Age-related impairment of macroautophagy/autophagy and loss of cardiac tissue homeostasis contribute significantly to
cardiovascular diseases later in life. MTOR (mechanistic target of
rapamycin kinase) signaling is the most well-known regulator of autophagy, cellular homeostasis, and longevity. The MTOR signaling consists of two structurally and functionally distinct
multiprotein complexes,
MTORC1 and
MTORC2. While
MTORC1 is well characterized but the role of
MTORC2 in aging and autophagy remains poorly understood. Here we identified TGFB-INHB/
activin signaling as a novel upstream regulator of
MTORC2 to control autophagy and cardiac health during aging. Using Drosophila heart as a model system, we show that cardiac-specific knockdown of TGFB-INHB/
activin-like
protein daw induces autophagy and alleviates age-related heart dysfunction, including
cardiac arrhythmias and
bradycardia. Interestingly, the downregulation of daw activates
TORC2 signaling to regulate cardiac autophagy. Activation of
TORC2 alone through overexpressing its
subunit protein rictor promotes autophagic flux and preserves cardiac function with aging. In contrast, activation of
TORC1 does not block autophagy induction in daw knockdown flies. Lastly, either daw knockdown or rictor overexpression in fly hearts prolongs lifespan, suggesting that manipulation of these pathways in the heart has systemic effects on longevity control. Thus, our studies discover the TGFB-INHB/
activin-mediated inhibition of
TORC2 as a novel mechanism for age-dependent decreases in autophagic activity and cardiac health. Abbreviations: AI:
arrhythmia index; BafA1:
bafilomycin A1; BMP:
bone morphogenetic protein; CQ:
chloroquine; CVD:
cardiovascular diseases; DI: diastolic interval; ER: endoplasmic reticulum; HP: heart period; HR: heart rate; MTOR: mechanistic target of
rapamycin kinase; NGS: normal goat serum; PBST: PBS with 0.1%
Triton X-100; PDPK1: 3-phosphoinositide dependent
protein kinase 1; RICTOR: RPTOR independent companion of MTOR complex 2; ROI: region of interest; ROUT: robust regression and outlier removal; ROS:
reactive oxygen species; R-SMAD: receptor-activated SMAD; SI: systolic interval; SOHA: semi-automatic optical heartbeat analysis; TGFB: transformation
growth factor beta; TSC1:
TSC complex subunit 1.