LongeCityNews Last Updated: 27 February 2026 - 02:19 PM

In recent years, the research community has developed a number of blood tests to assess risk and progression of Alzheimer's disease, relevant to the earliest, pre-symptomatic stages of the condition. Alzheimer's disease emerges very slowly over time, a process of damage and dysfunction that builds by stages over decades. The present consensus is that these early stages are dominated by amyloid-β misfolding and aggregation with only mild cognitive impairment at worst as the result. Only later is it the case that outright neuroinflammation and aggregation of phosphorylated tau protein come into play as the primary disease mechanisms. Nonetheless, forms of phosphorylated tau circulating in blood have proven useful as a marker of disease progression even in the early stages.

Today's research materials report on the use of one of the Alzheimer's blood tests based on phosphorylated tau to construct an aging clock specifically focused on predicting the time to development of Alzheimer's symptoms. Any set of markers that change with age can be used to produce a predictive clock, given enough data from enough people. The only question is how accurate it is; more data is generally better. Here, researchers work from only one assessment in a few hundred people to produce an estimated margin of error of 3 to 4 years over a time span of 10 to 20 years of disease development to first symptoms - a decent outcome given such a limited set of data.

Blood test "clocks" predict when Alzheimer's symptoms will start

Researchers have demonstrated models that predict the onset of Alzheimer's symptoms within a margin of three to four years. This could have implications both for clinical trials developing preventive Alzheimer's treatments and for eventually identifying individuals likely to benefit from these treatments. The models use a protein called p-tau217 in an individual's blood plasma to estimate the age when they will begin experiencing symptoms of the neurodegenerative disease. Levels of p-tau217 in the plasma can currently be used to help doctors diagnose Alzheimer's in patients with cognitive impairment. These tests are not currently recommended in cognitively unimpaired individuals outside of clinical trials or research.

To identify the interval between elevated p-tau217 levels and Alzheimer's symptoms, researchers analyzed data from volunteers in two independent long-running Alzheimer's research initiatives. The participants included 603 older adults who lived independently in the community. Plasma p-tau217 has previously been shown to correlate strongly with the accumulation of amyloid and tau in the brain as shown on PET scans. The key hallmarks of Alzheimer's disease, amyloid and tau are misfolded proteins that begin building up in the brain many years before Alzheimer's symptoms develop.

The models predicted the age of symptom onset within a margin of error of three to four years. Older individuals had a shorter time from when elevated p-tau217 appeared to the start of symptoms as compared to younger participants, suggesting that younger people's brains may be more resilient to neurodegeneration and that older people may develop symptoms at lower levels of Alzheimer's pathology. For example, if a person had elevated p-tau217 in their plasma at age 60, they developed symptoms 20 years later. If p-tau217 wasn't elevated until age 80, they developed symptoms only 11 years later.

Predicting onset of symptomatic Alzheimerʼs disease with plasma p-tau217 clocks

Predicting not just if, but also when, cognitively unimpaired individuals are likely to develop onset of Alzheimerʼs disease (AD) symptoms would be useful to clinical trials and, eventually, clinical practice. Although clock models based on amyloid and tau positron emission tomography have shown promise in predicting the onset of AD symptoms, a model based on plasma biomarkers would be more accessible. Using longitudinal plasma %p-tau217 (the ratio of phosphorylated to non-phosphorylated tau at position 217) from two independent cohorts (n = 258 and n = 345), clock models were used to estimate the age at plasma %p-tau217 positivity.

The estimated age at plasma %p-tau217 positivity was associated with the age at onset of AD symptoms with a median absolute error of 3.0-3.7 years. Notably, the time from %p-tau217 positivity to onset of AD symptoms was markedly shorter in older individuals. Similar models were constructed with data from one p-tau217/Aβ42 immunoassay and four plasma p-tau217 immunoassays. These findings suggest that the time until onset of AD symptoms can be estimated using a single blood test within a margin of error that is acceptable for use in clinical trials.

Researchers publishing in the Nature journal Cell Discovery have described how the age-related attenuation of a key metabolic axis causes human adipose-derived stem cells (hASCs) to lose functional capabilities.

Pinpointing the loss of function

This paper begins by highlighting a core problem of using self-derived (autologous) stem cells for treatments in older people: the cells themselves have aged, leading to a loss of basic self-renewal and inability to fulfill their natural functions, harming rather than helping recipients [1].

The paper also notes that mesenchymal stem cells (MSCs), a group that includes hASCs, have aging that is associated with key changes in several metabolic components. Reduced glutathione (GSH) is associated with senescence in these cells [2]. N6-Methyladenosine (m6A), a key component of RNA modification that is necessary for cellular function, has also been found to be responsible for the fates of bone marrow MSCs [3], and its link to GSH processing has also been found to be connected to cellular senescence [4]. These researchers, therefore, sought to find out just how much m6A and its related pathways affect stem cell aging.

Older stem cells cannot perform

In their first experiment, the researchers compared aged and young hASCs to determine the extent to which aging affects these cells’ function. Unsurprisingly, despite being passaged the same number of times, hASCs derived from infants (I-hASCs) were far more able to proliferate and less likely to become senescent than hASCs derived from elderly people around the age of 80 (E-hASCs). The I-hASCs also had better cell morphology, faster migration, and greater viability, along with a greater expression of genes related to fat creation (adipogenesis), blood vessel creation (angiogenesis), metabolic function, wound healing, and overall activity.

The researchers tested these cells in a mouse model of injury and fat transplantation, comparing I-hASCs, E-hASCs, and a control group given no stem cells at all. Unsurprisingly, the mice given I-hASCs healed more quickly and had more angiogenesis in the transplanted fat, along with reduced inflammation, very few cysts or vacuoles, and nearly no fibrosis. However, even compared to the control group, the group given E-hASCs had intense inflammation, a large number of cysts and vacuoles, and intense fibrosis.

A closer look at gene expression using single-cell RNA sequencing revealed potential reasons why. The researchers were able to divide cells into five functional clusters: Cluster 1 (ACTA2+TAGLN+), which was most common in the I-hASCs, was associated with more angiogenesis, bone formation, and metabolic processes; further work found that this group had more stemness and more functional ability than the other groups. Cluster 2 was related to certain metabolic pathways specific to lipids. Cluster 3, which was abundant in E-hASCs, was related to senescence and aging along with the destruction of proteins and the dissolution of the extracellular matrix. Cluster 4 involved cell adhesion, while Cluster 5 involved division and the cell cycle.

Even among all of these various clusters, E-hASCs had more upregulated age-related pathways while I-hASCs had more gene expression related to the synthesis of amino acids and overall metabolism.

A crucial gene is methylated with age

The researchers also found that I-hASCs had more gene expression of a fundamental GSH-related pathway. An upregulation of IGF2BP3 allowed these cells to produce more enzymes that processed branched-chain amino acids (BCAAs) and glutamine, thus prompting these cells to have more GSH than their older counterparts. The expression of IGF2BP3 was also linked to a reduction in senescence-related gene expression and cellular death by apoptosis along with increases in cell proliferation and migration. IGF2BP3 was specifically identified as being downregulated by epigenetic alterations in aging: this gene is hypermethylated with age, preventing its expression.

A further experiment involving BCAA and glutamine found that supplementing these two molecules to mice was able to slightly restore the wound healing abilities of E-hASCs. According to the researchers, “these findings underscore the promise of metabolic modulation as a translational approach to mitigate cellular aging and improve regenerative therapies.”

While supplementation cannot fully reverse the effects of the dwindling IGF2BP3 with age, this metabolic approach provides a crucial starting point for potential near-term therapies. Further work will determine if such an approach will allow for autologous or other stem cell-related therapies to become more effective.

Literature

[1] Wang, B., Liu, Z., Chen, V. P., Wang, L., Inman, C. L., Zhou, Y., … & Xu, M. (2020). Transplanting cells from old but not young donors causes physical dysfunction in older recipients. Aging cell, 19(3), e13106.

[2] Benjamin, D. I., Brett, J. O., Both, P., Benjamin, J. S., Ishak, H. L., Kang, J., … & Rando, T. A. (2023). Multiomics reveals glutathione metabolism as a driver of bimodality during stem cell aging. Cell metabolism, 35(3), 472-486.

[3] Wu, Y., Xie, L., Wang, M., Xiong, Q., Guo, Y., Liang, Y., … & Yuan, Q. (2018). Mettl3-mediated m6A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis. Nature communications, 9(1), 4772.

[4] Weng, H., Huang, F., Yu, Z., Chen, Z., Prince, E., Kang, Y., … & Chen, J. (2022). The m6A reader IGF2BP2 regulates glutamine metabolism and represents a therapeutic target in acute myeloid leukemia. Cancer cell, 40(12), 1566-1582.

Lifestyle choice relating to diet influences the pace of aging over the long term. A great deal of effort has been devoted to understanding why this is the case, focused on the specific effects of excess weight and various dietary components on metabolism. Researchers here make an effort to assess the effects of dietary choices on human life expectancy that emerge from the large amount of epidemiological data recorded in the UK Biobank. The results are in the same ballpark as the benefits to life expectancy indicated by some past large studies of the effects of moderate exercise.

Associations between healthy dietary patterns and life expectancy remain unclear. Here, we reported the prospective associations of five dietary patterns with mortality and life expectancy in 103,649 UK Biobank participants. Over a median follow-up period of 10.6 years, 4,314 total deaths were documented. Alternate Healthy Eating Index-2010, Alternate Mediterranean Diet (AMED), healthful Plant-based Diet Index (hPDI), Dietary Approaches to Stop Hypertension, and Diabetes Risk Reduction Diet (DRRD) were associated with lower all-cause mortality and longer life expectancy, with DRRD showing slightly stronger associations than hPDI.

Compared with the bottom quintile, achieving the top quintile of dietary scores was associated with 1.9 to 3.0 years of life gained at 45 years in men and 1.5 to 2.3 years in women. The life gained was longest in DRRD for males and AMED for females. The significant associations remained when accounting for genetic susceptibility. Our findings underscore the advantages of healthy dietary patterns in prolonging life expectancy, regardless of longevity genes.

Link: https://doi.org/10.1126/sciadv.ads7559

Researchers have in past years established that some degree of transmission of environmental information takes place from generation to generation. The epigenetic response to environmental factors such as abundance of food is partially passed on to offspring to result in changes in the operation of offspring metabolism. Epigenetic and metabolic reactions to abundance of food affect pace of aging and life span, and these outcomes are also changed in offspring, even when the offspring live in a different environment with different abundance of food.

Data in mice, nonhuman primates, and in humans demonstrate that exposure to maternal obesity increases the risk of multiple diseases in offspring. However, little is known about the aging effects of maternal obesity on the offspring. This study shows that maternal obesity significantly reduced the lifespan of both male and female mice born to obese dams despite being weaned onto a healthy diet at three weeks of age.

This reduction in longevity was linked to an increase in age-related fibrotic pathology across multiple organs, e.g., liver, heart, and kidney. Gompertz analysis of the lifespan data showed that maternal obesity offspring have reduced lifespan due to detrimental changes established early during development rather than factors that modify aging later-in-life. These findings are translationally significant as they demonstrate that the growing prevalence of maternal obesity may lead to a decrease in overall lifespan and increase in age-related diseases in the next generation.

Link: https://doi.org/10.64898/2026.02.04.703858