Reverse aging, the eternal pursuit of human beings.
Scientists want more "rejuvenation" in terms of physical function than looks. Among the many potential pathways to realization, targeted elimination of senescent cells has received widespread attention.
In a recent issue in the journal Science[1], researchers at the Institute of Medical Sciences at the University of Tokyo in Japan published their findings. They found that glutamine 1 (GLS1) is a key target, it breaks down a large amount of glutamine produced ammonia and neutralizes the acidosis in senescent cells that could have killed cells, so that senescent cells can continue to survive, inhibit this pathway, senescent cells to normal death, elderly mice physiological function and motor ability are improved.
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Senescent cells have lost both the ability to divide and do not apoptosis, stubbornly entrenched in the body, and their accumulation is related to a series of age-related pathological manifestations [2,3].
In order to identify molecules suitable as markers of senescent cells, the researchers developed a long-term method of culturing high-purity human senescent cells, instantaneously activating p53 through nutlin3a, so that the senescent cells constructed were highly expressed p16, CD26, interleukin-6 and interleukin-8, and cell purity (the proportion of constructed cells in all cultured cells) was close to 100%.
Using short hairpin RNA (shRNA) to screen the enzymes needed for senescent cell survival, the "hit rate" of a "target" is the highest "hit rate" is GLS1.
Expression of GLS1 in senescent cells increased significantly compared to untreated non-senescent cells. In senescent cells constructed by different methods, high levels of GLS1 were detected.
In 80-week-old mice, after the use of GLS1 inhibitors to eliminate senescent cells, the mice improved age-related glomerulosclerosis, renal macrophage infiltration and renal dysfunction, reflecting the normalization trend of plasma creatinine and urea.
Young mice (young), control group of elderly mice (Mock), and elderly mice using GLS1 inhibitors (BPTES) kidney slices and cases of glomerular sclerosis, plasma urea, creatinine level (top to bottom)
Like some drugs discovered in the past that can remove senescent cells, GLS1 inhibitors can also improve pulmonary fibrosis, liver macrophage infiltration, and serum albumin levels in older mice.
In addition, senescence of adipose progenitor cells and subsequent adipose tissue atrophy and macrophage infiltration are also characteristic of natural senescence [4,5], and GLS1 inhibitor therapy mitigates tissue atrophy and macrophage invasion in 100-week-old mice. Age-related weakness in mice was improved, with increased grip strength and short-term suspension endurance.
Whether it is GLS1 or glutamine, it is not a strange molecule to everyone. Glutamine was discovered as an amino acid needed in many cell line culture processes as early as the 1950s, and remained the most abundant amino acid in cell culture medium formulations for nearly 70 years.
Glutamine metabolism has many functions, including the tricarboxylic acid cycle and a series of biological processes that support cell proliferation.
In this study, the researchers also tried to explore the role that GLS1 and glutamine play in senescent cells.
They found that renal glutamine type (KGA)-GLS1 is expressed in senescent cells induced in different ways. In the process of cell senescence, insoluble macromolecules in lysosomal cause damage to the lysosomal membrane, resulting in hydrogen ions in the lysosomum leaking into the cells, decreasing intracellular pH, and cell acidosis.
Originally intracellular acidosis can activate BCL2, adenovirus E1B19-kDa interaction protein 3 (BNIP3) and mitochondrial permeability conversion hole (mPTP) axis, resulting in cell death, but in the low pH acidic environment, KGA expression increases, the ability to decompose glutamine is enhanced, which produces a large amount of ammonia, neutralizes the pH, and thus avoids the death of senescent cells.
By inhibiting KGA-dependent glutamine breakdown, the researchers found that intracellular acidosis in senescent cells could not be improved, and senescent cells inevitably died.
Overall, the study identified a target capable of killing senescent cells, and in a review article published contemporaneously[6], reviewers concluded that GLS1 is currently a very attractive target because glutamine metabolism also plays an important role in tumors, while clinical studies of GLS1 in tumor therapy have established safety profiles [7]. In the future, more research is needed to verify their effects on human aging.
Resources:
[1] https://science.sciencemag.org/content/371/6526/265
[2] Childs B G, Durik M, Baker D J, et al. Cellular senescence in aging and age-related disease: from mechanisms to therapy[J]. Nature medicine, 2015, 21(12): 1424-1435.
[3] He S, Sharpless N E. Senescence in health and disease[J]. Cell, 2017, 169(6): 1000-1011.
[4] Baker D J, Childs B G, Durik M, et al. Naturally occurring p16 Ink4a-positive cells shorten healthy lifespan[J]. Nature, 2016, 530(7589): 184-189.
[5] De Cecco M, Ito T, Petrashen A P, et al. L1 drives IFN in senescent cells and promotes age-associated inflammation[J]. Nature, 2019, 566(7742): 73-78.
[6] https://science.sciencemag.org/content/371/6526/234
[7] Altman B J, Stine Z E, Dang C V. From Krebs to clinic: glutamine metabolism to cancer therapy[J]. Nature Reviews Cancer, 2016, 16(10): 619.
The author of this article | Ying Yuyan