Long-term every-other-day administration of DMAMCL has little effect on aging

Long-term every-other-day administration of DMAMCL has little effect on aging

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.

Introduction

Aging is characterized by a progressive loss of various physiological functions at the molecular, cellular, tissue, and organismal levels, and ultimately 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 [2]. Among these, chronic, low-grade, sterile inflammation is one of the most important hallmarks in aged organisms, which is termed as ‘inflammaging’ [3]. Mounting evidences show that the blood levels of inflammatory cytokines, chemokines, and acute-phase 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].

The transcription factor NF-κB is a master regulator of the cellular response to inflammation [6]. Many studies demonstrate that the NF-κB activity is increased in multiple tissues and organs in old organisms compared to the young organisms [7–9], and in several premature mouse models [10–12]. Importantly, 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]. The aging-dependent NF-κB hyperactivation in the hypothalamus is recently also revealed to modulate systemic aging process [13]. Moreover, NF-κB activation has been linked to many age-related diseases, such as atherosclerosis, insulin resistance, neurodegenerative diseases, and cancer, etc [14–21].

Accumulating evidences demonstrate that genetic augment or impairment of NF-κB signaling pathway either accelerate or delay the aging process [22]. Nfkb1-deficient mice display NF-κB hyperactivation and systemic inflammation phenotypes which leads to premature aging and many age-related diseases [23,24], illustrating NF-κB as a bona fide driver of aging process. Genetic activation of NF-κB in hypothalamus also accelerates aging process and shortens lifespan in mice [13]. In Contrast, genetic depletion of NF-κB has demonstrated to extend lifespan in both wild-type and premature mouse models [10–13,25], and attenuate multiple age-related symptoms and pathologies. Similarly, NF-κB inhibition by pharmacological agents, for instance, an 11-amino acid peptide inhibitor of IKK, termed the NEMO-binding domain (8K-NBD), and pyrrolidine dithiocarbamate (PDTC), as well as hypochlorite (HOCl), increases lifespan and reduces age-related pathologies in various animal models [11,26,27]. However, the small molecular compound that can inhibit NF-κB activity and is suitable for long-term anti-aging intervention in mammals is currently still lacking.

Micheliolide (MCL) is a natural guaianolide sesquiterpene lactone (GSL) from Michelia compressa and Michelia champaca plants [28]. MCL has been reported to suppress dextran sodium sulphate (DSS)-induced inflammatory intestinal disease, colitis-associated cancer, rheumatic arthritis, and LPS-induced inflammatory response in microglial or immune cells via inhibition of NF-κB activity [29–32], as well as attenuate high glucose-stimulated activation of NF-κB [33]. The water-soluble Michael adduct of MCL, dimethylaminomicheliolide (DMAMCL, also known as ACT001), can slowly release MCL as a metabolite in plasma under physiological conditions [34]. DMAMCL can inhibit glioma cell growth in vitro and in vivo [35], and was recently approved for clinical trials in Australia to treat glioma tumor (trial ID: ACTRN12616000228482). DMAMCL also significantly prolongs the lifespan of a mouse model of human acute myelogenous leukemia (AML) through inhibiting NF-κB activity [36]. Moreover, DMAMCL is found to have very low side toxicities to animals which makes it a safe and suitable agent for a long-term treatment in vivo [35]. However, whether DMAMCL is suitable for anti-aging intervention in mammals, and whether it has an anti-aging effect via inhibition of NF-κB activity and can be a promising anti-aging agent remain totally unknown.

In the present study, we aimed to examine the effects of long-term administration of DMAMCL for 15 months with three different doses on the aging process in middle-aged male C57BL/6 mice, as well as long-term safety and toxicity. We presented evidences that chronic DMAMCL supplementation ameliorated or had little effect on some age-related degeneration and functional decline in mice without overt side effects. At a molecular level, we found DMAMCL treatment reduced serum levels of several important inflammatory cytokines, including IL-6, IL-1α, IL-1β, TNF-α, IFN-γ, and CXCL2, and suppressed NF-κB activity in several aged tissues. Our findings from this long-term administration study provide basic evidence to further study whether DMAMCL can be an effective anti-aging compound that prevents age-associated physiological decline.

When people speak of contemporary medicine, accuracy plays one of the most significant roles and people’s lives are directly dependent on it. Hence, any researches related to medicine are necessary to comply with the highest standards. The problem today is that any results of researches can be posted online and used as a reference without being precisely verified and approved. Mikhail (Misha) Blagosklonny of Oncotarget clearly understood this problem and decided to come up with an alternative solution. That’s how a weekly oncology-focused research journal called “Oncotarget” has been established back in 2010. The main principle of this journal is related to Altmetric scores that are used as a quality indicator. That assists both readers and authors to quality-check publications with Altmetric Article Reports that generate “real-time feedback containing data summary related to a particular publication.” Oncotarget website demonstrates a full publications list with corresponding scores above 100 as well as reports mentioned previously. Mikhail (Misha) Blagosklonny proud to share his new approach and hopes it provides the necessary assistance to anybody, who has interest in oncology.
https://www.nature.com/articles/cddis2014520
“A diagnostic autoantibody signature for primary cutaneous melanoma” has the Altmetric score of 594. This study was published back in 2018 by Oncotarget and completed by various experts from Hollywood Private Hospital, Edith Cowan University, Dermatology Specialist Group, St. John of God Hospital and The University of Western Australia. The introduction of the study mentions that “recent data shows that Australians are four times more likely to develop a cancer of the skin than any other type of cancer”, and provides an insight on melanoma that “is curable by surgical excision in the majority of cases, if detected at an early stage.”
The publication has got an Altmetric score of 594. Mikhail (Misha) Blagosklonny realizes that most of readers are aiming to understand the very meaning of it. Based on the Altmetric website, the score indicates “how many people have been exposed to and engaged with a scholarly output.” Hence, the publication about melanoma, was utilized for citations in various news articles 69 times. Besides that, it was quoted in 2 online blogs, as well as 25 Tweets on Twitter and 1 Facebook post. FOX23 of Tulsa, Oklahoma has headlined their report on July 20, 2018 as “New blood test could detect skin cancer early”, using the main content of Australia study
Another Oncotarget’s study with a top score of 476, is “Biomarkers for early diagnosis of malignant mesothelioma: Do we need another moon-shot,”. This research has appeared in 60 news stories, 1 online blog post and 6 Twitter posts. The majority of public may have seen a short overview only, however those who visit Mikhail (Misha) Blagosklonny at Oncotarget, do get helpful scientific facts. Oncotarget is glad to have the ability to share with online viewers this highly appreciated and high-quality information, that is trustworthy and reliable.
https://www.onacademic.com/search/list.html?q=Blagosklonny