%0 Journal Article %J Cell Metab %D 2021 %T Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis. %A Wiley, Christopher D %A Sharma, Rishi %A Davis, Sonnet S %A Lopez-Dominguez, Jose Alberto %A Mitchell, Kylie P %A Wiley, Samantha %A Alimirah, Fatouma %A Kim, Dong Eun %A Payne, Therese %A Rosko, Andrew %A Aimontche, Eliezer %A Deshpande, Sharvari M %A Neri, Francesco %A Kuehnemann, Chisaka %A Demaria, Marco %A Ramanathan, Arvind %A Campisi, Judith %X

Cellular senescence is a stress or damage response that causes a permanent proliferative arrest and secretion of numerous factors with potent biological activities. This senescence-associated secretory phenotype (SASP) has been characterized largely for secreted proteins that participate in embryogenesis, wound healing, inflammation, and many age-related pathologies. By contrast, lipid components of the SASP are understudied. We show that senescent cells activate the biosynthesis of several oxylipins that promote segments of the SASP and reinforce the proliferative arrest. Notably, senescent cells synthesize and accumulate an unstudied intracellular prostaglandin, 1a,1b-dihomo-15-deoxy-delta-12,14-prostaglandin J2. Released 15-deoxy-delta-12,14-prostaglandin J2 is a biomarker of senolysis in culture and in vivo. This and other prostaglandin D2-related lipids promote the senescence arrest and SASP by activating RAS signaling. These data identify an important aspect of cellular senescence and a method to detect senolysis.

%B Cell Metab %8 2021 Mar 31 %G eng %R 10.1016/j.cmet.2021.03.008 %0 Journal Article %J Mol Cell %D 2021 %T Proteome plasticity in response to persistent environmental change. %A Domnauer, Matthew %A Zheng, Fan %A Li, Liying %A Zhang, Yanxiao %A Chang, Catherine E %A Unruh, Jay R %A Conkright-Fincham, Juliana %A McCroskey, Scott %A Florens, Laurence %A Zhang, Ying %A Seidel, Christopher %A Fong, Benjamin %A Schilling, Birgit %A Sharma, Rishi %A Ramanathan, Arvind %A Si, Kausik %A Zhou, Chuankai %K Acclimatization %K Adaptation, Physiological %K Animals %K Environmental Exposure %K Gene Expression Regulation, Fungal %K Hot Temperature %K Proteome %K Saccharomycetales %K Stress, Physiological %K Transcriptome %X

Temperature is a variable component of the environment, and all organisms must deal with or adapt to temperature change. Acute temperature change activates cellular stress responses, resulting in refolding or removal of damaged proteins. However, how organisms adapt to long-term temperature change remains largely unexplored. Here we report that budding yeast responds to long-term high temperature challenge by switching from chaperone induction to reduction of temperature-sensitive proteins and re-localizing a portion of its proteome. Surprisingly, we also find that many proteins adopt an alternative conformation. Using Fet3p as an example, we find that the temperature-dependent conformational difference is accompanied by distinct thermostability, subcellular localization, and, importantly, cellular functions. We postulate that, in addition to the known mechanisms of adaptation, conformational plasticity allows some polypeptides to acquire new biophysical properties and functions when environmental change endures.

%B Mol Cell %V 81 %P 3294-3309.e12 %8 2021 08 19 %G eng %N 16 %R 10.1016/j.molcel.2021.06.028 %0 Journal Article %J Proteomics %D 2020 %T The Aging Metabolome-Biomarkers to Hub Metabolites. %A Sharma, Rishi %A Ramanathan, Arvind %X

Aging biology is intimately associated with dysregulated metabolism, which is one of the hallmarks of aging. Aging-related pathways such as mTOR and AMPK, which are major targets of anti-aging interventions including rapamcyin, metformin, and exercise, either directly regulate or intersect with metabolic pathways. In this review, numerous candidate bio-markers of aging that have emerged using metabolomics are outlined. Metabolomics studies also reveal that not all metabolites are created equally. A set of core "hub" metabolites are emerging as central mediators of aging. The hub metabolites reviewed here are nicotinamide adenine dinucleotide, reduced nicotinamide dinucleotide phosphate, α-ketoglutarate, and β-hydroxybutyrate. These "hub" metabolites have signaling and epigenetic roles along with their canonical roles as co-factors or intermediates of carbon metabolism. Together these hub metabolites suggest a central role of the TCA cycle in signaling and metabolic dysregulation associated with aging.

%B Proteomics %V 20 %P e1800407 %8 2020 03 %G eng %N 5-6 %R 10.1002/pmic.201800407