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Understanding how cells in the pancreas change with age

Researchers have used sophisticated technologies to examine individual cells from healthy human pancreata to understand how the cells change with age. As people and other organisms age, cells become damaged—e.g., they accumulate changes in their DNA sequence that could potentially be harmful. This damage eventually leads to reduced tissue and organ function, or could lead to diseases such as cancer. It is known that aging processes affect cells randomly, so it is possible that individual cells in an organ or tissue could be affected differently with age and that different organs or tissues may respond in varying ways to aging processes overall. However, changes at the level of a single cell have been difficult to tease out because of experimental limitations. Now, scientists are using a technique called single-cell RNA sequencing (sc-RNAseq) to examine gene activity in individual cells. In new research, scientists used this technique to study the effects of aging on cells in the pancreas, an organ that is associated with age-related diseases, such as type 2 diabetes.

The scientists used sc-RNAseq to measure gene activity in 2,544 human pancreas cells from 8 female and male non-diabetic organ donors ranging in age from 1 month to 54 years old. They found increased “transcriptional noise” in endocrine cells—i.e., pancreatic cells that secrete hormones—from older donors compared to cells from young adults and children. Transcriptional noise refers to differences in gene activity among cells from the same individual. This suggests that aging is a process of random, rather than programmed, changes in gene activity, but the functional significance of the increased transcriptional noise remains unknown. Researchers also observed that the glucagon-producing pancreatic α cells and insulin-producing pancreatic β cells from older people were more likely to produce both hormones simultaneously compared to cells from younger people. These so-called bi-hormonal cells have been observed previously, and have been linked to β-cell failure and type 2 diabetes. It is possible that the age-related increase in transcriptional noise could be driving this effect—i.e., the increased random variation in gene activity could give rise to bi-hormonal cells; this intriguing possibility remains to be tested. Finally, the scientists found a range in the number of genetic mutations in individual pancreatic cells, and, overall, discovered that the number of mutations increased with age. Further experiments suggested that oxidative stress, which can cause DNA damage, contributed to the age-related increase in the observed mutations. Oxidative stress has also been implicated in the development of type 2 diabetes.

The findings in this study are consistent with the notion that aging processes affect cells randomly, and provide an important look at how aging affects cells in the pancreas. They also show some surprising ways in which individual cells in a healthy pancreas change with age, stimulating questions about the factors driving these changes and the functional significance of them. Similar single-cell studies of pancreata from people with type 1 or type 2 diabetes could provide key information about the development of these diseases.

References

Enge M, Arda HE, Mignardi M,…Quake SR.  Single-cell analysis of human pancreas reveals transcriptional signatures of aging and somatic mutation patterns. Cell 171: 321-330.e14, doi: 10.1016/j.cell.2017.09.004, 2017
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