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Analysis of Expression Status and Relationship Between Senescence-related Genes and Pancreatic Function-related Genes in Human Islets of Langerhans from Donors of Various Ages

HAJIME IMAMURA, TOMOHIKO ADACHI, DAISUKE MIYAMOTO, TATSUYA KIN, MAMPEI YAMASHITA, HAJIME MATSUSHIMA, TAKANOBU HARA, AKIHIKO SOYAMA and SUSUMU EGUCHI
In Vivo September 2024, 38 (5) 2165-2171; DOI: https://doi.org/10.21873/invivo.13679

Abstract

Background/Aim: Although studies on senescence-related genes using human islets of Langerhans have been performed, the expression of senescence-related genes and their association with functional genes in islets remain insufficiently investigated. We aimed to determine whether and what types of senescent-related genes are expressed in islets and identify their correlations with pancreatic function-related genes by using islets isolated for transplantation from individuals of various ages. Materials and Methods: Islets from deceased donors of both sexes and different ages were used for analysis. The expression status of senescence-related genes (glutaminase 1, interleukin 6, interleukin 8, cyclin-dependent kinase inhibitor 2A, cyclin-dependent kinase inhibitor 1A, and senescence-associated beta-galactosidase) and pancreatic function-related genes (glucagon and insulin) was examined by reverse transcription-quantitative polymerase chain reaction, and their relationships with age were investigated. Results: We obtained isolated human islets from 18 deceased multiorgan donors. There was no correlation between donor age and expression of any of the senescence-related genes. Regarding correlations between donor age and pancreatic function-related genes, age was positively correlated only with INS (r=0.49, p=0.03). INS expression was not correlated with that of GLS1 (r=0.23, p=0.34), IL6 (r=−0.06, p=0.79), or IL8 (r=−0.1, p=0.12), but positively related with p16 (r=0.89, p<0.0001), p21 (r=0.51, p=0.02), and SA-β-gal (r=0.52, p=0.02). Conclusion: We showed the functional potential even of aged islets, which were originally thought to be functionally impaired. We were unable to identify any senescence-related genes expressed in islets from donors of different ages. Therefore, a new index is needed to evaluate not only actual chronological age but also organ- and cell-specific age.

Key Words:

The pancreas is one of the most important and complex organs in the human body. It consists of an exocrine component involving acinar and duct cells that facilitate nutrient digestion, and an endocrine component involving mainly organized structures containing hormone-producing cells that regulate glucose metabolism (1). The β-cells within them secrete insulin, and their dysfunction or loss is the primary factor in the development of diabetes in general. There are two types of diabetes mellitus: type 1 and type 2. Type 1 diabetes is caused by the destruction or loss of β-cells, while type 2 diabetes is caused by reduced insulin secretion or the development of insulin resistance. For the treatment of both diabetes types, it is important to maintain and restore β-cell function. Such maintenance and restoration include that of β-cells to be transplanted when performing islets of Langerhans transplantation as curative treatment for type 1 diabetes (2). The progressive decline in the secretory capabilities of β-cells has been explained in several different ways, with two of the most important thus far being compromised cell physiology and a reduced number of physiologically active β-cells (3). Aging inevitably has a major impact on the biology and physiology of human β-cells. Glucose tolerance decreases in the elderly because of an increase in resistance to insulin signaling in peripheral tissue and impaired insulin secretion (4-6), suggesting that β-cell function declines with age as a result.

With aging, the number of senescent cells in the body increases. As the aging immune system becomes less efficient, senescent cells accumulate and adversely affect the functioning of healthy cells. The accumulation of senescent cells is also associated with age-related pathologies (7, 8). Cellular senescence is a state in which cells cease to divide but remain metabolically active with an altered phenotype (9). However, because of the heterogeneity of senescence in vivo, it has no universal markers, and the markers that do exist are not consistent in every senescent tissue (10). Aging was reported to affect gene expression patterns in mouse (11) and human islets (12). As typical markers of senescence, cyclin-dependent kinase inhibitor 2A (p16, also known as CDKN2A) and cyclin-dependent kinase inhibitor 1A (p21, also known as CDKN1A) are routinely used. An increase in p21, an effector of cellular senescence, is thought to mark the entry into early senescence leading to increased p16 expression, which then maintains senescence, resulting in the expression of the senescence-associated secretory protein profile (13). These proteins include soluble and insoluble factors, such as chemokines, cytokines [interleukin-6 (IL6) and interleukin-8 (IL8)] (14), as well as extracellular matrix remodeling factors. These factors can induce dysfunction in surrounding cells and precipitate their entry into the senescence process (15). Another marker is senescence-associated beta-galactosidase (SA-β-gal), an enzyme that catalyzes the hydrolysis of β-galactosidase into monosaccharides, detected at certain pH in senescent cells, but not in quiescent or pre-senescent cells (16). In a recent study, a new marker essential for the survival of senescent cells, glutaminase 1, was reported (17).

Regarding the effect of aging on the capacity to secrete insulin, previous in vivo and in vitro evaluations of human β-cell function showed that insulin secretion decreases with age (18). On the other hand, there are also reports of an increase in secretory capacity with age (12), and opinions are therefore divided. Although studies on senescent cells using human islets have been reported as described above, the expression of senescent cell markers and association with functional genes (insulin and glucagon) in islets isolated from donor pancreas have not been sufficiently investigated. In this study, we aimed to determine whether and what types of senescent cell markers are expressed in islets and to correlate them with pancreatic function-related genes, using islets isolated for transplantation from individuals of various ages.

Materials and Methods

Compliance with ethical requirements. This study was made possible by the donation of human tissue from deceased organ donors. Consent for the use of islets in research was obtained from the donors’ next of kin.

This study was conducted in accordance with the Declaration of Helsinki and the ethical guidelines for clinical studies of the Ministry of Health, Labour, and Welfare of Japan. The study protocol was also approved by the Ethics Committee of Nagasaki University Hospital (Approval No. 13093050-5).

Human islet isolation and study population. The study covered the period from July 2021 to August 2022. During this period, human islets were isolated from deceased multiorgan donors at the University of Alberta in accordance with the guidelines of the Ethics Committee of the University of Alberta, as previously reported (19), and were transported by air to Nagasaki University. Because we aimed to analyze the data for various ages, we did not limit the target age of islet donors.

Gene expression: real-time quantitative polymerase chain reaction (RT-qPCR). On the same day that the human islets were received, total RNA was isolated from them using the NucleoSpin RNA kit (Macherey-Nagel, Düren, Germany). Complementary DNA (cDNA) was synthesized from total RNA using the High-Capacity cDNA Reverse Transcription Kit™ (4368813; Thermo Fisher Scientific, Waltham, MA, USA). RT-qPCR was performed using an Applied Biosystems StepOnePlus Real-Time PCR System with TaqMan® Fast Universal PCR Master Mix (2′) (Thermo Fisher Scientific) (20). The expression of the genes analyzed was normalized using glyceraldehyde-3-phosphate dehydrogenase as a housekeeping gene. RT-qPCR was performed with 0.5 L of the TaqMan® Gene Expression Assays Mix (20′; Thermo Fisher Scientific) with 10 ng of cDNA. The reaction conditions were automatically set at 95°C for 20 s, followed by 40 cycles of 95°C for 1 s and 60°C for 20 s. Cycle threshold values were determined automatically by the Applied Biosystems StepOnePlus Real-Time PCR System, and fold changes in gene expression were calculated using the ΔΔCT method. The Applied Biosystems TaqMan Gene Expression Assay Kits used were as follows: glucagon (GCG; Hs01031536_m1) and insulin (INS; Hs00355773_m1) as pancreatic function-related genes; glutaminase 1 (GLS1; Hs01014020_m1), IL6 (Hs00985639_m1), IL8 (Hs00174103_m1), p16Ink4a (p16; Hs00923894_m1), p21Cis1 (p21, Hs00355782_m1), and SA-β-gal (Hs01035168_m1) as senescence-related genes; and GAPDH (Hs02786624_g1) as a housekeeping gene.

Statistical analysis. Continuous variables are expressed as the median values with ranges. Pearson’s correlation coefficient was used to analyze the associations of donor age with senescence-related genes and pancreatic function-related genes, and senescence-related genes with pancreatic function-related genes. p-Values of less than 0.05 were considered to indicate statistical significance. Statistical analysis was performed using JMP Pro, version 16 (SAS Institute, Cary, NC, USA).

Results

Characteristics of the transported human islets. We transported isolated human islets from 18 deceased multiorgan donors by air. It took an average of 6 (4-9) days after isolation for the islets to be transported from Alberta, Canada, to Nagasaki, Japan. The details of the donor characteristics (age, sex, body mass index, HbA1c, cause of death, cold ischemic time, transported viability/purity) are summarized in Table I. The median donor age was 47 years and the age distribution ranged from 20 to 67 years.

View this table:
Table I.

Donor characteristics (n=18).

Expression of senescence-related genes and pancreatic function-related genes. The expression of GLS1, IL6, IL8, p16, p21, and SA-β-gal senescence-related genes in islets was confirmed. The median relative expression rate was highest for p21, followed by SA-β-gal (Figure 1A). Expression was also confirmed for pancreatic function-related genes (GCG and INS) (Figure 1B).

Figure 1.
Figure 1.

Expression of senescence-related genes and pancreatic function-related genes. (A) The expression of senescence-related genes glutaminase 1 (GLS1), interleukin 6 (IL6), interleukin 6 (IL8), cyclin-dependent kinase inhibitor 2A (p16), cyclin-dependent kinase inhibitor 1A (p21), and senescence-associated beta-galactosidase (SA-β-gal) in islets was confirmed. The median relative expression was highest for p21, followed by SA-β- gal. (B) The expression of pancreatic function-related genes glucagon (GCG) and insulin (INS) islets was confirmed.

Correlations of donor age with senescence-related genes and pancreatic function-related genes. The correlation of donor age with each senescence-related gene (GLS1, IL6, IL8, p16, p21, and SA-β-gal) was examined. In all analyses, no significant positive correlation between donor age and any senescence-related gene was identified. However, GLS1 expression tended to be positively correlated with age (r=0.44, p=0.06). The correlations of the other genes with age were as follows: IL6 (r=0.23, p=0.34), IL8 (r=0.30, p=0.22), p16 (r=0.38, p=0.11), p21 (r=0.26, p=0.27), and SA-β-gal (r=0.12, p=0.62) (Figure 2).

Figure 2.
Figure 2.

Correlations of donor age with senescence-related genes. The correlation between donor age and senescence-related genes glutaminase 1 (GLS1), interleukin 6 (IL6), interleukin 6 (IL8), cyclin-dependent kinase inhibitor 2A (p16), cyclin-dependent kinase inhibitor 1A (p21), and senescence-associated beta-galactosidase (SA-β-gal) in islets was examined. GLS1 showed a tendency to be positively correlated with age (r=0.44, p=0.06).

As for the correlations between donor age and pancreatic function-related genes (GCG and INS), no significant correlation between donor age and GCG was identified (r=0.29, p=0.23), but there was a significant positive correlation between age and INS (r=0.49, p=0.03) (Figure 3). Correlation between senescence-related genes and pancreatic function-related genes. The correlations between senescence-related genes and pancreatic function-related genes (GLS1, IL6, IL8, p16, p21, and SA-β-gal) were examined. A significant positive correlation of GCG was observed only for p16 (r=0.70, p=0.001), but there was no significant correlation with GLS1, IL6, IL8, p21, or SA-β-gal (Figure 4). No correlation of INS with GLS1, IL6, nor IL8 was observed, but it was significantly positively correlated with p16 (r=0.89, p<0.0001), p21 (r=0.51, p=0.02), and SA-β-gal (r=0.52, p=0.02) (Figure 5).

Figure 3.
Figure 3.

Correlations of donor age with pancreatic function-related genes. The correlations between donor age and pancreatic function-related genes Glucagon (GCG) and Insulin (INS) in islets was examined. There was no significant correlation between donor age and GCG, but INS was significantly positively correlated with age (r=0.49, p=0.03).

Figure 4.
Figure 4.

Correlation between senescence-related genes and pancreatic function-related genes (glucagon). Glucagon (GCG) was found to be positively correlated only with cyclin-dependent kinase inhibitor 2A (p16). No significant correlation was found with glutaminase 1 (GLS1), interleukin 6 (IL6), interleukin 8 (IL8), cyclin-dependent kinase inhibitor 1A (p21), nor senescence-associated beta-galactosidase (SA-β-gal).

Figure 5.
Figure 5.

Correlation between senescence-related genes and pancreatic function-related genes (insulin). For insulin (INS), no correlation with glutaminase 1 (GLS1), interleukin 6 (IL6), or interleukin 8 (IL8) was observed, but positive correlations with cyclin-dependent kinase inhibitor 2A (p16), cyclin-dependent kinase inhibitor 1A (p21), and senescence-associated beta-galactosidase (SA-β-gal) were observed.

Discussion

In this study, human islets from deceased organ donors of various ages were used to analyze the relationship between age and the expression status of senescence-related genes and pancreatic function-related genes. We found that GLS1 expression showed a tendency to be correlated with age in human islets but found no correlation with age for any of the other genes examined. Although hundreds of genes that are upregulated with aging have been identified so far in human islet cells, little is known about their roles in the pancreas (12, 21). As for the association with pancreatic function-related genes, we found correlations between INS and p16, p21, and SA-β-gal. Although we were unable to identify specific senescence-related genes expressed in islets, it is thought that aging itself is not necessarily associated with pancreatic functional decline, but rather that an element of the heterogeneity in individual islets influences pancreatic function.

In vitro measurement of insulin secretion from isolated islets is a complementary approach to the in vivo measurement of insulin secretion. Several in vitro studies have measured insulin secretion from islets of differently aged donors. One of these studies analyzed human islets from donors aged 16-70 years of age and used glucose-stimulated insulin secretion to evaluate β-cell function. It found that islets from younger donors (<40 years of age) had significantly higher secretion (22). As for the findings on the relationship between senescence genes and insulin secretion reported to date, the expression of p16 increases with age in human and mouse β-cells, and it has been reported that p16 simultaneously improves glucose-stimulated insulin secretion, a key function of β-cells (23). It has also been found that human islets isolated from middle-aged donors contained a significant proportion of SA-β-gal and it has been reported that the aging process is activated by multiple parameters, including the induction of SA-β-gal activity, either from multiple parameters or from β-cells in which p16 is expressed (23). Based on the analysis of the present study, expression of p16 and SA-β-gal was also associated with INS expression, which appears to be consistent with previous reports (23). In addition, an increase in p21, another effector of cellular senescence, which is thought to indicate entry into early senescence (13), has been reported to increase p16 expression and maintain senescence (23). This also matches the findings obtained in this study.

Although p16, p21, and SA-β-gal are known to be expressed as senescence markers in human pancreatic islets (13, 16), no positive correlation with age was observed in this study. GLS1, which was recently reported to be a gene essential for the survival of human senescent cells, was shown to be positively correlated with age in human dermal fibroblasts (17). GLS1 expression in human islets from deceased organ donors was examined in this study, but no correlation with age was found based on the results. The reason why we did not find a correlation between age and aging markers is unclear.

While no correlation was found between age and the expression of senescence-related genes, a positive correlation was found between age and the expression of pancreatic function-related genes, particularly insulin gene expression. This result contradicts the earlier statement that insulin secretory capacity declines with age, but Arda et al. in fact reported that the insulin secretory capacity of β-cells increases with age (12). However, there is no specific explanation for this, and the author states that analysis of data from many human donors is needed to prove that aging increases insulin secretion. Helman et al. reported that mature mouse and human β-cells secreted more insulin than young β-cells in response to high concentrations of glucose in a glucose-stimulated insulin secretion test (11). This functional change appears to be organized by p16-induced cellular senescence and downstream remodeling of chromatin structure and DNA methylation. They proposed that activation of the cellular senescence program promotes lifelong functional maturation of β-cells through hypertrophy, enhanced glucose uptake, and more efficient mitochondrial metabolism, while simultaneously confining these cells to a non-replicating state (23). It is inferred from this study that islet cells in the elderly, whose functions are thought to be declining, actually have sufficient potential for pancreatic functions such as by expressing insulin. The actual function of islet cells in vivo may be reduced by factors such as the in vivo environment and heterogeneity. At present, when setting the donor age for pancreas transplantation and islet transplantation, the actual chronological age of the donor is considered, while also considering the potential functions to be expressed. However, chronological age can only act as a guideline, and the degree of cellular senescence might be related to factors, such as individual background, heterogeneity and other factors. Study limitations. Firstly, the cells that we used for our analysis included not only islet cells but also some pancreatic exocrine cells, and we did not analyze islet cells as single cells. Therefore, the relationship among the cells (exocrine and endocrine component) may have affected the results. Secondly, the human islets were transported a long distance, as it is currently difficult to obtain human islets in Japan. The quality of the pancreatic islets will be discussed as several days elapsed due to air transport. Transported human islets have been valuable and have contributed to the continued progress of islet-based basic research in Japan (24). Although the conditions of transportation or handling of human islets would have been similar to those in that study, the islets used in the present study might not have had typical characteristics. Thus, our results might not be generalizable to healthier islets. We strongly acknowledge the value of analyzing human islets as soon as possible after isolation. Future studies should therefore attempt to avoid using human islets transported a long distance.

Conclusion

We analyzed islets from donors of various ages for the association of senescence-related genes and genes related to pancreatic function. We found no association between age and senescence-related genes, but we did find an association between age and INS, suggesting that the potential for pancreatic functional expression may increase with age. We believe that pancreatic islets of the elderly may have sufficient potential to express pancreatic functions, and the potential for intrinsic functional expression needs clarification, and multifaceted functional evaluation using new indices and biomarkers that can assess organ- and cell-specific age, in addition to actual age and senescence-related genes, will be necessary in the future.

Acknowledgements

The Authors thank the Clinical Islet Laboratory staff at the University of Alberta/Alberta Health Services for providing human islet research preparations.

We also thank Edanz (https://jp.edanz.com/ac) for editing a draft of this article.

Footnotes

  • Authors’ Contributions

    HI, TA and DM designed the study. HI and DM collected data. HI, TA and DM: analyzed the data. TK, MY, HM, TH, AS and SE contributed important reagents. HI, TA, TK, DM and SE reviewed and edited the article. All Authors contributed to the article and approved the submitted version.

  • Conflicts of Interest

    The Authors report there are no competing interests to declare.

  • Received April 19, 2024.
  • Revision received June 3, 2024.
  • Accepted June 6, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Analysis of Expression Status and Relationship Between Senescence-related Genes and Pancreatic Function-related Genes in Human Islets of Langerhans from Donors of Various Ages
HAJIME IMAMURA, TOMOHIKO ADACHI, DAISUKE MIYAMOTO, TATSUYA KIN, MAMPEI YAMASHITA, HAJIME MATSUSHIMA, TAKANOBU HARA, AKIHIKO SOYAMA, SUSUMU EGUCHI
In Vivo Sep 2024, 38 (5) 2165-2171; DOI: 10.21873/invivo.13679
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