New mechanism that accelerates aging of adipose tissues

A research team led by researchers from POSTECH, Korea University, and Korea Basic Science Institute (KBSI) announced the discovery of a new mechanism where the BCAA metabolic pathway becomes impaired due to aging, resulting in dysfunctions of adipose cells and chronic metabolic disorders. In their earlier research, the research team uncovered that over-activation of CRTC2 induces insulin resistance, fatty liver, and obesity. However, until now, no research findings explored the impact of CRTC2 in adipocytes on aging and its related disorders.

This recent research marks the first confirmation that an increase in adipose CRTC2 due to aging accelerates cellular senescence, leading to a loss of adipocyte functions and aging-related chronic metabolic disorders. CRTC2 reduces the expression of PPAR gamma in adipocytes and impairs the catabolism of branched-chain amino acid (BCAA). Consequently, the mechanistic target of rapamycin complex (mTORC1) becomes activated, as revealed by the composite analysis of metabolome-transcriptome. Increased mTORC1 activation triggers cellular senescence and controls mitochondrial hemostasis, thereby accelerating aging.

The analysis of single-cell transcriptome data showed that aged mice’s adipocytes had increased SASP, particularly IL-1beta and TNF-alpha. This leads to adipose tissue remodeling by inhibiting preadipocyte cell differentiation potency and immunocyte regulations. Notably, mice with CRTC2 removed from their adipocytes displayed limited activation of BCAA-mTORC1 axis, ultimately inhibiting the development of chronic metabolic disorders associated with aging. This suggests that aging can be mitigated by controlling CRTC2 or BCAA catabolism.

Reference: Nature Aging, DOI 10.1038/s43587-023-00460-8, Impaired BCAA catabolism in adipose tissues promotes age-associated metabolic derangement