Aging, which is associated with various pathologies such atherosclerosis and cancer, is characterized by an accumulation of senescent cells. Cellular senescence blocks cell proliferation, but it decreases the health of the old by littering tissues with dysfunctional senescent cells.
Investigators at the University of Tokyo have discovered that glutamine, the most abundant amino acid in blood, plays a key role in the survival of these senescent cells and an inflammatory senescence-associated secretory phenotype, a major factor in the aging process.
The study showed that glutaminase 1 (GLS1) was critical for the survival of human senescent cells. Lysosomal membrane damage in senescent cells induced GLS1 that resulted in glutaminolysis induced ammonia production. Intracellular ammonia neutralized the lower pH in the cell and improved cell survival.
The team reported its results in the January 14, 2021, online issue of Science.
Senior author Makoto Nakanishi, who is professor of medicine at University of Tokyo, told BioWorld Science that "we see GLS1 is upregulated in different cells in response to different senescent stimuli. Dysregulation of lysosomes is proposed to be one of the senescent hallmarks and senescent cells predominantly express kidney-type glutaminase (KGA) type GLS1 in vivo through lysosomal membrane damage-mediated acidosis. Depletion of GLS1 in senescent cells genetically and pharmacologically, both, improves various age-associated organ dysfunctions in mice."
Glutaminolysis produced three important metabolites: alpha-ketoglutarate (alpha-KG), glutathione (GSH) and ammonia. Addition of ammonia to the culture medium of senescent cells and incubation with an alkaline medium (pH 8.5) prevented the death of the senescent cells caused by glutaminolysis inhibitors like BPTES.
Senescent cells secreted several proinflammatory chemokines and cytokines, altering the surrounding microenvironment. The expression of GLS1 was upregulated in these cells, which resulted in glutaminolysis. This promoted senescent cell survival by producing ammonia, possibly by neutralizing the acidic intracellular pH that resulted 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.
Nakanishi also said that "recent observations in mice indicate that removal of senescent cells can extend healthy life span. Our results provide insights into the mechanisms underlying the relationship between protein quality control and aging in vivo. These findings also indicate that drugs inhibiting glutaminolysis can be used to induce selective death in senescent cells."
To support this hypothesis, Nakanishi and his team examined the effects of the glutaminolysis inhibitor BPTES administration on organ dysfunction in aged mice. BPTES administration improved age-associated kidney dysfunction and macrophage invasion in different organ systems.
Interestingly, BPTES treatment also improved serum free fatty acids (FFAs) in the aged mice and reduced the level of proinflammatory proteins in all the tested tissues. Next, Nakanishi and his team found that selective targeting of senescent cells by senolytic drugs like BPTES improved a myriad of age and inflammation-related pathologies like diabetes and atherosclerosis. This was accompanied by a concomitant decrease in the levels of proinflammatory cytokines like IL-16.
In a perspective published in the same issue of Science, Duke University's Christopher Pan and Jason Locasale emphasized that the identification of GLS1 as a target for inducing senolysis confirms metabolism as a major regulator of aging. GLS1 is an attractive target for antiaging therapies because clinical studies for GLS1 inhibitors used for cancer indications have so far established safety.
Glutamine addiction is well established as a hallmark of cancer cells and cellular senescence is a key biological process in carcinogenesis. However, Nakanishi noted that previous studies have indicated glutaminolysis in cancer cells to be driven by the oncogene c-myc.
"Our study provides insights on how inhibition of glutaminolysis can alleviate tissue microinflammation and provides broader perspective into the role of glutamine in age related disorders, including cancer, with underlying inflammatory pathologies," he said.
"Lysosomal degradation is a common feature in senescent cells. We have developed a strategy for senolysis targeting a specific metabolic feature of senescent cells. This approach should be able to target specific diseased cell subpopulations, thus increasing efficacy and minimizing adverse effects," he added. "We hypothesize that elimination of senescent cells and protection from senescence by inhibition of glutaminolysis in the aged body may also prevent age-associated disorders, and even extend life span and rejuvenate an aging individual." Nakanishi next hopes to investigate the role of glutaminolysis in other age-related disorders, such as Alzheimer's disease.