👤 Tamara Isakova

Aging is asynchronous across cells and organs, but whether plasma proteins can capture cell type-specific aging and predict disease and mortality remains unknown. We developed machine learning models to estimate the biological age of more than 40 distinct cell types-spanning neuronal, immune, glial, endocrine, epithelial, and musculoskeletal origins-using over 7,000 plasma proteins measured in 60,000 individuals across three cohorts, comprising the largest human plasma proteomics aging study to date. Individuals showed heterogeneous aging profiles, with 20-25% exhibiting accelerated aging in a single cell type and 1-3% across ten or more cell types. APOE genotype showed antagonistic aging effects in different cell types: APOE4 carriers exhibited older astrocytes but younger macrophages, while APOE2 carriers showed the inverse. Cellular aging signatures were uniquely associated with disease status and predicted incident disease and mortality over 15 years of follow-up. Amyotrophic lateral sclerosis (ALS) showed the strongest association with skeletal myocyte aging (hazard ratio = 12.7 for extreme accelerated versus youthful aging). In Alzheimer's disease (AD), prevalent cases showed accelerated aging across multiple neural and peripheral cell types, with extreme astrocyte aging conferring AD risk comparable to APOE4 carrier status. Moreover, extreme astrocyte aging increased AD risk in APOE4/4 carriers threefold, while youthful astrocytes strikingly reduced risk. Beyond neurodegeneration, respiratory cell aging identified smokers at 58% higher lung cancer risk, and myeloid aging identified normoglycemic individuals at higher diabetes risk. Both specific cellular vulnerabilities and cumulative aging burden influenced survival, wherein youthful immune or neuronal profiles were protective. A polycellular aging risk score provided robust mortality risk stratification across platforms and cohorts. These findings establish a framework for quantifying biological aging at the cellular resolution using plasma proteomics, revealing heterogeneity in aging trajectories and their impact on disease susceptibility and resilience. Show less

Fibroblast growth factor 23 (FGF23) is a phosphate-regulating hormone produced by osteocytes. In iron deficiency anemia (IDA) and in chronic kidney disease (CKD), FGF23 is also produced by erythroid cells. Recent studies have suggested that rising circulating FGF23 is negatively associated with erythropoiesis in IDA and CKD. However, the distinct contributions of bone- and erythroid-produced FGF23 to anemia in IDA remain unclear. Using the conditional deletion of Fgf23 in osteocytes (Fgf23Dmp1-cKO) and in erythroid cells (Fgf23HbB-cKO) in mice fed a control (Ctr) or an iron deficient (ID) diet, we first determined that in ID, osteocytes and erythroid cells are distinct sources of circulating intact FGF23 (iFGF23) and FGF23 cleaved peptides, respectively. We further show that erythroid-specific deletion of Fgf23 corrected anemia in ID mice, and overexpression induced anemia in Ctr mice unlike osteocyte-specific deletion or overexpression of Fgf23. Importantly, erythroid-specific deletion of Furin (FurinHbB-cKO), the enzyme responsible for FGF23 cleavage, led to increased production of iFGF23 from erythroid cells and aggravated ID-induced anemia. iFGF23 also dose-dependently blocked the differentiation of erythroid progenitors in culture triggering mitochondrial dysfunction leading to impaired erythropoiesis. These effects were fully suppressed by co-treatment with an FGFR1 inhibitor. Finally, erythroid-specific deletion of Fgf23 in an animal model of progressive CKD prevented the development of anemia of CKD. In aggregate, our results show that erythroid-expressed FGF23 is a negative regulator of erythropoiesis that contributes to anemia via direct paracrine FGFR1 activation in erythroid precursors. Show less

The cytokine TRAIL is distinguished by its remarkable ability to preferentially induce apoptosis in transformed, but not in normal, cells. The recombinant TRAIL extracellular domain and other first-generation agonists of DR4 and DR5 death receptors (DRs) have shown very limited antitumor activity in clinical trials. To enhance the antitumor effect, we developed the multitarget recombinant fusion protein SRH-DR5-B-p48 based on the DR5-selective TRAIL variant DR5-B to simultaneously affect tumor cells (DR5-B-mediated apoptosis) and tumor microenvironment, in particular, to suppress angiogenesis. For this purpose, we modeled and produced the recombinant SRH-DR5-B-p48 fusion protein containing antagonistic synthetic peptides (SRH and p48) to VEGFR2 and FGFR1 receptors, respectively. Analysis of molecular trajectories using molecular dynamics methods showed that the SRH and p48 peptides form non-specific temporary contacts with the DR5-B domain. Using enzyme-linked immunosorbent assay, we showed that SRH-DR5-B-p48 was similar to DR5-B in its affinity for the death receptor DR5 and demonstrated a high affinity for VEGFR2 and FGFR1 with nanomolar dissociation constants. SRH-DR5-B-p48 killed tumor cells of various origin more efficiently than DR5-B and destroyed tumor-like structures in 3D cell models, as well as inhibited FGF2-mediated stimulation of fibroblast proliferation. Therefore, the SRH-DR5-B-p48 fusion protein can be considered as a promising agent for the therapy of solid tumors of various origin. Show less