Targeting metabolism to influence aging

doi:10.1126/science.abf6368

GSTDTAP > 气候变化

DOI	10.1126/science.abf6368
	Targeting metabolism to influence aging
	Christopher Pan; Jason W. Locasale
	2021-01-15
发表期刊	Science
出版年	2021
英文摘要	Glutamine has a host of metabolic functions, including biosynthesis, redox maintenance, and chromatin biology. Drugs are currently available to target glutamine and related metabolism. However, the use of these compounds has been limited by finding appropriate applications because the role of glutamine in health and disease is still poorly understood. Some studies have pointed to a limited role of glutamine metabolism in vivo; others have found specific roles in critical areas of biomedical interest, such as the potentiation of immune responses in cancer. On page 265 of this issue, Johmura et al. ([ 1 ][1]) report a role for glutamine in maintaining the viability of senescent cells and the senescence-associated secretory phenotype, which may be a major factor in the aging process. Thus, targeting glutamine and associated metabolic processes could be an attractive, clinically feasible way to modify the aging process. It was noted in the 1950s that culture of cell lines such as mouse fibroblasts and human HeLa cells requires copious amounts of glutamine, which was counter to its identification as a nonessential amino acid ([ 2 ][2]). Almost 70 years later, glutamine continues to be the most abundant amino acid in many formulations of cell culture media ([ 3 ][3]). Glutamine metabolism has many functions, including the use of the carbon atoms of glutamine to fuel the biosynthetic tricarboxylic acid (TCA) cycle in mitochondria, a process called anaplerosis ([ 4 ][4]). Furthermore, nearly all other functions of glutamine have been found to have some role in supporting cell proliferation. Moreover, many of the major oncogenes and tumor suppressor genes, such as KRAS, MYC , and TP53 , can influence the activity of glutamine metabolism ([ 5 ][5]). Other studies have indicated that tumor glutamine metabolism and cancer phenotypes could be affected by dietary glutamine ([ 6 ][6]). Drug development efforts to target glutamine metabolism have focused on glutaminase 1 (GLS1), the enzyme that converts glutamine to glutamate and ammonia as the initial step in the breakdown of glutamine (glutaminolysis). For example, CB-839, a small molecule derived from the parent compound bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES), and the compound IACS-6274 have been administered in humans with, for example, renal cell carcinoma ([ 4 ][4]). Additionally, analogs and derivatives of glutamine involving 6-diazo-5-oxo-l-norleucine (DON) have been developed as agents that have pleiotropic effects on glutamine metabolism ([ 7 ][7]). The role of glutamine metabolism has had its controversies. One study concluded that the use of glutamine, particularly in the TCA cycle, in vivo was less than anticipated in certain mouse cancer models, which suggested that the importance of glutamine may have been overemphasized in part owing to stronger effects in cell culture that result from high concentrations of glutamine in culture media ([ 8 ][8]). Nevertheless, several studies have found an essential role for glutamine in mice, including situations that have clinical application, such as combining GLS1 inhibition with immunotherapies in mice ([ 7 ][7]). 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 ][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 ][10], [ 11 ][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 ][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 ][13]). Given the pleotropic roles of glutamine metabolism, more work is needed to better define the metabolic requirements of senescent cells. ![Figure][14] Glutamine in senescence Senescent cells up-regulate the expression of glutaminase 1 (GLS1), which mediates glutaminolysis. This promotes senescent cell survival, possibly by producing ammonia (NH3), which may neutralize the acidic intracellular pH that results from senescence-associated lysosomal dysfunction. In geriatric mice, bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) administration cleared senescent cells and improved various age-related disorders. GRAPHIC: KELLIE HOLOSKI/ SCIENCE The general molecular traits of senescent cells and their contribution to aging and related diseases remain open questions ([ 14 ][15]). The identification of GLS1 as a senolytic target confirms metabolism as a major regulator of aging, thus providing some rationale for how therapeutics that target metabolism might achieve specificity for senescent cells as anti-aging agents. GLS1 is an attractive target for anti-aging therapies because clinical studies for cancer indications have so far established safety ([ 4 ][4]). Much attention has been focused on the use of dietary supplementation or possibly metformin or rapamycin use to manipulate aging. 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/311478
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Christopher Pan,Jason W. Locasale. Targeting metabolism to influence aging[J]. Science,2021.
APA	Christopher Pan,&Jason W. Locasale.(2021).Targeting metabolism to influence aging.Science.
MLA	Christopher Pan,et al."Targeting metabolism to influence aging".Science (2021).