LongeCityNews Last Updated: 16 April 2026 - 03:41 AM

The tau protein is involved in maintaining stability of microtubule structures in the axons that connect neurons. It isn't the only protein that undertakes this task, and loss of functional tau doesn't produce immediate issues. Tau is important in some functions of memory, however, and mice lacking tau exhibit a range of cognitive defects that grow with age. Tau is well studied not for these aspects of its function, but because it is one of the few proteins that can be altered in a way that allows it to form solid aggregates that are disruptive to cell function. Tau aggregation to form the structures known as neurofibrillary tangles is a feature of late stage Alzheimer's disease. The consensus view of this stage of the condition is that tau aggregation and chronic inflammation form a feedback loop that accelerates dysfunction into widespread cell death in the brain.

The progression of Alzheimer's disease provides the appearance of a spread of tau aggregation from region to region in the brain. Study of the brain is challenging, however, and while there is a consensus on this point - that altered forms of tau can seed more dysfunction in a prion-like way and spread from cell to cell via synapses - there are other potential explanations for the observed outcomes. For example tau aggregation could be universal in the brain, but some regions are more vulnerable to the aggregation processes than others, and therefore exhibit a greater burden of neurofibrillary tangles earlier in the progression of the condition. Today's open access paper is an example of the way in which researchers must strive to circumvent the inability to directly access a large number of living human brains at various stages of Alzheimer's disease. Instead, the researchers synthesize a number of indirect approaches - models, genetics, postmortem tissues, and imaging data - to produce supporting evidence for the consensus view of a synaptic spread of tau aggregation.

Tau seeds induce neurofibrillary tangle formation across brain regions via individual-specific connectivity

Tau protein promotes assembly and stabilization of microtubules. In normal aging and Alzheimer's disease (AD), tau can become hyperphosphorylated, which reduces its affinity for microtubules and drives its mislocalization from axons to the body of the neuron and dendrites. Aberrant tau accumulation in the form of neurofibrillary tangles (NFTs) is a strong pathological correlate of cognitive decline. Based on postmortem human brain studies, the spatiotemporal progression of NFTs begins in layers II and III of the entorhinal cortex (EC), extends to the hippocampus and temporal cortex, entering the limbic system before reaching broader neocortical regions, which subsequent tau positron emission tomography (PET) studies confirmed in vivo. When tau is confined to the medial temporal lobe, patients typically experience memory problems, but once tau enters the neocortex, broader cognitive impairment often emerges.

The mechanisms underlying tau spread are unclear, but may rely on a process, referred to as tau seeding, in which abnormal forms of tau protein induce misfolding and aggregation of normal tau proteins in a template-dependent manner. Prior studies using cell cultures, mouse models, and human neuroimaging have each explored certain facets of tau pathology progression. However, whether endogenous tau seeds are the entities that induce NFTs across the aging human brain via naturally occurring connectivity remains to be confirmed. An alternative hypothesis that accounts for the observed NFT distribution is a gradient in region vulnerability, which does not involve tau seeds spreading from early-affected regions.

To investigate this question, we measured tau seed bioactivity data in synaptosomes from postmortem inferior temporal gyrus (ITG) and superior frontal gyrus (SFG) tissues of 128 individuals and combined this data with genotype and antemortem fMRI measurements from the same individuals. Via multimodal integration of these data, we provided supporting evidence that tau seeds from an early-affected brain region induce local NFTs as well as drive tau seeds and NFTs in a late-affected, far-removed region. Also, extending past tau-PET studies that demonstrated spatial correspondence between tau deposition and connectivity patterns, we further showed that individual-specific intrinsic connectivity modulates tau seed-NFT relationships. Our results thus support the hypothesis that tau seeds use synaptic connections to spread tau across connected regions in the human brain.

A recent study described a process called ferro-aging, in which iron accumulation leads to oxidative damage and cellular senescence. This process can be delayed by Vitamin C [1].

A two-faced atom

Iron, like many components of biological systems, has two faces. On the one hand, it’s essential for developmental and metabolic processes [2, 3]. On the other hand, it is a catalyst for reactive oxygen species (ROS) generation and lipid peroxidation, processes that are linked to aging [4-6].

While disruptions in iron metabolism and iron-dependent programmed cell death (ferroptosis) have been linked to multiple age-related diseases [7-11], there is still an unsolved question of whether “aging involves a coordinated, iron-dependent metabolic program that promotes cellular senescence and progressive organ decline”. This study was created to address this question.

Defining ferro-aging

The researchers began by assessing iron accumulation across multiple human cellular aging models, including human mesenchymal stem cells induced to senesce, cells expressing mutated genes associated with various accelerated aging diseases (progerias), and terminally differentiated cells. In aged or senescent cells, they detected iron accumulation as well as changes in gene expression related to iron metabolism, including one of the drivers of lipid peroxidation, the lipid-metabolism enzyme ACSL4, which plays a role in the metabolism of long-chain polyunsaturated fatty acids (PUFAs). In line with those observations, they also reported increased levels of ROS, membrane lipid peroxidation, and the lipid peroxidation end-product malondialdehyde (MDA).

These cell culture observations prompted experiments on the organismal level. A serum sample from elderly humans also showed increased free ferrous iron, a highly redox-active form of iron that contributes to ROS generation, along with the iron storage protein ferritin (FTH). Peripheral blood mononuclear cells showed higher ACSL4 and MDA levels. Iron deposition and increased markers of lipid peroxidation, including ACSL4, were also observed in samples from multiple organs of aged human tissues and cynomolgus monkeys.

The authors proposed the term ‘ferro-aging’ to describe these processes, which they believe to constitute a “coordinated program” in which iron accumulation leads to oxidative damage and thus cellular senescence.

Further experiments confirmed a causal role of iron in senescence. The researchers treated cells in cultures with two different forms of iron. Both treatments increased iron levels, ACSL4, and MDA while inducing senescence.

ACSL4 levels were consistently elevated across various iron overload-induced senescence experiments, suggesting that it may play a central role in this process. Overexpressing ACSL4 in cell cultures led to elevated lipid peroxidation and accelerated senescence, whereas knocking down its activity in senescent cells reduced lipid peroxidation and reversed senescence phenotypes.

The key roles of iron and ACSL4 were confirmed in mouse experiments. The researchers fed 5-month-old mice a high-iron diet for 2 months. As in cell cultures, multiple tissues in mice exposed to high iron levels showed increased lipid peroxidation, senescence, and inflammatory markers. At the functional level, those mice exhibited impaired cognitive function, reduced exploratory behavior, diminished muscle strength and endurance, and poorer motor coordination.

Additionally, aged mice, like primates, had increased hepatic ACSL4 levels and lipid peroxidation. To test whether decreasing those levels would have geroprotective properties, the researchers designed a genetically engineered virus to inactivate ACSL4 in the livers of aged mice. A single dose of this treatment improved cognitive function, exploratory behavior, and motor coordination, as well as markers of liver function and senescence. Similar effects were seen in a mouse model of progeria.

Fighting back

Knowing the molecular processes that contribute to aging is one thing, but finding a way to counteract them is another. These researchers moved beyond describing a process of ferro-aging to addressing how to remedy it. For this, they performed a screen of a selected library of 100 molecules previously linked to ferroptosis-related pathways. The most potent hit from the screen was vitamin C. It was able to reduce lipid peroxidation, partially restore senescent cells’ self-renewal capacity, and suppress both ferro-aging biomarkers and hallmarks of cellular senescence.

Further investigation into the mechanism of vitamin C’s effectiveness revealed that it binds to the central regulator of ferro-aging, ACSL4, and strongly inhibits this protein in a dose-dependent manner.

Treatment with vitamin C had the same effect on lipid profiles as inactivating ACSL4, and it strengthens the cells’ antioxidant capacity by activating molecular pathways governed by the master regulator of the oxidative stress response.

These findings prompted further testing in 12- to 16-year-old cynomolgus monkeys, which translates to around 40–50 years in humans. The monkeys received a daily dose of vitamin C at 30 mg/kg for 40 months. This treatment appeared not to cause any adverse effects.

However, vitamin C treatment affected ferro-aging processes. Monkeys that received vitamin C supplementation had reduced levels of ferro-aging-related genes across multiple tissues, including ACSL4; reduced age-related increases in plasma iron; decreased lipid peroxidation and MDA levels; and increased levels of the activated master regulator of the oxidative stress response.

Subsequent analysis of a broad spectrum of aging biomarkers across various tissues from aged cynomolgus monkeys receiving vitamin C suggested widespread geroprotective activity. The researchers reported improved aging hallmarks in cardiovascular tissues, lungs, liver, kidney, and pancreas, decreased adipocyte size in visceral fat, and neuroprotective effects.

The geroprotective effects of vitamin C in monkeys were also confirmed by epigenetic, transcriptomic, and metabolomic aging clocks as well as a structural MRI analysis, which showed that vitamin C supplementation helped alleviate age-related brain atrophy. The treatment also improved metabolic parameters of the animals and “reduced age-associated expansions in visceral and total fat area.”

A druggable target

As the authors summarize, this study identified “a specific, druggable pathway contributing to aging: an iron-triggered, lipid peroxidation-dependent process we term ferro-aging.” They also identify vitamin C as an inhibitor of this pathway with geroprotective potential.

This study was conducted on cell cultures and model organisms (mice and monkeys). Since monkeys are more closely related to humans than other model systems, vitamin C having positive effects in these animals makes it a promising candidate for human trials. However, since there is still a need to better understand the full impact of vitamin C on different aspects of health and to optimize its dosage and treatment timing; rigorous long-term safety evaluation is also necessary.

Literature

[1] Liu, L., Zheng, Z., You, W., Yang, P., Wen, Y., Qiao, Y., Ma, S., Zhang, H., Zhang, S., Xu, G., Ma, C., Tian, A., Jiang, M., Zhang, T., Geng, L., Li, J., Sun, X., Wang, F., Xiong, M., Yang, Y., … Liu, G. H. (2026). Vitamin C inhibits ACSL4 to alleviate ferro-aging in primates. Cell metabolism, 38(4), 673–693.e17.

[2] Hentze, M. W., Muckenthaler, M. U., & Andrews, N. C. (2004). Balancing acts: molecular control of mammalian iron metabolism. Cell, 117(3), 285–297.

[3] Donker, A. E., van der Staaij, H., & Swinkels, D. W. (2021). The critical roles of iron during the journey from fetus to adolescent: Developmental aspects of iron homeostasis. Blood reviews, 50, 100866.

[4] Minotti, G., & Aust, S. D. (1989). The role of iron in oxygen radical mediated lipid peroxidation. Chemico-biological interactions, 71(1), 1–19.

[5] Yang, W. S., Kim, K. J., Gaschler, M. M., Patel, M., Shchepinov, M. S., & Stockwell, B. R. (2016). Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proceedings of the National Academy of Sciences of the United States of America, 113(34), E4966–E4975.

[6] HARMAN D. (1956). Aging: a theory based on free radical and radiation chemistry. Journal of gerontology, 11(3), 298–300.

[7] Belaidi, A. A., Gunn, A. P., Wong, B. X., Ayton, S., Appukuttan, A. T., Roberts, B. R., Duce, J. A., & Bush, A. I. (2018). Marked Age-Related Changes in Brain Iron Homeostasis in Amyloid Protein Precursor Knockout Mice. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 15(4), 1055–1062.

[8] Fang, X., Wang, H., Han, D., Xie, E., Yang, X., Wei, J., Gu, S., Gao, F., Zhu, N., Yin, X., Cheng, Q., Zhang, P., Dai, W., Chen, J., Yang, F., Yang, H. T., Linkermann, A., Gu, W., Min, J., & Wang, F. (2019). Ferroptosis as a target for protection against cardiomyopathy. Proceedings of the National Academy of Sciences of the United States of America, 116(7), 2672–2680.

[9] Levi, S., Ripamonti, M., Moro, A. S., & Cozzi, A. (2024). Iron imbalance in neurodegeneration. Molecular psychiatry, 29(4), 1139–1152.

[10] Ru, Q., Li, Y., Chen, L., Wu, Y., Min, J., & Wang, F. (2024). Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects. Signal transduction and targeted therapy, 9(1), 271.

[11] Zhang, Y. Y., Han, Y., Li, W. N., Xu, R. H., & Ju, H. Q. (2024). Tumor iron homeostasis and immune regulation. Trends in pharmacological sciences, 45(2), 145–156.

Dysfunction in the cells making up the inner lining of blood vessels, the vascular endothelium, is thought to be an important first step in the aging of the vasculature more generally, setting the stage for the development of atherosclerotic lesions, a declining capacity of smooth muscle to contract and dilate vessels in order to control blood pressure, and leakage of the blood-brain barrier, among other issues. Researchers here review the contribution of two important aspects of cellular aging to the aging of the vascular endothelium; firstly the growing number of senescent cells, and secondly the decline in mitochondrial function. These are connected, as mitochondrial dysfunction is considered to contribute to an increased pace at which cells become senescent.

The vascular endothelium performs numerous regulatory functions that impact inflammatory responses, thrombosis, vascular tone, and angiogenesis. Endothelial dysfunction is a key contributor to the pathogenesis of various human diseases, either as a primary trigger or as a consequence of organ damage. This review examines how ageing reshapes endothelial cell metabolism and mitochondrial function, progressively undermining endothelial homeostasis and resilience.

Age-related endothelial alterations, including reduced nitric oxide bioavailability, heightened oxidative stress, impaired vasodilatory capacity and pro-inflammatory activation, arise from coordinated shifts in energy production, substrate utilization and redox signaling. In this context, cellular senescence, a stable arrest of the cell cycle accompanied by distinct metabolic, secretory, and inflammatory changes, appears to be an important response to cumulative metabolic and mitochondrial stress. Senescent endothelial cells not only reflect this stress burden but also actively propagate dysfunction through sustained pro-inflammatory and pro-oxidant signalling, thereby accelerating vascular ageing. We highlight the central role of mitochondria in these events. Age-associated mitochondrial dysfunction disrupts bioenergetics, enhances reactive oxygen species generation, and fuels chronic low-grade inflammation, amplifying endothelial decline.

By bringing together current evidence-based knowledge on endothelial cell bioenergetics, mitochondrial impairment, and metabolic reprogramming, this review identifies mitochondria-driven metabolic deterioration as a key mechanism underlying endothelial ageing and underscores mitochondrial metabolism as a promising, yet underexploited, therapeutic target in age-related vascular dysfunction.

Link: https://doi.org/10.1016/j.arr.2026.103119

The extremely high cost of obtaining clinical approval for a new drug incentivizes the research and development communities to focus on finding new uses for existing drugs in place of the rational design of new drugs. This likely contributes to a reduced quality of therapies; we live in a world in which the creation of marginally effective drugs is favored over the search for better drugs because it is cheaper to find marginally effective drugs. One of the few drug repurposing exercises that is producing interesting results is the search for senotherapeutic therapies among drugs approved for the treatment of various cancers, as many of these drugs have positive effects on cancer precisely because they selectively destroy or otherwise suppress the inflammatory signaling of senescent cells, but were developed prior to an understanding of the importance of this mechanism.

The accumulation of senescent cells in white adipose tissue (WAT) is closely associated with the functional decline of WAT and plays a causal role in the pathogenesis of metabolic diseases. Therefore, the elimination of senescent cells in WAT holds promise for the treatment and prevention of age-related metabolic diseases. Using a drug-repositioning strategy for 2,150 clinically applied compounds, we discover that homoharringtonine (HHT), an FDA-approved anti-leukemic drug, manifests senotherapeutic activity in vitro in multiple cell types including human preadipocytes, while inflicting minimal cytotoxicity to non-senescent cells.

HHT treatment prevents diet- or age-induced metabolic abnormalities in male mice targeting senescent adipocytes and preadipocytes to improve WAT function and reduce WAT inflammation. Moreover, HHT treatment attenuates age-associated phenotypes of human adipose tissue. Mechanistically, the senotherapeutic effects of HHT are mediated through the direct interaction of HHT with heat shock protein family A member 5 (HSPA5). Importantly, we found that HHT treatment delays aging and extends the lifespan in progeroid and aged mice. Our study demonstrates the novel senotherapeutic potential of HHT to mitigate age- and obesity-related metabolic dysfunction and extend longevity in mice.

Link: https://doi.org/10.1038/s41467-026-70475-3