New mechanism that accelerates aging of adipose tissues

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