Aged liver secreted factors lead to aging of human iPSC-derived heart muscle cells

Aging is a complex, systemic process often driven by both intrinsic and extrinsic factors. Recent evidence suggests that secretions from aging organs may influence the function of distant tissues. This study investigates the impact of liver-derived secretions from oxidatively aged cells on induced pluripotent stem cell-derived cardiomyocytes (iCMs). Here, we exposed HepG2 liver cells to hydrogen peroxide at varying concentrations (25–300muM) and durations with regular intervals to model aging. Post-treatment validation confirmed increased oxidative stress, lipofuscin accumulation, p21 expression, and senescence, particularly in the 15-day 100 muM group. Conditioned media from aged HepG2 cultures were then applied to healthy, differentiated iCMs at various dilutions including undiluted, 1:1, and 1:3 with iCM media. iCMs exposed to aged liver secretions exhibited significantly increased aging phenotypes, including elevated lipofuscin and p21 expression, as well as increased senescent cell populations, with the strongest effects observed in undiluted and 1:1 treatment conditions. While senescence levels peaked at the 1:1 dilution rather than in undiluted media, a dose-dependent response to secreted stress factors was observed. Control experiments with untreated liver media showed no significant effects, confirming that the aging phenotypes observed in iCMs were driven specifically by the secretome of aged liver cells. These findings reveal a clear mechanism by which hepatic aging can promote cardiac aging and dysfunction, offering insight into liver-heart crosstalk in the context of human aging.