Exploring the impact of diabetes on aging: insights from TERT and COL1A1 methylation

Abstract

Background/aim: Aging, a multifaceted biological process, leads to diminished physical performance, especially in older adults with diabetes, where a mismatch between biological and chronological age is noticeable. Numerous studies have demonstrated that diabetes accelerates aging at the cellular and organ levels. Notable aging markers are telomerase reverse transcriptase (TERT), related to telomere length, and type 1 chain collagen (COL1A1), a key component of skin collagen. Additionally, age-related methylation increases, as revealed through methylation analysis, augmenting aspects of aging. However, the detailed interplay between aging and diabetes, particularly regarding methylation, remains underexplored and warrants further study to elucidate the biological links between the two.

Materials and methods: In this study, we elucidate the modulatory influence of diabetes on the aging process, focusing specifically on the modifications in TERT in the kidney and COL1A1 in the skin using mice of Swiss Webster strain as the diabetes model. Specimens were categorized into three distinct chronological cohorts: chronologically young (16 weeks; n = 5), chronologically old (40 weeks; n = 5), and a periodically assessed group (16 weeks; n = 30), from which five mice were systematically sacrificed on a weekly basis.

Results: Our findings reveal a marked impact of diabetes on the methylation statuses of TERT and COL1A1, characterized by an elevation in methylation levels within the periodic group (1st-6th week) and a simultaneous, progressive attenuation in the expression of TERT and COL1A1 genes.

Conclusion: The observed alterations in the methylation levels of TERT and COL1A1 propound the hypothesis that diabetes potentially expedites the aging process, concomitantly impinging on the production of TERT and COL1A, ostensibly through the mechanism of promoter gene hypermethylation.

Keywords: Aging; diabetes; marker; methylation; promoter.

Figure 1

Experimental design. Following a week of acclimatization to the new environment, the mice were divided into three large groups. STZ was administered to the treated mice to induce diabetes. OGTT was performed once a week for weekly observation; 5 mice were sacrificed weekly to collect kidneys, skin, and blood. Methylation analysis was performed on skin, kidney, and blood samples, followed by gene expression analysis on kidney and skin samples.

Figure 2

Oral glucose tolerance test between young control mice, old control mice, and treatment group mice before induction (a). Comparisons were made between the OGTT results of the treatment group after induction with the baseline glucose levels of the control group (b); (* = p < 0.05 from the young control group; ▪ = p < 0.05 from the old control group).

Figure 3

Islets of Langerhans differences in the young control (a) and periodic groups (6th week) (b) at a magnification of 40×. The arrows show islets of Langerhans (IL) and islets of Langerhans of the periodic group suffering from hypertrophy and vacuolization (V). Scale bar = 50 μm.

Figure 4

TERT and COL1A1 methylation in kidney (a) and skin (b); (* = p < 0.05 from the young control group; ▪ = p < 0.05 from the old control group).

Figure 5

TERT and COL1A1 gene expression. TERT expression (a) and COL1A1 expression (b). Correlations between the methylation percentage and relative expression of TERT (c) and COL1A1 (d); (* = p < 0.05 from the young control group; ▪ = p < 0.05 from old control).

Figure 6

Impact of diabetes on aging processes. Diabetes mellitus is implicated in accelerated aging, primarily through the hypermethylation of telomerase reverse transcriptase (TERT) and collagen type I alpha 1 chain (COL1A1) promoters. This hypermethylation leads to a series of cellular and molecular alterations, including the shortening of telomeres and compromised DNA repair mechanisms, which are integral components of cellular aging. Specifically, the shortened telomeres induce a repair response in β cells located within the islets of Langerhans. Furthermore, this metabolic condition is associated with diminished collagen synthesis, a hallmark of aging, especially in elevated blood glucose levels prevalent in diabetes mellitus. These pathological alterations collectively serve as indicators of premature aging. They can be instrumental in evaluating aging processes and developing potential therapeutic interventions targeting aging-associated pathologies in diabetic populations.