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New Mechanism Discovered That Accelerates Aging of Adipose Tissues

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A research team led by Professor Jong Kyoung Kim from the Department of Life Sciences at POSTECH along with Professor Seung-Hoi Koo from the Division of Life Sciences at Korea University and principal researcher Geum-Sook Hwang from Korea Basic Science Institute (KBSI) announced the discovery of a new mechanism where BCAA*1 metabolic pathway becomes impaired due to aging, resulting in dysfunctions of adipose cells and chronic metabolic disorders. The research findings were published in Nature Aging (IF=16.6) on July 24 (local time in London).

Adipocytes play a crucial role in controlling energy metabolic homeostasis. These cells along with preadipocyte cells and various immune cells comprising adipose tissues undergo cellular senescence. The release of the senescence associated secretory phenotype (SASP)*2 from these cells accelerates aging and diminishes the functions of adipose tissues. Consequently, fat accumulation occurs in liver and muscle cells, leading to the onset of metabolic disorders and ultimately reducing health span.

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In their earlier research published in Nature Communications, the research team led by Professor Seung-Hoi Koo uncovered that over-activation of CRTC2 induces insulin resistance*3, fatty liver, and obesity. However, until now, no research findings explored the impact of CRTC2*4 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*5 in adipocytes and impairs catabolism of branched-chain amino acid (BCAA). Consequently, the mechanistic target of rapamycin complex (mTORC1*6) 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.

On the significance of the study, Professor Seung-Hoi Koo explained, “This study employed the latest convergent omics technology to unveil, for the first time, that an increase of CRTC2 in adipocytes due to aging leads to impaired BCAA catabolism, which is the primary cause of cell aging and metabolic disorders. Consequently, selective inhibition of CRTC2 or activation of PPAR gamma in adipocytes may hold the potential to inhibit aging and extend health span.”

*1 BCAA stands for branched-chain amino acid, a collective term encompassing essential amino acids such as leucine, isoleucine and valine. Elevated BCAA concentration levels have been observed in human and mouse models exhibiting obesity and insulin resistance. Interestingly, diets limiting BCAA intake have shown to improve insulin sensitivity and induce weight loss in obese mouse models as well as extend lifespan in fruit flies and mouse models.

2* Senescence associated secretory phenotype is a broad term describing senescent cells that secrete inflammatory cytokine, growth factors, and proteases. The SASP factors promote cellular senescence, chronic inflammatory reactions, and cell fibrosis while inhibiting stem cell functions. Additionally, it has been reported that SASP contributes to insulin resistance by suppressing adipocyte differentiation.

3* Impaired response of insulin that regulates blood sugar levels, leading to ineffective suppression of glucose production in the liver and reduced glucose absorption in fat and muscle cells.

4* As a transcription factor of CREB, CRTC2 fosters insulin resistance, a fatty liver, and obesity by controlling expression of pivotal genes responsible for glucose and miR-34a in the liver.

5* A type of nuclear receptor that plays a central role in adipocyte differentiation. Its activation can be enhanced by Thiazolidinedione drugs and has been explored as a target to increase insulin sensitivity in individuals with type 2 diabetes.

6* mTORC1 stands for mechanistic target of rapamycin complex 1, and its activation is regulated by factors such as growth factors, cell energy status, stress or amino acids. Normally, mTORC1 stimulates anabolic processes, promoting the growth and synthesis of proteins and lipids while impairing catabolism. However, over-activation of mTORC1 has been linked to conditions like cancer, cardiovascular diseases and diabetes, and is also considered a contributing factor to aging.

Reference: Han HS, Ahn E, Park ES, et al. Impaired BCAA catabolism in adipose tissues promotes age-associated metabolic derangement. Nat Aging. 2023:1-19. doi: 10.1038/s43587-023-00460-8

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