LongeCityNews Last Updated: 18 December 2025 - 10:52 AM

Alzheimer's disease is the most prominent of the tauopathies. This is a class of neurodegenerative conditions in which large enough amounts of tau protein become excessively altered by phosphorylation and aggregate into solid deposits, causing inflammation, loss of function, and cell death in the brain. The various isoforms of tau play an important role in maintaining the structure of axons that connect neurons, but aggregation would be problematic regardless of the normal function of tau.

Just as much of Alzheimer's research and development has long focused on trying to prevent, clear, or disarm misfolded amyloid-β and its toxic aggregates, a similar range of efforts is focused on finding ways to prevent, clear, or disarm hyperphosphorylated tau and its aggregates. Progress to date has been frustrating slow, just as it was for amyloid-β clearance via immunotherapy. Many of the possible paths forward appear challenging to implement well.

Today's research materials present an example of the type, an approach that potentially allows dramatic reduction in overall tau levels. Yet tau is important to axonal function, one can't just get rid of it, which presents developers with the much harder goal of achieving a balancing act with dose and outcome. Even then it tends to be the case that therapies that treat a condition in which a protein becomes altered into a toxic form by reducing overall expression of that protein tend to have unpleasant side-effects.

Novel discovery reveals how brain protein OTULIN controls tau expression and could transform Alzheimer's treatment

The research team initially hypothesized that inhibiting the enzyme activity of the OTULIN protein would enhance tau clearance through cellular garbage disposal systems. However, when they completely knocked out the OTULIN gene in neurons, tau disappeared entirely - not because it was being degraded faster, but because it wasn't being made at all. "This was a paradigm shift in our thinking. We found that OTULIN deficiency causes tau messenger RNA to vanish, along with massive changes in how the cell processes RNA and controls gene expression."

The study used neurons derived from a patient with late-onset sporadic Alzheimer's disease, which showed elevated levels of both OTULIN protein and phosphorylated tau compared to healthy control neurons. This correlation suggested OTULIN might be contributing to disease progression. "OTULIN could serve as a novel drug target, but our findings suggest we need to modulate its activity carefully rather than eliminate it completely. Complete loss causes widespread changes in cellular RNA metabolism that could have unintended consequences."

The deubiquitinase OTULIN regulates tau expression and RNA metabolism in neurons

The degradation of aggregation-prone tau is regulated by the ubiquitin-proteasome system and autophagy, which are impaired in Alzheimer's disease (AD) and related dementias (ADRD), causing tau aggregation. Protein ubiquitination, with its linkage specificity determines the fate of proteins, which can be either protein degradative or stabilizing signals. While the linear M1-linked ubiquitination on protein aggregates serves as a signaling hub that recruits various ubiquitin-binding proteins for the coordinated actions of protein aggregate turnover and inflammatory nuclear factor-kappa B (NF-κB) activation, the deubiquitinase OTULIN counteracts the M1-linked ubiquitin signaling. However, the exact role of OTULIN in neurons and tau aggregates clearance in AD are unknown.

Based on our quantitative bulk RNA sequencing analysis of human induced pluripotent stem cell-derived neurons (iPSNs) from an individual with late-onset sporadic AD (sAD2.1), a downregulation of the ubiquitin ligase activating factors (MAGE-A2/MAGE-A2B/MAGE-H1) and OTULIN long noncoding RNA (OTULIN lncRNA) was observed compared to healthy control iPSNs. The downregulated OTULIN lncRNA is concurrently associated with increased levels of OTULIN protein and phosphorylated tau.

Inhibiting the deubiquitinase activity of OTULIN with a small molecule UC495 reduced the phosphorylated tau in iPSNs and SH-SY5Y cells, whereas the CRISPR-Cas9-mediated OTULIN gene knockout (KO) in sAD2.1 iPSNs decreased both the total and phosphorylated tau levels. CRISPR-Cas9-mediated OTULIN KO in SH-SY5Y resulted in a complete loss of tau at both mRNA and protein levels, and increased levels of polyubiquitinated proteins, which are being degraded by the proteasome. In addition, SH-SY5Y OTULIN KO cells showed downregulation of various genes associated with inflammation, autophagy, ubiquitin-proteasome system, and the linear ubiquitin assembly complex that consequently may prevent development of an autoinflammation in the absence of OTULIN gene in neurons.

Together, our results suggest, for the first time, a noncanonical role for OTULIN in regulating gene expression and RNA metabolism, which may have a significant pathogenic role in exacerbating tau aggregation in neurons. Thus, OTULIN could be a novel potential therapeutic target for AD and ADRD.

Researchers have investigated the reporting quality of preclinical studies’ outcomes in anti-aging research. They analyzed how study quality changed over time, shortcomings in research, and the improvements that can be made in the future in order to yield as many valuable insights as possible [1].

The need for quality

Aging research has grown substantially; however, conducting human trials in the aging field is time-consuming and requires substantial resources. Therefore, initial testing is done in preclinical models, such as mice, worms, fruit flies, and other model animals, as many genes, molecular processes, and aging mechanisms are conserved between those animals and humans [2]. To increase the likelihood of translating results from animal models to humans, high-quality studies are essential.

To assess the quality of preclinical studies in the anti-aging field, the researchers analyzed 667 studies published in peer-reviewed journals between 1948 and 2024, which included 720 experiments, from the DrugAge database. This is “a curated database of preclinical experiments investigating the effects of interventions on aging and lifespan in non-human animals.” The analyzed studies varied in the animal species they used, with a small fraction including more than one model organism. The researchers aimed to assess the quality of reporting, methodological rigor, the distribution of observed effect sizes, and the presence of biases in those studies.

Assessing quality

The researchers assessed the studies using the CAMARADES (Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies) score. This score, which usually involves scoring studies accordingly to a 10-item checklist, allows for assessing methodological quality and risk of bias.

The median CAMARADES score across the analyzed studies was 3, but the researchers observed differences depending on the species used. Only two assessed parameters were consistent across all studies. First, all studies went through peer review. Second, blinding was generally absent. Specifically, blinding to intervention was discussed in only 4% of studies and blinded assessment of outcomes in 3%.

Among the assessed parameters, the researchers noted that almost one-fifth of studies mention randomization. Randomization, along with sample size calculation, was rarely reported when Caenorhabditis worms and Drosophila fruit flies were used, and overall, it was uncommon, with only 6% of all studies reporting it. However, studies using Caenorhabditis and Drosophila almost always gave information regarding the temperature at which animals were undergoing experiments. Temperature information was also common across all experiments, regardless of species used, with over 90% of analyzed studies reporting it. Those who didn’t report it mainly used mice. However, mouse studies did better with other parameters assessed by the researchers.

Other measured parameters included animal welfare, reported in 13.9% of studies, and conflict of interest statements, reported in more than half of the studies.

Since the studies used in the analysis spanned eight decades, the researchers analyzed how reporting changed over time. They noted that reporting of some parameters, especially conflicts of interest, compliance with animal welfare regulations, temperature control, and sample size calculations, increased over time, contributing to an increase in the CAMARADES score. However, there was no significant increase in reporting of randomization and blinding.

The critical parameters

The critical parameter for anti-aging interventions is the timing of initiation, since there is a need for effective interventions that can extend lifespan when taken in mid-life or in the elderly, and the intervention’s effect might differ depending on the start time. However, among the analyzed experiments, the vast majority (over 80%) begin early in life, while only around 8% start at 50% of average lifespan or later, a gap that future studies should address. The researchers also note that, in the pre-clinical studies analyzed, mammal experiments tend to start later in lifespan than non-mammal experiments.

Another critical component in aging research is the animal’s sex. It is well known that there are sex-dependent differences in aging trajectories, and interventions should be assessed in both sexes, as they may respond differently to the same treatment. However, among the experiments analyzed by the authors that included animals that reproduce sexually, fewer than half used both sexes; 35.7% used only males, 12.9% used only females, and some didn’t report the sexes used at all.

Anti-aging compounds

The researchers noted that, among the studies in the DrugAge database, most compounds tested in non-mammalian models increased lifespan.

Additionally, the researchers compared the results between the mammalian and non-mammalian models. They noted that of 35 compounds tested in both mammalian and non-mammalian models, 21 significantly increased lifespan in non-mammalian models, but only one-third of those also significantly increased mammalian lifespan: curcumin, spermidine, epithalamin, D-glucosamine, estradiol, SKQ, and taurine. At the same time, two showed inconsistent results when compared to non-mammalian models, decreasing mammalian lifespan (quercetin and butylated hydroxytoluene). This suggests that in the case of those experiments, “non-mammal results do not seem to reliably predict mammal results, raising further concern for translation.”

The experiments in mammalian and non-mammalian models also differed in other parameters across compounds, including the median percentage increase in lifespan, which was smaller in mammalian models at 7.4% than in non-mammalian models at 17.5%.

Room for improvement

This study suggests that there is room for improvement in the way preclinical antiaging research is performed. The researchers noted that “important design features such as randomization, blinding of intervention, blinded assessment of outcome, compliance with animal welfare regulations, and sample size calculations were infrequently reported, despite evidence that the absence of such features can bias experimental results.” [3,4,5] Some of the most essential experiment design features, such as randomization and blinding, didn’t see substantial improvements over time. They conclude that “generally, most studies did not meet standard reporting guidelines for preclinical experiments.”

While this is not an excuse for failing to meet the standards necessary for high-quality research, those flaws are not limited to anti-aging research, as many studies addressing various diseases exhibit similar reporting and study design problems [6], suggesting a need for improvement.

Literature

[1] Parish, A., Ioannidis, J. P. A., Zhang, K., Barardo, D., R Swindell, W., & de Magalhães, J. P. (2025). Reporting quality, effect sizes, and biases for aging interventions: a methodological appraisal of the DrugAge database. npj aging, 11(1), 96.

[2] Kenyon C. (2001). A conserved regulatory system for aging. Cell, 105(2), 165–168.

[3] Schulz, K. F., Chalmers, I., Hayes, R. J., & Altman, D. G. (1995). Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA, 273(5), 408–412.

[4] Schulz, K. F., & Grimes, D. A. (2002). Blinding in randomised trials: hiding who got what. Lancet (London, England), 359(9307), 696–700.

[5] Kringe, L., Sena, E. S., Motschall, E., Bahor, Z., Wang, Q., Herrmann, A. M., Mülling, C., Meckel, S., & Boltze, J. (2020). Quality and validity of large animal experiments in stroke: A systematic review. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 40(11), 2152–2164.

[6] Kilkenny, C., Parsons, N., Kadyszewski, E., Festing, M. F., Cuthill, I. C., Fry, D., Hutton, J., & Altman, D. G. (2009). Survey of the quality of experimental design, statistical analysis and reporting of research using animals. PloS one, 4(11), e7824.

Like the gut microbiome, the composition of the oral microbiome changes with age. Some of these changes have been shown to correlate with health status, but research into this part of the commensal microbiome is nowhere near as advanced as is the case for the gut microbiome. It is unclear as to the degree to which the oral microbiome is causing issues in aging, even where mechanisms are known to exist, such as leakage of bacteria and bacterial products associated with gingivitis into the bloodstream. It is also unclear as to whether the classes of strategy shown to rejuvenate the composition of the gut microbiome can work effectively for the oral microbiome.

Evidence indicates that the composition of the oral microbiome changes with age, although findings on diversity are inconsistent, with reports of both increases and decreases in older adults. These shifts are influenced by factors such as diet, oral hygiene, and immune function. Unhealthy aging, including conditions like frailty, neurodegenerative diseases, and sarcopenia, is associated with distinct oral dysbiosis. Potential mechanisms linking the oral microbiome to aging include chronic inflammation and immunosenescence.

Although research on the oral microbiome is still in its early stage compared to that on the gut microbiome, existing studies still indicate a link between the oral microbiome and aging. The purpose of this review is to explore whether the oral microbiome, which serves as a common gateway for the microbiota of the respiratory and digestive systems, should be considered a target for predicting and delaying aging. We focus primarily on the changes in the oral microbiome during healthy aging, the characteristics of the oral microbiome in unhealthy aging states such as frailty and age-related diseases and the possible mechanisms underlying the association between the oral microbiome and aging. Finally, we summarize the current research findings and provide possible directions for microbiome-based aging interventions.

Link: https://doi.org/10.1080/20002297.2025.2589648

The balance of microbial populations making up the gut microbiome changes with age in ways that are detrimental to health. Microbes generating necessary metabolites diminish in number, while microbes that provoke chronic inflammation grow in number. Further, researchers have established that is a tendency towards a distinctly different gut microbiome composition in some age-related conditions, such as Alzheimer's disease. Whether this difference over and above the more usual age-related changes acts to contribute directly to Alzheimer's disease, or is a side-effect of a dysregulated immune system or other aspect of aged metabolism, remains to be concretely determined. Here, researchers focus on microglia, the innate immune cells of the brain. Dysfunctional, inflammatory microglia are thought to be involved in neurodegenerative conditions, and one can argue for a connection to the gut microbiome.

Alzheimer's disease (AD) is a complex neurodegenerative disorder that can be caused by multiple factors, such as abnormal amyloid-beta (Aβ) deposition, pathological changes in Tau protein, lipid metabolism disorders, and oxidative stress. For decades, research into AD has been dominated by the amyloid cascade hypothesis. However, amyloid-beta (Aβ) clearance alone slows progression by only 35%. This compels increasing attention to peripheral factors in AD pathophysiology, redirecting the field from a brain-centric, amyloid-focused model toward a systemic perspective that emphasizes peripheral-central interactions.

It is now increasingly recognized that chronic, low-grade systemic inflammation, a condition often termed "inflammaging," acts as a critical driver of neuroinflammation and accelerates neurodegenerative processes. Within this framework, the gastrointestinal tract, which harbors the body's largest immune cell population and the vast metabolic capacity of the gut microbiome, emerges as a pivotal hub for originating peripheral signals that shape brain health and disease. This article reviews the direct and indirect effects of gut microbiota and its derivatives on microglia, explores their role in the pathogenesis of AD, and discusses therapeutic strategies based on gut microbiota. Although existing studies have shown the potential of these interventions, further research is needed to completely understand their application in the treatment of AD.

Link: https://doi.org/10.3389/fragi.2025.1704047