Abstract
Lipid-derived electrophiles induce carbonyl stress, mitochondrial dysfunction, and cellular senescence: 4-hydroxynonenal as a physiological determinant of adipose senescence in obesity and aging
Free radical biology & medicine, Vol.233(Supplement 1), p.S101
06/2025
DOI: 10.1016/j.freeradbiomed.2025.05.359
Abstract
Senescent cell burden in adipose tissue is an important driver of age- and obesity-associated metabolic dysfunction. However, mechanisms underlying senescent cell accumulation in adipose remain poorly defined. The correlative association between lipid peroxidation and longevity/age-related pathologies is becoming increasingly appreciated. Our lab has documented avid production of electrophilic lipid peroxidation products (e.g. 4-HNE) in visceral adipose of mouse models of aging and obesity. We posit that, via covalent modification of DNA and proteins, carbonyl stress exerts genotoxicity and mitochondrial dysfunction to induce senescence in adipose progenitor cells. IMR90 fibroblasts and murine adipose stem cells continuously exposed to lipid electrophiles exhibit classic senescence markers. We’ve termed this novel type of senescence Biogenic Lipid Induced Senescence (BLIS). The mechanisms of BLIS are multifaceted and likely to involve both DNA and mitochondrial protein modification, as we observed hallmarks of both genotoxicity and aberrant mitochondrial function concomitant with development of BLIS markers and alkylation of mitochondrial proteins. Indeed, 4-HNE exposure effects γH2AX foci and downstream p53/p21 signaling, as well as phosphorylation of AMPK and increased ADP:ATP ratios. Furthermore, we discovered that exposure to 4-HNE is associated with an attenuation of sirtuin 1 and sirtuin 3 activity. The loss of deacetylase activity, a putative regulator of p53 signaling, could account for important molecular mechanisms underlying BLIS. L-carnosine, a carbonyl scavenger, ameliorated the development of the senescent phenotype in cultured cells and blunted expression of key senescence markers, including p21Cip1 and PLAUR, in visceral fat of diet-induced obese C57/Bl6J mice. Decreased adipose senescence occurred concomitant with an improvement in metabolic endpoints and reduced 4-HNE protein adducts. Taken together, our results suggest that lipid electrophiles can represent a mechanistic link between obesity, adipose senescence, and downstream systemic insulin resistance. Importantly, they provide proof-of-concept for biogenic.
Details
- Title: Subtitle
- Lipid-derived electrophiles induce carbonyl stress, mitochondrial dysfunction, and cellular senescence: 4-hydroxynonenal as a physiological determinant of adipose senescence in obesity and aging
- Creators
- T. Blake MonroeAnn V. HertzelDeborah M. DickeyThomas HagenSimon Vergara SantibanezIslam BerdaweelCatherine HalleyPatrycja PuchalskaEthan J. AndersonChristina D. CamellPaul D. RobbinsDavid A. Bernlohr
- Resource Type
- Abstract
- Publication Details
- Free radical biology & medicine, Vol.233(Supplement 1), p.S101
- DOI
- 10.1016/j.freeradbiomed.2025.05.359
- ISSN
- 0891-5849
- eISSN
- 1873-4596
- Publisher
- ELSEVIER SCIENCE INC
- Language
- English
- Date published
- 06/2025
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984843590002771
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