LongeCityNews Last Updated: 13 February 2026 - 05:38 AM

Nuclear DNA is surrounded by transcriptional machinery, protein structures that will attempt to transcribe any gene sequence they encounter. Where DNA is compacted into regions of heterochromatin by being spooled onto histones, genes are silenced because their sequences are hidden from transcriptional machinery. Whether a given stretch of DNA is compacted or not is determined by epigenetic mechanisms, largely decorations (such as methyl groups) attached to DNA and histones that alter their structural behavior. A general feature of aging is a loss of heterochromatin and increasing expression of genes and other sequences that are usually silenced in youth. This leads to, for example, the expression of transposons that can drive DNA damage and inflammation, but also disruption and change in normal cell function.

Some time ago, researchers established a way to visualize whether or not a given region of DNA is compacted into heterochromatin. Flies can be genetically engineered with suitably placed genes that change the color of some of their features, such as eye segments, depending on whether or not they are expressed. Thus just by looking at the fly, researchers will know whether or not the region of DNA containing the inserted gene is compacted. A number of different fly lineages have been constructed over the years, as researchers needed a solution for one region or another. This approach is called position effect variegation.

Today's open acccess paper is a discussion of position effect variegation as a tool to inspect changes in DNA compaction into heterochromatin that occur with age and their correlation with high level outcomes such as mortality risk and longevity. Since increased loss of heretochromatin appears to correlate with longevity in flies, position effect variegation could be used to build aging clocks (in flies at least) that primarily reflect alterations to DNA structure rather than other mechanisms.

Position effect variegation (PEV) as an aging clock: visualization of age-dependent loss of heterochromatin and longevity associated with enhanced heterochromatin

The heterochromatin loss model of aging suggests there is an age-dependent reduction in epigenetic factors that form and maintain the heterochromatin state of chromosomes. Position Effect Variegation (PEV) can visually report phenotypes of heterochromatin mediated silencing in Drosophila Melanogaster eyes and we use PEV to examine the association between heterochromatin state changes and aging.

Pericentric inserts causing PEV showed suppressed variegation phenotypes in old age compared to young age and were confirmed to be associated with progressively increasing transcription, indicating loss of heterochromatin mediated silencing. Within a single population, animals with enhanced PEV phenotypes live longer than those with more suppressed PEV phenotypes, suggesting that small differences in environmental or genetic factors within this population could be responsible for differences in heterochromatin and lifespan.

Environmental factors could enhance heterochromatin, reduced nutrient diet and lower temperature coincided with enhanced heterochromatin and longer life. Furthermore, genetic variants associated with long life, including chico mutants, lead to increased heterochromatin and enhanced PEV phenotypes. Therefore, aging can be linked to heterochromatin loss and developmental increases in heterochromatin are associated with longevity. Thus, PEV reporters act as aging clocks demonstrating loss of heterochromatin that progresses with age and epigenetic alterations that can promote longevity.

A team of researchers has biologically engineered T cells with currently available Alzheimer’s drugs in order to directly attack the characteristic amyloid plaques of Alzheimer’s disease.

Building on the current paradigm

Most Alzheimer’s treatments used in the clinic are -mabs, monoclonal antibodies that are designed to attack the amyloid beta plaques that accumulate in the brains of people with Alzheimer’s. However, while they have been found to have enough meaningful benefits in clinical trials to be approved by the FDA, they are not a cure, and some analyses question their effectiveness [1].

The immune system has been documented to play various roles in neurodegenerative diseases, although those roles can be both beneficial [2] and harmful [3]. CD4+ T cells, which were engineered in this study, naturally have beneficial effects against Alzheimer’s [4] and protect injured neurons [5].

The chimeric antigen receptor (CAR) approach also uses antibodies; however, these antibodies are attached to immune cells in an effort to encourage them to destroy pathologies. Most research in this area has focused on cancer; particularly leukemia [6], and we have written about this technology being used against a broad variety of cancers and senescent cells in the gut.

Instead of destroying cells, however, these researchers want their engineered cells to destroy the Alzheimer’s plaques themselves and to home in on damaged sites in the hope that their presence might protect the damaged area [5]. The CARs they used were built with two of the same -mabs currently used in the clinic: aducanumab and lecanemab.

Tentatively positive initial results

Testing against various forms of amyloid beta peptides, they found that the lecanemab-derived CAR (Lec28z) was significantly more responsive than the aducanumab-derived one (Adu28z). Only assembled fibrils were targeted; neither of the CARs was responsive to the monomer or oligomer forms of this amyloid. Lec28z was also more responsive to brain extracts derived from mice modified to get Alzheimer’s; therefore, the researchers continued using this version throughout the rest of their experiments.

The researchers injected a key vein of Alzheimer’s model mice with Lec28z-modified T cells derived from wild-type mice, and then delivered another injection three weeks later. After three more weeks, the brains of the injected mice were examined.

Compared to control groups injected with saline or unmodified T cells, the CAR-T-injected mice had significant increases of both CAR T cells and regular T cells at the sites of amyloid beta plaques. The overall amount of amyloid beta was reduced, both near the injection site and throughout the brain’s dura.

However, there was no decrease in amyloidosis throughout the bulk of the brain. While these cells were in fact dispersed throughout the brain and homing in on plaque sites, they also activated the local T cells and microglia, “raising concerns about prolonged T cell activation and the potential emergence of detrimental phenotypes including cytotoxicity.”

Transience is highly beneficial

Therefore, the researchers attempted a more transient approach. Three doses of CAR-T cells transfected with Lec28z mRNA were given ten days apart, with a brain examination conducted 10 days after the final dose. This approach was found to be more effective; the treated animals had less microglial activation and amyloid throughout the brain along with less overall pathology.

These findings, while positive and potentially groundbreaking, are very preliminary. The researchers did not conduct behavioral tests, and mice do not naturally get Alzheimer’s disease. Substantial further work, including a trial involving human beings, needs to be done to determine if -mab drugs can be replaced in the clinic with CAR-T versions.

Literature

[1] Knopman, D. S., Jones, D. T., & Greicius, M. D. (2021). Failure to demonstrate efficacy of aducanumab: An analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019. Alzheimer’s & Dementia, 17(4), 696-701.

[2] Marsh, S. E., Abud, E. M., Lakatos, A., Karimzadeh, A., Yeung, S. T., Davtyan, H., … & Blurton-Jones, M. (2016). The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function. Proceedings of the National Academy of Sciences, 113(9), E1316-E1325.

[3] Chen, X., Firulyova, M., Manis, M., Herz, J., Smirnov, I., Aladyeva, E., … & Holtzman, D. M. (2023). Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy. Nature, 615(7953), 668-677.

[4] Mittal, K., Eremenko, E., Berner, O., Elyahu, Y., Strominger, I., Apelblat, D., … & Monsonego, A. (2019). CD4 T cells induce a subset of MHCII-expressing microglia that attenuates Alzheimer pathology. Iscience, 16, 298-311.

[5] Walsh, J. T., Hendrix, S., Boato, F., Smirnov, I., Zheng, J., Lukens, J. R., … & Kipnis, J. (2015). MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4. The Journal of clinical investigation, 125(2), 699-714.

[6] Grupp, S. A., Kalos, M., Barrett, D., Aplenc, R., Porter, D. L., Rheingold, S. R., … & June, C. H. (2013). Chimeric antigen receptor–modified T cells for acute lymphoid leukemia. New England Journal of Medicine, 368(16), 1509-1518.

The addition and removal of methyl groups from specific locations on the genome is one of the epigenetic mechanisms used to control the structure of DNA in the cell nucleus, such as which sequences are hidden via compaction into heterochromatin and which remain accessible to allow the expression of genes. That the pattern of DNA methylation changes with age in characteristic ways is what allows the existence of epigenetic clocks, the use of DNA methylation status to assess biological age. That epigenetic control over gene expression changes with age also makes it a potential target for the development of therapies to treat aging, particularly now that partial reprogramming studies have amply demonstrated that reversing age-related epigenetic changes is possible in principle.

As individuals age, the precise regulation of DNA methylation gradually deteriorates, leading to widespread epigenetic drift. This loss of control results in both global hypomethylation and site-specific hypermethylation, disrupting normal gene expression patterns. Global hypomethylation can lead to genomic instability, activation of transposable elements, and oncogene expression, while localized hypermethylation may silence tumor suppressor genes or genes critical for immune regulation and metabolic function. These changes are increasingly recognized as contributors to the development of chronic diseases. For example, aberrant DNA methylation patterns have been implicated in cancer, cardiovascular disease, type 2 diabetes, and neurodegenerative disorders such as Alzheimer's disease.

One of the most promising trends is the integration of DNA methylation data with other layers of biological information, such as transcriptomics, proteomics, metabolomics, and microbiomics. This multi-omics approach offers a holistic view of aging by capturing complex molecular interactions/network that DNA methylation alone cannot fully explain. Combining these datasets can refine biological age estimates, identify novel aging biomarkers, and uncover mechanisms driving age-related functional decline.

Parallel to these analytical advances, there is growing interest in interventions targeting epigenetic aging. Lifestyle modifications, including diet, exercise, and stress management, have demonstrated potential to modulate DNA methylation patterns and slow epigenetic age acceleration. Pharmacological approaches, such as senolytics, epigenetic modulators, and novel small molecules, are under investigation for their ability to reverse or delay methylation-based biological aging. Clinical trials integrating methylation clocks as endpoints are beginning to evaluate the efficacy of these interventions, potentially enabling real-time monitoring of biological age and intervention impact.

Link: https://doi.org/10.3389/fmolb.2025.1734464

Rapamycin is the most well studied of the mTOR inhibitors. It produces immunosuppression at high doses, and has been used in this context in the clinic for more than twenty years. At lower doses it mimics aspects of the beneficial metabolic response to calorie restriction, om particular an increased operation of the cellular maintenance processes of autophagy. In animal studies this has been demonstrated to slow aging and extend healthy life. Human clinical trial data for this lower dose anti-aging usage remains relatively sparse, unfortunately, but the results that do exist are interesting.

Rapamycin is one of the most intensively studied compounds with potential effects on longevity. Available experimental data indicate that inhibition of the mTOR pathway and activation of autophagy lead to improved cellular homeostasis, reduced oxidative stress, and a slowing of aging processes across multiple model organisms.

Current clinical studies in humans, although limited in number and involving small populations, suggest that low doses of rapamycin may enhance immune function, reduce visible signs of skin aging, and positively influence well-being and metabolic parameters.

Despite these promising findings, knowledge regarding the long-term safety, efficacy, and optimal dosing regimens of rapamycin remains limited. Further, multicenter, randomized clinical trials are needed to determine whether modulation of the mTOR pathway can represent an effective and safe strategy to support healthy human aging.

Link: https://doi.org/10.7759/cureus.98514