging, including stroke and brain cancer, can induce epilepsy in addition to all of the other attendant consequences. Interestingly, researchers have found that there is a clear correlation between an excessive burden of senescent cells in the brain and temporal lobe epilepsy. Senescent cells are by now well established to disrupt tissue structure and function via their inflammatory signaling when present in significant numbers over the long term. Typically this only happens in old age, but some other events such as infection, cancer therapies, and injury can result in a lasting excessive burden of senescent cells that emerges earlier in life.

Fortunately there is a low cost therapy that clears some fraction of lingering senescent cells, and has been shown to do so in early human trials, alongside a reasonable safety profile. This is the combination of dasatinib and quercetin. Unfortunately, there is little financial incentive for those organizations capable of conducting large scale clinical trials of dasatinib and quercetin to actually do so; low cost generic drugs and supplements are not a good source of revenue. Thus this approach to therapy remains stuck in the state of being available to the adventurous, prescribed by a small number of anti-aging physicians, and in much need of a far greater body of human clinical trial data than is likely to arrive any time soon.

Clearing the Brain of Aging Cells Could Aid Epilepsy and Reduce Seizures

Temporal lobe epilepsy (TLE) can be caused by several factors, including brain injuries from trauma or stroke, infections like meningitis, brain tumors, blood vessel malformations, and genetic syndromes. TLE is the most common type of drug-resistant epilepsy, affecting about 40% of patients with the condition. In one part of their study, the investigators looked at donated brain tissue in the lab that had been surgically removed from the temporal lobes of people. They found a five-fold elevation of senescent glia cells in human TLE cases compared to autopsy tissue from people without the disease. Glia cells support and protect neurons but do not produce electrical neuronal impulses.

Based on their human brain tissue investigation, the researchers suspected there could be an abundance of senescent cells in a mouse model that mimics TLE. Indeed, within two weeks of the initial injury that triggered TLE in the mice, the investigators found increases in cellular markers of senescence at both gene and protein levels. Treatment to remove the aging cells in mice resulted in a 50% reduction in these senescent cells, normalized their ability to navigate mazes, reduced seizures, and protected a third of animals from epilepsy altogether.

The drug treatment tested in the mice was a combination of dasatinib, a targeted therapy used to treat leukemia, and quercetin, a plant flavonoid found in fruits, vegetables, tea, and wine that can act as a powerful antioxidant and have anti-inflammatory properties. The combination of the two drugs has been widely used to kill senescent cells in a range of diseases modeled in animal studies.

Senescent Cell Clearance Ameliorates Temporal Lobe Epilepsy and Associated Spatial Memory Deficits in Mice

The pharmacological treatment of temporal lobe epilepsy (TLE), a disorder characterized by recurrent seizures and cognitive dysfunction, is limited to symptomatic control. Cellular senescence has been recently implicated in the development and progression of other neurodegenerative diseases, but its role in TLE is unstudied. We found a 5-fold elevation of senescent glia in human TLE cases as compared with controls. In a mouse model of TLE, we found increases in senescence markers at both the transcript and protein level and predominantly expressed in microglia, which developed within 2 weeks following induction of TLE. Senolytic treatment in mice produced a 50% reduction in senescent cells, rescued long-term potentiation deficits, normalized spatial memory impairments, reduced seizures, and protected a third of animals from epilepsy.