Abstract
The activation of transcription factor NF-κB is currently identified as one of the driving forces to the aging process. Genetic impairment of NF-κB signaling pathway or pharmacological inhibition of NF-κB activity has been shown to extend healthspan and lifespan in animal models, and delay or reduce many age-related symptoms. However, the aging intervention strategies based on NF-κB inhibition by the suitable small molecular compound is currently still lacking. The water-soluble dimethylaminomicheliolide (DMAMCL), can inhibit NF-κB activity and is currently undergoing clinical trials. In this study, we showed that 15 months of DMAMCL administration started in 1-year old male mice was well-tolerated and safe, and improved or had little effect on some age-associated symptoms, such as neurobehavioral phenotypes, physical performance, cardiac function, hematological parameters, immune aging phenotypes, clinical chemistry parameters, and glucose homeostasis. At the molecular level, DMAMCL administration mitigated serum levels of several age-associated inflammatory cytokines, including IL-6, IL-1α, IL-1β, TNF-α, IFN-γ, and CXCL2, and inhibited NF-κB activity in several aged tissues. Collectively, our results indicate that current strategy of DMAMCL administration may has little effect on aging process in mice, and provide basic clues to further exploit the possibility of DMAMCL-based aging intervention to promote healthy aging.
Highlights
Aging is characterized by a progressive loss of various physiological functions at the molecular, cellular, tissue, and organismal levels, and leading to the death of organisms
NF-κB activity increases with aging in a variety of tissues of mammals [7,8,9,10,11,12,13] and contributes to a number of age-related disorders and pathologies [14,15,16,17,18,19,20,21]
Mounting evidences demonstrate a causal relationship between NF-κB activation and aging process, and NF
Summary
Aging is characterized by a progressive loss of various physiological functions at the molecular, cellular, tissue, and organismal levels, and leading to the death of organisms. Aging is a major risk factor for most human chronic diseases, including cancer, diabetes, cardiovascular diseases, osteoporosis, arthritis, and neurodegenerative diseases [1]. Multiple mechanisms are proposed to contribute to the mammalian aging process, such as genomic instability, telomere erosion, epigenetic alterations, mitochondrial dysfunction, nutrient sensing malfunction, inflammation, and etc. Mounting evidences show that the blood levels of inflammatory cytokines, chemokines, and acute-phase www.aging-us.com proteins, including interleukin-6 (IL-6), IL-1β, tumor necrosis factor alpha (TNF-α), and high-sensitive C reactive protein (hsCRP), are increased in the older subjects compared to the young subjects, and contribute to many age-related pathologies [4, 5]. NF-κB is identified as a major regulator of gene expression programs most strongly associated with mammalian aging in multiple human and mouse tissues [9]. NF-κB activation has been linked to many age-related diseases, such as atherosclerosis, insulin resistance, neurodegenerative diseases, and cancer, etc. [14,15,16,17,18,19,20,21]
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