Senescent, dysfunctional human cardiac progenitor cells (CPCs) accumulate in the aged heart and elimination of senescent cells enhances CPC activation and cardiomyocyte proliferation in aged mice

Lewis-McDougall, F. C.; Ruchaya, P. J.; Domenjo-Vila, E.; Teoh, T. S.; Prata, L.; Cottle, B. J.; Clark, J. E.; Punjabi, P. P.; Awad, W.; Torella, D.; Tchkonia, T.; Kirkland, J. L.; Ellison-Hughes, G. M.

doi:10.1101/397216

bioRxiv · 10.1101/397216

Senescent, dysfunctional human cardiac progenitor cells (CPCs) accumulate in the aged heart and elimination of senescent cells enhances CPC activation and cardiomyocyte proliferation in aged mice

Lewis-McDougall, F. C.·Ruchaya, P. J.·Domenjo-Vila, E.·Teoh, T. S.·Prata, L.·Cottle, B. J.·Clark, J. E.·Punjabi, P. P.·Awad, W.·Torella, D.·Tchkonia, T.·Kirkland, J. L.·Ellison-Hughes, G. M.

View original source ↗Export metadata ↓

Abstract

Aging leads to increased cellular senescence and is associated with decreased potency of tissue-specific stem/progenitor cells. Here we have done an extensive analysis of cardiac progenitor cells (CPCs) isolated from human subjects with cardiovascular disease (n=119), aged 32-86 years. In aged subjects (>74 years old) over half of CPCs are senescent (p16INK4A, SA-{beta}-gal, DNA damage {gamma}H2AX, telomere length, Senescence-Associated Secretory Phenotype (SASP)), unable to replicate, differentiate, regenerate or restore cardiac function following transplantation into the infarcted heart. SASP factors secreted by senescent CPCs renders otherwise healthy CPCs to senescence. Elimination of senescent CPCs using senolytics abrogates the SASP and its debilitative effect in vitro. Global elimination of senescent cells in aged mice (INK-ATTAC or wildtype mice treated with D+Q senolytics) in vivo activates resident CPCs (0.23{+/-}0.06% vs. 0.01{+/-}0.01% vehicle; p<0.05) and increased the number of small, proliferating Ki67-, EdU-positive cardiomyocytes (0.25{+/-}0.07% vs. 0.03{+/-}0.03% vehicle; p<0.05). Therapeutic approaches that eliminate senescent cells may alleviate cardiac deterioration with aging and rejuvenate the regenerative capacity of the heart.

Source connections

Published article ↗

Explore related subjects

physiology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Lewis-McDougall, F. C., Ruchaya, P. J., Domenjo-Vila, E., Teoh, T. S., Prata, L., Cottle, B. J., Clark, J. E., Punjabi, P. P., Awad, W., Torella, D., Tchkonia, T., Kirkland, J. L., Ellison-Hughes, G. M.. 2018-08-21. Senescent, dysfunctional human cardiac progenitor cells (CPCs) accumulate in the aged heart and elimination of senescent cells enhances CPC activation and cardiomyocyte proliferation in aged mice. https://doi.org/10.1101/397216

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Leg blood flow and muscle oxygenation are reduced when exercising with loads >=40% 1RM compared to loads <=30% 1RM due to increases in contraction induced intramuscular pressure

The critical occluding tension (COT) is the load at which contraction-induced increases in intramuscular pressure (IMP) collapse intramuscular vasculature and impair oxygen delivery. For knee extension resistance exercise, the COT occurs at ~30-40% 1RM, yet few studies have measured IMP alongside convective oxygen delivery. This study examined the interaction between IMP, leg blood flow, and muscle oxygenation during resistance exercise. Twelve participants completed knee extension bouts across a range of loads while vastus lateralis IMP, femoral blood flow (Doppler), blood pressure, muscle oxygenation (NIRS), and electromyography (EMG) were recorded. Mean IMP increased alongside relative load (20% 1RM=19.1(9.4) mmHg; 30% 1RM=22.4(10.4) mmHg; 40% 1RM=27.0(8.7) mmHg; 50% 1RM=31.5(11.5) mmHg; 60% 1RM=41.14(13.8) mmHg; p<0.05). Leg blood flow scaled to rest was similar between 20% and 30% 1RM (p=0.13), 40%, 50%, and 60% 1RM (p>0.05), but different between the 20-30% 1RM and 40-60% 1RM groupings (p<0.05) (20% 1RM=2.6(1.4) times rest; 30% 1RM=1.8(0.5) fold of rest; 40% 1RM=1.4(0.6) fold of rest; 50% 1RM=1.1(0.4) fold of rest; 60% 1RM=1.1(0.5) fold of rest). Muscle oxygenation was lower at 40%, 50%, and 60% 1RM compared to 20% and 30% 1RM (p<0.05). Thus, at [≤]30% 1RM exercising blood flow increased well above rest, indicating preserved microvascular perfusion, whereas at [≥]40% 1RM the rise in IMP was sufficient to impair perfusion and limit blood flow increases. Exercise at or above the COT restricts convective oxygen delivery due to contraction-induced increases in IMP.

physiology↗

bioRxiv2026

Female biases in islet cell gene expression, alpha cell number, and glucagon are present early in postnatal life

Biological sex significantly affects glucose homeostasis. Sex differences in insulin sensitivity in peripheral tissues play a role in this difference; however, a growing body of evidence suggests sex differences in islet cells also contribute to differential glucose homeostasis. Studies in rodent and human models have identified sex differences in alpha- and beta-cell gene expression, in islet cell composition, metabolism, and stress responses, and in circulating levels of glucoregulatory hormones. However, most of these studies used adult humans or mice, leaving the age at which these differences emerge less clear. We performed a detailed characterization of glucose homeostasis and islet biology in young male and female mice from two mouse strains widely used in diabetes research to model both Type 1 (non-obese diabetic, NOD) and Type 2 diabetes (C57BL/6J). We uncovered male-female differences in islet cell gene expression and composition, and in circulating levels of glucagon. Importantly, these differences were reproducible across both models and were present prior to diabetes-like phenotypes. Together, our data suggest sex differences in aspects of islet biology begin early in postnatal life.

physiology↗

bioRxiv2026

Quantitative imaging of native tissue architecture combined with deep multi-omics reveals the spatial biology of kidney aging

Aging alters tissue architecture and metabolism in spatially heterogeneous ways, yet the connections between these measurable structural and compositional phenotypes and underlying molecular changes are largely unknown. Here, we introduce NORIGAMI (NoRI-Guided AI for Multimodal Integration), a pipeline combining Normalized Raman Imaging (NoRI), deep learning, quantitative morphology, deep proteomics, and metabolomics to investigate renal aging. Unlike conventional histology, NoRI provides label-free, scattering-corrected measurements of absolute total protein and lipid mass concentrations (mg/mL). In 32 male rats aged 9, 18, 21 and 25 months, NORIGAMI predicted the chronological age of held-out rats from NoRI images (mean absolute error 0.78 months; R^2 = 0.97), and whole-tissue images outperformed models trained on isolated tubules. Quantitative imaging identified 41 age-associated morphological and compositional features (FDR < 0.05), revealing anatomically heterogeneous and non-linear changes in lipid droplet concentration, droplet size, cytoplasmic lipid concentration and tubular architecture. Deep molecular profiling quantified 11,485 proteins and 269 metabolites, revealing coordinated declines in differentiated proximal tubule (PT) identity and oxidative metabolism, selective increases in basement-membrane collagen-IV chains, and increasing molecular heterogeneity with age. A protein clock, built mainly from extracellular-matrix and heparan-sulfate proteins, predicted age with a mean absolute error of 1.6 months. Old kidneys diverged along a dominant injury-remodeling axis, seen separately in the proteome, in kidney RNA from 54 other rats and in the metabolome, in which tubular-injury and immune proteins, including the NAD+ consuming enzyme CD38, rise as differentiated-tubule proteins and NAD+ fall. NORIGAMI subsequently linked NAD+ associated molecular changes to quantitative features of tubular geometry and protein-lipid organization, while complementary KIM-1-centered analyses identified overlapping morphological associations involving epithelial injury and lipid handling and yielded additional molecular candidates for mechanistic validation. Collectively, these findings suggest that declining tubular metabolic function, altered lipid organization and injury-associated molecular programs represent interconnected features of renal aging. NORIGAMI establishes a framework for identifying the quantitative structural manifestations of molecular aging and generating spatially informed, experimentally testable hypotheses about tissue dysfunction.

physiology↗