Biology subjects

Aviv, A.

Publications and source records attributed to Aviv, A..

4 recordsLinked to original sources

bioRxiv2026

Erythrocyte Count and the Human Natural Lifespan Limit: Evidence from the Long Life Family Study

Erythropoiesis is the most replication-intensive process in the body. Its lifelong replicative demands may erode hematopoietic cells replicative capacity, leading to a decline in erythrocyte count (EC) in older adults and limiting their lifespan. We examined the relationship between EC and mortality among 1,620 participants aged [≥]70 years in the Long Life Family Study and found that lower EC further augmented the exponential, age-dependent rise in mortality. We identified an EC threshold (ECT) (3.8x1012/L) below which mortality was amplified (p=9.3x10-6). As EC declined with age (p=8.2x10-18), it fell below this threshold in many participants, sharply increasing their mortality risk. This mortality-based ECT emerged from modeling, independent of the World Health Organization anemia definition, which is based on statistical thresholds (5th centiles) of hemoglobin distribution in populations [≤] 65 years. Thus, declining EC may be one of the biological factors imposing a natural lifespan limit on many older adults.

physiology↗

bioRxiv2025

The Magnitude of Telomere Shortening per Cell Division In Vivo: Implications for Lifelong Hematopoiesis in Humans

The magnitude of telomere shortening per cell division in human somatic cells in vivo (MTSIV) is a fundamental but unquantified parameter. MTSIV is essential for understanding how telomere-length (TL)-dependent hematopoietic cell division influences age-related health and longevity. By leveraging sex differences in leukocyte TL and the differential dosage of DKC1, a telomerase-regulating gene, during early embryonic cell divisions, we estimate the MTSIV to be 28 base pairs per cell division (95% CI: 23 - 32). Using this estimate and leukocyte TL data from newborns and centenarians, we infer that hematopoietic stem cells (HSCs) undergo approximately 156 divisions (95% CI: 130-183) over a 100-year lifespan. Using longitudinal data on leukocyte telomere shortening in adults, we further estimate that HSCs divide about 0.97 times yearly (95% CI: 0.80 - 1.13) after age 20. These findings provide a quantitative framework for understanding TL-dependent hematopoiesis, the most proliferative process in the human soma. They also highlight that if telomere shortening affects age-related health and longevity, it acts primarily through its impact on hematopoiesis. Our results refine hematopoietic stem cell replicative history estimates and might guide treatments involving hematopoietic cell expansion, such as hematopoietic cell transplantation and immunotherapies. Significance StatementWhen human somatic cells divide, their telomeres shorten. This process drives age-related shortening of leukocyte telomeres and reflects hematopoietic stem cell (HSC) division at the top of the hematopoietic hierarchy. The magnitude of telomere shortening per somatic cell division in vivo (MTSIV) is a critical yet previously unquantified parameter essential for providing insights into the pace of HSC division in humans. This study estimates that the MTSIV is about 28 base pairs. Using the MTSIV and leukocyte telomere length data from newborns and centenarians, we calculated that HSCs divide approximately 156 times over a 100-year lifespan. This knowledge improves our understanding of HSC replication dynamics and their implications for human health and longevity.

cell biology↗

bioRxiv2018

An epigenetic biomarker of aging for lifespan and healthspan

Identifying reliable biomarkers of aging is a major goal in geroscience. While the first generation of epigenetic biomarkers of aging were developed using chronological age as a surrogate for biological age, we hypothesized that incorporation of composite clinical measures of phenotypic age that capture differences in lifespan and healthspan may identify novel CpGs and facilitate the development of a more powerful epigenetic biomarker of aging. Using a innovative two-step process, we develop a new epigenetic biomarker of aging, DNAm PhenoAge, that strongly outperforms previous measures in regards to predictions for a variety of aging outcomes, including all-cause mortality, cancers, healthspan, physical functioning, and Alzheimers disease. While this biomarker was developed using data from whole blood, it correlates strongly with age in every tissue and cell tested. Based on an in-depth transcriptional analysis in sorted cells, we find that increased epigenetic, relative to chronological age, is associated increased activation of pro-inflammatory and interferon pathways, and decreased activation of transcriptional/translational machinery, DNA damage response, and mitochondrial signatures. Overall, this single epigenetic biomarker of aging is able to capture risks for an array of diverse outcomes across multiple tissues and cells, and provide insight into important pathways in aging.

epidemiology↗

bioRxiv2017

GWAS of epigenetic ageing rates in blood reveals a critical role for TERT

DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9,907 individuals, we found gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in 3 loci associated extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggested causal influences of menarche and menopause on IEAA and lipid levels on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) locus at 5p15.33 confer higher IEAA (P<2.7x10-11). Causal modelling indicates TERT-specific and independent effects on LTL and IEAA. Experimental hTERT expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the DNA methylation clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.

genetics↗