Biology subjects

Few-Cooper, T. J.

Publications and source records attributed to Few-Cooper, T. J..

4 recordsLinked to original sources

bioRxiv2026

Immune aging captures complementary aging biology beyond epigenetic clocks

Biological aging clocks are typically evaluated through competitive benchmarking, implicitly assuming that a single metric can sufficiently capture the complexities of aging1-6. Here, we tested an alternative hypothesis: that distinct clock types capture orthogonal dimensions of aging and therefore yield greater value when integrated. Using the Framingham Heart Study, we compared the immune-aging metric, IMM-AGE, with established DNA methylation clocks and found that integrated models consistently outperformed single-clock approaches. To investigate the basis of this complementarity, we derived IMMAGE-Epi, a 22-CpG methylation surrogate of IMM-AGE which exhibited minimal overlap with canonical epigenetic clock CpGs, suggesting that immune aging is associated with a distinct methylomic feature and pathway space rather than representing a reformulation of existing clock architectures. Together, our findings support an emerging multidimensional model of biological aging in which integrating orthogonal biological clocks may offer greater translational utility than competitive single-clock optimization.

immunology↗

bioRxiv2026

Immune Aging is an Independent Risk Factor for Cardiovascular Disease

Cardiovascular disease remains the leading cause of mortality, yet current clinical predictors miss substantial disease-risk. While the immune system contributes to this residual risk, its complexity has hindered broadly applicable, clinically scalable metrics of immune-state. Here, we establish the prognostic relevance of IMM-AGE, a system-level metric of immune-aging, to cardiovascular disease. We learn reference-free, low-dimensional representations of IMM-AGE across cell, protein, and mRNA measurements, enabling high-fidelity quantification across modalities, blood fractions, and platforms, including standard hospital flow cytometers. Among UK-Biobank participants, 56.9% of IMM-AGE variation remained unexplained by routine clinical measures, and across diverse cohorts totaling ~48,000 individuals, elevated IMM-AGE was independently associated with future cardiovascular risk, intervention outcomes, and mortality. Moreover, incorporation of IMM-AGE into the PREVENT 10-year risk equation significantly improved risk stratification. These findings establish immune-aging as an independent biological dimension of cardiovascular disease-risk and support IMM-AGE as a practical tool for precision risk assessment.

immunology↗

bioRxiv2026

Aging restricts maturation of CXCL13+ T follicular helper cells in human immunity

A decline in specific antibody responses is a hallmark of human aging, yet the differential contributions of B and T lymphocytes and their interactions remain unclear. CXCL13 is a critical chemokine that shapes germinal center organization, but the regulation of human-specific CXCL13+ Tfh cells during aging is not known. Using human tonsil organoids, single-cell RNA sequencing, and CRISPR perturbations, we mapped age-associated changes in T follicular helper (Tfh) cells, the cell type that provides T cell "help" to B cells in germinal centers (GCs). Tonsil organoids from older donors generated weaker influenza-specific antibody responses, which we traced to Tfh cell defects rather than B cells. Single-cell profiling revealed a selective loss of mature CXCL13 GC-Tfh cells accompanied by accumulation of Tfh precursor states. Trajectory analysis showed that aging arrests Tfh cell maturation at the early activated precursor transition, and CRISPR perturbations identified BACH2 and SOX4 as transcriptional regulators of differentiation reduced with age. These findings reveal a human-specific mechanism of immune aging with implications for strategies to restore humoral immunity.

immunology↗

bioRxiv2025

Systems level analysis of B-cell development identifies BDNF as a driver for human B lymphopoiesis

B-cell aplasia is a major consequence of aging, chemotherapy, and B-cell-depleting immunotherapies, compromising immune protection against infections, cancer, and vaccines. Yet, unlike the myeloid and erythroid lineages, no strategy exists to accelerate human B-cell reconstitution. Here, we used an integrative systems biology approach to identify regulators of human B lymphopoiesis in the bone marrow (BM) microenvironment. By combining single-cell transcriptomic analysis of human BM with intercellular communication mapping, we generated an initial set of candidate factors predicted to act on developing B cells. To distinguish biologically meaningful putative regulators from a broad candidate space, we further intersected these findings with orthogonal human datasets capturing age-impaired B lymphopoiesis and protein dynamics associated with B-cell depletion and reconstitution. This convergent prioritization strategy highlighted a focused set of putative regulators, among which brain-derived neurotrophic factor (BDNF) emerged repeatedly as a top putative regulator. Functional interrogation in progenitor BM cells showed that several prioritized putative regulators induced transcriptional programs linked to early immune development, with BDNF consistently promoting pathways associated with B-cell differentiation. Importantly, in a human in vitro BM co-culture system, BDNF enhanced the differentiation of CD34+ hematopoietic progenitors into CD19+ progenitor B cells. Together, these findings identify BDNF as a previously unrecognized regulator of early human B lymphopoiesis and establish a general framework for uncovering functional hematopoietic regulators by integrating single-cell analysis with complementary biological and clinical signals. This approach may support future strategies to improve immune reconstitution in settings of prolonged B-cell depletion.

systems biology↗