LongeCityNews Last Updated: 31 January 2026 - 11:53 AM

Type 2 diabetes is largely a self-inflicted problem, a consequence of becoming overweight. Aging makes it easier to reach the threshold needed for a diagnosis of diabetes, but the condition remains in principle avoidable for the majority of people, were they making better choices about diet and exercise. In recent years, researchers have linked an increased burden of cellular senescence to the pathology of type 2 diabetes; the aberrant diabetic metabolism encourages more cellular senescence, and the presence of lingering senescent cells is in turn inflammatory and disruptive to tissue function.

In today's open access paper, researchers focus on cellular senescence in diabetic kidney disease. In this context the increased burden of senescent cells actively sabotages the function of the kidney. Thus senolytic therapies capable of selectively destroying some fraction of senescent cells can produce measurable improvements in kidney function following a single course of treatment. Given time, and no correction of the lifestyle and physiology that drives diabetes, senescent cells and kidney dysfunction will reemerge, of course. But senolytic drugs nonetheless offer the prospect of meaningfully reducing some of the harms done by aging and obesity.

Senolytics, dasatinib plus quercetin, reduce kidney inflammation, senescent cell abundance, and injury while restoring geroprotective factors in murine diabetic kidney disease

Maladaptive inflammation and cellular senescence contribute to diabetic kidney disease (DKD) pathogenesis and represent important therapeutic targets. Senolytic agents selectively remove senescent cells and reduce inflammation-associated tissue damage. In our pilot clinical trial in patients with DKD, the senolytic combination dasatinib plus quercetin (D + Q) reduced systemic inflammation, senescent cell abundance, and macrophage infiltration in fat. However, D + Q senotherapeutic effects on diabetic kidney injury, senescence, inflammation, and geroprotective factors have not been established.

Diabetes mellitus was induced with intraperitoneal streptozotocin in male C57BL/6J mice, followed by a 5-day oral gavage regimen of either D + Q (5 and 50 mg/kg, respectively) or vehicle. Kidney function and markers of injury, fibrosis, inflammation, cellular senescence, and geroprotective factors were measured. In vitro studies examined reparative effects of D + Q in high glucose-treated human renal tubular epithelial cells (HK2), endothelial cells (HUVECs), and U937-derived macrophages.

D + Q improved kidney function and reduced markers of kidney injury (glomerular and tubular), fibrosis, senescence (p16Ink4a), macrophage- and senescence-associated inflammation (versus diabetic controls) without altering glucose levels. Additionally, geroprotective factors (α-Klotho, Sirtuin-1) increased. D + Q treatment in vitro reduced high glucose-induced senescence and inflammation (NF-κB) in HK2, HUVECs, and macrophages.

Using an ingenious CRISPR-based screening technique, scientists have found a protein that tags tau for degradation and is more strongly expressed in tau-resilient neurons [1].

Some neurons are more equal than others

The accumulation of tau protein fibrils in neurons is a hallmark of Alzheimer’s and several other diseases [2]. Scientists have long noticed that even in the brains of people who died of Alzheimer’s, some neurons are markedly healthier than others, suggesting that neurons differ in how they handle tau and that these differences may explain selective vulnerability in tauopathies [3].

In a new study published in the journal Cell, scientists from the University of California San Francisco built a human-neuron CRISPR interference (CRISPRi) screening platform and asked, genome-wide, which genes push tau toward or away from oligomer accumulation. Tau oligomers, which consist of chains of several tau molecules, are considered a crucial step in the formation of tau fibrils.

Full-genome screening

The team compared isogenic iPSC-derived neurons with or without a familial tauopathy mutation (V337M) in the gene MAPT. Using the oligomer-selective antibody T22, they found elevated tau oligomer levels in the mutated neurons. The signal dropped with MAPT knockdown, showing that the assay depends on tau expression and can report genetically driven changes.

The researchers used a genome-wide CRISPR “turn-down” screen in human neurons to find genes that control tau oligomers – without having to test 20,000 genes one by one. Essentially, they washed the cells in a cocktail of viral vectors, each one carrying a CRISPR-based construct to silence a particular gene. The concentration was such that the vast majority of cells received only one vector or none at all, creating a variety of cells with one different gene turned down.

The researchers then stained the neurons with T22, an antibody that recognizes tau oligomers, and used flow cytometry to sort cells into low-oligomer and high-oligomer bins. They then sequenced the CRISPR guide RNAs present in each bin to see which genes were knocked down.

This produced a ranked list of candidate genes, which the authors stress-tested in follow-up screens. One gene in particular, CUL5 – part of the ubiquitin-proteasome machinery that tags proteins for degradation – was a top hit across these different screens, making it a natural focus for a deeper mechanistic analysis.

CUL-ling tau

Because CUL5 is a key component of an E3 ubiquitin ligase, which is part of the cellular machinery that tags specific proteins for proteasomal destruction, the authors suspected that altering CUL5 would change how efficiently neurons can clear tau. To test this, they used individual CRISPRi guides to dial down CUL5 and RNF7, its core partner, and then directly measured tau.

The team found that tau levels rose when this ligase machinery was impaired. They then showed that the effect was post-translational, meaning that, with CUL5 knocked down, tau was becoming more stable, not just more expressed. Blocking the proteasome eliminated the CUL5-linked difference, tying the pathway to proteasomal clearance. Finally, they found the specific region of tau (around residues 80-130) that the ligase complex uses to target it for disposal.

In multiple human single-cell datasets, higher expression of CUL5 and key complex members was linked to neuronal resilience in Alzheimer’s disease and other tauopathies, suggesting that stronger CUL5-based ubiquitin-proteasome capacity may help certain neuron populations better withstand tau stress.

“CUL5 is uniquely suited to getting rid of tau,” said Martin Kampmann, Ph.D., professor of Biochemistry and Biophysics at UCSF. “Maybe a future therapy could enhance the body’s natural mechanism for avoiding neurodegeneration. It’s the first time we’ve been able to screen human neurons for genes that determine their resilience to tau. We hope that CUL5 can be the first of many new targets for drug discovery against dementias.”

Mitochondrial function flagged, too

A separate signal from the same CRISPRi screens also demanded attention: beyond the CUL5 “tau clearance” pathway, the strongest pathway-level hits pointed to mitochondrial oxidative phosphorylation/ETC (electron transport chain) genes as major modifiers of tau-oligomer burden.

The authors pivoted to ask what mitochondrial dysfunction does to tau. Using drugs that inhibit the ETC (notably rotenone and antimycin A), they caused tau levels to rise. Moreover, neurons started producing a form of tau that resembles what Alzheimer’s biomarker tests are designed to detect.

They traced this effect to oxidative stress (ROS) rather than generic energy failure: ROS increased alongside fragment formation, adding hydrogen peroxide to generate ROS could reproduce the effect, and antioxidants blunted it. While the role of mitochondrial dysfunction in dementias is known, this study provides more details that may be relevant for future therapies.

Literature

[1] Samelson, A. J., Ariqat, N., McKetney, J., Rohanitazangi, G., Parra Bravo, C., Bose, R. S., Travaglini, K. J., Lam, V. L., Goodness, D., Ta, T., Dixon, G., Marzette, E., Jin, J., Tian, R., Tse, E., Abskharon, R., Pan, H. S., Carroll, E. C., Lawrence, R. E., … Kampmann, M. (2025). CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis. Cell.

[2] Serrano-Pozo, A., Frosch, M. P., Masliah, E., & Hyman, B. T. (2011). Neuropathological alterations in Alzheimer disease. Cold Spring Harbor perspectives in medicine, 1(1), a006189.

[3] Roussarie, J. P., Yao, V., Rodriguez-Rodriguez, P., Oughtred, R., Rust, J., Plautz, Z., … & Greengard, P. (2020). Selective neuronal vulnerability in Alzheimer’s disease: a network-based analysis. Neuron, 107(5), 821-835.

The balance of microbial species making up the gut microbiome changes with age. More inflammatory microbes win out over microbes that generate beneficial metabolites, and this contributes to degenerative aging. Restoring a more youthful composition of the gut microbiome has been demonstrated to improve health and extend life in aged animals. Human data for gut microbiome rejuvenation remains very sparse, however. That said, a growing body of observational data from human patients demonstrates that various age-related conditions correlate with an altered, pro-inflammatory gut microbiome. In particular, evidence suggests that Alzheimer's disease - and the mild cognitive impairment that marks its earliest stages - correlate well with specific harmful alterations in the gut microbiome.

The gut microbiome serves a central role in maintaining homeostatic balance or disease pathogenesis, including neurological disorders such as Alzheimer's disease (AD). The mechanisms by which the microbiota and associated metabolites influence the development and/or exacerbation of disease states are multifaceted and multidirectional, involving the central and autonomic nervous systems and neuroimmune, neuroendocrine, and enteroendocrine pathways. This complex interplay involves a bidirectional communication system, often referred to as the microbiota-gut-brain-immune relationship, which connects the brain and gastrointestinal tract through various pathways.

Communication from the brain to the gut occurs via sympathetic and parasympathetic nervous systems and hormones. Conversely, the gut communicates with the brain through pathways such as the vagus nerve, the hypothalamic-pituitary-adrenal (HPA) axis, and a range of microbial products including bacterially synthesized neurotransmitters (e.g., GABA, dopamine, serotonin, noradrenaline), branched-chain amino acids, short-chain fatty acids (SCFAs), aryl hydrocarbon receptor agonists, and bile acids.

This scoping review of gut microbiomes in mild cognitive impairment (MCI) and AD included dietary and probiotic interventions. Our results demonstrated that gut dysbiosis was frequently reported in MCI and AD, including increased Pseudomonadota and Actinomycetota in AD and reduced diversity in some cases. Probiotic and dietary interventions showed promise in modulating cognition and microbiota, but inconsistently. Emerging evidence links dysbiosis to cognitive decline; however, methodological heterogeneity and limited follow-up impede causal inference. Research should prioritize standardized protocols, functional microbiome analysis, and longitudinal human studies to clarify therapeutic potential.

Link: https://doi.org/10.1002/alz.71023

Relative to skin elsewhere on the body, facial skin is less prone to scarring following regeneration from injury. Researchers have identified how this difference is regulated, and here demonstrate that they can influence the relevant mechanisms in order to reduce scarring during regeneration of skin injuries elsewhere on the body. It is also possible that further investigation of this biochemistry may yield approaches to reduce scarring more generally. This is of interest in the context of aging, as tissue maintenance becomes dysfunctional in many organs in ways that lead to excessive formation of disruptive small-scale scar-like structures.

Surgeons have known for decades that facial wounds heal with less scarring than injuries on other parts of the body. This phenomenon makes evolutionary sense: Rapid healing of body wounds prevents death from blood loss, infection or impaired mobility, but healing of the face requires that the skin maintain its ability to function well. Exactly how this discrepancy happens has remained a mystery, although there were some clues.

The face and scalp are developmentally unique. Tissue from the neck up is derived from a type of cell in the early embryo called a neural crest cell. Researchers identified changes in gene expression between facial fibroblasts and those from other parts of the body and followed these clues to identify a signaling pathway involving a protein called ROBO2 that maintains facial fibroblasts in a less-fibrotic state. They also saw something interesting in the genomes of fibroblasts making ROBO2. These fibroblasts more closely resemble their progenitors, the neural crest cells, and they might be more able to become the many cell types required for skin regeneration.

ROBO2 doesn't act alone. It triggers a signaling pathway that results in the inhibition of another protein called EP300 that facilitates gene expression. EP300 plays an important role in some cancers, and clinical trials of a small molecule drug that can inhibit its activity are underway. Researchers found that using this small molecule to block EP300 activity in fibroblasts prone to scarring caused back wounds in mice to heal like facial wounds.

Link: https://med.stanford.edu/news/all-news/2026/01/why-the-face-scars-less-than-the-body.html