A recent study published in Science Advances on June 22 reveals that researchers have mapped the single-nucleus transcriptomic landscape of the human heart from fetal development to older adulthood, identifying PRDM16 as a potential molecular target for future cardiac aging research.
The study analyzed 442,239 single nuclei from nonfailing hearts and found age-associated transcriptional states in heart muscle cells. These states were linked to a progressive loss of gene-expression homeostasis, stress responses, and inflammatory signaling. The most notable finding was the identification of PRDM16, whose activity and expression declined with age. Knocking down PRDM16 in human cardiomyocyte models induced senescence-like phenotypes, while overexpressing Prdm16 in aged mouse hearts improved systolic function and partially reversed aging-associated transcriptional programs.
Researchers collected 54 nonfailing transmural tissue samples from 29 donors across six life stages, spanning early fetal development to older adulthood. High-throughput single-nucleus RNA sequencing was used to analyze individual nuclei and capture transcriptional states. The study also utilized human-induced pluripotent stem cell models for genetic manipulation experiments and tested intramyocardial adenoviral delivery of Prdm16 in aged mice.
Key findings include the rapid decline of proliferative cells before birth and the emergence of a stress-induced state (CM4) dominating hearts aged 60 to 75 years. This CM4 state showed increased CRYAB expression—a biomarker of cellular stress—and higher senescence scores. Statistical analyses indicated that PRDM16 expression was inversely associated with aging scores (R = -0.6). Knocking down PRDM16 triggered increased p21 levels and interleukin-8 production; conversely, overexpression improved cardiac function by increasing ejection fraction and fractional shortening while reducing hypertrophy.
The study establishes a detailed resource on how the human heart changes over time and suggests that some molecular features of age-related cardiac decline may be modifiable experimentally. Researchers developed transcriptomic aging clocks showing high accuracy when correlating with gestational age or detecting accelerated transcriptional aging in diseased hearts.
Authors note limitations, such as not systematically analyzing sex-specific effects, focusing only on nonfailing hearts, and needing further spatial or longitudinal datasets for region- or time-dependent aspects.
