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GLS1 inhibitor selectively eliminates senescent cells, ameliorates age-associated disorders
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https://www.news-medical.net/news/20210205/GLS1-inhibitor-selectively-eliminates-senescent-cells-ameliorates-age-associated-disorders.aspx
Senescent cells accumulate in organs during aging, promote tissue dysfunction, and cause numerous aging-related diseases like cancer. The cells arise through a process called "cellular senescence," a permanent cell cycle arrest resulting from multiple stresses.
A collaborative research group led by Professor Makoto Nakanishi of the Institute of Medical Science, The University of Tokyo (IMSUT), and co-researchers have identified an inhibitor of the glutamate metabolic enzyme GLS1so that its administration selectively eliminates senescent cells in vivo.
They confirmed that the GLS1 inhibitor eliminated senescent cells from various organs and tissues in aged mice, ameliorating age-associated tissue dysfunction and the symptoms of obese diabetes, arteriosclerosis, and NASH. The results of this research were published in "Science" on January 15, 2021.
Previous studies have shown that genetically engineering removal of senescent cells from aged mice delays the onset of geriatric diseases such as arteriosclerosis and renal damage and extends the healthy life expectancy. However, those studies have not led to identifying useful drug candidates.
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Our results can contribute to the development of new anti-aging therapies that remove senescent cells by targeting these cells' metabolic characteristics."
Makoto Nakanishi, Professor, Institute of Medical Science, University of Tokyo (IMSUT)
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Lysosomal membranes hold the key to senescent cell removal
The research team has developed a new method for producing purified senescent cells to search for genes essential for senescent cells' survival. This new method activates the p53 gene in the G2 phase, which can efficiently induce cellular senescence.
They used purified senescent cells to search for genes essential for senescent cells' survival, then identified GLS1, which is involved in glutamine metabolism, as a potential candidate gene.
When they examined the effect of GLS1 inhibitor on the mortality of senescent cells, senescent cells were more sensitive to GLS1 inhibition due to damage to the lysosomal membrane and decreased intracellular pH. When they administered GLS1 inhibitors to aged mice, senescent cells in various tissues and organs were removed, and the aging phenomenon was significantly improved.
Organelles called lysosomes to play an essential role in the regulation of intracellular pH. The team analyzed the dynamics of lysosomes and found the vital fact that damage to the lysosomal membranes in senescent cells lowers intracellular pH.
Expectations for innovative anti-aging therapies and treatments for geriatric diseases
The results of this study show more interesting results. As aging progresses, motor function declines due to muscle loss, and metabolic disorders due to adipose tissue atrophy occur.
But, when the research team injected GLS1 inhibitors into mice suffering age-related disorders, the progression of these age-related symptoms was suppressed. Moreover, GLS1 inhibitors were able to relieve the symptoms of obese diabetes, arteriosclerosis, and NASH.
According to the team, GLS1 inhibitors are currently in clinical trials as effective cancer treatments. "We hope that innovative anti-aging therapies and treatments for geriatric diseases will be developed that can remove senescent cells by treatment with GLS1 inhibitors," said Professor Nakanishi.
Source:
The Institute of Medical Science, The University of Tokyo
Journal reference:
Johmura, Y., et al. (2021) Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders. Science. doi.org/10.1126/science.abb5916.
study below
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Targeting metabolism to influence aging
Christopher Pan and Jason W. Locasale
Department of Pharmacology and Cancer Biology,
Duke University School of Medicine, Durham, NC, USA
Aging can be defined by a progressive decline in tissue function and is a risk factor for many pathologies, including fibrosis and cancer. There is emerging evidence suggesting that cellular senescence, which has been studied in cancer, is a key biological process that links multiple pathologies of aging. Cellular senescence is characterized by a stable cell cycle arrest that is thought to occur after exposure to stress, including oxidative, mitochondrial, and replicative stress (9). Senescent cells secrete a myriad of proinflammatory chemokines and cytokines, called the senescence-associated secretory phenotype (SASP). SASP alters the surrounding microenvironment and may propagate tissue senescence though paracrine signaling. Senescent cells have been proposed to accumulate during aging and underlie chronic inflammation mediated by SASP, eventually leading to tissue dysfunction and the onset of various age-associated pathologies. Recent observations in mice support the idea that removal of senescent cells can extend healthy life span (10, 11). These findings have led to the exploration of pharmacological approaches to induce selective death in senescent cells (senolysis).
Although it has been found that metabolism can influence cellular senescence, a general understanding of the links between metabolism, senescence, and aging is still in its early stages (12). Johmura et al. reveal that glutamine metabolism may contribute to the pathogenesis of age-related disorders (see the figure). They found that GLS1 expression was up-regulated in multiple cell types in response to diverse senescent stimuli, and its depletion induced senolysis and improved various age-associated organ dysfunctions in mice. As a possible mechanism, the authors present evidence that senescent cells utilize glutamine to neutralize the intracellular acidosis that results from senescence-associated lysosomal dysfunction. Indeed, supplementation of ammonia could ablate the senolytic activity of GLS1 inhibition. A number of interpretations are consistent with this finding, including the anabolic functions of ammonia that could then couple to the activity of the TCA cycle. More analysis of metabolic pathway activity in the presence of ammonia and supplementation with other nutrients might address this. These possibilities could be separate or interconnected metabolic mechanisms from those that involve nicotinamide adenine dinucleotide (NAD+), which along with mitochondrial metabolism are perhaps the most studied molecular features associated with aging (13). Given the pleotropic roles of glutamine metabolism, more work is needed to better define the metabolic requirements of senescent cells.
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Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders
Science 15 Jan 2021
Yoshikazu Johmura1*, Takehiro Yamanaka1†, Satotaka Omori1†, Teh-Wei Wang1†, Yuki Sugiura2, Masaki Matsumoto3, Narumi Suzuki1, Soichiro Kumamoto1, Kiyoshi Yamaguchi4, Seira Hatakeyama4,
Tomoyo Takami3, Rui Yamaguchi5, Eigo Shimizu5, Kazutaka Ikeda6, Nobuyuki Okahashi6, Ryuta Mikawa7, Makoto Suematsu2, Makoto Arita6,8, Masataka Sugimoto7, Keiichi I. Nakayama3, Yoichi Furukawa4, Seiya Imoto9, Makoto Nakanishi1*
Accumulation of senescent cells (SnCs) is associated with age-related pathologies (1, 2), which can be alleviated by senolytic compounds (3-7). However, because of the heterogeneity of senescence in vivo, molecular targets that induce mortality in various types of SnCs have not yet been identified. To identify senolytic compounds, we developed a method for long-term culturing of human SnCs (hSnCs) of high purity (8) (fig. S1A).
We developed a strategy for senolysis targeting a specific metabolic feature of SnCs. Elimination of SnCs and protection from senescence by inhibition of glutaminolysis in the aged body may ameliorate tissue microinflammation, prevent age-associated disorders, and even extend life span and rejuvenate an aging individual.
Targeting SnCs with senolytic drugs was reported to alleviate obesity-induced disorders (28, 29). High-fat diet (HFD)-induced adipocyte hypertrophy, increased SA-β-gal-positive population, and macrophage invasion in adipose tissue were improved by 1 month of BPTES injection in obese mice (48-week-old mice on HFD) (Fig. 4H), accompanied by an increase in the lamin B1-positive population and a reduction in the expression of IL-6, KGA, and p16 (fig. S14A). BPTES treatment also improved glucose tolerance and insulin sensitivity in the obese mice (fig. S14B). Atherosclerosis of thoracic aorta in apolipoprotein E (ApoE) knockout mice (16-week-old mice) fed an atherogenic diet (AD) was alleviated by BPTES treatment with a reduced plaque numbers and lesions, accompanied by reduction in the expression of p16, KGA, and IL-6 in abdominal aorta of the same mice (Fig. 4I and fig. S14C). In a nonalcoholic steatohepatitis model (16-week-old males), BPTES treatment also improved liver function, showing reduced concentrations of serum hydroxyproline and aspartate aminotransferase (fig. S14D). However, BPTES injection also modestly suppressed the rate of dorsal skin wound healing in mice (8-week-old males) (fig. S14E) (30). Overall, in addition to the clearance of SnCs, protection from senescence improved age- and senescence-associated pathogenesis.
Selective destruction of senescent cells
Senescent cells are associated with a variety of age-related medical conditions and thus have been proposed as potential targets for therapy, but we do not yet have a full understanding of the underlying mechanisms. Johmura et al. used RNA interference to screen for enzymes essential to the survival of senescent cells (see the Perspective by Pan and Locasale). The authors identified a key role for glutamine metabolism, particularly the enzyme glutaminase 1, and demonstrated that inhibition of this pathway induced the death of senescent cells. Glutaminase targeting also ameliorated aging-related organ dysfunction and obesity-related disorders in mouse models, suggesting the potential therapeutic value of this approach.
Abstract
Removal of senescent cells (senolysis) has been proposed to be beneficial for improving age-associated pathologies, but the molecular pathways for such senolytic activity have not yet emerged. Here, we identified glutaminase 1 (GLS1) as an essential gene for the survival of human senescent cells. The intracellular pH in senescent cells was lowered by lysosomal membrane damage, and this lowered pH induced kidney-type glutaminase (KGA) expression. The resulting enhanced glutaminolysis induced ammonia production, which neutralized the lower pH and improved survival of the senescent cells. Inhibition of KGA-dependent glutaminolysis in aged mice eliminated senescent cells specifically and ameliorated age-associated organ dysfunction. Our results suggest that senescent cells rely on glutaminolysis, and its inhibition offers a promising strategy for inducing senolysis in vivo.
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