LongeCityNews Last Updated: 11 February 2026 - 02:23 PM

Structures of the endoplasmic reticulum are where the folding of newly synthesized proteins takes place in the cell. The endoplasmic reticulum is also involved in a range of other activities relevant to the manufacture of proteins and other molecules, such as quality control and recycling of misfolded proteins. Researchers here describe how the endoplasmic reticulum changes in structure with age, and link this to changes in the recycling of endoplasmic reticulum structures via autophagy. They suggest that these changes are compensatory, but become maladaptive in later life.

The morphological dynamics of the endoplasmic reticulum (ER) have received little attention in the context of ageing. Here we established tools in C. elegans for high-resolution live imaging of ER networks in ageing metazoans, which revealed profound shifts in ER network morphology that are driven by autophagy of ER components (ER-phagy). Across a variety of tissues, we consistently found a decrease in ER protein levels and cellular ER volume, and a structural shift from densely packed sheets to diffuse tubular networks. The ER content also declined in yeast and mammalian systems, and proteomic atlases of the ageing process in worms and mammals showed that age-onset collapse in ER proteostasis function is a broadly conserved aspect of the ageing process

We found that Atg8-dependent ER-phagy is the key mechanism driving turnover and remodelling of the ER network during ageing. A targeted screen for mediators in C. elegans revealed that the physiological triggers of ER-phagy in an ageing metazoan model are cell-type specific. Tissue-specific roles of ER-phagy receptors may help to explain why the ubiquitous macroautophagy machinery seems to be a universal requirement for longevity assurance in metazoan genetic studies, whereas the importance of selective ER-phagy mediators has been slower to emerge. Subsequently, we demonstrate that the two pathways capable of blocking age-associated ER-phagy, TMEM-131 and IRE-1-XBP-1, are required for mTOR-dependent lifespan extension in C. elegans.

Importantly, not all changes that occur during ageing reflect pathogenesis. The earliest remodelling events are likely to be adaptive responses to the cessation of developmental programmes and rising metabolic and cellular damage. We propose a model where age-dependent ER remodelling serves as an adaptive step in the ageing process associated with reprogramming of the proteostasis network. However, although data indicate that the net effect of ER-phagy on lifespan is positive, we speculate that early pronounced remodelling of ER structures is likely to trigger pleiotropic trade-offs later, especially in longer-lived cells and animals.

Link: https://doi.org/10.1038/s41556-025-01860-1

In recent years, researchers have established that a great many proteins can aggregate to some degree in cells of the aging brain, and that this likely contributes to loss of function. This issue is distinct from the few well-known proteins such as amyloid-β that aggregate to a very large degree in the context of neurodegenerative conditions. Here, researchers provide evidence for this generalized aggregation across more than a thousand proteins to contribute to impaired maintenance of synapses in the aging brain.

Neurodegenerative diseases affect 1 in 12 people globally and remain incurable. Central to their pathogenesis is a loss of neuronal protein maintenance and the accumulation of protein aggregates with ageing. Here we engineered tools that enabled us to tag the nascent neuronal proteome and study its turnover with ageing, its propensity to aggregate and its interaction with microglia. We show that neuronal protein half-life approximately doubles on average between 4-month-old and 24-month-old mice, with the stability of individual proteins differing among brain regions. Furthermore, we describe the aged neuronal 'aggregome', which encompasses 1,726 proteins, nearly half of which show reduced degradation with age.

The aggregome includes well-known proteins linked to diseases and numerous proteins previously not associated with neurodegeneration. Notably, we demonstrate that neuronal proteins accumulate in aged microglia, with 54% also displaying reduced degradation and/or aggregation with age. Among these proteins, synaptic proteins are highly enriched, which suggests that there is a cascade of events that emerge from impaired synaptic protein turnover and aggregation to the disposal of these proteins, possibly through microglial engulfment of synapses. These findings reveal the substantial loss of neuronal proteome maintenance with ageing, which could be causal for age-related synapse loss and cognitive decline.

Link: https://doi.org/10.1038/s41586-025-09987-9

Cryonics refers to the low-temperature storage of the body (or at least the brain) at death to offer the chance that a more technologically capable future can restore that individual to life. It is an unknown chance, possibly a small and unknown chance, but cryonics is certainly a better option that the other end of life alternatives facing someone who is going to age to death before rejuvenation biotechnology and the medical control of aging becomes a reality. Cryonics remains a very good idea that should be far more widely used, significantly supported, and undergoing aggressive technological development to improve capabilities. But it is very far from being widely used and suffers from the same situation that afflicted the aging research community thirty years ago: a minority field with too little financial and popular support to generate the desired degree of progress.

Newfound enthusiasm for the development of means to treat aging has led to a vast (if very unevenly distributed) investment in the field, hundreds of companies working on all sorts of approaches. A tiny fraction of that enthusiasm for doing something to address age-related disease and mortality has spilled over into support for cryonics. Even that tiny fraction is proving to be transformative. I pick on Alcor as the example because I am signed up with Alcor, and therefore do pay more attention to what is going on there, but the field as a whole is showing progress. Europe has its own modern cryopreservation organization these days, Tomorrow.bio, their focus on customer service raising the bar for the community. Meanwhile Until Labs is working on making reversible vitrification of organs a commercial possibility, a best foot forward to generate further capital and legitimacy for cryonics.

After years of little visible progress and too little funding to improve on that situation, Alcor has of late acquired what is for a non-profit a sizable influx of capital. Enough to not just establish new research programs with new equipment, but to address look and feel and customer service priorities, such as a modernization of the website and creating a portal and modern relationship management system for their customers - and no doubt more under the hood than that. Alcor comes to the table with the DNA of decades of year to year struggle as a small non-profit serving a small community. Shedding some of those historical habits and culture will be necessary in order for a commercial industry of cryopreservation to emerge.

In a better world, this could have happened decades ago, driven by a broad popularist realization that cryopreservation to travel into a potentially far better future is the best of all options, turning an end into a hiatus. But it didn't. At least the first increments of such a sea change are happening now. A few excepts from a recent Alcor newsletter follow, for those who don't keep tabs on how this industry is modernizing.

Fundraising & Endowment: 2025 closed out as one of the stronger fundraising years in Alcor's history, including a major gift from the Rothblatt family - one of the largest individual donations Alcor has ever received. About 75% of donations came from people who hadn't given at that level before. The goal is to build an operational endowment similar to what exists for the Patient Care Trust, which is very healthy. The operations and administrative side, however, has historically struggled to keep pace. A comparable endowment would allow Alcor to focus on growth rather than making ends meet. Expect a significant fundraising initiative announcement in the near future.

First-Ever In-House Whole Body CT Scan: The team performed Alcor's first-ever in-house whole body CT scan. The scan itself went smoothly: they used the new ceiling trolley and hoist to transfer the patient from the perfusion table directly onto a radiotranslucent scanning tray, completed the scan in just a few minutes, transferred the patient back, and proceeded directly to cooldown. That patient is now in long-term storage. After everything it took to get here, it was well worth the wait. Being able to validate cryoprotectant distribution in-house and in real time opens up a lot of doors for quality assessment and research.

CT Scanning for Vitrification Assessment: we are putting the CT scanner to good use and have already started producing valuable data. Pre- and post-cooling scans show clear differences between frozen kidneys and vitrified kidneys. The next step: quantifying exactly how much ice forms in different regions using a newly purchased differential scanning calorimeter. This will let the team precisely correlate CT images with ice content - a tool that could become standard for assessing cryopreservation quality in organs and patients alike

Organ Cryopreservation: The team continues refining porcine kidney cryopreservation protocols. About 40% of kidneys show excellent vitrification with minimal ice formation. The other 60% show small ice crystals in the inner medulla - the part of the kidney that's hardest to perfuse.

Brain Slice Cultures: we are developing long-term brain slice cultures that can survive 2-3 weeks in a CO2 incubator. Using assays to measure metabolic activity, they've established a baseline comparing fresh tissue versus straight-frozen tissue. The goal: cryopreserve brain slices, rewarm them, and show maintained viability and functionality over time. This would be a significant contribution to the literature - evidence that brain tissue can remain alive and functional after proper cryopreservation. Additional human brain tissue experiments are also in the works, with a neurosurgery partnership nearly finalized.

New Project: Antifreeze Protein Gene Integration: A particularly exciting update is that we are developing a project to integrate antifreeze protein genes directly into cells via gene therapy. The idea is that if cells can produce their own antifreeze proteins internally, they might survive freezing and thawing better without needing external cryoprotectants. This is early-stage - they're still screening candidate proteins from fish, beetles, and other organisms. Potential applications include improving CAR-T cell therapy, which could be relevant for both cryonics and mainstream medicine.

A new study links sleep loss to the thinning of the myelin layer, which slows signal transmission in axons. Restoring cholesterol homeostasis reverses the damage [1].

Sleep loss hurts myelin

Sleep quality is a strong extrinsic determinant of longevity [2]. Not only does sleep loss affect cognitive function [3], it has also been linked to a plethora of health problems, including increased dementia risk, cardiovascular disease, and immune dysfunction [4]. However, the underlying mechanisms are still being investigated. In a new study, published in the Proceedings of the National Academy of Sciences, a team of researchers from Italy and Spain has shed new light on this question.

The team started with scouring through the Human Connectome Project database for correlations between sleep loss and structural problems in the brain. They found a significant negative correlation between sleep quality and MRI-measured white matter microstructural integrity. In other words, poor sleep was linked to worse white matter, and this effect was brain-wide.

Oligodendrocytes are the cells that build myelin sheaths around axons; this myelin layer insulates axons, ensuring swift and faithful signal transmission. The researchers subjected rats to 10 days of sleep restriction and found widespread reductions in white matter integrity, reduced myelin basic protein (MBP) staining in the corpus callosum, thinner myelin sheaths, and fewer oligodendrocyte precursor cells (OPCs), all of which point to myelin deficiency.

Importantly, the team then ran a separate chronic mild stress cohort to rule out stress as the driver. Cortico-cortical evoked responses and corticosterone levels were unchanged with stress alone, suggesting that the effects are specific to sleep loss.

Sleep-restricted rats showed approximately 33% increased latency in transcallosal conduction; essentially, signals traveling between hemispheres were substantially slower. Sleep loss also affected cognitive function, causing worse novel object recognition and motor performance on rotarod, and impaired interhemispheric synchronization of neuronal activity, particularly during NREM sleep.

It’s all about cholesterol

Using transcriptomic data from oligodendrocyte-specific datasets, the researchers found that sleep loss massively dysregulated cholesterol-related pathways: biosynthesis and transport genes were downregulated, while endoplasmic reticulum (ER) stress and lipid degradation genes were upregulated. “In summary, the analysis of gene expression in oligodendrocytes revealed that sleep loss significantly impaired ER and lipid homeostasis, particularly affecting cholesterol metabolism,” the paper says.

Direct measurements confirmed markedly reduced cholesterol in purified myelin fractions from sleep-deprived mice. This cholesterol loss increased membrane fluidity in the inner leaflet of the myelin membrane, which would weaken the insulating properties of myelin. “Optimal membrane fluidity and curvature in myelin necessitate high cholesterol levels,” the authors explain. “This ensures membrane stability, minimizes ion leakage, and reinforces the insulating properties of myelin membranes.”

The researchers link the observed reduction in myelin cholesterol to deficits in intracellular trafficking and transport mechanisms. Sleep loss caused minimal changes in other lipids. “The impact of sleep loss on major cholesterol-related transcripts was more pronounced in oligodendrocytes than in other brain cell types,” the paper clarifies.

An almost complete rescue

The team reasoned that by boosting cholesterol redistribution during sleep loss, it would be possible to minimize or prevent myelin dysfunctions and restore optimal conduction velocity in rats. They performed a rescue experiment, administering 2-hydroxypropyl-β-cyclodextrin (cyclodextrin), a drug that promotes cholesterol redistribution to myelin membranes, via three subcutaneous injections during the 10-day sleep restriction.

When they measured cholesterol in purified myelin fractions afterward, the sleep-loss-plus-cyclodextrin group was statistically indistinguishable from normally sleeping controls: the drug completely prevented the myelin cholesterol depletion that sleep restriction would otherwise cause. Cyclodextrin partially fixed myelin ultrastructure, although it did not reduce the proportion of unmyelinated axons back to control levels, and it didn’t fully restore OPC density in the corpus callosum. The treated animals showed no significant change from baseline, meaning that the conduction delay was fully prevented.

Importantly, the treatment also achieved behavioral rescue. For novel object recognition, sleep-restricted rats had a significantly reduced discrimination index (couldn’t distinguish new from familiar objects), but cyclodextrin-treated sleep-restricted rats performed comparably to controls. On the rotarod, where untreated sleep-restricted rats showed lower motor performance scores, the cyclodextrin group again performed at control levels. The authors note that since animals were given 24 hours of recovery before behavioral testing, residual physical fatigue is unlikely to explain the motor deficits.

Cyclodextrin, however, is not a precision tool. It facilitates broad cholesterol redistribution. While recent work suggests its effects are predominantly on oligodendrocytes, the authors admit that it also might be helping other cell types. While the rescue demonstrates that restoring cholesterol homeostasis is sufficient to prevent the behavioral deficits, further research is required to prove oligodendrocytes are the only cell population that matters.

Literature

[1] Simayi, R., Ficiarà, E., Faniyan, O., Cerdán Cerdá, A., Aboufares El Alaoui, A., Fiorini, R., … & Bellesi, M. (2026). Sleep loss induces cholesterol-associated myelin dysfunction. Proceedings of the National Academy of Sciences, 123(4), e2523438123.

[2] Cappuccio, F. P., D’Elia, L., Strazzullo, P., & Miller, M. A. (2010). Sleep duration and all-cause mortality: a systematic review and meta-analysis of prospective studies. Sleep, 33(5), 585-592.

[3] Killgore, W. D. (2010). Effects of sleep deprivation on cognition. Progress in brain research, 185, 105-129.

[4] Shi, L., Chen, S. J., Ma, M. Y., Bao, Y. P., Han, Y., Wang, Y. M., … & Lu, L. (2018). Sleep disturbances increase the risk of dementia: a systematic review and meta-analysis Sleep medicine reviews, 40, 4-16.