Cellular aging in the blood reveals disease risks

A deep analysis of more than 7,000 plasma proteins in 60,000 individuals has enabled the development of models capable of estimating the biological age of over 40 cell types, ranging from neurons to muscle cells and immune cells. The results show that aging does not affect all cells in the same way: between 20 and 25% of individuals exhibit accelerated aging in a single cell type, while 1 to 3% have at least ten affected.

These cellular aging signatures are closely linked to the onset of diseases and mortality over a 15-year period. For example, individuals carrying the APOE4 gene, known to increase the risk of Alzheimer’s disease, show accelerated aging of astrocytes, a type of brain cell, but relative rejuvenation of macrophages, immune cells. Conversely, carriers of the APOE2 gene exhibit the opposite profile, with younger astrocytes and older macrophages. These differences could be explained by evolutionary mechanisms where the APOE4 gene, by enhancing immune vigilance, may have provided a survival advantage against pathogens in the past, at the cost of accelerated brain aging.

Extreme aging of astrocytes triples the risk of developing Alzheimer’s disease in individuals with two copies of the APOE4 gene, while rejuvenation of these same cells significantly reduces this risk. Similarly, marked aging of skeletal muscle cells multiplies the risk of amyotrophic lateral sclerosis, a severe neurodegenerative disease, by 12.7. In smokers, accelerated aging of respiratory epithelial cells increases the risk of lung cancer by 58% compared to smoking alone.

Cellular aging signatures also help predict other diseases. Extreme aging of type 2 alveolar cells, which play a key role in lung repair, is associated with an increased risk of lung cancer, even in non-smokers. For type 2 diabetes, marked aging of myeloid lineage cells, involved in inflammation, significantly increases the risk, even in the absence of traditional factors such as high blood sugar levels.

The study also reveals that lifestyle directly influences cellular aging. Individuals adopting a healthy lifestyle, characterized by non-smoking, moderate alcohol consumption, a normal body mass index, regular physical activity, and sufficient sleep, have generally younger cells. Conversely, those combining smoking and obesity show accelerated aging in many cell types.

The cumulative burden of cellular aging has a major impact on survival. Individuals with more than 20 cell types aging at an accelerated rate have a 15-year survival rate of about 34%, compared to 90% for those whose cells age normally. Conversely, rejuvenated immune or neuronal cells improve longevity. A polycellular risk score has been developed to stratify mortality risk, demonstrating robust predictive capacity across different proteomic analysis platforms.

These findings offer a new way of understanding human aging at the cellular level. They pave the way for personalized approaches to assess disease risks and identify potential therapeutic targets by specifically targeting the most vulnerable cell types. Aging is no longer seen as a uniform process, but as a mosaic of distinct cellular trajectories, each contributing differently to health and disease.

Attributions and Sources

Origin of the Study

DOI: https://doi.org/10.1038/s41591-026-04446-y

Title: Plasma proteomic signatures of cellular aging predict human disease

Journal: Nature Medicine

Publisher: Springer Science and Business Media LLC

Authors: Daisy Yi Ding; Veronica Augustina Bot; Kenneth L. Chen; James W. Groves; Róbert Pálovics; Daisuke Masuda; Amelia Farinas; Hamilton Se-Hwee Oh; Viktoria Wagner; Nannan Lu; ; Carlos Cruchaga; Alina Isakova; Jonathan M. Schott; Tony Wyss-Coray