Age-related oxidative changes in pancreatic islets are predominantly located in the vascular system

Abstract

Aged tissues usually show a decreased regenerative capacity accompanied by a decline in functionality. During aging pancreatic islets also undergo several morphological and metabolic changes. Besides proliferative and regenerative limitations, endocrine cells lose their secretory capacity, contributing to a decline in functional islet mass and a deregulated glucose homeostasis. This is linked to several features of aging, such as induction of cellular senescence or the formation of modified proteins, such as advanced glycation end products (AGEs) - the latter mainly examined in relation to hyperglycemia and in disease models. However, age-related changes of endocrine islets under normoglycemic and non-pathologic conditions are poorly investigated. Therefore, a characterization of pancreatic tissue sections as wells as plasma samples of wild-type mice (C57BL/6J) at various age groups (2.5, 5, 10, 15, 21 months) was performed. Our findings reveal that mice at older age are able to secret sufficient amounts of insulin to maintain normoglycemia. During aging the pancreatic islet area increased and the islet size doubled in 21 months old mice when compared to 2.5 months old mice, whereas the islet number was unchanged. This was accompanied by an age-dependent decrease in Ki-67 levels and pancreatic duodenal homeobox-1 (PDX-1), indicating a decline in proliferative and regenerative capacity of pancreatic islets with advancing age. In contrast, the number of p16Ink4a-positive nuclei within the islets was elevated starting from 10 months of age. Interestingly, AGEs accumulated exclusively in the islet blood vessels of old mice associated with increased amounts of inflammatory markers, such as the inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine (3-NT). In summary, the age-related increase in islet size and area was associated with the induction of senescence, accompanied by an accumulation of non-enzymatically modified proteins in the islet vascular system.

Redox homeostasis and cell cycle activation mediate beta-cell mass expansion in aged, diabetes-prone mice under metabolic stress conditions: Role of thioredoxin-interacting protein (TXNIP)

“…For immunohistochemical and immunofluorescent analysis, longitudinal, serial sections (2 μm) of young and aged mice before and after 2 as well as 21 days of the +CH intervention were processed as previously described [ 19 ]. Pancreatic tissue slices were incubated with primary antibodies against rabbit Ki67 (1:1000, Abcam, Cambridge, UK) and mouse caspase-3 (1:100, Life Technologies, Darmstadt, Germany) for 1 h at room temperature.…”

“…Besides dietary factors, aging and related alterations have been shown to influence beta-cell characteristics. Recently, we demonstrated that pancreatic islets of normoglycemic wild-type mice progressively lose their proliferative and regenerative potential, associated with the induction of cellular senescence, known to induce an irreversible cell cycle arrest [ 19 ]. Furthermore, different well-known hallmarks of aging, such as mitochondrial dysfunction, elevated oxidative stress and inflammation, all linked to a dysregulated redox balance, affect beta-cells by impairing their secretory function and survival.…”

Endogenous advanced glycation end products in pancreatic islets after short-term carbohydrate intervention in obese, diabetes-prone mice

“…Immunohistochemical labeling and quantitative analysis was performed as previously described 15 . A list of used antibodies and applied concentrations are provided as supplementary information (SI Table 1 ).…”

β cell aging and age-related diabetes

“…The previous studies suggested the β cell dysfunction with age is mainly caused by the loss of functional β cell mass. However, in recent years, some researchers have put forward different opinions, suggesting that the intrinsic function of β cells does not significantly change with age, but their fully functioning is affected by the systemic senescent environment [ 68 , 69 ].…”