LongeCityNews Last Updated: 13 December 2025 - 09:18 PM

Even in this age of single cell sequencing, a great deal of the categorization and counting of cells is still accomplished via assessment of cell surface proteins. The ability to cheaply create and manufacture novel antibodies that selectively bind to specific proteins naturally led to technologies such as flow cytometry that can separate and count cells that express a specific surface protein, or high versus low levels of that surface protein. The large number of proteins with names that start with "CD" for cluster of differentiation are so named because researchers have spent a lot of time looking for ways to distinguish different populations of immune cells with very different behaviors.

Recognizing specific surface markers is also an important foundation for the development of cell killing technologies and immunotherapies. Thus the cancer research field is very interested in categorizing cells by their markers. Similarly, now that the research community recognizes that senescent cells accumulate with age and are harmful, an important contribution to age-relaed loss of function and disease, there is interest in distinct markers of senescence. Firstly, senescent cells are not uniform, and it may be useful to distinguish their types. Secondly, cell killing technologies that are highly selective for senescent cells are very much a desirable goal. Thirdly, the well established approaches to assess the burden of senescence in tissues are likely suboptimal in a number of ways.

The exploration of markers of senescence is a work in progress, with ongoing debate over the merits of one approach over another, particularly when it comes to the immune system. To come full circle, cellular senescence in the immune system appears important to immune system aging - but so are a range of other issues. The immune system is very complex, and far from fully mapped. There is a great deal of room for improvement to the present state of knowledge, and today's open access paper is an example of this sort of ongoing work on the topic of immune cell senescence and how to best identify this state.

Re-evaluating CD57 as a marker of T cell senescence: implications for immune ageing and differentiation

Ageing is accompanied by a decline in immune function, associated with susceptibility to infections and malignancies, and reduced vaccine efficacy. These immunological changes, affect multiple components of the immune system, particularly T lymphocytes, which exhibit altered subset distributions and accumulate senescent features.

CD57, a surface glycoprotein expressed on T cells, has emerged as a potential marker of terminal differentiation and senescence used for immunomonitoring in infection or cancer contexts. However, the use of CD57 as a marker of T cell senescence remains unclear. To investigate this, we analyzed CD57 expression on CD8+ and CD4+ T cells in healthy donors from two independent cohorts, considering cellular differentiation, age, cytomegalovirus status, and other senescence markers.

Our findings reinforce the association between CD57 expression, T cell differentiation, and cytomegalovirus seropositivity, but not with chronological age. Although CD57 is associated with altered proliferation and survival in all T cell differentiation subsets, it does not fully align with a senescent phenotype. Therefore, we propose that CD57 may be better appreciated as a marker of immunological age. Moreover, the interpretation of CD57 expression must account for cytomegalovirus serostatus to avoid misleading conclusions, especially in oncology and ageing research.

A new observational study spanning two human cohorts has found a link between theobromine, a phytochemical abundant in cocoa, and slower epigenetic aging [1].

A yummy geroprotector?

Popular wisdom has it that not many things in life are both healthy and delicious, but according to research, one of them is chocolate. Studies have repeatedly linked chocolate and cocoa consumption with improved health outcomes, including beneficial effects on cholesterol, inflammation, and cellular senescence [2].

Cocoa and coffee share a family of alkaloids called methylxanthines, which includes caffeine, theophylline, paraxanthine, theobromine, and 7-methylxanthine. Coffee is caffeine-heavy, while cocoa is theobromine-heavy.

Theobromine has been reported to extend lifespan in certain strains of C. elegans nematode worms [3] and has been linked to cardiovascular and other health benefits in observational human data [4]. A new study conducted by scientists from King’s College London and several German institutions, published in Aging, looks at theobromine in the context of human aging by analyzing the correlation between the chemical’s blood levels and biological age acceleration.

Two clocks confirm slower aging

The team used two metrics: GrimAge, one of the most robust methylation clocks and trained to predict mortality, and DNAmTL, a DNA methylation-based estimator of telomere length. The latter predicts telomere length in leukocytes from methylation at a specific set of CpG sites.

The researchers pulled together two population cohorts in which people had both blood metabolomics and DNA methylation data. TwinsUK, which includes 509 women with a median age of around 60, served as the discovery cohort. The results were then replicated in KORA, a cohort of 1,160 German adults of both sexes.

They started by measuring the association between the difference between the GrimAge reading and the person’s chronological age (clock acceleration) and six coffee/cocoa-related metabolites: five methylxanthines and the amino acid theanine.

Theobromine immediately stood out, showing the strongest negative correlation. In the researchers’ main model, higher theobromine levels were linked to roughly 1.6 years less GrimAge acceleration per standard step up in theobromine. Theobromine levels were also associated with higher DNAmTL readings, suggesting slower telomere attrition.

Testing the results

The researchers then extensively stress-tested these results. To see if this was just a generic “coffee drinker” signal, they added caffeine and its breakdown products to the model and asked whether the theobromine effect would disappear. It did not; the association with slower GrimAge acceleration stayed, becoming only slightly weaker.

Next, they used penalized regression models (LASSO and elastic net), which automatically shrink or drop less informative variables. Even under these harsher conditions, theobromine consistently remained one of the key predictors of GrimAge acceleration.

In TwinsUK, metabolomics and methylation measurements could be taken up to 5 years apart, so the researchers re-ran the analyses within narrower time windows to see how the association would change. The shorter the distance between the two readings (latency), the stronger the effect size became, strengthening their confidence that this was not just an artifact of long gaps between measurements.

In the KORA replication cohort, higher serum theobromine again tracked with younger epigenetic profiles. After adjustment for age, BMI, blood cell composition, technical factors, and the other methylxanthines, each standard step up in theobromine was linked to about one year of reduced GrimAge acceleration and to slightly longer telomeres.

Because the discovery cohort consisted entirely of women, the authors checked whether the pattern held in women from the KORA study and found a similar, slightly weaker association there, reinforcing their original discovery. In the full KORA cohort, which includes both men and women, the overall effect of theobromine on GrimAge was actually stronger than in women alone. This suggests that men also show a negative association between theobromine and epigenetic age that is at least as strong, if not stronger, than in women.

Dr. Ramy Saad, lead researcher at King’s College London, who is also a researcher at University College London and holds a doctorate in clinical genetics, said: “This is a very exciting finding, and the next important questions are what is behind this association and how can we explore the interactions between dietary metabolites and our epigenome further? This approach could lead us to important discoveries towards ageing, and beyond, in common and rare diseases.”

Dr. Ricardo Costeira, a Postdoctoral Research Associate from King’s College London, added: “This study identifies another molecular mechanism through which naturally occurring compounds in cocoa may support health. While more research is needed, the findings from this study highlight the value of population-level analyses in aging and genetics.”

Caveats and limitations

Being observational and cross-sectional, this study cannot prove a causal relationship between theobromine and aging or even the methylation-based aging metrics that the researchers used. While they adjusted for age, BMI, blood cell counts and several related metabolites, residual confounding by factors like overall diet, lifestyle, socioeconomic status, or other cocoa components, especially flavanols, remains a real possibility.

Both cohorts are European and middle-aged/older, and the discovery sample is composed entirely of female twins, which limits generalization to men, younger people, and other ancestries. Finally, epigenetic clocks and DNAm-based telomere estimates are useful but still imperfect proxies for biological aging. Nevertheless, it’s more encouraging news for chocolate lovers.

Literature

[1] Bell, J., Saad, R., Costeira, R., Garcia, P. M., Villicaña, S., Gieger, C., … & Waldenberger, M. (2025). Theobromine is Associated with Slower Epigenetic Ageing. Aging.

[2] Arranz, S., Valderas‐Martinez, P., Chiva‐Blanch, G., Casas, R., Urpi‐Sarda, M., Lamuela‐Raventos, R. M., & Estruch, R. (2013). Cardioprotective effects of cocoa: Clinical evidence from randomized clinical intervention trials in humans. Molecular Nutrition & Food Research, 57(6), 936-947.

[3] Li, H., Roxo, M., Cheng, X., Zhang, S., Cheng, H., & Wink, M. (2019). Pro-oxidant and lifespan extension effects of caffeine and related methylxanthines in Caenorhabditis elegans. Food Chemistry: X, 1, 100005.

[4] Sharifi‐Zahabi, E., Hajizadeh‐Sharafabad, F., Nachvak, S. M., Mirzaian, S., Darbandi, S., & Shidfar, F. (2023). A comprehensive insight into the molecular effect of theobromine on cardiovascular‐related risk factors: A systematic review of in vitro and in vivo studies. Phytotherapy Research, 37(9), 3765-3779.

Given the ability to accurately map the microbial species and relative population sizes of the gut microbiome via 16S rRNA sequencing, researchers are generating an enormous amount of data linking specific characteristics of the gut microbiome to specific medical conditions, including the changes that take place with age. Here, researchers use data from patients with fibrosis in the lungs to mount an argument for Bifidobacterium adolescentis to be a beneficial species, and then test this proposal in aged mice. Increasing the presence of Bifidobacterium adolescentis in the gut microbiome of mice proves capable of attenuating fibrosis in the lung, making it a potentially interesting intervention. At present many forms of lung fibrosis are hard to treat and largely irreversible.

The global burden of pulmonary fibrosis is increasing. Recent studies have shown that some pulmonary fibrotic lesions caused by COVID-19 infection may persist for a long time. Emerging evidence suggested a critical association between gut microbiota and pulmonary fibrosis. In this study, the clinical follow-up data from post-COVID-19 patients indicated that those with higher CT image scores were older, had a significantly lower Blautia and Bifidobacterium to Streptococcus ratio (B/S index).

We examined whether Bifidobacterium adolescentis could attenuate bleomycin-induced pulmonary fibrosis in mice, with particular attention in the aging mice. Aging mice exhibited more severe pulmonary fibrosis after bleomycin induction, while the intervention of B. adolescentis attenuated the degree of pulmonary fibrosis in aging mice to a state similar to that of young mice. B. adolescentis alleviated inflammatory responses by enhancing the gut barrier, and reduced fibrotic marker expression (TGF-β, IL-17, α-SMA, Collagen I, Collagen III) by modulating PPAR and Th17 signaling pathways. Furthermore, B. adolescentis stabilized gut microbiota and increased the abundance of Bifidobacterium, Turicibacter, and norank_f_Desulfovibrionaceae, thereby suppressed the prostaglandin E2 (PGE2) and affected collagen deposition.

In conclusion, B. adolescentis alleviates pulmonary fibrosis through the gut-lung axis by regulating PGE2/PPAR/Th17 signaling, providing a promising therapeutic approach for pulmonary fibrosis management.

Link: https://doi.org/10.1038/s41538-025-00613-6

Excess weight is a risk factor for Alzheimer's disease, but nowhere near as strongly as, say, for type 2 diabetes. It is likely not as straightforward a relationship in terms of the underlying biochemistry. Here, researchers note that obesity correlates with low levels of choline in blood samples, and low levels of choline in turn are established in animal studies to worsen age-related inflammation and progression of neurodegeneration. The researchers propose that low choline contributes to the metabolic consequences of obesity, but note that it is unclear as to whether obesity causes low choline. As is usually the case when looking at human data, correlations are easily established, but finding definitive evidence of causation is challenging.

Here, we demonstrate a relationship between early-life obesity, insulin resistance, circulating choline, and inflammation, emphasizing their potential as risk factors for disorders such as Alzheimer's disease (AD). Choline levels were lower in obese participants compared to those with a healthy body mass index (BMI). Importantly, several metabolic indicators were elevated in the obese group, and body composition markers (BMI and %Body Fat) and insulin sensitivity markers (insulin levels and HOMA-IR) were negatively correlated as well as associated with choline levels.

Obese participants also exhibited dysregulated inflammatory profiles; 11 cytokines were elevated. Additionally, levels of aldolase B and sorbitol dehydrogenase - liver enzymes involved in sugar metabolism - were higher in obese individuals and negatively correlated with choline levels, paralleling our previous findings in AD mice on a choline-deficient diet. Evidence of neuronal axonal damage was observed in obese participants; as plasma NfL was elevated and inversely correlated with choline levels, this relationship was validated in independent mild cognitive impairment (MCI) and AD cohorts.

Collectively, these findings support the idea that low circulating choline levels may contribute to the metabolic and inflammatory dysfunctions associated with obesity and may increase the risk of neurodegenerative diseases.

Link: https://doi.org/10.14336/AD.2025.1207