Disclosure: some of the thinking behind this paper -including the donor label “Super Agers” (ΔAge = predicted – chronological age < −15 years) - was inspired by the work and writing of @erictopol.bsky.social, whose book I happened to be reading while developing this story
As always, this work involved a whole village of friends and colleagues at:
Vitalant
@cuanschutz.bsky.social
@columbiauniversity.bsky.social
@ubcpress.bsky.social
@uvapress.bsky.social
@ucsfhealth.bsky.social
Special thanks to
NHLBI
@aabbupdates.bsky.social
for their continued support
Large-scale RBC omics may enable:
• precision transfusion medicine
• biomarkers of systemic and organ-specific aging
• population-scale monitoring of metabolic health
Conceptually, this supports a broader idea:
Red blood cells are not just oxygen carriers, rather they are circulating reporters of systemic metabolic health.
The story goes beyond transfusion medicine. RBC aging-clock omics signatures are also linked to brain iron, myelin-related phenotypes, and neurocognitive test performance.
This suggests RBC omics captures stable biological features of donors, bridging:
genetics → cellular physiology → clinical blood product quality → population-scale donor biology.
Even more interesting:
RBC aging signatures also predict future donor behavior - including long-term donation trajectories >12 years later.
Importantly, this is not irreversible. In donors repleted with IV iron dextran, the RBC aging signal is reset toward a younger state — supporting a direct link between systemic iron biology and RBC molecular age.
The clock is also informative in healthy donors. High-frequency donors tend to show signatures of slower biological RBC aging.
But that advantage is not unconditional: when frequent donation leads to iron depletion, RBC biological aging appears to accelerate.
By studying orthogonal cohorts of >1k patients, we found that accelerated RBC aging is not random. It tracks with hemolysis-related biology, including conditions such as G6PD deficiency, sickle cell trait, and sickle cell disease, which shift RBCs toward an older biological state
Deviation between predicted and chronological age (ΔAge) correlates with RBC storage quality and hemolysis susceptibility, linking aging signatures to transfusion-relevant phenotypes, including post-transfusion boost in >10k recipient hemoglobin levels.
Age acceleration was associated with certain genetic traits linked to inflammation and ECM remodeling, but also by blood donor BMI, sex and ethnicity.
Using machine learning, we leveraged these protein signatures to build RBC aging clocks.
These clocks predict chronological age from RBC proteomes, but also reveal individuals whose RBC biology appears “older” or “younger” than expected.
We found that RBC protein abundance is highly structured by genetics.
Many proteins show strong protein quantitative trait loci (pQTLs), revealing that the RBC proteome is partly hard-wired in the genome.
Obese and morbidly obese donors show elevated circulating markers of inflammation - including complement and coagulation components - linked to accelerated aging.
Ethnicity also plays a role, suggesting that genetic traits may impact RBC proteomes (e.g., G6PD status).
Biological sex shows sexually dimorphic omics trajectories, with converging clusters after 51, the average age for menopause in the United States
RBC proteins and metabolites clustered along aging trajectories, linked to inflammation (complement and coagulation cascades) and antioxidant capacity (glutathione homeostasis, pentose phosphate pathway)
To address this, we profiled the RBC proteome and metabolome in >13,000 blood donors from the REDS-III RBC-Omics cohort, also genotyped at >800k SNPs.
This generated one of the largest multi-omics resources ever produced for a circulating human cell.
But despite transfusing ~110+ million units annually worldwide, we still know surprisingly little about:
• the full RBC proteome at population scale
• how genetics shapes RBC biology
• whether RBC molecular signatures predict transfusion outcomes
Red blood cells (RBCs) circulate for ~120 days and continuously exchange metabolites with every organ.
This makes them a unique integrative biosensor of systemic physiology — capturing genetics, metabolism, environment, and lifestyle (the "exposome").
In our new preprint, we built a population-scale red blood cell proteome atlas across >13,000 blood donors and discovered genetically encoded aging clocks that predict RBC quality and donor trajectories.
www.biorxiv.org/content/10.6...
Blood offers a window on systemic metabolic health — a founding principle of clinical biochemistry.
How much information about human aging is encoded in a drop of blood?
Profiling the RBC proteome in >13,000 donors reveals genetically encoded aging clocks predicting RBC quality
@ishahjain.bsky.social sorry! Forgot to tag
RBCs are not passive bystanders in systems metabolism. We had been saying this for years. This time, in collaboration with Isha Jain @gladstoneinst.bsky.social
By the way, the Jain lab is on a roll, with ever more elegant science at each paper. It was a pleasure to collaborate!
New study shows red blood cells act as hidden glucose sponges in low-oxygen conditions, explaining why people living at high altitude have lower diabetes rates.
@dalessandrolab.bsky.social
@medschool.umaryland.edu
@cp-cellmetabolism.bsky.social
@arcinstitute.org
@ishahjain.bsky.social
Outside back cover of issue 1 of Lab on a Chip: Five channels of lysing blood cells leading to humanoid silhouettes
On the outside back cover of issue 1 of Lab on a Chip:
Surface acoustic wave hemolysis assay for evaluating stored red blood cells.
#OpenAccess from Angelo D'Alessandro, Xiaoyun Ding et al @dalessandrolab.bsky.social @cuanschutz.bsky.social @colorado.edu
Read now: pubs.rsc.org/en/content/a...
Cracking the code of blood: How genetics and metabolism are transforming transfusions
🔗 Read the full Transfusion Today article here: https://isbtweb.foleon.com/transfusion-today/transfusion-today-october-2025/cracking-the-code-of-blood
#TransfusionMedicine #ISBT #TransfusionToday
Terrific to have our paper, led by @tjflemin.bsky.social, featured as a plenary article in @bloodjournal.bsky.social today: ashpublications.org/blood/articl...
link.springer.com/article/10.1...
The transaminase-ω-amidase pathway senses oxidative stress to control glutamine metabolism and α-ketoglutarate levels in endothelial cells
